Diana Noland

Jeanne A. Drisko
Leigh Wagner
Editors

Integrative and
Functional Medical
Nutrition Therapy
Principles and Practices
Integrative and Functional Medical Nutrition Therapy
Diana Noland
Jeanne A. Drisko
Leigh Wagner
Editors

Integrative and
Functional Medical
Nutrition Therapy
Principles and Practices
Editors
Diana Noland Jeanne A. Drisko
Noland Nutrition Professor Emeritus
Burbank, CA, USA School of Medicine
University of Kansas Health System
Leigh Wagner Kansas City, KS, USA
Department of Dietetics & Nutrition
University of Kansas Medical Center
Kansas City, KS, USA

ISBN 978-3-030-30729-5    ISBN 978-3-030-30730-1 (eBook)

https://doi.org/10.1007/978-3-030-30730-1

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 V

I wish to dedicate this book to the enlightened mentors in the field of integrative and functional medicine
with whom I have had the honour to interact: Doctors Jeff Bland, Jeanne Drisko, Sam Queen, Roger Newton,
Sidney MacDonald-Baker, Douglas Hunt and Robert P Heaney. Through their gifts of knowledge, they have
provided the foundation for the powerful impact nutrition is experiencing in influencing human health. This
textbook is a tribute to their genius.
–Diana Noland

This textbook is dedicated to all the integrative practitioners who taught me how to care for patients as
people, those practitioners who are living and those who have slipped away and especially my students who
taught me to keep up and stay on my toes. But most of all, what is important for practitioners who are finding
their way, “Listen with your heart”.
–Jeanne A. Drisko

This book is dedicated to my family, friends and close colleagues who’ve provided unconditional love and
support throughout this and all my work; it is for my teachers, professors and students who’ve been my
patient and unwavering mentors. Finally, this is for my patients and clients who have taught me more than I
imagined possible about what it means to be a healthcare provider.
–Leigh Wagner
Foreword

The incidence of almost every chronic disease has With the genomics revolution, we now know that
increased relentlessly in every age group for the there is a huge variation between nutritional
past 50 years. Diabetes which was once rare (<0.7% needs and toxin susceptibility. For example,
of the population) is now projected to affect 35% some people’s single nucleotide polymorphisms
of the people in their lifetime. For the first time in (SNPs) result in the lower functioning of their
American history, life expectancy has gone down vitamin D receptor sites and need ten times the
several years in a row. Healthcare costs (or, more recommended daily allowance (RDA) of vitamin
accurately, disease treatment costs) are now 20% of D to maintain their bones. Another example is
the GDP, increasing inevitably and bankrupting the huge 1000-fold variation in the activity of
the country. Why is the healthcare system—which liver Phase I detoxifying enzyme CYP2D6. This
obviously has several areas of great success—fail- enzyme detoxifies 25% of prescription drugs and
ing dramatically everywhere else? a number of environmental toxins. Those with a
poorly functioning version of this detoxification
Because the common causes of disease are not enzyme are not only much more likely to have an
being addressed. adverse drug reaction to the standard dose of a
prescription but also more likely to suffer a
Conventional medicine has been incredibly effec- ­number of diseases, such as Parkinson’s disease,
tive in many areas, such as injuries, overwhelming if they are exposed to neurotoxins. With over 2
infections, congenital malformations and some million SNPs, there are a huge number of
cancers. However, this model does not work for ­examples of SNP variants requiring specialized
everyday health and disease prevention. Unfortu- attention.
nately, the burden of chronic disease has become
so widespread and severe that most medical treat- This is why Integrative and Functional Medicine
ment is now primarily for symptom control and Nutrition Therapy: Principles and Practices is such
prevention of even worse sequelae. Very little of an important textbook. Every clinician who wants
medicine as actually practiced today addresses the to care for their patients in a curative way must
real reasons why people are suffering such a huge recognize and understand the clinical presenta-
and progressively increasing disease burden. tions of functional nutritional deficiencies and
toxin overload. Relying on blood (or other tissue)
What are those unaddressed causes? To quote an levels of nutrients or environmental toxins is an
inspirational functional medicine expert Sid ineffective diagnostic strategy for many reasons.
Baker, MD: “Most of medicine is quite simple, get For example, measuring blood levels of B-vitamins
into people what they uniquely need and get out is very misleading. Using the conventional range
what they uniquely do not need”. In other words, standards, only a small percentage of the public is
nutrition and detoxification—according to patient’s deficient. But measuring levels of toxic metabo-
unique biochemical needs. lites, such as homocysteine and methylmalonic
acid, which build up when a person has a func-
Nutritional deficiencies are rampant in the popu- tional deficiency of B-vitamins, elevated levels
lation and are getting worse. Not only is the gen- indicate increased risk of tissue damage. This
eral public choosing food with lower nutrient means increased risk for heart disease, Alzheim-
density but also hybridization and synthetic fer- er’s disease, osteoporosis and other chronic degen-
tilizers have decreased the trace nutrient content erative diseases.
of the food. Almost the entire population is defi-
cient in at least one nutrient and over half has We see the same pattern with environmental tox-
multiple nutritional deficiencies according to ins. For example, the “safe” levels of most toxins
conventional standards. But even worse, the envi- are established according to population norms.
ronment has become increasingly contaminated But the “normal” population suffers a huge disease
by toxic metals and chemicals that displace nutri- burden! And as mentioned above, using absolute
ents, poison enzymes, damage DNA, disrupt cel- levels of toxin misses the huge variation in detoxi-
lular communications, increase inflammation fication function found in the general population.
and dramatically increase oxidative stress in all Some people can smoke their entire life without
systems of the body. apparent problems while a non-smoking spouse
 VII
Foreword

gets lung cancer. There are numerous examples of The only effective clinical strategy is that which
common chronic diseases being primarily caused thoughtfully integrates multiple diverse interven-
by the combination of nutritional deficiencies and tions that not only address the actual causes of
toxin load in the context of biochemical suscepti- disease but also utilizes safe therapies that opti-
bility. Drugs do not reverse deficient nutrients or mize each person’s unique physiological function.
help increase toxin excretion. In fact, almost all
drugs are yet another load on the already over- This is the premise and promise of IFMNT.
loaded detoxification systems.

Joseph Pizzorno, ND
Co-Author, Textbook of Natural Medicine
Chair of Board, Institute for Functional Medicine
Seattle, WA, USA
Preface

Over the past 50–60 years, the world has seen an exposures, fractured human interactions, infre-
unparalleled and unprecedented growth in non-­ quent physical movement, stress, poor sleep and
communicable (chronic) disease. Chronic disease other lifestyle problems.
has replaced acute infectious disease and trauma
as the dominant influence on healthcare delivery. As editors with a collective 65 years of practice in
Our current healthcare model is no longer sustain- integrative and functional medicine nutrition ther-
able, i.e. the captain of the ship making a brilliant apies, we have witnessed (and practiced) a new
diagnosis and delivering the silver bullet cure or healthcare delivery system that incorporates impor-
surgically repairing the problem. No silver bullet tant advances of conventional medical care that,
exists that satisfactorily addresses the chronic, combined with the original roots of healthcare,
complex disorders that currently clog our health- returns the patient back to the centre of the process.
care systems. The health of our nation and world Partnering with patients fosters better understand-
has changed rapidly while healthcare delivery has ing of the chronic disorders that plague them. We
remained stagnant. But change, it must! have witnessed how teams of practitioners with
diverse healthcare backgrounds work together to
This urgently needed change does not appear to be find solutions to our looming healthcare crisis.
coming from within large healthcare systems. How-
ever, healthcare consumers, especially those with Although our backgrounds are in integrative and
chronic and life-threatening disorders, are demand- functional medicine, the model we present tran-
ing a different delivery of care. As one patient with scends and defies all labels and simply should be
chronic disease relayed, her primary care physician called “good medicine”. In this textbook, we pro-
told her that she had so many problems he wouldn’t vide principles to illuminate understanding of how
be in practice long enough to solve them all. This is healthcare can be delivered to get to the root of
a message devoid of hope and care. In this setting, chronic disorders. After the principles are laid out,
“care” is a misnomer as it has been stripped from the practice of “good healthcare” is described in
healthcare by the abbreviated allotted visit times, detail. The reader will see that there is again hope
and with practitioners no longer allowed to interact for finding satisfaction in healthcare careers when
with those entrusted to their charge and prevented burnout rates are soaring.
from knowing their patients as people.
Within, you will find the underlying principles
The unifying theme of this textbook is the under- and practices laid out that give you, the reader, an
standing of the nutritional status of patients. With- understanding of the science of integrative and
out a strong nutritional foundation, healing of functional medicine nutrition therapies with real-
chronic disease is impossible. Unlike conventional world examples. The authors were selected because
medical care that narrowly defines nutrition, dis- of their notable experience in integrative and func-
misses its importance and marginalizes its deliv- tional medical nutrition therapies. This textbook
ery, we propose that nutrition become a will augment your journey back to the heart and
fundamental part of healthcare providers’ broad soul of the practice of good healthcare.
scope. Without this foundation, our ability to suc-
cessfully deliver care is limited. You will find The 10-year journey to writing Integrative and
within these pages authors with all types of back- Functional Medicine Nutrition Therapy: Principles
grounds who have found success using integrative and Practices was the brainchild of editor Diana
and functional medicine nutrition therapies when Noland. Diana collaborated with colleagues Jeanne
faced with chronic health conditions. Drisko and Leigh Wagner to successfully launch a
master-level certificate program in integrative
We wrote this textbook to help practitioners, nutrition at the University of Kansas Health System
health system leaders and policy makers to under- in conjunction with the Department of Dietetics
stand that there is a different and novel approach and Nutrition and the University of Kansas Integra-
to address complex chronic disorders. Human tive Medicine. We crafted materials to be used in
physiology has not changed. What has changed are the education of dietetic students but also used the
those factors acting on human physiology in the materials in training all practitioners and students
form of poor nutrition, environmental toxicant under our guidance. Their care for patients has
 IX
Preface

thrived with this underpinning. The development Many thanks to our faithful and accomplished
of this textbook provides a roadmap for care. copy editors, Matt Erickson and Jeffrey Field,
who polished every chapter over the 2-year
The editors and authors of this textbook have writ- project.
ten this book in the hope that the knowledge it
provides will help to achieve the day when all Thanks to Michael D. Sova, our Springer develop-
medical healthcare practices appreciate and mental editor, who conducted the conversion from
include nutrition and lifestyle assessment and a vision to a reality. He brought together the work
intervention for each unique individual. of individual authors to a cohesive collection of
contributions toward providing the science and
We are thankful that this journey was guided by the practical aspects of integrative and functional
Coco and Roger Newton, who shared our vision medical nutrition therapy. Michael guided us in
for Integrative and Functional Medicine Nutrition the preparation for a finished product and became
Therapy: Principles and Practices. We also an integral member of our team.
acknowledge our families who, for the past 3 years,
have stood by us, supported our efforts and nur- And finally, we would like to thank our friend, Dr.
tured us while we wrote and edited, even during Joe Pizzorno, for writing the Foreword of the text-
nights, weekends and family vacations. Special book as he joins us to express his common vision
thanks to our spouses, Steve Noland, Robert of the importance of nutrition therapy in the quest
Drisko II and Rob Bauer, who gave us insights and to quell the epidemics of chronic diseases in the
advice along this journey. twenty-first century.

Diana Noland
Burbank, CA, USA

Jeanne A. Drisko
Kansas City, KS, USA

Leigh Wagner
Kansas City, KS, USA
 XI

Contents

I Global Healthcare Challenge of the Twenty-First Century

and the Future of Chronic Disease

1 The History and Evolution of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Jeanne A. Drisko

2 Influences of the Nutrition Transition on Chronic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Sudha Raj

3 Nutritional and Metabolic Wellness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Diana Noland

4 Nutritional Ecology and Human Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

David Raubenheimer and Stephen J. Simpson

5 The Radial: Integrative and Functional MNT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Kathie M. Swift, Elizabeth Redmond, and Diana Noland

6 The Power of Listening and the Patient’s Voice: “Please Hear Me” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Carolyn L. Larkin

II Metabolic Characteristics and Mechanisms of Chronic Disease

7 Metabolic Correction Therapy: A Biochemical–Physiological
Mechanistic Explanation of Functional Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Michael J. Gonzalez

8 The Nutrition Assessment of Metabolic and Nutritional Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Margaret Gasta

9 IFMNT NIBLETS Nutrition Assessment Differential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Robyn Johnson and Lauren Hand

10 Nutritional Role of Fatty Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Vishwanath M. Sardesai

11 Lipidomics: Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

Diana Noland

12 Structure: From Organelle and Cell Membrane to Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

David Musnick, Larissa Severson, and Sarah Brennan

13 Protective Mechanisms and Susceptibility to Xenobiotic Exposure and Load . . . . . . . . . . . . . . . . . . 191

Robert H. Verkerk

14 Detoxification and Biotransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Janet L. Black

15 Drug–Nutrient Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Mary Demarest Litchford
 Contents
XII

16 The Enterohepatic Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Robert C. Barton Jr.

17 A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease . . . . . . . . . . . . . . . 235

Christy B. Williamson and Jessica M. Pizano

18 Nutritional Influences on Methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

Jessica M. Pizano and Christy B. Williamson

19 The Immune System: Our Body’s Homeland Security Against Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Aristo Vojdani, Elroy Vojdani, and Charlene Vojdani

20 Nutritional Influences on Immunity and Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

Joel Noland and Diana Noland

21 Body Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323

Sue Ward and Diana Noland

22 The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism . . . . . . . . 335
Miriam Kalamian

23 The GUT-Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Elizabeth Lipski

24 Centrality of the GI Tract to Overall Health and Functional Medicine

Strategies for GERD, IBS, and IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Ronald L. Hoffman

25 The Microbiome and Brain Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Sharon L. Norling

26 The Role of Nutrition in Integrative Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Cynthia Henrich

27 The Microenvironment of Chronic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

Steven Gomberg

28 Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447

Jena Savadsky Griffith

29 Nutrition and Behavioral Health/Mental Health/Neurological Health . . . . . . . . . . . . . . . . . . . . . . . . . . 473

Ruth Leyse Wallace

30 Neurodevelopmental Disorders in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

Mary Anne Morelli Haskell

31 Nutritional Influences on Hormonal Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

Filomena Trindade

32 Nutritional Influences on Reproduction: A Functional Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533

Brandon Horn and Wendy Yu

33 Lifestyle Patterns of Chronic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563

Sarah Harding Laidlaw
 XIII
Contents

34 Circadian Rhythm: Light-Dark Cycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577

Corey B. Schuler and Kate M. Hope

35 Nutrition with Movement for Better Energy and Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595

Peter Wilhelmsson

36 Mental, Emotional, and Spiritual Imbalances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

Muffit L. Jensen

III IFMNT Nutrition Care Process

37 The IFMNT Practitioner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Robin L. Foroutan

38 The Patient Story and Relationship-Centered Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633

Leigh Wagner

39 The Nutrition-Focused Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

Mary R. Fry

40 Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships . . . . . . . . . . . . . . . . . . . . . . . . . 695

Margaret Christensen

41 Developing Interventions to Address Priorities: Food, Dietary Supplements,

Lifestyle, and Referrals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
Aarti Batavia

42 Therapeutic Diets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743

Tracey Long and Leigh Wagner

43 Dietary Supplements: Understanding the Complexity of Use and

Applications to Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755
Eric R. Secor

44 Clinical Approaches to Monitoring and Evaluation of the Chronic Disease Client . . . . . . . . . . . . . . 769
Cynthia Bartok and Kelly Morrow

45 Ayurvedic Approach in Chronic Disease Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783

Sangeeta Shrivastava, Pushpa Soundararajan, and Anjula Agrawal

IV Cases & Grand Rounds

46 Cardiometabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
Anup K. Kanodia and Diana Noland

47 Revolutionary New Concepts in the Prevention and Treatment of

Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
Mark C. Houston

48 Immune System Under Fire: The Rise of Food Immune Reaction and Autoimmunity . . . . . . . . . . . 843
Aristo Vojdani, Elroy Vojdani, and Charlene Vojdani
 Contents
XIV

49 Amyotrophic Lateral Sclerosis (ALS): The Application of Integrative and

Functional Medical Nutrition Therapy (IFMNT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
Coco Newton

50 Gastroenterology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913
Jason Bosley-Smith

51 Respiratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
Julie L. Starkel, Christina Stapke, Abigail Stanley-O’Malley, and Diana Noland

52 The Skin, Selected Dermatologic Conditions, and Medical Nutrition Therapy . . . . . . . . . . . . . . . . . . 969
P. Michael Stone

53 Movement Issues with Chronically Ill or Chronic Pain Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003

Judy Hensley, Julie Buttell, and Kristie Meyer

V Practitioner Practice Resources

54 Systems Biology Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Jeanne A. Drisko, Diana Noland, and Leigh Wagner

55 Initial Nutrition Assessment Checklist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019

Leigh Wagner, Diana Noland, and Jeanne A. Drisko

56 Nutritional Diagnosis Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043

Leigh Wagner, Diana Noland, and Jeanne A. Drisko

57 Specialized Diets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045

Leigh Wagner, Diana Noland, and Jeanne A. Drisko

58 Motivational Interviewing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1051

Leigh Wagner, Diana Noland, and Jeanne A. Drisko

59 Authorization for the Release of Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055

Leigh Wagner, Diana Noland, and Jeanne A. Drisko

60 Patient Handouts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057

Leigh Wagner, Diana Noland, and Jeanne A. Drisko

Supplementary Information
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
 XV

Contributors

Anjula Agrawal, BDS, RAP Robin L. Foroutan, MS, RDN

Private Practice New York, NY, USA
Rancho Mission Viejo, CA, USA rforoutan@mac.com
anjulaag@gmail.com
Mary R. Fry, BSC, ND
Cynthia Bartok, PhD, RDN Department of Nutrition & Integrative Health
Department of Nutrition and Exercise Science Maryland University of Integrative Health (MUIH)
Bastyr University Laurel, MD, USA
Kenmore, WA, USA mfry@muih.edu
cbartok@bastyr.edu
Margaret Gasta, RDN, DCN
Robert C. Barton Jr., MD Nutrition By Margo, LLC
Family Medicine Boulder, CO, USA
Northridge, CA, USA Margo@nutritionbymargo.com
rcbmd@bartonshealth.com
Steven Gomberg, LAc, MTOM
Aarti Batavia, MS, RDN, CLT, CFSP, IFMCP Lotus Center for Integrative Medicine
Nutrition and Wellness Consulting Los Angeles, CA, USA
Novi, MI, USA taohongjing@yahoo.com
aartibatavia@gmail.com
Michael J. Gonzalez, DSc, NMD, PhD
Janet L. Black, MSN, MPH, FNP certification, BSN Human Development, Nutrition Program
LLC, Candler, NC, USA University of Puerto Rico, Medical Sciences Campus,
healthfromjanet@gmail.com School of Public Health
San Juan, PR, Puerto Rico
Jason Bosley-Smith, MS, LDN, CNS, FDN michael.gonzalez5@upr.edu
Center for Integrative Medicine, University of Maryland
Baltimore, MD, USA Jena Savadsky Griffith, RDN, IHC
jbosley-smith@som.umaryland.edu Aroda, VA, USA
jenas_mailbox@yahoo.com
Sarah Brennan
Portland State University Lauren Hand, MS, RDN, LD
Portland, OR, USA Exercise, Diet, Genitourinary, & Endocrinology (EDGE)
sar26@pdx.edu Research Lab, Department of Dietetics and Nutrition
University of Kansas Medical Center
Julie Buttell Kansas City, KS, USA
Department of Physical Therapy lhand2@kumc.edu
Redefine Wellness and Physical Therapy
Overland Park, KS, USA Mary Anne Morelli Haskell, DO
Julie1buttell@yahoo.com Osteopathic Center of Coronado
Coronado, CA, USA
Margaret Christensen, MD www.drmaryanne.com
Carpathia Collaborative
Dallas, TX, USA Cynthia Henrich, BA
drmargaret@carpathiacollaborative.com Certified Integrative Nutritionist
Woodcliff Lake, NJ, USA
Jeanne A. Drisko, MD, CNS, FACN cynthiafhenrich@gmail.com
Professor Emeritus, School of Medicine,
University of Kansas Health System
Kansas City, KS, USA
jdrisko@kumc.edu
 Contributors
XVI

Judy Hensley, PT, DPT, MHS, OCS, MTC Sarah Harding Laidlaw, MS, RDN, CDE
Transformative Physical Therapy Peak Nutrition Consultants
Lenexa, KS, USA Montrose, CO, USA
judyahensley@gmail.com peaknut70@gmail.com

Ronald L. Hoffman, MD, PLLC Carolyn L. Larkin

Private Practice, New York, NY, USA Human Perspectives Int’l
drrhoffman@aol.com Laguna Niguel, CA, USA
carolyn.larkin@hpiintl.com
Kate M. Hope, MS, CNS
Department of Nutrition Ruth Leyse Wallace, PhD, RDN
Atlantic Medicine and Wellness Chandler, AZ, USA
Wall, NJ, USA ruthwallace78@gmail.com
khope@amwwall.com
Elizabeth Lipski, PhD, CNS, BCHN, IFMCP
Brandon Horn, PhD, JD, Lac Department of Nutrition
Department of Obstetrics and Gynaecology Maryland University of Integrative Health
Lotus Center for Integrative Medicine Portland, OR, USA
Los Angeles, CA, USA llipski@muih.edu
LL@innovativehealing.com
Department of Anesthesiology and
Critical Care Medicine
Mary Demarest Litchford, PhD, MS, RDN, LDN
Children’s Hospital of Los Angeles
CASE Software & Books
Los Angeles, CA, USA
Greensboro, NC, USA
bhorn@lotuscenter.com
mdlphd@casesoftware.com

Mark C. Houston, MD, MS, MSc, FACP, FAHA, FASH

Tracey Long, MPH, RDN
Department of Medicine
Big Picture Health LLC
Vanderbilt Medical School and Hypertension Institute,
Hendersonville, NC, USA
Saint Thomas Hospital
tlong@bigpicturehealth.com
Franklin, TN, USA
boohouston@comcast.net
Kristie Meyer, PT, MPT, COMT
Department of Physical Therapy
Muffit L. Jensen, DC
Elite Sports Medicine & Physical Therapy
Integrated Wellness Solutions
Kansas City, MO, USA
Burbank, CA, USA
meyer_kristie@yahoo.com
info@drmuffitjensen.com

Kelly Morrow, MS, RDN

Robyn Johnson, MS, RDN, LD
Department of Nutrition and Exercise Science
Nutrition by Robyn, LLC
Bastyr University
Bend, Oregon, USA
Kenmore, WA, USA
robynjohnson.rdn@gmail.com
kmorrow@bastyr.edu

Miriam Kalamian, EdM, MS, CNS

David Musnick, MD
Dietary Therapies LLC
Peak Medicine
Hamilton, MO, USA
Bellevue, WA, USA
info@dietarytherapies.com
office@peakmedicine.com

Anup K. Kanodia, MD, MPH

Coco Newton, MPH, RD, CNS
Department of Family Medicine
Lifetime Nutrition, LLC
The Ohio State University Wexner Medical Center
Maple City, MI, USA
Columbus, OH, USA
coco@coconewton.com
doctor@kanodiamd.com
 XVII
Contributors

Diana Noland, MPH, RDN, CCN, IFMCP, LD Eric R. Secor, ND, PhD, MPH, MS, LAc, NCCAOM
Noland Nutrition Department of Integrative Medicine
Burbank, CA, USA Hartford HealthCare Cancer Institute, Hartford Hospital
diana@diananoland.com Avon, CT, USA
eric.secor@hhchealth.org
Joel Noland, ND, LAc
Sequoia Family Medicine, LLC Larissa Severson, BS
Burbank, CA, USA Bastyr University
drjoel@sequoiamedicine.com Seattle, WA, USA
larissa.severson@bastyr.edu
Sharon L. Norling, MD, MBA, ABIHM, DABMA
Mind Body Spirit Center Sangeeta Shrivastava, PhD, RDN
Hendersonville, NC, USA California State Polytechnic University, Pomona
dr_norling@msn.com Irvine, CA, USA
a.sangeeta.aa@gmail.com
Jessica M. Pizano, MS, CNS
Mast Cell Advanced Diagnostics/ Stephen J. Simpson, PhD
Zebra Diagnostics/SNPed Charles Perkins Centre and School of Life and
Chesterfield, VA, USA Environmental Sciences, The University of Sydney
jessicapizano@comcast.net Camperdown, NSW, Australia
stephen.simpson@sydney.edu.au
Joseph Pizzorno, ND
Co-Author, Textbook of Natural Medicine Pushpa Soundararajan, MBA, RDN, LD, AHE, AFNC
Chair of Board, Institute for Functional Medicine Private Practice, Medical Nutrition Therapy
Seattle, WA, USA Willowbrook, IL, USA
www.drpizzorno.com vpknutrition@yahoo.com

Sudha Raj, PhD, RD, FAND Abigail Stanley-O’Malley, MS, RDN, LD, CLT

Department of Nutrition and Food Studies Revive Nutrition Solutions, LLC
Syracuse University St. Joseph, MO, USA
Syracuse, NY, USA dietitianabby@gmail.com
sraj@syr.edu
Christina Stapke, RDN, CD
David Raubenheimer, D Phil Christina Stapke, RDN , LLC
Charles Perkins Centre and School of Life and Environ- Seattle, WA, USA
mental Sciences, The University of Sydney christinastapke@gmail.com
Camperdown, NSW, Australia
david.raubenheimer@sydney.edu.au Julie L. Starkel, MS, MBA, RDN, CD
Starkel Nutrition
Elizabeth Redmond, PhD, MMSc, RDN Seattle, WA, USA
Nutrition Provisions, LLC julie@starkelnutrition.com
Atlanta, GA, USA
bredmond@nutritionprovisions.com P. Michael Stone, MD, MS
Ashland Comprehensive Family Medicine-Stone Medical
Vishwanath M. Sardesai, PhD Ashland, OR, USA
Department of Surgery
Institute for Functional Medicine
Wayne State University School of Medicine
Federal Way, WA, USA
Detroit, MI, USA
vsardesa@med.wayne.edu Asante Ashland Community Hospital
Ashland, OR, USA
Corey B. Schuler, RN, MS, CNS, LN, DC mstone@ashlandmd.com
Department of Clinical Affairs
Integrative Therapeutics, Green Bay, WI, USA
corey.schuler@integrativepro.com
 Contributors
XVIII

Kathie M. Swift, MS Leigh Wagner, PhD, MS, RDN, LD

Integrative and Functional Nutrition Academy Department of Dietetics & Nutrition
Saratoga Springs, NY, USA University of Kansas Medical Center
kathie@kathieswift.com Kansas City, KS, USA
lwagner@kumc.edu
Filomena Trindade, MD, MPH, ABFM, FAARM,
IFMCP Sue Ward, MS, CNS
Saudade Wellness Sanoviv Medical Institute
Capitola, CA, USA Rosarito, BC, Mexico
www.drtrindade.com sward8@mac.com
info@drtrindade.com
Peter Wilhelmsson, MA, ND
Robert H. Verkerk, PhD IFM Klinik, Falun, Sweden
Science Unit, Alliance for Natural pow@alpha-plus.se
Health International
Christy B. Williamson, DCN, MS, CNS
Dorking, Surrey, UK
Nutritional Genomics Institute, SNPed, OmicsDx
rob@anhinternational.org
Chesterfield, VA, USA
DrChrissie@NGIva.com
Aristo Vojdani, PhD, MSc, CLS www.nutritionalgenomicsinstitute.com
Immunosciences Lab., Inc. www.omicsdna.com
Los Angeles, CA, USA www.snppros.com
drari@msn.com smsilva10@gmail.com

Charlene Vojdani, PsyD Wendy Yu, MS, LAc

Immunosciences Lab., Inc. Department of OBGYN
Los Angeles, CA, USA Lotus Center for Integrative Medicine
charlenevojdani@gmail.com Los Angeles, CA, USA
wyu@lotuscenter.com
Elroy Vojdani, MD
Regenera Medical
Los Angeles, CA, USA
evojdani@gmail.com
 XIX

Abbreviations

5-HIAA 5-Hydroxyindoleacetic acid DHF Dihydrofolate

5-MTHF 5-Methylenetetrahydrofolate DHFR Dihydrofolate reductase
5-OH-TRP 5-Hydroxytryptophan DHGL/DGLA Dihomo-gamma-linolenic acid
DMG Dimethylglycine
A1AT Alpha-1 antitrypsin DMT2 Diabetes mellitus type 2
AA Arachidonic acid DXA/DEXA Dual-energy X-ray absorptiometry
AADC Aromatic L-amino acid decarboxylase
ABPM Allergic bronchopulmonary mycosis ECW Extracellular water
ACD Anemia of chronic disease ED Erectile dysfunction
ACE American Council on Exercise EEI Equilibrium Energy Intake
ACSM American College of Sports Medicine EFA Essential Fatty Acids
AERD Aspirin-exacerbated respiratory disease eNCPT Electronic Nutrition Care Process
ALA Alpha-lipoic acid Terminology

ALA α-linolenic acid eNOS Endothelial nitric oxide synthase

ALS Amyotrophic lateral sclerosis EPA Eicosapentaenoic acid

AMDR Approximate Macronutrient Distribution ET Exercise training

Ranges
ARDS Acute/Adult Respiratory Distress Syndrome FAD Flavin Adenine Dinucleotide

ATP Adenosine triphosphate FDA US Food and Drug Administration

FeNO Exhaled fractional nitric oxide
BCM Body cell mass FEV Forced expiratory volume
BCMO1 β-carotene 15,15′-monooxygenase FIGLU Formiminoglutamate
BCNH Bastyr Center for Natural Health FIP Familial interstitial pneumonia
BH4 Tetrahydrobiopterin FPF Familial pulmonary fibrosis
BHMT Betaine homocysteine methyltransferase FUT2 Fucosyltransferase 2
BIA Bioelectrical impedance analysis
BIS Bioimpedance spectroscopy GBS Guillain Barre syndrome

BMI Body mass index (body weight (kg)/height (m)2) GERD Gastroesophageal reflux disease

BMR Basal metabolic rate GFN Geometric Framework for Nutrition

BRCA1 Breast cancer type 1 susceptibility protein GGT Gamma-glutamyl transpeptidase

BRCA2 Breast cancer type 2 susceptibility protein GLA Gamma-linolenic acid

GMP Guanosine monophosphate
C Capacitance GPx Glutathione peroxidase
CBS Cystathione beta synthase GSH Reduced glutathione
CF Cystic fibrosis GSSG Oxidized glutathione
CGL Cystathionine gamma-lyase GTP Guanosine triphosphate
cGMP Cyclic guanosine monophosphate
CH3 Methyl group HAP Hospital-acquired pneumonia

CHD Coronary heart disease HDL High-density lipoprotein

CLA Conjugated linoleic acid henceforth NPE Non-protein energy

CLIA Clinical Laboratory Improvement Amendments HFE Hemochromatosis gene

COMT Catechol-O-Methyltransgerase HGBA1C Hemoglobin A1c

COOH Carboxyl group HIIT High-intensity interval training

COPD Chronic obstructive pulmonary disease HTN Hypertension

CT Computed tomography HVA Homovanillate
CTH Cystathionine gamma-lyase
ICW Intracellular water
CVD Cardiovascular disease
IFMNT Integrative and Functional Medical
Nutrition Therapy
DASH Dietary Approaches to Stop Hypertension
IFN Integrative and functional nutrition
DHA Docosahexaenoic acid
ILD Interstitial lung disease
XX
Abbreviations

IP3 Inositol triphosphate P Protein

IPF Idiopathic pulmonary fibrosis P5P Pyridoxal-5-phosphate
IR Insulin resistance PA Phase angle
IRDS Infant Respiratory Distress PAH Phenylalanine hydroxylase
Syndrome PAH Pulmonary arterial hypertension
ISMET Integrated standing, movement, PDE5 Phosphodiesterase type 5
and exercise training
PDXK Pyridoxal kinase
PES statement Problem-etiology-signs and symptoms
LA Linoleic acid
PG Prostaglandins
LC Lung cancer
PGE Prostaglandin E2
LDL Low-density lipoprotein
PGG Prostaglandin G2
LT Leukotrienes
PGH Prostaglandin H2
LTB Leukotriene B4 (LTB4)
PLH Protein leverage hypothesis
LTD Leukotriene D4 (LTD4)
PN Parenteral nutrition
LTE Leukotriene E4 (LTE4)
PNMT Phenylethenolamine N-methyltransferase

MAO-A Monoamine Oxidase A PUFA Polyunsaturated fatty acids

MAO-B Monoamine oxidase-B

RA Rheumatoid arthritis
MCT Medium-chain triglycerides
RBC Red blood cell
MetSyn Metabolic syndrome
RMT Right-angled mixture triangle
MMA Methylmalonic acid
MNT Medical nutrition therapy
SAH S-Adenosylhomocysteine
MRI Magnetic resonance imaging
SAM S-Adenosylmethionine
MSQ Medical symptoms questionnaire
SCFA Short-chain fatty acids
MTHFR Methylenetetrahydrofolate
SCLC Small-cell lung cancer
reductase
SIT Sprint intensity training
MTR Methionine synthase
SMA α-smooth muscle actin
MTRR Methionine synthase reductase
SMART goal Specific, measurable, accountable,
MUFA Monounsaturated fatty acids
reachable/realistic, and timely
SNP Single-nucleotide polymorphism
NAC N-acetyl cysteine
SOD Superoxide dismutase
NADPH, NADP+, iNOS Inducible nitric oxide synthase
sTFR Soluble transferrin receptor
NAFLD Nonalcoholic fatty liver disease
SUOX Sulfite oxidase
NASH Nonalcoholic steatohepatitis
NCP Nutrition Care Process
TBW Total body water
NIBLETS Nutrition, inflammation,
TETR Therapeutic ET for Rehabilitation
biochemical individuality,
lifestyle, energy and metabolism, TG Triglycerides
toxic load, and stress TH Tyrosine hydroxylase
NIH National Institute of Health THF Tetrahydrofolate
nNOS Nitric oxide synthase 1 TIBC Total iron binding capacity
NO Nitric oxide TPH Tryptophan hydroxylase
NOS Nitric oxide synthase TX Thromboxanes
NOS1 Nitric oxide synthase 1 TXA Thromboxane A
NOS2 Nitric oxide synthase 2
NOS3 Nitric oxide synthase 3 VAP Ventilator-associated pneumonia
NPE Nutrition physical exam
NSAID Nonsteroidal anti-inflammatory W3 Omega-3
drugs W6 Omega-6
NSCLC Non-small-cell lung cancer WHR Waist-to-hip ratio
 1 I

Global Healthcare
Challenge of the Twenty-
First Century and the
Future of Chronic
Disease
Contents

Chapter 1 The History and Evolution of Medicine – 3

Jeanne A. Drisko

Chapter 2 Influences of the Nutrition Transition on Chronic

Disease – 17
Sudha Raj

Chapter 3 Nutritional and Metabolic Wellness – 31

Diana Noland

Chapter 4 Nutritional Ecology and Human Health – 39

David Raubenheimer and Stephen J. Simpson

Chapter 5 The Radial: Integrative and Functional MNT – 57

Kathie M. Swift, Elizabeth Redmond, and Diana Noland

Chapter 6 The Power of Listening and the Patient’s Voice:

“Please Hear Me” – 73
Carolyn L. Larkin
 3 1

The History and Evolution

of Medicine
Jeanne A. Drisko

1.1 Introduction: The Problem – 4

1.2 Brief History of Medicine – 6

1.3  hanges Needed: Nutrition Education Across All Medical

C
Education Systems, Interprofessional Teams, and New
Systems of Care – 8
1.3.1  utrition Education Across All Medical Education Systems:
N
The Foundation – 8
1.3.2 Interprofessional Teams: The Way Forward – 11
1.3.3 New Systems of Care: The Way Forward – 12

1.4 Conclusion – 14

References – 14

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_1
 4 J. A. Drisko

1.1 Introduction: The Problem Electronic health record (EHR) technology, another

1 growing concern for medical practices, grew out of billing
At an interim meeting of the American Medical Association software and works for payers whether they are private or
in November 2018, AMA President Barbara McAneny, MD, federal [1, 3]. The EHR industry remains fragmented across
called the current US health system “dysfunctional” [1]. As the United States with large vendors dominating but not con-
Dr. McAneny stated, “the current system is working to trolling the market [1, 3]. A single EHR seems unlikely and,
improve hospital and insurance-payer bottom lines, but not as a result, chronic care providers will continue to struggle to
working as intended for patients or the doctors who care for capture, share, and use data from the wide number of dispa-
them.” She went on to describe how the system, with its ever-­ rate EHR systems. Most current EHR system users aren’t sat-
growing appetite for consolidating businesses and health isfied and many patients question who will have access to
systems, is getting in the way of actual healthcare. As insur- their personal data. We need technology that works for
ance payers place egregious restrictions on healthcare pro- patient care, not proprietary software that blocks informa-
viders, the health plan determines the course of care, tion gathering between different healthcare providers. The
regardless of the patient’s needs or the provider’s preferred archaic paper documentation, data entry, and faxing must
interventions. Dr. McAneny stated, “We are witness to greater cease [1]. A RAND Corporation study of physician payment
concentration of wealth and power in the hands of ever-­ methods found an overemphasis on EHR data entry payment
larger corporations with more and more middlemen pulling models rather than documentation of the healthcare
down large salaries while our patients go broke and physician provider-­patient relationship that is essential for the success
practices struggle to survive.” of patient care [5].
An example of a recent merger is the pharmacy giant, The gold standard for clinical decision-making, evidence-­
CVS, joining insurance company, Aetna [2]. CVS CEO Larry based medicine (EBM), has been called into question with its
Merlo said he envisions “CVS Pharmacy evolving from not narrowly designed definition and increasing conflicts of
just a store that happens to have a pharmacy and products” interest. As early as 2005, concerns about falsification in pub-
into “more of a healthcare destination.” Merlo added that CVS lished research were raised [6]. The author went on to claim
will continue to offer retail products, though its retail sales there was proof that most research findings are false.
grew only 1.5% in the first 9 months of 2018. CVS already has Subsequently, Horton’s 2015 Lancet editorial made a straight-
MinuteClinic locations at many of its stores, but the company forward case against EBM in which he said, “much of the
plans to branch out into other comprehensive, community- scientific literature, perhaps half, may simply be untrue” [7].
based healthcare services in the wake of the Aetna deal. Specific concerns that included invalid exploratory analysis,
With more than 500 hospital mergers between 2010 and flagrant conflicts of interest, and an obsession for pursuing
2015, nearly half of the hospital markets in the United States fashionable trends in science of dubious importance led him
are now highly concentrated, with many areas of the country to write, “[S]cience has taken a turn towards darkness.” The
dominated by one or two large health systems [3]. Large sys- editorial goes on to highlight the fact that research universi-
tems are less nimble and have difficulty responding to market ties are in a struggle for money and talent and these and other
shifts. As healthcare markets concentrate, CEOs focus more reductive metrics incentivize bad practices. One of the most
on growth than cost-cutting. In addition, hospital mergers significant concerns about bias in EBM is financial conflicts
have been leading to ever-increasing prices for healthcare of interest [8, 9]. As the growing cost of science and research
consumers. Healthcare systems are also facing challenges to has outstripped the ability of federal funding, industry and
their business models because new types of healthcare ven- the private sector have stepped into the gap. Unfortunately,
ues will shake up the market. These new venues include retail those in industry who give the research dollars and support
clinics, outpatient urgent care centers, laboratory service-­ the infrastructure also have a hand in research design, con-
based providers in shopping centers, upcoming projects duct, and publication of findings with significant concerns
from tech giants like Amazon and Apple, telehealth services, regarding bias. Financial conflicts of interest with ties to
and the potential for additional mergers between payers and industry are placing undue influence on researchers. A recent
retail pharmacies [3]. prominent example is José Baselga, MD, who was forced to
The insurance payer market is also consolidating, with resign as chief medical officer of Memorial Sloan Kettering
many large metropolitan areas dominated by companies that after it came to light that he failed to disclose millions of dol-
make up at least 50% of the market share [3, 4]. As reim- lars in payments from pharmaceutical companies in dozens
bursement rates to healthcare consumers decline, many now of published research articles [10]. Although Dr. Baselga
pay more out-of-pocket expenses and are willing to switch claimed the oversight was inadvertent, The New England
healthcare providers to get faster appointments, more conve- Journal of Medicine editors described his failure as a “breach
nient locations, better services, and greater cost transparency. of trust” [11]. This and other breaches of trust have confirmed
This chaos will certainly tax the large conglomerates to pro- that EBM has been hijacked, placing limitations on use of the
vide models of healthcare delivery and payment that will published evidence that degrade the doctor-­patient relation-
further stress their infrastructure. Currently, the dominant ship and flagrantly disregard patient values [9]. As top
payer system keeps healthcare providers dependent on its researchers, federal funders, and most journals call for action,
strategies instead of emphasizing quality and value. the bad news is no one seems ready to act.
The History and Evolution of Medicine
5 1
The above changes and challenges have resulted in greater care and financial responsibilities. A futuristic view of med-
frustrations for practitioners in the trenches caring for icine demands a consumer-centric healthcare delivery
patients, leading to burnout and increased suicides [1, 12, system, and the question remains if the current system can
13]. Healthcare providers feel a loss of control over delivery provide it [4].
of care with more patient encounters shoehorned into the The long-term goal for care delivery is change in the
workday. For every patient they see, they spend two or three model and a predominant focus on preventive care [3, 4]. The
times as much time on EHR documentation, with approxi- patient will be a consumer of the healthcare system and will
mately 25% of it spent outside of the clinic. Healthcare pro- demand transparency in billing and access to medical infor-
viders are not feeling good about the entire structure at the mation (see . Fig.  1.1). This will require engaged medical
 

end of the day. It is this loss of autonomy and control over the personnel who are transparent and willing to embrace neces-
practice of medicine that is leading to the crisis. And, as Dr. sary change, especially in technology with interactive plat-
McAneny says, “Yoga at lunch won’t fix this” [1]. forms and computer software that interfaces with medical
Healthcare costs at the current growth rate are unsus- records, physician offices, and all members of the health
tainable at $3 trillion, and chronic noncommunicable dis- team. This will include integrated devices that transmit
ease accounts for the vast majority of every healthcare dollar patient health data to providers. New ways to manage chronic
expenditure [14–17]. It is time to reimagine medical educa- disease effectively and efficiently while keeping patients at
tion, chronic disease care, and EHR data liquidity and to home will be required. Consumer input will be expected,
eliminate dysfunctional healthcare. The traditional health- making clear what they need and want from their healthcare
care model focuses on acute care with a singular focus on providers. Guidance will come from leading consumer-­
hospital-centered care built around ever-expanding large centered practices from industries outside of healthcare. In
health systems [4]. This current system seeks to continue the the end, there will be transparency of pricing, quality data,
status quo and is attempting to improve the current pro- and technology that engages patients, as well as personalized
cesses within an unsustainable environment. To correct this care delivery. When patients and their healthcare providers
destructive path, there is a call to change medical education are engaged in this process, it will become a powerful disrup-
with focus on chronic disease inside this current model. tive force to the current model. The mandate is on healthcare
This will include short-term supplementation of the current systems to transform or become obsolete. It is important for
conventional care system models with alternative care mod- change agents and disruptors to take risks, partner with
els. However, there are no processes in place or systems built innovators, be creative, and engage healthcare team members
in to help patients navigate and take charge of their health- in the process.

What patients want

Choose their providers Regular communication Easy access to health data Technology to support
self-care

Choose appointments Personalized healthcare Online cost transparency Transparency of quality

and schedule when outcomes
and where

..      Fig. 1.1  What patients want. (Reprinted with permission from iStockphoto LP)
 6 J. A. Drisko

Who will lead the charge for change? It will not be Big ease. It was also during the time of the Greeks that shrines
1 Pharma or healthcare insurance plans or health systems. It is and temples arose where climate, diet, and hygiene became
the burden of medical professionals and consumers to important in healing. These locations were often associated
become the agents for change and disruptors of this dysfunc- with mineral springs and incorporated exercise, baths, and
tional system. Healthcare providers need training to inter- the use of oils and ointments on the body. Prescribed diets,
vene early in the continuum of chronic disease and be able to along with prayers and sacrifice, were administered. Libraries
teach patients to stay healthy, exercise, and choose nutritious with records of treatments, therapies, operations, and all
foods. The healthcare workforce needs to become partners types of medicines were established with some of these
and educators of patients and speak up for patient equity and records surviving to modern times.
ethical treatment and demand that patients have a voice. We Hippocrates is the father of modern medicine and he
have been called to a mission to be dedicated medical profes- richly influenced the evolution of its science and art. He
sionals and, as such, willing to design a system that values noted that the healer provides service to the community and
health over money, power, and politics. must aim to be useful and make men better. Hippocrates
directed the healer to correct lives and ethically conduct his
own life. He must make the beautiful soul harmonize with
1.2 Brief History of Medicine the beautiful body, as it is the duty of the healer to respect and
care for the body [18]. Hippocrates instructed healers to
A brief history of medicine is in order to understand its employ consultations when necessary and pushing for fees
evolution and how we have found ourselves at this cross- was discouraged. The healer was to choose the least sensa-
road. Medicine arose from a superstitious approach of tional method and not pretend to be infallible. Above all,
ancient civilizations with the healer as a philosopher, physi- cleanliness was to be valued. Because of the high order of
cian, and priest [18]. This mindset continued until the mandates established by Hippocrates, bylaws were instituted
Renaissance and  blossoming of scientific approaches dur- regulating the personal behavior of physicians. By setting
ing the Enlightenment. Medicine likely developed out of aside the roots of mysticism, superstition, and religious rit-
the primal sympathy of man for fellow man and out of the ual, Greeks began looking to nature and the science of man to
desire to help those in sorrow, need, and sickness. This basis base accurate observations. There is no mention of divina-
of compassionate medicine continues and is rooted in sym- tion, incantations, or charms from the Greeks. They recog-
pathy and the desire to help others. nized that disease is part of nature, not divine or sacred, and
For many millennia, priests and physicians were co-­ the old beliefs were ascribed to ignorance.
identified in the practice of medicine and medicine was never The Greeks expanded the understanding of anatomy as it
fully dissociated from religion. Because of evil spirits and pertained to the heart, circulation, and pulmonary system,
angry gods, man needed emetics, purgatives, enemas, diuret- although accurate circulation was not described until much
ics, and bleeding to rid these demons from the ailing body later. The Alexandrian school under the Ptolemies opened a
[18]. A rich pharmacopeia was available during this time as university with the study of literature, science, arts, and
has been identified from recovered papyri. The community medicine, and early understanding of the structure of the
used animal body parts and secretions and other elements human body was defined by limited dissection. Physical
derived from nature such as opium, hemlock, copper, salts, exam, to include pulses and other observations, was
and castor oil. Crude surgical procedures were employed developed to look for the cause of disease. Galen’s program
with historical records of some of these interventions surviv- began teaching by example, visiting the ill at the bedside, and
ing to modern times. this method of ward rounds continues to this day.
Medicine passed from the rich Egyptian culture to the Medieval medicine saw the light of learning burn low and
Assyrians and Babylonians with the ascendancy of these later flicker almost to extinction. The gifts of knowledge from
cultures and the decline of Egypt. Medicine developed to a Athens and Alexandria were deliberately cast aside after the
higher stage but continued to ascribe to evil spirits and barbarians invaded Rome and civilization was reduced to a
demons as the cause of illness and use practices to predict the wilderness [18]. During this time, Christianity wrought
future. One practice was for physicians to examine animal changes in the approach to medicine by reviling the body and
organs, particularly the liver, which was believed to be an all evil on earth. This had profound negative effects by stag-
important seat of the soul, vitality, mind, and emotions. This nating the evolution of medicine. Science was disregarded as
led to anatomical models and the understanding and obser- unnecessary. The light of scientific medicine from the
vation of anatomy. These were related to the priest/healer’s ancients was almost lost in the morass of the Middle Ages,
yearning to peer into the minds of the gods. but was revived in the Renaissance. With the reintroduction
Greek medical schools arose as early as the fifth century of universities in the thirteenth century, guilds of students
BCE where the appreciation between anatomy and ­physiology were attached to a famous teacher, and the study of anatomy
was recognized [18]. It was at this time that the doctrine of was revived [18]. The rising of the sun of science dawned,
humors arose. Healers strove to keep equilibrium of the and of many, one notable, Roger Bacon, advocated experi-
humors – blood, phlegm, yellow bile, and black bile – because mental science. Treatments were prescribed accordingly and
health maintenance and disturbances were equated with dis- some of these doctrines reach into modern days.
The History and Evolution of Medicine
7 1
As the Greek writers of medicine were rediscovered in the immunity. Rene Laennec described the use of the stetho-
fifteenth century, physicians became naturalists and botanists scope and began the practice of rigorous physical diagnosis.
and interested in humanities. The sixteenth and seventeenth Richard Bright described renal disorders; Rudolph Virchow
centuries saw the foundation laid for accurate knowledge of became the father of cellular pathology; Humphrey Davy
the structure and function of the human body and how it described the use of nitrous oxide; and William Morton used
should be studied. Chemistry was elevated with many impor- ether, beginning the advent of surgical anesthesia. Louis
tant discoveries advanced. It was during this time that Pasteur developed the understanding of plagues, fevers, and
Vesalius, a Belgian by birth but a teacher in Padua, began the pestilence and described the epidemic spread of infection,
study of anatomy through dissection of the human body with which destroyed the spontaneous generation theory. Robert
one of the greatest books of the world published with his ana- Koch showed the life cycle of infectious disease and devel-
tomical dissections. However, Vesalius was reviled for his oped Koch’s postulate, while Joseph Lister developed the
work because it was so revolutionary and unfavorable false germ theory and destroyed the belief in miasmas or bad air
reports about his character were spread widely [18]. causing disease. Great strides were taken at the close of the
William Harvey was trained by the Paduan Italian anato- 1800s in the area of tuberculosis, malaria, sleeping sickness,
mists and returned to England, eventually teaching at the and syphilis, and the ancient doctrine of Celsus was proved
College of Physicians in 1604. He was the first to thoroughly true: to determine the cause of the disease often leads to the
describe structure and function of the organs of the thorax remedy [18]. Thomas Addison, a physician at Guy’s Hospital,
with accurate understanding of the workings of the heart and described the adrenal glands and their function, which was
circulation of the blood. It has been stated what Vesalius did followed closely by others with descriptions of the pancreas
for anatomy, Harvey did for physiology [18]. Harvey had a and its relation to diabetes, the thyroid, and the pituitary. Out
special gift to prove experimentally what he hypothesized of this grew chemistry and laboratory medicine with the
and developed the spirit of modern sciences. It was through foundation of the physiology and composition of expired air,
luminaries like Harvey, Bacon, and Descartes that experi- blood, food components, excrement, urine, and metabolism.
mental research became the mode, with superstition and With the understanding of the germ theory and attention
religion finally removed. The beginnings of modern medi- to sanitation, preventive medicine was born. The attempts to
cine began in the 1680s by incorporating anatomy and physi- fight poverty, filth, poor living conditions, and other public
ology into education, and the use of postmortem dissection health measures helped stamp out typhus and reduce infec-
facilitated the association of illness with death. Systematic tions of malaria and yellow fever. Sanitation and improved
description and experiments ruled with truth overcoming living conditions reduced the burden of tuberculosis from
dogma. about one million in the eighteenth century to half that num-
Herman Boerhaave’s Dutch school was the epicenter of ber by 1911. The dawn of modern medicine through the first
European medical learning in the early 1700s, with training half of the twentieth century saw the reduction in acute ill-
in medicine, scientific method, and patient observations. ness or communicable disease and the ascendancy of chronic
Students were attracted to the Dutch school from all over the disease or noncommunicable disease that now plagues man-
civilized world during this period. The Dutch method of kind worldwide [14].
instruction was brought back to Edinburgh by John The history of twentieth-century medicine would not be
Rutherford in 1747, augmenting the rise of the age of the complete without discussion of the Flexner report. Published
Scottish Enlightenment. Rutherford taught at the Royal infir- in 1910 after the Carnegie Foundation commissioned the
mary and was followed by William Cullen and Robert Whytt. study of US medical education [20], the project’s overarching
It is important to note that Benjamin Rush, a young American goal was to weed out medical schools that had no prerequi-
physician and one of the signers of the Declaration of site educational requirements and no preparation in the basic
Independence, studied under Cullen in Edinburgh before sciences, those not associated with a university, and those
returning to Philadelphia and establishing American medi- with no systematic teaching of patient care by hospital
cine [19]. John Hunter organized pathological processes and rounds. Abraham Flexner felt his mission was to eliminate
determined that they were governed by laws of nature and those who called themselves physicians but had received very
subsequently accumulated, tabulated, and systematized this little scientific education before or during medical school.
field of thought. Hunter reestablished the close union Certainly, there was the need to elevate medical teaching and
between medicine and the natural sciences and laid the foun- training with expansion of the medical sciences.
dation for collections and museums connected to medical In Chapter X of the groundbreaking report, he detailed
schools. The systematic teaching of clinical medicine by ward “illegitimate nonscientific” approaches that he called
rounds followed by amphitheater lectures became the stan- “Medical Sects” [20]. These groups included naturopaths or
dard mode of medical education. eclectic practitioners, herbalists, psychologists, homeopaths,
By the end of the 1700s and through the 1800s, many chiropractors, and osteopaths, and these groups very quickly
great medical advances were made with only a few noted found their education and practice driven underground by
here. This included the birth of smallpox eradication by the polemics of Flexner’s disdain [20, 21]. The report also
Edward Jenner through inoculation with cowpox. Jenner marginalized practices he felt to be unscientific, like social
contributed to the beginning understanding of acquired work and other disciplines like nutrition [20, 22].
 8 J. A. Drisko

Flexner advocated for the state board system that contin- ancient ways while retaining the good parts, so should we let
1 ues to license medical practitioners to this day [20, 23]. He go of the acute care model that is collapsing and join forces
noted that the state boards could reject applicants as an indi- with all types of practitioners to build a new model, with
rect method of discrediting the school which had given them patient-centered humanistically oriented community medi-
their medical degree and, in his words, “[T]he board should cine focusing on subduing chronic disease and supporting
summarily refuse to entertain the applicant’s petition because health-oriented citizens.
his medical education rests upon no proper preliminary train-
ing. The full weight of its refusal would fall with crushing effect
upon the school which sent him forth.” In 1912, a group of the 1.3  hanges Needed: Nutrition Education
C
state licensing boards joined together to create the Federation Across All Medical Education Systems,
of State Medical Boards [23]. This is neither a federal agency Interprofessional Teams, and New
nor an independent governing body as the group voluntarily Systems of Care
agreed to base its accreditation policies on academic standards
determined by the American Medical Association’s Council 1.3.1  utrition Education Across All Medical
N
on Medical Education policies. Consequently, these decisions Education Systems: The Foundation
became the law of the medical land. A great deal of political
power was placed in the hands of the American Medical Worldwide, chronic disease will cause $17.3 trillion of accu-
Association that continued to suppress competing forms of mulated economic losses over the next 20 years [16, 17]. These
medical practice well into the late twentieth century. economic burdens are related to healthcare expenditures,
Although many excellent advances occurred because of reduced productivity, and lost capital and are the leading pri-
improvements in the medical education system, there was a orities of our time. The predominant risk factor for chronic
chilling effect of contracting medicine to reductionist strate- disability and death worldwide is related to suboptimal diet
gies with established hierarchies. The job of medical care and poor lifestyle choices [14, 24]. Diet-related coronary heart
morphed in the early twentieth century after the develop- disease, stroke, type II diabetes, and obesity produce ever-
ment of drugs and advances in surgery. This led to drugs and growing global health burdens [14]. It is now evident that
surgery as the purview of physicians in dealing with acute poor dietary habits contribute to obesity, low-­density lipopro-
care until the shift to chronic diseases made these approaches tein cholesterol increases, increased blood pressure, glucose-
less successful. What suffered with the Flexner report was insulin irregularities, oxidative stress, inflammation, poor
patient-centered humanistically oriented community medi- endothelial health, fatty liver, irregular adipocyte metabolism,
cine [21, 22]. Medical schools to this day continue to struggle abnormalities in hormone pathways of weight regulation, vis-
to overcome the effects of standardization of American med- ceral adiposity, and destruction of the gut microbiome [17].
ical education [23]. All accredited American medical schools Unfortunately, the focus for decades has been a preoccupation
apply Flexner’s “uniformly arduous and expensive” goals in on dietary recommendations that limit fat and cholesterol. It
medical education [23]. Unfortunately, with the rise in cost is now acknowledged the full health impact of fat-limited
of chronic healthcare, many schools have been forced to diets extend far beyond cholesterol pathways.
make curricular changes and form corporate alliances Dietary research and interventions evaluating overall
because of the need to balance academic ideals with eco- metabolic risks have up to the present focused on single iso-
nomic and social realities. lated nutrients rather than broad dietary patterns. Rather
It is clear our current education and treatment systems than isolated nutrients, a food-based approach better serves
are administered on the old foundations built during the era the general populations and minimizes industry manipula-
of acute communicable disease with heavy reliance on hospi- tion [17]. Pushed by burgeoning obesity rates, nutrition
tal rounds. But acute communicable disease has given way to research is beginning to focus on the quality and types of
dominance of chronic noncommunicable disease. Medical foods consumed that influence diverse pathways such as
education must now include a curriculum that addresses the glucose-insulin response, hepatic lipogenesis, fat storage, and
major cause of mortality and morbidity in the population the microbiome. Armed with this new information, it is up to
that the health workforce serves and in the systems where the healthcare team to work with individual patients and
they practice [22]. Will we be able to rebuild within the cur- meet them in their sociocultural communities to create last-
rent system or find the need to construct a new model that ing changes in chronic disease burdens. However, new para-
will give home to the treatment of chronic noncommunicable digms in nutrition are not being translated into clinical
disease? It is without question that medical education needs practice because of limits in medical education.
to undergo radical change and this poor foundation in Medical education has a mandate to prepare students to
­education and treatment of chronic disease is largely to blame face the types of clinical problems they will see in their every-
for the dysfunctional medical system, burnout of its caregiv- day practices [25]. Medical education has predominantly
ers, dissatisfied patients, and skyrocketing costs. Even Flexner occurred in a hospital setting with didactic lectures in amphi-
believed that medical education must be accountable to the theaters and ward rounds consisting of education at a patient’s
society that it serves [22]. Just as the Greeks and those physi- bedside. There is a failure of medical education, and as a
cians in the Renaissance and Enlightenment let go of the result the healthcare delivered, to adapt to transformations
The History and Evolution of Medicine
9 1
that have occurred in the past 50 years, with chronic disease add 5 years of life. Conversely, consuming 1 egg daily would
replacing acute disease as the dominant problem. While reduce life expectancy by 6 years, and eating 2 slices of bacon
acute disease is episodic, commonly associated with hospital- (30 g) daily would shorten life by a decade, an effect worse
ization and a return to baseline health, chronic disease is than smoking. Could these results possibly be true?” New
constant with the prevailing belief there is rarely a cure. It can paradigms of nutrition research are desperately needed.
be argued that in order to find relief and possibly cures, As nutrition science research matures, there is agreement
chronic disease requires a change in delivery of care and its that diet, nutritional status, and lifestyle choices predispose
location with a broader emphasis on lifestyle and diet. Diet or protect against many chronic diseases including heart dis-
and nutrition are the foundation of health. Currently, medi- ease, diabetes, and cardiovascular disease. Yet, uncertainty
cal education does not value nutrition education or under- remains in evaluating dietary evidence for federal policy rec-
stand its contributing role in chronic disease. ommendations and broad public health statements. Unlike
Poor nutrition as a leading cause of morbidity and mor- the pharmaceutical industry, where evidence-based medi-
tality is competing with and perhaps outpacing the deleteri- cine (EBM) evaluates drug effects and has done so for many
ous effects of tobacco and physical inactivity, but is largely years, this type of research and evidence has proved challeng-
unrecognized by conventional primary care providers related ing when attempting to adapt it to nutrition and diet research.
to limited nutrition education opportunities. As early as Notwithstanding the concerns regarding traditional EBM
1963, there were reports of deficiencies in nutrition educa- [6–9], researchers have not established clear guidelines to
tion in conventional medical schools [26]. The authors point the way to study the effects of nutrients in complex
acknowledged, “a close relationship between nutrition and human systems combined with a lack of consensus on how to
the individual’s response to pathologic stress, such as severe evaluate findings and establish policy and dietary guidelines.
infections or trauma.” They also acknowledged the relation- It is imperative to remember that pharmaceutical drugs
ship between nutrition and degenerative disease, atheroscle- are often studied in a therapeutic intervention context, that
rosis, hypertension, and neoplasia. At the time, there was a is, to treat, cure, or mitigate disease. However, nutrients are
call to improve medical education and medical practice to studied with a focus on health promotion or disease risk
keep “abreast of the tremendous advances in nutritional reduction, again supporting the idea that there needs to be
knowledge” [26]. Yet this call was not heeded. fundamentally different approaches in researching the two
Over the ensuing decades, the increasing burden of chronic, models. What is needed is evidence-based nutrition not built
diet-related disease, including the obesity epidemic, was not on principles of EBM or reliance on randomized controlled
matched with nutrition education in conventional medical trials [30]. When comparing food and nutrients to pharma-
education [27–29]. The neglect in teaching nutrition is a grow- ceuticals, it is best to remember that drugs usually have single
ing problem as the workforce is not armed with tools to address and targeted effects, are not homeostatically controlled by
patients’ lifestyle issues. The average amount of required nutri- the body, and can be contrasted with true placebo. By way
tion education, at the time of one report, was noted to be of comparison, nutrients work in complex systems, within
19.6 hours, while the number of schools offering a dedicated an epigenetic framework, and in concert with other nutrients
nutrition course fell 25% [28]. Rather than measuring hours of and simultaneously affect multiple cells, tissues, and organs
nutrition education and coursework, the focus should be on because they are homeostatically controlled. An added con-
competencies. In fact, most medical education across disci- sideration is how the research participant’s baseline nutrient
plines does not even teach diet and nutrition beyond a few status will affect the response to nutrient intervention. Finally,
metabolic pathways. Barriers to the inclusion of nutrition in in the EBM research model, single isolated nutrients are
medical education include such factors as the focus on treating required to be evaluated; however, this approach could never
disease with drugs and surgery and the erroneous belief system be effective in the complex biochemical mammalian envi-
that nutrition is insufficiently evidenced-based [28]. ronment. Nutrients function in a vastly complex biochemical
The research evidence base for nutrition is only in its network subject to interplay of genetics, diet, lifestyle, activ-
infancy, having begun in earnest in the beginning of the ity, stress, and environmental toxins. Single-nutrient studies
twentieth century. It wasn’t until the 1980s that US dietary can never answer questions in this complex system, and their
guidelines focused on the nutritional basis of chronic disease effects in long-latency chronic disease cannot be adequately
[24, 27–29]. However, because of the historical emphasis in assessed. Until a new paradigm is developed, it is likely that
nutrition research on deficiency disease, the single-nutrient healthcare providers in the trenches caring for those with
paradigm continued to dominate research approaches. As a chronic disease will be reduced to technicians delivering
result, the literature oversimplified the impact of dietary fac- evidence-based algorithms and guidelines. It is up to leaders
tors in chronic disease [17]. In addition, nutrition epidemiol- in the field of nutrition to establish evidence-­based nutrition
ogy is in need of “radical reform” [6]. As an example of the research guidelines.
absurdity of focusing on the previous research paradigm, the An example of this misguided research approach occurred
author states “ [E]ating 12 hazelnuts daily (1 oz) would pro- in the 1980s and 1990s. Policymakers and healthcare practi-
long life by 12 years (i.e., one year per hazelnut), drinking 3 tioners believed saturated fats and cholesterol were the cause
cups of coffee daily would achieve a similar gain of 12 extra of coronary heart disease and obesity [17]. Over the past
years, and eating a single mandarin orange daily (80 g) would 30 years, the substitution of fats with simple carbohydrates
 10 J. A. Drisko

and sugar in processed food led to the rapid rise in the obe- patients with chronic disease will be better cared for. Educating
1 sity epidemic and skyrocketing type II diabetes rates. Based patients and their families in self-management methods will
on evidence, the 2015 Dietary Guidelines Advisory make them a valuable member of this team as well.
Committee concluded that low-fat diets had no effect on car- Successful and sustainable improvements in patients with
diovascular disease and recommended focus on healthful chronic disease can occur but will require close collaboration
food-based dietary recommendations rich in healthful fats among multiple stakeholders, including interprofessional
[31]. Fortunately, more sophisticated approaches are being healthcare teams and the health systems they work in, policy-
discussed with a rapid transition away from the single-nutri- makers, researchers, community organizations, schools,
ent theories and surrogate outcomes. farmers, retailers, restaurants, and food manufacturers. In
We see a transition in a more modern understanding of the clinic setting, evidence-based dietary interventions are
diet in its relationship to chronic disease. The science of obe- needed for individual behavior changes. These approaches
sity in more educated circles is shifting away from simplistic include goal-setting, in collaboration with the patient, that
ideas of energy balance and calorie counting with new includes a personalized diet plan; self-monitoring that could
research focused on the effects of food and diet patterns on be achieved with electronic diaries through web-based apps;
complex physiologic pathways. Healthful food-based pat- regularly scheduled follow-ups with feedback on progress
terns of intake have been shown to be the most important for through telehealth, telephone, or electronic feedback; the use
fighting obesity [31]. Poor dietary quality is associated with of interventions that include motivational interviewing; and
an increase in processed foods, resulting in loss of nutrients consistent use of family and peer support. See . Table  1.1  

and fiber, including polyphenols, minerals, essential fatty [17]. This will necessitate training interprofessional teams on
acids, vitamins, and other bioactive food ingredients. Poor
diet quality is a driver of excess dietary intake, which in turn
influences metabolic risk and the increase in abdominal adi- ..      Table 1.1  Evidence-based approaches for individual
posity. Independent of calories, poor dietary quality strongly behavior change in the clinic setting
influences metabolic dysfunction and drives the increased
risk of diabetes. With increases in processed carbohydrates Intervention
and simple sugars, these diets contribute to insulin dysregu- 1 Specific, proximal, shared goals. Set specific,
lation and resistance over time [17]. proximal goals in collaboration with the
Evidence shows that an educated patient achieves better patient, including a personalized plan to
outcomes and a collaborative medical environment further achieve the goals (e.g., increase fruits by
enhances this [32]. Patients need education in healthful 1 serving/day over the next 3 months)
dietary choices. Sadly, the public considers physicians to be 2 Self-monitoring. Establish a strategy for
one of the most trusted sources of nutrition-related informa- self-­monitoring, such as a dietary or physical
tion [25, 27–29]. Yet physicians and other healthcare provid- activity diary or web-based or mobile phone
application
ers lack core competencies to properly counsel and educate
patients about nutrition and diet-related disease. Additional 3 Scheduled follow-up. Schedule regular follow-up
barriers beyond education in instituting these goals in the (in-person, telephone, written, or electronic),
with clear frequency and duration of contacts,
conventional medical encounter include shrinking medical
to assess success, reinforce progress, and set
encounter time and increased EHR burdens, leaving little new goals as necessary
room for discussion of diet and lifestyle interventions. There
is a need for creativity and innovation for approaches in 4 Regular feedback. Provide feedback on progress
toward goals, including using in-person,
chronic disease intervention, beginning with medical educa- telephone, or electronic feedback
tion and extending into the care setting. Imaginative ways of
interacting with patients besides a traditional physical 5 Self-efficacy. Increase the patient’s perception
that they can successfully change their behavior
encounter should be employed such as telemedicine, tele-
phone, and email [4]. This model needs to be incorporated in 6 Motivational interviewing. Use motivational
conventional medical education across all disciplines, and interviewing when patients are resistant or
ambivalent about behavior change
these shared learning experiences need to be coupled with
new understanding and new behaviors [25, 32]. This in no 7 Family and peer support. Arrange long-term
way conflicts with medical science or the care of acute dis- support from family, friends, or peers for
behavior change, such as in workplace, school,
ease in the hospital setting but rather allows the best of med-
or community programs
ical science and technology to care for all patients.
The Institute of Medicine report, Crossing the Quality 8 Multicomponent approaches. Combine two or
Chasm [32] reported, “[T]he fundamental approach to medi- more of the above strategies into the behavior
change effort
cal education has not changed since 1910.” There is now a call
for medical care teams to be educated and to work together in Adapted from Mozaffarian [17]. With permission from Wolters
a manner that shares management responsibilities and deci- Kluwer Health
sions for these new challenges. With this shared responsibility,
The History and Evolution of Medicine
11 1
evidence-based behavior change strategies and adopting new Education Collaborative (IPEC) with the goal of working
techniques such as telehealth and electronics systems to help together to promote and encourage interprofessional learn-
assess, track, and report what specific dietary behaviors are ing experiences [38]. This vision grew out of a desire to
occurring. form an interprofessional collaborative practice to deliver
safe, high-quality, accessible, patient-centered care. The
intent was not to harmonize the educational experience but
1.3.2 I nterprofessional Teams: The Way to build on each profession’s expected competencies to
Forward enhance the interprofessional experience in patient care. To
enable the vision to be fulfilled, it was acknowledged that
Lifestyle and behavioral risks resulting in complex chronic students needed to interact with one another in a learning
disease along with shortages in the health workforce are tax- environment so that they would effectively become mem-
ing the medical system. It has been argued that even though bers of a clinical team. This was to help prepare future
the 1910 Flexner report sparked groundbreaking reforms in health professions for enhanced team-based care of patients
medical education, medical education has not kept pace with and improve population health outcomes particularly with
the current challenges that have produced ill-equipped grad- the growth of chronic disease. A report published in 2011
uates [33]. Because of the structure of medical education detailed the core competencies for interprofessional collab-
post-Flexner report, there was a tendency of various medical orative practice [38]. This report and its goal to change were
professionals to act in isolation from or even in competition widely accepted and adopted with dissemination of the
with one another. There has been a call to redesign profes- competencies across multiple colleges of medical learning
sional health education to capitalize on the interdependence with increased incorporation as part of the required cur-
of health professionals in this new age of complex chronic riculum.
disease. The idea of a team of medical professionals joining Between 2011 and 2016, the interprofessional collabora-
forces to deliver patient-centered care for complex medical tive team grew from 6 core members to 15, along with input
disorders in the community setting has been discussed for from 60 other health professions [40], with expanded goals
several decades [32, 34–38]. to create a shared taxonomy among all the health professions
Chronic disease evolves over time with waxing and waning and to streamline and synergize educational activities,
severity. Compared to acute disease in a hospital setting where related assessments, and evaluation efforts. The updated
the patient submits themselves to treatment, complex chronic 2016 report highlighted the Triple Aim, which includes
disease demands involving the patient as an active partner in improve the patient experience of care, improve the health of
their care; and because of the complexity of chronic illness, it is populations, and reduce the per capita cost of healthcare
essential that a coordinated team of healthcare providers unite [40]. The group articulated shared ideals that translated to
in its management. The team provides continuity and competencies and include professionalism and respect,
organized integration of care that are essential elements and using knowledge for the benefit of patients and populations,
helps create a healing relationship with the patient. Because improving communication to promote and maintain health
the patient is now an active partner, education of the patient as and prevent disease, and using teams to plan, deliver, and
well as family members or other social support groups is evaluate patient-­centered care that is safe, timely, efficient,
paramount. It is important for the professional group of effective, and equitable [40]. But can the current conven-
providers, the interprofessional team, to understand that their tional health system with shrinking office visit times and
role has changed from the time when acute disease treatment increasing EHR demands successfully deliver interprofes-
was delivered to the patient to our current era of chronic sional team medicine?
disease where the patient is part of the decision-making team. It is the belief of this author and the authors of this text-
The interprofessional team members are now professional book that an effective model of interprofessional teams has
guides and advisors, teaching the patient healthcare skills, and been in existence for several decades. An integrative and
there is shared decision-making between the patient and the functional healthcare team has brought together a partner-
healthcare team demanding a treatment program tailored to ship of multiple types of providers with the focus on the
the patient’s specific needs and wishes. In addition, the location patient [39, 41]. With the patient at the center, attention is on
of treatment intervention changes from the hospital ward to the roots of chronic disease with diet as the foundation,
the ambulatory setting, which can take on a variety of requiring a team of professionals with a wide variety of
appearances and locations such as traditional outpatient expertise. This type of practice is bringing enjoyment back
clinics, health clubs, home settings, community centers, into the practice of medicine. Integrative and functional
telemedicine, email, or group educational programs [4, 5, 39]. medicine is using paradigms to address chronic disease,
The location is of less importance than the partnership and while conventional medicine remains stuck in its acute care
relationship of the patient and the interprofessional team, model. As spiraling rates of burnout and suicides occur,
which is central to the healing encounter. conventional providers are finding their way into new models
In 2009, six organizations representing schools of health of practice, and as a result, the dominance of the acute care
education came together to form the Interprofessional model will wane.
 12 J. A. Drisko

1.3.3 New Systems of Care: The Way Forward ting. However, a barrier to implementing this style of medi-
1 cine is modest research underpinnings and tepid
In the Introduction, . Fig 1.1 highlighted what patients want
 
recommendations from policymakers.
from their healthcare providers. Patients want to be part of Another barrier to instituting a patient-centered diet and
the healthcare team with their preferences valued. lifestyle approach includes the challenge in dealing with the
Information sharing is the answer and educating patients is complexity and the often-insidious transition from health to
the key. The future of medicine depends on the partnership chronic disease with late onset of symptoms. This requires a
of the interprofessional team with patients while avoiding workforce willing and trained to reconsider reactionary
methods that limit patient access to self-care information. A treatments and interventions as first-line treatments and to
startling example of the attempt to reduce patient self-care is shift toward diet and lifestyle interventions first, with an eye
seen in the recent report stating patients with type II diabetes on long-term prevention. A framework for this type of medi-
are testing their blood sugar by glucometer more often than cine has been proposed and is labeled “P4” for predictive,
they need to [42]. Three medical societies, the American preventive, personalized, and participatory [46]. The authors
Academy of Family Physicians, the Society of General state this system was developed to move away from a reactive
Internal Medicine, and the Endocrine Society, released a medical approach with expensive episodic acute care inter-
statement that type II diabetics do not benefit from tracking ventions delivered in conventional settings that results in
daily blood sugars. The information was collected from minimal interactions between specialists and general practi-
insurance data with a look at expense. This flies in the face of tioners, fragmented healthcare approaches with multiple
good medicine and reduces the partnership with patients. prescription medications, scattered follow-up, and a subopti-
Patients are no longer to glean information from self-testing mal cost-effectiveness ratio of care delivered [46]. Chronic
to learn what effects food and lifestyle factors have on blood disease care under these new models can be preventive with
sugar levels. As conventional frontline medical practitioners drug and surgical interventions delayed until significantly
are no longer encouraged to partner with their patients, there later in life. This is proposed by adoption of a healthy lifestyle
has been the growth of other types of healthcare delivery that throughout the lifespan resulting in an extended healthspan
look at root cause with more effective models of intervention. with the duration of one’s life spent in a state of wellness. The
An example of one of these models is the Virta Health system P4 framework also believes in reversing chronic disease once
that was developed to intervene in type II diabetes with diet, it has begun by lifestyle and dietary interventions, but must
lifestyle, and patient education [43]. When patients under- include the patient as a partner. It is also acknowledged that
stand their disease and can discuss information with their at some point in the continuum of chronic disease, it may be
healthcare providers, remarkable changes can occur even in necessary to intervene with traditional healthcare with phar-
such significant debilitating chronic illnesses as type II diabe- macotherapy, surgery, and other interventions as manage-
tes. Drugs and surgery are held in reserve and used only ment tools.
when necessary. These alternate models of healthcare deliv- The P4 model and other models such as integrative medi-
ery treat the root cause of chronic disease rather than imme- cine, naturopathy, functional medicine, nutritional medicine,
diately intervening with drugs and surgery, long the and other systems capture this belief and put it into practice.
prevailing paradigm in conventional medicine. Moving toward a modern, proactive healthcare system, dif-
As the Centers for Disease Control and Prevention ferent levels of intervention must be clearly defined, and the
(CDC) warns, obesity, cardiovascular disease, and diabetes list of stakeholders invested in the implementation of this
are the leading causes of preventable mortality [24]; person- model must be expanded. Training programs have sprung up
alized lifestyle medicine is a growing paradigm that delivers to fulfill the need for retooling the interprofessional work-
a different approach to conventional acute care medicine. force, but effective change demands an orchestrated language
Personalized medicine is specifically tailored to the individ- to help researchers, healthcare professionals, and stakehold-
ual patient’s lifestyle, environment, genetics, and preferences ers across a multitude of sectors to collaborate as efficiently as
to develop strategies for improving health outcomes and possible [44–46]. Businesses are being developed to help
managing chronic disease [44–46]. To address the crisis, per- practitioners become financially successful in establishing
sonalized lifestyle medicine requires a new set of healthcare these types of clinics but will certainly expand over the next
practitioner skills and competencies to address multiple risky decade [3, 4, 39].
behaviors and improve patient self-management. This can A “Blueprint” for health system sustainability was recently
lead to designing patient-specific prescriptions for diet, exer- released as a community-based model to help reduce the
cise, stress reduction, and avoiding environmental toxicity by burden of preventable disease on the financially strapped
taking advantage of identification of genetic variants and National Health Service in the United Kingdom, but could
functional laboratory biomarkers. This comprehensive per- also serve as a blueprint for the world as a whole [47]. The
sonalized approach promises to promote the safety of con- Blueprint identifies 12 domains of human health thrown out
ventional therapeutics while reducing the long-term cost of of balance by contemporary lifestyles (see . Fig.  1.2) [47].
 

chronic disease care. Information gathered from this The most effective way of treating lifestyle disorders is with
approach empowers patients to have more control over their appropriate lifestyle changes that are tailored to individuals,
health with partnership at the center in the therapeutic set- their needs, and their circumstances. Such approaches,
The History and Evolution of Medicine
13 1
..      Fig. 1.2  The ecological
terrain of an individual including
12 inter-connected domains of
12 1
health and resilience

11 2

10

3
9

4
5
8

7 6

Genetic and epigenetic background Neuroendocrine system function

Glycaemic control and metabolic Circulatory system function

flexibility
Gastrointestinal system and Toxic burden and biotransformation
microbiome function
Mitochondrial function Structural integrity status
immune system function and
inflammatory status Psychological and cognitive function

Oxidative stress status Psychosocial−emotional health status

guided by the trained interprofessional team, tend to be far orders, financial and social frameworks that encourage the
more economical and more sustainable as a means of main- use of non-drug, lifestyle “prescriptions,” and much greater
taining or restoring people’s health. At the core of a sustain- engagement and autonomy by the individual.
able health system is one with individuals more responsible The Blueprint acknowledges that implementing such
for maintaining their own health and where more effort is seismic changes in the way healthcare is managed will be met
invested earlier in an individual’s life prior to the manifesta- with opposition [47], notably from those with interests in
tion of downstream chronic, degenerative, and preventable maintaining the status quo; however, identifying and address-
diseases. The report outlines hallmarks of sustainable health ing the barriers could transform some into opportunities.
systems that are centered on the needs of individuals while The most substantial and complex impediment will likely
also being focused on health creation or regeneration. arise from the scientific community with the associated and
Hallmarks include significantly reduced pharmaceutical use limiting model of evidence-based medicine (EBM) as out-
as first-line treatment for dietary and lifestyle-mediated dis- lined above. New approaches to building evidence to guide
 14 J. A. Drisko

clinical decisions are being called for by federal agencies [48, »» They’re difficult because they resist simple solutions. Glib
1 49]. It is imperative that we place the patient and practitioner answers and over-simplification have been tried before,
back to the center of the decision-making process so that and failed.
clinical choices can be based on evidence, personal experi-
ence of the doctor, and expectations of the patient [9]. Just as
»» People have tried all of the obvious solutions. They
haven’t worked. That’s why we’ve resorted to calling
the promise of EBM has been the use of the best evidence,
them difficult problems.
personalized precision medicine must also reintroduce the
use of judgment. As one size does not fit all, it must be »» Difficult problems require emotional labor, approaches
remembered that evidence-based medicine regards disease at that feel risky and methods that might not work. They
the population level with minimal consideration of individu- reward patience, nuance and guts, and they will fight off
als. It is the call for personalized precision medicine brute force all day long.
approaches that need to be implemented allowing us to tailor
interventions to our individual patients [9].
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 17 2

Influences of the Nutrition
Transition on Chronic Disease
Sudha Raj

2.1  utrition Transition: A Model of Changing Dietary

N
Patterns – 18

2.2 The Changing Face of Food Over Time and Space – 19

2.3 The Globalization of Food – 19

2.3.1  hanging Trajectory of Populations’ Lifestyles – 20
C
2.3.2 Is the Nutrition Transition Experience Different Between the
Developed and Developing World? – 21
2.3.3 A Growing Double Burden of Disease – 21
2.3.4 The Overlap Between Undernutrition and Overnutrition – 22
2.3.5 Metabolic Programming and NCDs – 22

2.4 Pathophysiological Consequences of NT – 23

2.5 Anthropogens and Chronic Inflammation – 23

2.5.1  ehavior Change for Positive Vitality – 24
B
2.5.2 Initiatives Addressing the Nutrition Transition – 24

2.6 Conclusion – 26

References – 26

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_2
 18 S. Raj

2.1 Nutrition Transition: A Model different time periods. Each stage is marked by specific pat-
of Changing Dietary Patterns terns of food acquisition, food use, and physical activity with
the ensuing stature, body composition, and nutrition-related
2 Nutrition transition (NT) is a complex conceptual frame- health outcomes that affect individuals and, consequently,
work. It is rooted in the historic processes of demographic populations [5]. Transitory changes in food acquisition exist
and epidemiological transition theories that describe trajec- along a continuum, beginning with subsistence agriculture,
tories in fertility, mortality, disease patterns, and causes of progressing through industrialized agriculture to a global-
morbidity and mortality, respectively [1]. Nutrition transi- ized food system. Concomitant changes related to nutritional
tion is described by Barry Popkin as evolutionary stages or status lie along a spectrum of malnutrition ranging from
patterns (. Fig. 2.1) that occur globally in a nonlinear fash-
 
undernutrition and nutritional deficiency to overnutrition
ion over time and space. Stage 1 is referred to as the “hunter-­
gatherer”; Stages 2 and 3 are termed “famine” and “receding
famine”; Stages 4 and 5 are termed as “degenerative disease” ..      Table 2.1  Nutrition transition stages
and “behavioral change,” respectively [please refer to
. Table  2.1] [2]. A majority of the writings on the subject
  Stage Description
draw attention to Stages 4 and 5, where dramatic shifts in
Stage 1 Hunter-gatherer
diets, activity patterns, and health outcomes have been
observed in different parts of the world over the last three Stage 2 Famine
centuries [3, 4]. Each stage is viewed as a pattern of food use Stage 3 Receding famine
and corresponding nutrition-related disease that affects indi-
viduals in the short term and populations in the long term Stage 4 Degenerative disease
[3]. In this view, each stage is a roadmap that highlights his- Stage 5 Behavioral change
torical developments that occur in global societies during

Stage 1 Stage 3 Stage 4 Stage 5

Stage 2
“Hunter- “Receding “Degenerative “Behavioral
“Famine”
Gatherer” Famine” Disease” Change”

Initial Introduction to
Subsistence domestication horticulture, Globalized food
Food Acquisition agriculture of plants and pastorialism and/or system Behavior change
animals intensive cultivation

Nutritional Status Overnutrition

Nutritional Salutogenic
“malnutrition Nutritional deficiency; increase in dietary diversity (nutritional
deficiency behaviors
spectrum” imbalances)

High Double burden: Healthy

communicable overweight Ageing; Eating
disease rate(s) mothers and Healthy;
Decline in
underweight Lifestyle
health and
children; modification
nutritional
Fetal origins of
status
adult onset
Non- diseases
communicable (FOAD)
disease
unknown Stress
Little known
reduction;
about non-
increased
communicable
High physical
diseases
prevalence of activity
non-
communicable
diseases

..      Fig. 2.1  Stages of nutrition transition

Influences of the Nutrition Transition on Chronic Disease
19 2
and non-­communicable diseases. The timing and degree to the establishment and specialization of agriculture for the
which these changes occur depends on the degree of devel- expanding populations. Cereals, legumes, and starchy foods
opment experienced by various global societies. Sociocultural became predominant dietary staples. Food was polysemic and
and political factors, environmental conditions, degree of served roles beyond sustenance. For instance, cultural anthro-
urbanization, industrialization, population demographics, pologists note that the first domesticated animals and plants
migration dynamics, physical activity patterns, dietary accul- were primarily bred and cultivated to be used as foods during
turation, and the ability of the individual country’s healthcare feasts and for trading; they were symbols of power and status in
infrastructure to simultaneously handle infectious and addition to serving a hunger need [13]. Although the agricul-
chronic disease prevalence and incidence mediate these tran- ture-oriented food system at that time ensured food security, it
sitions and their health outcomes [6, 7]. was limited in its resiliency to withstand shocks and vulnera-
bilities, such as droughts or floods that led to production
swings and unpredictable availability [14]. Stages 2 and 3 were
2.2  he Changing Face of Food Over Time
T marked by gradual decreases in diet diversity compared to
and Space Stage 1. Populations were subject to cycles of plenty and scar-
city caused by migrations, political conflicts, overuse and deg-
Stage 1  Stage 1 describes the myriad ways in which early radation of natural resources, including soil fertility, arability,
global societies or “hunter-gatherers” engaged in food procure- and unpredictable climatic conditions [8]. History is replete
ment and consumption practices. Stages 2 and 3 mark the tran- with instances of geographical regions subjected to such vul-
sition from a “hunting-gathering” society to a “food-producing” nerabilities resulting in famines, increased nutritional deficien-
milieu. The latter was created with the advent of agriculture cies, and a generalized weakened food supply with a growing
and the industrial revolution, along with the climatic and pro- dependence on foods from elsewhere [14]. Concomitantly,
duction fluctuations associated with these respective mile- demographic changes marked by expanding populations and
stones. Regardless of location, dietary choices in Stage 1 were sociocultural and economic factors led to stratification by gen-
limited to wild plant and animal foods indigenous to the geo- der and social status, inequities, and unequal access to food
graphic areas of inhabitance. For example, high-­latitude popu- and other basic necessities [15]. Historical records note the
lations such as the Inuits relied on seafood with almost no plant overall decline in health and nutritional status, citing maladies
foods, while populations in the lower latitudes depended on such as dental caries, anemia, and enamel defects, reduced stat-
fruits, nuts, roots, berries, and hunted or scavenged animal ure and cortical bone thickness in various geographical loca-
foods [8]. Stage 1 was noted for its (1) high degree of ecological tions [16, 17], yet through this period, little was known about
availability, nutrient density, and need for dietary flexibility and the incidence and prevalence of non-communicable diseases.
(2) energy-intense food procurement activities. In general,
humans experienced a shorter lifespan and non-communica-
ble diseases were unknown [9]. However, at that time, there 2.3 The Globalization of Food
was a high probability of mortality from communicable dis-
eases, inhospitable environmental conditions, and dangerous By the turn of the twentieth century, food procurement no
encounters [8]. longer remained an isolated activity that fostered self-­reliance
and kinship. Instead, the era’s prevailing political, socioeco-
Stage 2  The transition to Stage 2 occurred with the initial nomic, and technological environments influenced food-­
domestication of plants and animals around 11,000 BCE, fol- related activities. For instance, the industrial revolution, rise
lowed by the introduction of horticulture, pastoralism, and/or of mechanization, new seed varieties, and the introduction of
intensive cultivation. synthetic fertilizers caused massive shifts in the production,
processing, distribution, and consumption of foods. The
Stage 3  In Stage 3, the domestication of plants and animals Green Revolution in South Asia in the 1960s and 1970s was
and the cultivation of one or more plant foods such as rice, credited as a success for its increased global yields; however,
wheat, or maize intensified. This shift is believed to have the following decades witnessed its consequences in the form
occurred in various locations around the globe at different of greater socioeconomic divides, poverty, catastrophic envi-
times [8]. These activities provided populations with a plethora ronmental degradation, and farmer suicides [18]. Parallel
of locally harvested traditional or indigenous foods. Foods advancements in medicine; immunizations; antibiotics; sani-
produced were native to the geographic area and not necessar- tation and access to safe, good-quality water; the discovery of
ily uniform across the globe; however, they were adequate in micronutrients; and, more recently, the expansion of health-
quantity and quality to meet the nutritional needs of the local care technologies, e.g., telemedicine [19, 20], have since
population. For example, the Inuits’ seafood-dominated diets facilitated gradual improvements in the public’s health.
were high in saturated fats with few carbohydrates, while the Agriculture in the 1980s became a “global phenomenon”
Balinese rice farmers [10], the Nigerian Kofyars [11], and the as its focus shifted from one of “traditional or indigenous
Papua New Guinea Tsembaga [12] relied on diets that were foods” to a “cash crop” economy. Sugarcane, palm oil, wheat,
high in carbohydrates, including fiber, but low in fat, particu- soy, and animal source foods became agricultural trading
larly saturated fats. Stability and abundance was ensured with commodities moving to the forefront to meet processing
 20 S. Raj

demands [21]. At present, the scope of the food system has globe have experienced a mixed bag of positive and negative
broadened from one of ensuring adequate food supplies to consequences and health outcomes [31, 32]. On the one
that of a financial enterprise governed by consolidation, hand, enormous economic developments and benefits to
2 economies of scale, money, and markets [22–24]. Selective health and nutritional status have accrued in industrialized
breeding techniques, biotechnology, genetic engineering, societies and the LMICs transitioning to Stage 4 of the NT
fortification, enrichment strategies, expansion of the func- process [3]. Incomes have risen for many, poverty has
tional foods and nutraceutical categories, novel food process- declined, standards of living have improved, healthcare is
ing and packaging technologies, and the introduction of more accessible, and these societies have seen a wider variety
information and communication technologies (ICTs) have of processed foods, energy-saving devices, and technologies.
facilitated increased yields of agricultural commodities, Easy access to a globalized food system has fostered increased
product innovation, diversification, and volume production and varied consumption patterns worldwide, changing the
of value-added processed and ultra-processed foods [25]. trajectory of cultural foodways, value systems, human behav-
Precision agriculture or site-specific farming that combines iors, and lifestyles of global populations [33, 34].
global positioning systems (GPS) and geographic informa- On the other hand, myriad challenges signaled by nutri-
tion systems (GIS) to monitor climatic conditions and pro- tional imbalances consequent to dietary pattern shifts,
vide farmers site-specific information is one such innovation occupation-­related stress, sharp divides in socioeconomic
in the agriculture realm [26, 27]. Farmers use this informa- status, inequities in healthcare access, and chronic disease tra-
tion to efficiently utilize and monitor their agricultural envi- jectories have risen for selected population segments such as
ronments for crop planning, soil sampling, pest control, the poor, women, and children [35]. A major consequence is
application, and yield mapping, mitigating several climatic the increased reliance on and dietary convergence of food
fluctuations of previous centuries. components such as fats and oils, sugars, animal products,
Advances in retailing, marketing, advertising, and the and processed and prepared products, all at the expense of
introduction of formalized markets provide a platform to traditional, indigenous foods [36]. High-, middle-, and low-­
inform and sell consumers the cornucopia of processed foods income countries experience concomitant dietary pattern
with different qualitative and nutritional attributes. Improved changes, such as increased portion sizes, eating out, and
transportation, the development of domestic and interna- snacking frequency at varying rates [37, 38]. These patterns,
tional markets fueled by the expansion of global trade, and the coupled with a high degree of dietary convergence, are col-
introduction of high speed connectivity ensure better global lectively referred to as the “Westernized diet or dietary pat-
food systems management while guaranteeing food access to terns” [21, 36]. For instance, in the United States between
large populations worldwide [27]. Continued urbanization, 1977 and 2006, the overall energy intake from sweetened bev-
expanding populations consequent to global migration, and erages increased by 135% while that from milk decreased by
natural increases provide the necessary consumer base that 38% [39, 40]. Sugar-sweetened beverages contributed a sub-
sustains demand for these products. Further, the liberalization stantial amount of energy to the diet of Australian children,
of trade policies is a key facet of the twenty-­first-­century glo- with mean intakes ranging from 4% in children 2–3 years of
balization phenomenon facilitating trade across national bor- age to 7.5% in adolescents [41]. Mexico had the largest per
ders. Low- and middle-income countries (LMICs), such as capita (163 liters) intake of soft drinks in 2011 [42]. A market
China, India, and Brazil, recognize the incentives and eco- data analysis between 2000 and 2013 for ultra-processed food
nomic advantages of market-oriented agricultural policies consumption by Euromonitor International for four lower-
[22] and have gradually liberalized their agricultural markets middle-income, three upper-middle-­income, and five high-
both domestically and internationally. Imports, exports, con- income Asian countries raised concerns about the growth in
solidation and merger activity in the food system, foreign the carbonated soft drinks sector in the LMICs while their
direct investments (FDI), and the establishment of transna- sales were declining or stagnating in high-income countries
tional food and beverage companies [28] have boosted eco- such as the United States [34]. Specifically, soft drink sales and
nomic developments in their food sectors [22]. Transnational volume were reported to be high in Thailand and in the
entities such as Coca-Cola, PepsiCo, Nestle, Kraft, Carrefour, Philippines, while sales of oils and fats were high in Malaysia.
Danone, and Walmart have consequently expanded their mar- Since the mid-1950s, developed countries have used spe-
kets and gained a significant foothold in emerging economies cialized technologies such as oilseed breeding and oil extrac-
such as China, India, Brazil, and Mexico, thereby changing the tion techniques to increase seed oil content, contributing to
scope and nature of these countries’ food systems [29, 30]. the widespread availability of cheap vegetable oils such as soy-
bean, palm, and canola oils in LMICs of Asia and Latin
America [43]. Between 1985 and 2010, vegetable oil consump-
2.3.1 Changing Trajectory of Populations’ tion increased three- to sixfold in LMICs such as India and
Lifestyles China. In India, the consumption of edible vegetable oils in
urban and rural areas rose from 24 g/day to 36 g/day and 36 g/
The evolution of the globalized food system has proven to be day to 48 g/day, respectively [44]. Data from China indicate
a double-edged sword. Depending on the degree, pace of that between 1994 and 2004, edible oil production increased
industrialization and globalization, different parts of the nearly twofold in China, and 83% of the population had cook-
Influences of the Nutrition Transition on Chronic Disease
21 2
ing oil intakes over 28 g/day by 2010 [45]. Shifts in easy acces- Second, according to Popkin [31, 32], there is ­considerable
sibility to vegetable oil [46], increasing market concentration intra- and inter-country heterogeneity in transition patterns
in other food sectors, e.g., the beverage industry, coupled with and health outcomes within and between different popula-
growing fast food sales [21] have and continue to contribute to tion segments. Ecological, internationalization, political,
increased dietary fat intakes and global obesity rates. technological, and socioeconomic climates that prevail in the
individual countries and/or regions during the transition
phases are responsible for this heterogeneity. For instance,
2.3.2 I s the Nutrition Transition Experience within Asia, China experienced great shifts in dietary and
Different Between the Developed physical activity patterns between 1985 and 2000, while
and Developing World? India’s transition is still in the early stages and gaining
momentum in urban areas [50, 51]. While the Chinese expe-
Despite varied and limited global epidemiological data on rience a high burden of hypertension followed by diabetes
diet and physical activity, certain key differences exist and cardiovascular disease, diabetes rates and susceptibility
between developed and developing countries. Developed to cardiovascular disease in the South Asian region have sky-
countries, like the United States, carry a large burden of heart rocketed in the last decade. India ranks highest in the world
disease, cancer, diabetes, chronic pulmonary, and mental dis- for diabetes incidence; Bangladesh accounts for 40% of all
ease with a lower proportion of infectious diseases [47]. diabetes among the least developed countries and 10% of
Pakistanis suffer from diabetes [52–54].
Stage 4  Since the 1980s, these countries have experienced Third, obesity rates in many LMICs are two to five times
Stage 4 of the transition phenomenon with massive shifts in greater than those of the industrialized countries with stark
dietary and physical activity patterns resulting in body compo- changes in specific subsets of the population  – the poor,
sition changes [32]. Adiposity, marked by a high BMI with the women, and children [55]. The UNICEF–World Bank–WHO
associated chronic inflammation and oxidative stress, is one of group reports that the overweight prevalence in children is
the well-documented risk factors at the nexus of the NCD con- on the rise; between 1990 and 2014, the numbers have risen
cerns in this part of the world. Considerable scientific evidence from 31 million to 41 million [56]. Since 2000, obesity rates
reports that the high glycemic load, undesirable dietary fatty for children under 5  years of age have risen by more than
acid composition, altered macro- and micronutrient status, 50% in Africa and 40% in Asia [57]. Myriad reasons are fuel-
disturbed acid-base balance, unbalanced sodium and potas- ing the obesity pandemic across the lifespan, increasing vul-
sium ratios, and decreased dietary fiber content exacerbate the nerability and impacting health outcomes. These include
morbidities associated with NCDs [36]. unhealthy food choices, energy imbalances caused by seden-
Increasing dietary convergence to a more processed, tarism, chronic stress, and genetic and ethnic body composi-
westernized diet, a decline in traditional, indigenous food tion predispositions that favors adiposity [58, 59]. Further
consumption, sedentary lifestyles, changes in average stature exposure to environmental toxins, inequities in income and
and body composition, and NCD morbidity and mortality healthcare, healthcare systems that are unable to simultane-
are reflective of the LMICs transition phenomenon [21]. The ously handle chronic diseases caused by under- and overnu-
complexity of these transitory changes and their contextual trition, and epigenetic fetal programming changes only make
occurrence are noted by Corinna Hawkes as particularly per- the situation worse [59].
tinent to the nutrition-related non-communicable diseases
or Stage 4 in the nutrition transition spectrum. In a recent
ecological analysis using multiple regression and cluster 2.3.3 A Growing Double Burden of Disease
analysis on a sample of 98 countries across the globe, Oggioni
et al. studied the association of obesity and diabetes with the The rising prevalence of obesity promotes a misconception
agricultural, transitional, and Westernized dietary patterns. that communicable and nutritional deficiency diseases are
The Westernized dietary pattern had a direct dose-response eradicated and supplanted by obesity and NCDs. However,
association with diabetes prevalence, while the agricultural this is far from reality [60]. Instead, global epidemiological
diet had the lowest prevalence of obesity and diabetes asso- data reflect the concurrent existence of undernutrition and
ciation [48]. Yet the NT experience of the LMICs is different overnutrition referred to as the double burden of disease.
and unique for several reasons. Compared to the developed world, the LMICs experience
First, the NT and disease pattern shifts in the LMICs of disproportionately large problems given the rapid globaliza-
Asia, Africa, the Middle East, Latin America, and Oceania tion, economic growth, and population expansion these
are occurring at an accelerated pace. Compared to the nearly countries face [61, 62]. LMICs have always experienced a
five decades of transitory changes in the industrialized world, high incidence and prevalence of undernutrition, infectious
the LMIC transition has occurred over the last two decades. and deficiency diseases driven by socioeconomic challenges,
Further, the simultaneous population expansion consequent poverty, food insecurity, famine, and poor healthcare qual-
to a demographic transition from a high fertility and mortal- ity, access, and utilization. However, with nutrition and epi-
ity pattern to one of low fertility and mortality has exacer- demiological transitions, LMICs face the additional
bated the situation [49]. challenge of a rapid increase in obesity and overweight sta-
 22 S. Raj

tus. Accompanied by pathophysiological metabolic risk tion of the double burden is the dual occurrence of energy
mediators such as hs-CRP, IL-6, obesity increases vulnera- imbalance and micronutrient deficiency. For example,
bility to NCDs across the lifespan [63]. According to the between 1990 and 2005, obesity rates in West Africa increased
2 annual WHO report, nearly 40 million people succumb to by 114%, with more women affected than men [73]. In urban
NCDs, accounting for 70% of all global deaths. Approximately Burkina Faso, 73 out of 310 apparently healthy adults had
17 million die before age 70 and 87% of these premature one marker of overnutrition concurrently with at least one
deaths occurred in LMICs [64]. The metabolic syndrome, in nutritional deficiency [61]. Studies using nationally repre-
which abdominal obesity and insulin resistance play a cen- sentative data from three developing countries, Mexico, Peru,
tral role, is associated with a doubling of cardiovascular dis- and Egypt, showed that overweight women were deficient in
ease risk [65]. iron and other micronutrients such as vitamin A [74].
In a recent pooled analysis of 1698 population-based Reports from Sub-Saharan Africa note that while obesity is
studies consisting of over 19 million male and female partici- more prevalent among the affluent, more than 20% of women
pants in over 180 countries, the prevalence of overweight and have BMIs of less than 18.5, 57.1% are anemic, and 18.5% are
underweight using body mass indexes (BMIs) was studied deficient in vitamin A [75, 76]. At the household level, the
over the 1975–2014 period. BMIs increased from 21.3 (1975) most common occurrence is a stunted child coexisting with
to 24.2 (2014) in men and from 21.7 to 24.6  in women, an overweight mother [77]. The WHO classifies a country as
respectively [66], with some regions experiencing more experiencing a double burden of disease when at least 30% of
accelerated rates than others. For instance, regional BMIs children under 5 years old are stunted with an age-adjusted
were highest for men (21.4–29.2) and (21.8–32.8) women in overweight rate for females above 25% [69].
South Asia and the Polynesian islands, respectively. The prev- Researchers interested in the fetal origins of adult-onset
alence of being underweight globally decreased from 13.8% disease view undernutrition and overnutrition as being
to 8.8% in men and 14.6% to 9.7% in women; however, South linked at the level of developmental programming and meta-
Asia had the highest prevalence of underweight individuals bolic adaptation in the fetus, with important health conse-
at 23.4% and 24% in men and women, respectively. In 2014, quences as individuals age and their environments change
of the 667 million children under five in the world, 159 mil- [78, 79]. In this regard, the double burden of disease in
lion were stunted and 50 million were wasted [56]. LMICs poses a threat both as a metabolic programming con-
Short-term consequences of the double burden of disease sequence of maternal undernutrition and a cause for NCDs
include malnutrition-related stunting and premature child in adult life. Epidemiologists attribute the NCD incidence in
deaths and compromised immunity, physical development, LMICs to perinatal and postnatal influences and reduced
and cognitive abilities; long-term consequences include obe- birth weight [80–82]. While public health focus continues to
sity, NCD-associated morbidities, and mortality. Ultimately center on the mitigation of undernutrition [83], there is con-
this results in a lower productivity and quality of life in sensus that undernutrition, obesity, and NCDs are linked
adulthood and higher healthcare costs [67]. The impact of through the processes of developmental programming and
these changes is variable between urban and rural popula- metabolic adaptation that require immediate attention and
tions, escalating with increased migration and changing action [84].
food environments. The healthcare systems in LMICs lack
the capacity and governance to address the double burden
efficiently and adequately and the costs of treating NCDs are 2.3.5 Metabolic Programming and NCDs
rising, consuming larger proportions of health budgets in
LMICs. Initiatives such as the Millennium Development Developmental programming and metabolic adaptation are
Goals, which were originally designed to combat undernu- the major principles underlying the fetal origins of adult-­
trition, are underway and need to keep pace with the NCD onset diseases (FOAD) hypothesis, also known as the devel-
trajectory [68]. opmental origins of adult disease proposed by Barker in 1986
[85]. According to Barker, “adverse influences early in devel-
opment and particularly during intrauterine life can result in
2.3.4  he Overlap Between Undernutrition
T permanent changes in physiology and metabolism, leading to
and Overnutrition an increased disease risk in adulthood” [86]. Prenatal insults
include acute and chronic nutritional deficiencies, environ-
The causes and consequences of both undernutrition and mental influences such as smoking, exposure to endocrine
overnutrition as distinct health status entities are well disruptors, limitations in maternal physical stature, exposure
described [48]; however, recent WHO reports and research to steroid hormone excesses, and maternal physiological and
from Africa, Mexico, the Middle East, and South Asia [69] psychosomatic stress marked by elevated glucocorticoid hor-
highlight overlap of these two conditions, sometimes within mones. These adverse influences pose several constraints
the same household or individual. While the poor and uned- during critical periods of fetal development, consequently
ucated are disproportionately affected, of particular concern altering tissue and organ development, structure and func-
are the long-term consequences in women at the population tion which are also referred to as developmental program-
level [70–72]. At the individual level, the common manifesta- ming [75, 87]. For instance, lowered intra-uterine protein
Influences of the Nutrition Transition on Chronic Disease
23 2
availability can modify pancreatic islet cell proliferation, are also pro-inflammatory. Viewed in the broader social,
causing future alterations in glucose homeostasis [88]. economic, and environmental contexts, anthropogens are
Undesirable fetal developmental programming in a compro- extremely detrimental to human health. Anthropogens fos-
mised nutritional environment results in dysfunctional meta- ter a chronic stress milieu, promoting a low-level, sustained
bolic capacity and physiological function as future chronic inflammation response. The innate immune system
consequences. For instance, in utero stresses alter mitochon- and the central stress axes are constantly activated without
drial activity that influence the function of oxidative phos- opportunity for the resolution and termination of the natural
phorylation linked to skeletal muscle insulin resistance in inflammatory response as seen in the acute stress response
type 2 diabetics [89]. The ensuing metabolic maladaptations [95]. The proinflammatory cytokines either cause or are
in early life owing to inadequate maternal nutrition reflect the caused by dysmetabolic responses, leading to core imbalances
development of a thrifty phenotype with an altered metabo- in one or more of the body’s physiological systems [100]. For
lism that is beneficial to the survival of the fetus and anticipa- example, unhealthy, calorie-­dense, highly processed diets
tory of a similar future postnatal environment. However, a increase NCD risk, while feasting, cultural foodways, and
mismatch occurs when there is a discrepancy in this expecta- changing food habits can act as moderators to enhance or
tion upon exposure to a food and a nutrient-rich environ- decrease risk; chronic stress determined by an individual’s
ment, resulting in a greater susceptibility eventually coping capacity leads to elevated adrenocortical hormones
culminating in obesity and metabolic disease [90]. While and activation of the hypothalamic–pituitary–adrenal axis
epidemiological and animal studies have garnered a large resulting in a host of vascular, metabolic, and inflamma-
body of evidence, the mechanisms are yet to be elucidated. tory processes; obesogenic endocrine-disrupting chemicals
Suggested mechanisms include permanent alterations in cell (EDCs) and persistent organic pollutants (POPs) are docu-
numbers affecting structure and function of organs, inherit- mented to cause significant physiological and behavioral
able epigenetic changes that affect DNA methylation patterns changes, e.g., increased appetite, ultimately contributing to
consequent to an altered maternal nutrient supply. These obesity. Individual responses to the anthropogens are not
alterations potentially mediate the metabolic priming process uniform and dictated by genetic and epigenetic predisposi-
very subtly through gene expression modulations [87, 91]. tions, as well as fetal programming [93, 101].

2.4 Pathophysiological Consequences of NT 2.5 Anthropogens and Chronic

Inflammation
Just as the germ theory provided a monocausal focus for infec-
tious and communicable diseases [92], modern lifestyles are Inflammation is the body’s natural response to damage after
proposed as a major contributor to the NCD pandemic. Egger injury or pathogen invasion. It is a self-limiting process con-
and Dixon [93], in a recent review on chronic disease deter- sisting of an initiation, a resolution, and a termination phase.
minants, describe the role of “anthropogens” in the etiology Its action is controlled by the synergistic roles of the innate
of meta-inflammation [94]. Anthropogens are man-made immune system, the sympathetic nervous system, and the
environments, their by-products and/or lifestyles encour- hypothalamus pituitary adrenal axis [95, 102]. The stress axes
aged by these, some of which may be detrimental to health are involved in the response primarily through the action of
[93]. Meta-inflammation is a low-grade, chronic systemic norepinephrine and cortisol by modulating insulin and cor-
inflammation linked to a dysfunctional immune response. tisol sensitivity. The efficiency of the response depends on the
It differs from the classic, acute inflammatory response to capability of the glucocorticoid and catecholamine receptors
infection and injury initiated by the body’s innate immune of the innate immune system. The inflammatory response is
system [95] in the following ways: first, chronic inflamma- initiated by polymorphonuclear neutrophils that generate
tion is low grade with systemic effects causing small rises in proinflammatory cytokines like leukotriene B4 and prosta-
immune system markers such as proinflammatory cytokines, glandins from arachidonic acid with the help of lipoxygenase
e.g., TNF alpha, hs-CRP, and interleukin 6; second, it is per- 5 and cyclooxygenase 2 enzymes. While the leukotrienes
sistent, resulting in a chronic activation of the immune and exert their strong chemo-toxic response to the invading
neuroendocrine systems in an effort to bring about homeo- pathogen or stimulus, the prostaglandins regulate the switch
stasis; and third, it perpetuates a chronic, dysmetabolic state to the second or resolution phase when their concentration
induced by anthropogens [93]. Although obesity is thought equals that of the leukotrienes primarily by limiting the
of as a prerequisite [96, 97], several behaviors linked to post- lipoxygenase enzyme activity. This phase is marked by high
industrial, globalized lifestyles, e.g., poor diets, inactivity, anti-inflammatory activity as seen in the production of spe-
stress, inadequate sleep, occupation, prescription and non- cialized pro-resolving mediators (SPMs) such as lipoxins,
prescription drugs, smoking, toxic exposures, dysfunctional resolvins, protectins, and maresins from eicosapentaenoic
relationships, the social factors that encourage such lifestyle acid (EPA) and docosahexaenoic acid (DHA) [103, 104].
patterns over time, and the obesogenic environments in SPMs are described recently to be involved in myriad mecha-
which they occur, e.g., technology, environment, occupation, nisms that promote the resolution and termination of the
air pollution [98], and ­endocrine-­disrupting chemicals [99] inflammatory response, such as switching off the stress axes,
 24 S. Raj

enhancing microbial clearance through generation of non-­ health [116–118] as well as facilitate the identification of clini-
cytotoxic macrophages. Both omega-6 and omega-3 fatty cal imbalances at an earlier stage before they become patho-
acids play critical roles in their biosynthesis and are expected logical.
2 to be of potential therapeutic value in microbial defense,
pain, organ protection and tissue regeneration, wound heal-
ing, cancer, reproduction, and cognition [105–107]. 2.5.2 I nitiatives Addressing the Nutrition
Transition

2.5.1 Behavior Change for Positive Vitality Nutrition transition underscores the need for all nations to
build healthcare capacity and infrastructure, regardless of
Stage 5  A growing awareness of the negative consequences their economic status, to address the dual burden of malnu-
of NCDs and/or the diagnosis of a chronic disorder such as trition. This requires immediate action which necessitates
diabetes prompts motivated individuals and communities to healthcare and nutrition policies in developing countries to
try and adopt a healthy lifestyle through behavior modification offer a more comprehensive integrated approach to address
strategies. Stage 5, referred to as the behavior change stage, both undernutrition and overnutrition simultaneously. In a
encompasses the various initiatives at the individual and popu- recent review of nutrition policies of 36 low-income, 48 low-
lation level that prevent or delay degenerative diseases and pro- and middle-income, and 55 upper-middle-income countries,
long life through healthy aging. It includes the practice of only 39.6% had nutrition policies that addressed the dual
salutogenic behaviors that promote robust lifestyles, such as burden of disease, while a majority of the countries’ nutrition
eating healthy foods, stress reduction, and increased physical policies continue to focus on the mitigation of undernutri-
activity. Healthy aging is “the condition of being alive, while tion [119]. The study further pointed out that having a nutri-
having a highly preserved functioning of the metabolic, hor- tion policy in place did not necessarily translate into positive
monal and neuroendocrine control systems at the organ, tissue health outcomes. This highlights two important issues.
and molecular levels” [108, 109]. Maintaining functional organ The first is the importance of a strong governance to
reserves and biological resiliency or the ability to adapt and/or facilitate the translation of the nation’s policies into sustain-
withstand environmental stressors are at the core of the healthy able action and initiatives that are context-specific to indi-
aging concept. Furthermore, it is well recognized that healthy vidual countries [119]. Strong governance entails (1)
aging can be successful, provided a holistic multidimensional stewardship; (2) development of surveillance systems that
approach that addresses environmental, physiological, and facilitate early detection of NCDs; (3) collaborative partner-
psychological factors and healthy lifestyles is taken. For ships between stakeholders such as government, industry,
instance, a multifactorial behavior modification approach that health sector, consumers, and policymakers; (4) learning
includes programmed exercise activities, stress-reduction from previous experiences in other countries; and (5)
techniques like yoga and meditation, eating healthy foods like strengthening the evidence base to enhance and support the
fruits and vegetables, and purchasing organic foods due to design and implementation of health-promoting interven-
environmental concerns [110] can independently and syner- tions [120–123].
gistically contribute toward building and sustaining biological The second is the need to focus policies that take on a life
resiliency over the course of a lifetime. Personalized lifestyle course approach to a healthy diet and physical activity life-
medicine is one such approach that builds on the healthy aging style using culturally appropriate methods and messages ini-
concept using a combination of functional medicine principles tiated early in life [124]. This is the focus of the World Cancer
[111] and innovative emerging omic technologies such as Research Fund International’s ongoing NOURISHING
genomics, epigenetics, and diagnostic assessment tools [100]. framework [125] for obesity prevention in 11 high-, middle-,
Identifying the root cause of the disease rather than a symptom and low-income countries (. Fig.  2.2). The policy recom-
 

resolution approach, assessing for antecedents, triggers, and mendations span across three critical factors that impact
mediators, and keeping the biological uniqueness of the indi- healthy eating and physical activity: food environment, food
vidual in perspective are major principles of functional medi- system, behavior change, and communication. This frame-
cine [112, 113]. Specialized assessment techniques such as work informs governments in these countries regarding
nutrition-focused physical assessments and other functional appropriate interventions, such as restricting marketing of
diagnostic assessments, such as organic acid testing for assess- unhealthy foods to children, salt reduction strategies, using
ing mitochondrial health and stool tests for gut permeability, existing policies designed for combating micronutrient defi-
are then employed to analyze an individual’s NCD health met- ciency to simultaneously address the obesity problem by pro-
rics. Genomic analysis and testing [114, 115], molecular diag- moting local fruits and vegetables via local farm networks.
nostics, and tailored biomarkers are examples of specialized Another major initiative is the Global Strategy on Diet,
functional diagnostic techniques that provide personalized Physical activity, and Health action plan aimed at prevention
assessments and advice so that treatments can be individual- and control of NCDs between 2013 and 2020. The action
ized. They have the potential to improve health outcomes by plan resulted from a multi-stakeholder consultation process
developing sustainable lifestyle medicine-­oriented strategies, consisting of the WHO member states, relevant UN agencies,
empowering individuals so that they can be in control of their funds and programs, international financial institutions,
Influences of the Nutrition Transition on Chronic Disease
25 2
..      Fig. 2.2 Nourishing
framework. (Used with permis- World
sion from World Cancer Research
Cancer
Fund International. Wcrforg.
Research
2017. Available at: 7 http://
 
Fund International wcrf.org/NOURISHING
www.­wcrf.­org/int/policy/
nourishing-framework)

N O U R I S H I N G

FOOD FOOD BEHAVIOUR CHANGE

ENVIRONMENT SYSTEM COMMUNICATION

POLICY AREA

Nutrition label standards and regulations on the use of claims

N
and implied claims on food

Offer healthy food and set standards in public institutions and other
O
specific settings

U Use economic tools to address food affordability and purchase incentives

R Restrict food advertising and other forms of commercial promotion

I Improve nutritional quality of the whole food supply

Set incentives and rules to create a healthy retail and food service
S
environment

Harness food supply chain and actions across sectors to ensure

H
coherence with health

I Inform people about food and nutrition through public awareness

N Nutrition advice and counselling in health care settings

G Give nutrition education and skills

© World Cancer Research Fund International

banks, NGOs, professionals, academicians, the civil society, responsible for action and monitoring. The overarching prin-
and the private sector [126]. It operationalizes the tasks artic- ciples are as follows:
ulated in the Political Declaration of the General Assembly’s 1. Highest quality and standard of health is a fundamental
initiative on the prevention and control of NCDs. The action human right.
plan focuses on four major chronic diseases, namely, cardio- 2. Social determinants of health should be addressed to
vascular disease, cancer, chronic obstructive pulmonary dis- create equitable, productive healthy societies.
ease, and diabetes; several chronic conditions, e.g., mental 3. Member governments and international agencies should
illness; disabilities; and four shared behavioral risk factors – create alliances and foster high-level multi-­sectoral
tobacco use, unhealthy diet, physical inactivity, and harmful engagement.
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117. Bloch P, Toft U, Reinbach HC, Clausen LT, Mikkelsen BE, Poulsen K, 125. Hawkes C, Jewell J, Allen K.  A food policy package for healthy
et al. Revitalizing the setting approach – supersettings for sustain- diets and the prevention of obesity and diet related non-­
able impact in community health promotion. Int J Behav Nutr Phys communicable diseases: the NOURISHING framework. Obes Rev.
Act. 2014;11:118. https://doi.org/10.1186/s12966-014-­0118-8. 2013;14(2):159–68. https://doi.org/10.1111/obr.12098.
118. Fardet A, Rock E. Toward a new philosophy of preventive nutri- 126. 2008–2013 Action Plan for the Global Strategy for the Prevention and
tion: from a reductionist to a holistic paradigm to improve nutri- Control of Noncommunicable Diseases. http://www.­who.­int/nmh/
tional recommendations. Adv Nutr. 2014;5(4):430–46. https://doi. publications/ncd_action_plan_en.­pdf. Last accessed 21 Apr 2017.
org/10.3945/an114.006122. 127. Mattei J, Malik V, Wedick N, Hu FB, Spiegelman D, Willett WC,
119. Sunguya BF, Ong KI, Dhakal S, Mlunde LB, Shibanuma A, Yas- et al. Reducing the global burden of type 2 diabetes by improv-
uoka J, et al. Strong nutrition governance is a key to addressing ing the quality of staple foods: the global nutrition and epide-
nutrition transition in low and middle-income countries: review miologic transition initiative. Glob Health. 2015;11:23. https://doi.
of countries’ nutrition policies. Nutr J. 2014;13:65. https://doi. org/10.1186/s12992-015-0109-9.
org/10.1186/1475-2891-13-65. 128. Doak C.  Large scale interventions and programmes addressing
120. Buckinx F.  The public health challenge of ending malnu-
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 31 3

Nutritional and Metabolic
Wellness
Diana Noland

3.1 Introduction to Human Wellness – 32

3.2 What Is Wellness? – 32

3.3 Biomarkers of Wellness – 33

3.4  iochemical Individuality/Health Standards Through the

B
Lifespan – 33
3.4.1 I n Utero – 34
3.4.2 Infant (From Birth to 6–24 Months) – 34
3.4.3 Young Adult (20–34 Years) – 35

3.5 Nutritional Wellness – 36

3.6 Community of Wellness – 36

3.7 Summary – 37

References – 37

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_3
 32 D. Noland

Health is a state of complete harmony of the body, mind and maximum potential as a human being. Individual lives are
spirit. When one is free from physical disabilities and mental made up of many facets, all interconnected. Nutrition pro-
distractions, the gates of the soul open. vides the energetic and physical foundation for achieving
–B.K.S. Iyengar, yoga master wellness as defined by Hershoff in all its dimensions.
Before exploring the principles surrounding restoration of
Learning Objectives wellness from chronic disease, it is important to recognize
3 55 Current “normal” has transitioned away from genuine that we must set a clear vision of the health goals for each
wellness. patient. Throughout human history, humanity has faced many
55 Genuine wellness must remain the plumb line for human challenges in the search for health and longevity, and people
wellness. have culturally developed ways of life to function successfully.
55 Salutogenesis is an important foundation for wellness There is ongoing speculation by experts in human biology
healthcare. that the current state of global health is being challenged by
the beginning of declining lifespan [2, 3] and fertility [4].
It is important that we identify the biomarkers that define
3.1 Introduction to Human Wellness and characterize the human wellness we are striving to
restore in our patients. The “normal” of current populations
Have you noticed the trend to perceive type 2 diabetes as a has already deviated significantly from states of wellness.
“normal” condition after age 50? Have you noticed the trend There is no better example than the current epidemic of obe-
to perceive a little arthritis pain in the joints as a “normal” sity that is being predicted as the twenty-first century begins:
condition after age 40? These conditions have become so Upwards of three-fourths or more of industrialized coun-
prevalent that adults are trending to consider these condi- tries’ populations are predicted to be obese (>30% ideal body
tions as the “normal” for states of health. The “normal” today weight) by 2030 [5]. In 1962, research statistics showed that
in this time of epidemic chronic disease is promoting amne- 13% of America’s population was obese. By 1980 it had risen
sia of true wellness. to 15%, to 23% by 1994, and to an unprecedented 39.8% of
adults by 2016. According to the Centers for Disease Control
and Prevention, the percentage of overweight children ages
3.2 What Is Wellness? 6–11 has nearly doubled since the early 1980s, while the per-
centage of overweight adolescents has almost tripled [6].
Wellness certainly means freedom from the debilitating, weak- These overwhelming research statistics reveal an alarming
ening effects of chronic disease. As a side product of this level of obesity trend, the need for diagnosis, and a call to action [7,
wellness, one feels dynamic, energetic, alive, vital, and vibrant. 8] (. Fig. 3.1).
 

From this healthy state, we can respond effectively to environ- CDC research statistics on American obesity tell us that
mental stress, toxins, or infections, quickly returning to our 63% of adult Americans and 18.5% of children and adoles-
previous state of health and wellness [1]. cents have a body mass index (BMI) in excess of 25.0 and are
Health and vitality refer to your life energy and the power therefore overweight; more than a quarter surpass 30.0, qual-
to live, grow, know the purpose in life, and express your ifying as obese [9]. Obesity is becoming the “norm,” even

..      Fig. 3.1  Trends in obesity

prevalence among adults aged 39.6
20 and over (age-adjusted) and 40 37.7
youth aged 2–19 years: United 35.7 34.9
34.3 33.7
States, 1999–2000 through 32.2
2015–2016 (Hales 2017). 30.5 30.5
1Significant increasing linear 30
Adults1
trend from 1999–2000 to
2015–2016. NOTES: All estimates
for adults are age adjusted by the
Percent

direct method to the 2000 US 20 18.5

17.1 16.8 16.9 16.9 17.2
census population using the age 15.4 15.4
groups 20–39, 40–59, and 60 and 13.9
over. Access data table available Youth1
at 7 https://www.­cdc.­gov/nchs/
 
10
data/databriefs/db288_table.­
pdf#5. (SOURCE: NCHS, National
health and Nutrition Examination
Survey, 1999–2016)
0
1999– 2001– 2003– 2005– 2007– 2009– 2011– 2013– 2015–
2000 2002 2004 2006 2008 2010 2012 2014 2016
Survey years
Nutritional and Metabolic Wellness
33 3
though it is not an example of wellness. That is a staggering
thought when we realize the relatively short period of time
during which this epidemic has occurred. Obesity is strongly
related to the incidence of chronic disease. As the obesity Self-
actualization:
Self-fulfillment
needs
trend increases, human models of wellness are becoming achieving one’s
full potential,
rarer. Humans tend to gravitate toward acceptance of what is including creative
prevalent as “normal” and may tend to forget the real well- activities
Esteem needs:
ness we are seeking to restore. Health practitioners must keep prestige and feeling of
Psychological
the definition of true wellness before them as a standard with accomplishment
needs
which to compare their patients. Belongingness and love needs:
intimate relationships, friends

Safety needs:
security, safety
3.3 Biomarkers of Wellness Basic
needs
Physiological needs:
food, water, warmth, rest
What are the biomarkers for wellness? This chapter pres-
ents suggestions for a framework for markers to assess
wellness, for which further development is welcome. At ..      Fig. 3.2  Hierarchy of needs
least it is a good foundation developed from many studies
in the last century that evaluated common characteristics
of human populations who achieved excellent function, life The way you think, the way you behave, the way you eat,
fulfillment, and good reproduction capacity during their can influence your life by 30 to 50 years. –Deepak Chopra
relative longevity. Currently, it is proposed within the lon-
gevity science community that a 115-year lifespan is a real-
istic goal [10]. Throughout the community of integrative and functional
Thanks to the efforts of various scientists in the past medicine practitioners’ concepts like Maslow’s hierarchy of
70  years, there has been research stimulated by scientific needs have developed [13] has agreement that the following
curiosity regarding the populations who have stretched lon- factors are key influencers that summarize the findings of
gevity and wellness to the upper limits. Humans confirmed many studies on longevity and wellness:
to have attained the age of 110 years or more are referred to “Basic needs”: Biological, physiological, and safety needs
as supercentenarians. Identifying factors that help people 1. Foods (protein, fats, carbohydrates, fiber)
remain healthy, vigorous, and disability-free at older ages is a 2. Vitamins, minerals, accessory, or conditionally essential
major research priority of longevity scientists. The most nutrients
recent study is that of Dan Buettner named The Blue Zones – 3. Light, water, and air
those pockets of societies with the most healthy centenarians 4. Movement rhythm
and generally healthy populations [11]. 5. Circadian rhythm balance
Common factors that have measurable biomarkers 6. “Mind-body needs”: Love, belongingness, self-esteem,
among the healthiest societies are repeatedly found to be: cognitive, aesthetic, and self-actualization needs
1. Unprocessed, whole foods, plant-rich diet (diet history; 7. Meaning and purpose
nutrient status) 8. Love, community, connection
2. Caloric and nutrient intake so as to maintain a healthy
Weight (anthropometrics) All seven are inherently interrelated in the context of the
3. Regulating insulin production [12] (blood glucose/ human experience that affects wellness (. Fig. 3.2).  

insulin fasting; HgbA1C)

4. Moderate daily physical activity (minutes per day or 3.4 Biochemical Individuality/Health
week; handgrip strength) Standards Through the Lifespan
5. Small amount of alcohol frequently (daily female </= 1
serving; men 1-2 servings daily) As the professional rules of thumb for nutritional status
6. Strong community and social connectivity (1–10; assessment are developed in subsequent chapters, it will be
10 highest) seen that the environmental conditions necessary to produce
7. Meditation and spiritual beliefs (time per week) the identified markers of wellness are biochemical, clinical,
8. Feeling of purpose in life (1–10; 10 highest) behavioral, and functional and change throughout develop-
mental stages of the lifespan. The following are some of the
The diets of these longevity-rich societies vary according to primary stages of the lifespan with suggestions for consider-
cultural traditions, but all contain a high intake of whole veg- ations to assess and manage to promote wellness for each
etables and fruits and beneficial food oils. Interestingly, these stage. These are of particular importance to increase the
foods are rich in the phytonutrients, the most recently identi- health of a person and their nutritional status within the area
fied nutrient group [11]. of chronic disease management:
 34 D. Noland

3.4.1  In Utero 55 Child safety environment.

55 Nutrition: Regular meals of organic/low-toxin food con-
55 Fetal nutrition: promote healthy musculoskeletal-organ-­ tainers and nutrient-dense, balanced whole foods.
tissue fetal growth 55Protein
55 Maternal: 55Calcium- and mineral-rich foods
55Hormonal health: adrenal, thyroid, insulin, and others 55Nuts/seeds
3 55Blood glucose management 55Fish or fish oils/EFA balance
55Emotional environment: calm and joyful 55Whole grains
55Rest: adequate rest, sleep, and exercise 55Sea salt/herbs/spices
55Nutrition status: adequate vitamin D25-hydroxy, 55Fruits and vegetables
iodine, DHA, iron, folic acid, protein, minerals, 55Onions/garlic (sulfur/bioflavonoid)
beneficial oils, antioxidants, and phytonutrients, to 55Cruciferous vegetables (sulfur/indole-3-carbinol)
promote good growth and protect tissue from free 55Leafy greens (folic acid, chlorophyll, magnesium,
radical damage [14] etc.)
55Avoid toxin exposure 55Fermented or cultured foods (yogurt/kefir/sauer-
55 Grandmaternal nutrition status: same as mother, avoid- kraut/miso/tempeh)
ance of toxins to avoid epigenetic transgenerational 55Sea vegetables (iodine/minerals)
effects 55Vitamin A- and D-rich foods/supplements if indi-
55 Paternal nutrition status: important 2 years prior to cated
conception, avoid toxins, and especially 14 days prior to 55 Sun exposure (promote Vitamin D) (or supplementation
fertilization cod liver oil >40° latitude).
55 Play and exercise.

3.4.2  Infant (From Birth to 6–24 Months) 3.4.2.2  Childhood (3–12 Years)

55 Continue toddler recommendations.
55 Breastfeeding infant nutrition: promote healthy 55 Educational programs.
musculoskeletal-­organ-tissue fetal growth 55 Self-esteem-building lifestyle.
55 Maternal lactation and caretaker: 55 Nutrition: Ensure adequate protein/calcium/minerals for
55Emotional environment: calm and joyful rapid musculoskeletal growth – possible increased needs
55Rest: adequate rest, sleep, exercise during this growth period.
55Hormonal health: adrenal, thyroid, insulin especially 55 Sun exposure almost daily – cod liver oil during winter if
55Nutrition status: adequate vitamin D25-hydroxy, >40° latitude.
iodine, DHA, iron, protein, minerals, antioxidants, 55 Develop food preparation self-skills.
and phytonutrients to promote good growth and 55 Develop hygiene practices – especially oral and dental
protect tissue from free radical damage and adequate care habits.
fluid intake 55 Sleep: 9–10 hours with bedtime routine/quiet and dark
55 Home environment: stable, caring, joyful environment.
55 Infant 6 months + oral nutrition: balanced organic 55 Focus on oral/dental care: avoid mercury amalgams,
whole foods, hypoallergenic diet orthodontics that include removal of teeth, as well as
55 Infant: prevent periodontal diseases and decay by daily dental
55Vaccination wisdom hygiene and regular dental cleanings.
1. Never when sick
2. Wait until 4+ months if possible 3.4.2.3  Teenage (13–19 Years) (.   Fig. 3.3)
3. Mercury- and formaldehyde-free 55 Continue childhood nutrition recommendations.
4. Extra nutritional antioxidant support and folic 55 Strong family base/good relationships with parents and
acid prior to a vaccination teachers.
5. Consider vaccination alternatives for at-risk 55 Avoid “junk food” and “toxin exposure” (cigarettes,
infants with poor methylation family history or drugs, environmental).
genetics 55 Possible need for extra sleep.
55Safe sun exposure for vitamin D production (never 55 Weight-bearing regular exercise (peak time for bone
burn) density building for adulthood).
55Fresh air and exercise and play 55 Develop advanced food preparation and self-care skills.
55 Creative outlets for interests.
3.4.2.1  Toddler (12–36 Months) 55 Begin to develop purpose in life.
55 Positive parenting. 55 Abstinence/avoid communicable diseases/avoid birth
55 Seriously consider vaccination need/avoid unnecessary/ control pills (upsets hormonal balance, depletes folic
mercury- and formaldehyde-free. acid).
Nutritional and Metabolic Wellness
35 3
folic acid, magnesium, zinc, and other B complex vita-
mins to promote select malnutrition (i.e., those depleted
in folic acid are at more risk for HPV infection which is
related to increased sexual activity, more prevalent with
use of BCP).

3.4.3.1  Middle-Age Adult (35–54 Years)

55 Continue young adult recommendations with nutrition
focus.
55 Focus on nutrition to support healthy aging with phyto-
nutrients, healthy fatty acid balance, minerals, methyla-
tion and sulfation nutrients, and hormonal and immune
support nutrition like vitamin D.
55 Focus on oral/dental care: avoid periodontal diseases/
decay/misalignment.
55 Continue to focus on weight-bearing exercise to main-
tain good bone density throughout the lifespan.

3.4.3.2  Seniors (54–74 Years)

55 Continue to focus on nutrition to support healthy aging
with phytonutrients, healthy fatty acid balance, minerals,
methylation and sulfation nutrients, and hormonal and
immune support nutrition like vitamin D.
55 Focus on gastrointestinal health as digestive function
wanes naturally in elderly.
55 Good oral hygiene and health.
55 Maintain healthy percentage of body fat composition
and weight.
55 Weight-bearing exercise.
55 Emphasize social connectedness, especially around food
quality and meal time.
55 Stress management.
55 Adequate sleep.

..      Fig. 3.3  Teenage energy and vitality. (2005© Diana Noland) 3.4.3.3  Old-Old Seniors [15] (75–99 Year)
55 Continue to focus on nutrition to support healthy aging
with phytonutrients, healthy fatty acid balance, minerals,
55 Focus on oral/dental care: avoid mercury amalgams, methylation and sulfation nutrients, and hormonal and
orthodontics that include removal of teeth, as well as immune support nutrition like vitamin D.
prevent periodontal diseases and decay by daily dental 55 Focus on gastrointestinal health as digestive function
hygiene and regular dental cleanings. wanes naturally in elderly.
55 Weight-bearing exercise.
55 Safe environment to meet basic needs.
3.4.3  Young Adult (20–34 Years) 55 Emphasize social connectedness, especially around food
quality and meal time.
55 Continue teenage nutrition recommendations. 55 Maintain healthy percentage of body fat composition
55 Whole foods; low-toxin organic foods, containers, and and weight.
cookware; balanced, nutrient-rich diet. 55 Weight-bearing exercise.
55 Moderate daily exercise. 55 Continue to focus on nutrition to support healthy aging
55 Avoid toxins. with phytonutrients, healthy fatty acid balance, minerals,
55 Seriously consider vaccination need/avoid unnecessary/ methylation and sulfation nutrients, and hormonal and
mercury- and formaldehyde-free. immune support nutrition like vitamin D.
55 Prepare health for possible pregnancy or fathering – 55 Safe environment to meet basic needs.
even if not planning. Caution about use of birth control 55 Residential support system with family or caring friends
pills (BCP) related to the nutrient-drug depletions of (7 Boxes 3.1 and 3.2).
 
 36 D. Noland

55 Safe environment to meet basic needs.

Box 3.1  Key Markers of Childhood Wellness 55 Residential support system with family or caring friends.
55 No cavities
55 Sturdy
55 Strong
55 Cheerful disposition 3.5 Nutritional Wellness
55 Not overweight
3 55 No allergies Nutrients come from food, and food comes from the envi-
55 Manages stress ronment. While taken for granted at an intellectual level, this
55 Emotionally stable
55 Sleeps soundly
nutrient-food/food-environment relationship is not some-
55 Straight teeth thing citizens of industrialized nations usually consider in
55 Learns easily their everyday lives [16]. Consumer awareness of food-toxic
55 Good concentration harmful events over the past 30 years due to media reporting
55 Optimistic has increased consumer food safety concerns. The increasing
55 Lots of energy
55 Rarely sick
frequency of recalls of contaminated food, findings of ani-
55 Strong digestion mals with “mad cow disease,” chickens with avian flu viruses,
the fish supply testing high in mercury and PCBs, endocrine
disruptors, and others presents a growing concern for the
quality of the food supply. The message is coming through
loud and clear to society that environment plays an integral
Box 3.2  Key Markers of Human Wellness
1. HEALTHY BODY WEIGHT: +/− 10%; %BODY FAT:
part in food safety.
M < 18%/F < 25% with no observable central adiposity The human community must ensure safe food and agri-
2. HEALTHY SKIN: color, tone, texture, free of lesions, cultural practices as a priority in this new era of toxicity,
abnormal moles, itching, pain superbugs, and depleted soils, ensure to reverse trends,
3. HEALTHY DIET: balanced whole foods and low-toxin diet, ensure environmental safety of the food supply, and enable
water
4. HEALTHY EMOTIONS: caring, social connectedness,
humanity to have wellness within its grasp.
relationships, purpose in life, self-esteem, community/ A nutritional environment for wellness results from an
family involvement, appropriate emotions attitude of guardianship over the food supply. A wellness
5. HEALTHY ORGAN SYSTEMS FUNCTION: including blood environment requires a global food supply of diversity in
glucose management resulting in stable insulin blood geography, climate, exposure to toxins, and many other vari-
levels
6. HEALTHY IMMUNE SYSTEM: infrequent illness, illness only
ables. It involves ensuring the food is not depleted and does
of mild nature with quick recovery, absence of chronic not contain dangerous level of toxins [17]. The food that pro-
disease, absence of allergies duces wellness requires human care in policies and agricul-
7. HEALTHY MOVEMENT: adequate energy and ability to ture in every stage from soil to plate.
exercise, run, jump, play, and lift appropriate weight, no pain
8. HEALTHY MUSCULOSKELETAL: Strong grip, strong muscles
for walking and running, no aches and pain, no broken
bones or sprains
3.6 Community of Wellness
9. HEALTHY REPRODUCTION/FERTILITY: Throughout lifespan
normal gonadal development, fertile, no pain with menses Throughout history, humans have been brought together
(F), no STDs, sexual health, healthy birth delivery, symp- around the table, a symbol of congregation, family, and com-
tom-free menopause munity, where we celebrate loved ones. Food is a central part
10. HEALTHY GASTROINTESTINAL SYSTEM: 2–3 BM/day, good
digestion, no flatulence
of a healthy community. It provides not only bodily nourish-
11. LONGEVITY to >110 years old with high-quality function ment but also nourishment to the soul from the care taken in
and life raising, gathering, and preparing the food and in the rela-
12. LOW-TOXIN exposure lifestyle tionships and connectedness forged and strengthened during
the meal. In the larger community of a nation, the societal
mores about food and the wellness of the population affect
3.4.3.4  Centenarians/Supercentenarians people’s health. It is important to elevate the societal value of
(100+ Years) health and wellness within global communities so they guard
55 Emphasize social connectedness, especially around food the soil, water, food supply, food industry, healthcare sys-
quality and meal time. tems, and governmental policies. The tremendous knowl-
55 Maintain healthy percentage of body fat composition edge of human metabolism gained by each generation has
and weight. the potential to positively influence populations to improve
55 Weight-bearing exercise. every individual’s opportunity to be well and live a full life.
55 Continue to focus on nutrition to support healthy aging There is an imminent need for an alignment of society’s
with phytonutrients, healthy fatty acid balance, minerals, thinking with the newer discoveries of nutrition science to
methylation and sulfation nutrients, and hormonal and implement lifestyle basics and policies that are key to thriv-
immune support nutrition like vitamin D. ing in wellness.
Nutritional and Metabolic Wellness
37 3
Salutogenesis is a concept that literally means “that which 3. Lederberg J, Shope RE, Oaks SC Jr, editors. Emerging infections,
gives birth to health.” It is a term that has not been well microbial threats to health in the United States. Institute of Medi-
cine (US) Committee on Emerging Microbial Threats to Health.
known since its creation by Antonovsky in 1979 [18]. In tra- Washington, DC: National Academies Press (US); 1992. ISBN-10:
ditional public health and community medicine approaches, 0-309-04741-2.
the focus is the opposite: on disease or illness and its preven- 4. W.H.O.  Infertility is a global public health issue. http://www.­who.­
tion or treatment. This latter focus most often dominates int/reproductivehealth/topics/infertility/perspective/en/ Accessed
interventions. In the communities where longevity and qual- 30 Nov 2018.
5. de Martel C, Ferlay J, et al. Global burden of cancers attributable to
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vails. Adoption of a salutogenic perspective highlights the 2012;13(6):607–15. Epub 2012 May 9. -Associated Press posted Fri-
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created and maintained. Contrary to industrialized societies 6. National Obesity Rates & Trends. https://stateofobesity.­org/obesity-­
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7. Carmona RH statement: The Obesity Crisis in America: Testimony
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being rather than the origins of specific disease processes. The testimony/obesity07162003.­html. Accessed 10 Jan 2019.
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man DS. Prevalence of obesity among adults, by household income
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maximal life span. J Gerontol A Biol Sci Med Sci. 2018;73(11):1465–
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3.7 Summary ber 6, 2012).
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55 True wellness achieves a life that is dynamic, energetic, tivity define adipocyte transcriptional programs in human obesity.
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 39 4

Nutritional Ecology and Human

Health
David Raubenheimer and Stephen J. Simpson

4.1 Introduction – 40

4.2 “Nutrition” and “Ecology” – 40

4.2.1  uman Nutrition – 40
H
4.2.2 Ecology and Anthropology – 41
4.2.3 Nutritional Ecology and Human Health – 41

4.3 The Importance of Appetite – 41

4.3.1  ultiple Appetites – 42
M
4.3.2 Appetites Interact – 42

4.4  rom Concepts to Models: Introduction to the Geometric

F
Framework for Nutrition – 43
4.4.1  odel Selection – 43
M
4.4.2 Selecting an Intake Target: Nutritionally Balanced and
Complementary Foods – 44
4.4.3 Negotiating a Compromise: When the Intake Target Cannot Be
Reached – 44

4.5 The Geometry of Nutrition in Humans: Protein Leverage – 45

4.5.1  o Humans Select an Intake Target? – 45
D
4.5.2 What Is the P:NPE Rule of Compromise in Humans? – 46

4.6 Beyond Appetites – 47

4.6.1 T he Geometry of Mixtures: Three Components
in Two Dimensions – 47
4.6.2 A Hierarchy of Mixtures – 47
4.6.3 Dietary Macronutrient Balance – 48
4.6.4 Relationships Between Macronutrient Balance
and Energy Intake – 49
4.6.5 Energy Balance – 49
4.6.6 Beyond Energy: Protein Intake – 50
4.6.7 Interactions of Appetite with the Food Environment – 51

4.7 Conclusions – 52

References – 53

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_4
 40 D. Raubenheimer and S. J. Simpson

4.1 Introduction tribute toward bridging the gap between the food and
nutrition system that we currently have and the system we
Barely a year into the United Nations Decade of Action on would prefer. We begin by clarifying how we use the term
Nutrition, the global community of researchers and practi- “nutritional ecology” to place it in the context of related
tioners in nutrition and associated fields has its work cut out. approaches. We then discuss some biological insights from
Malnutrition, which includes overnutrition, undernutrition, nutritional ecology that we think can make a significant con-
and imbalanced nutrition, affects at least a third of the earth’s tribution to nutrition research and practice and thereafter
population and is by far the greatest contributor to the global introduce a geometric framework for implementing this
4 burden of disease [1]. For the period 2014–2016, it is esti- theory. We end with examples showing how the implementa-
mated that more than 794 million people (10.9% of the world tion of biological thinking via nutritional geometry can pro-
population [2]) were undernourished and concurrently 2.1 vide a concrete step toward a fresh, systems-based, view of
billion were overweight or obese [3]. Both overweight and human nutrition.
underweight are significantly associated with premature
death [4], as are many other diet-related factors including
excess sodium intake and micronutrient deficiencies [5]. 4.2 “Nutrition” and “Ecology”
Every year, more than 3 million children die of causes related
to undernutrition [6], and in 2010 alone, overweight condi- An important first step is to define what is meant by the term
tions and obesity are estimated to have resulted in 3.4 million “nutritional ecology” as used in the ecological sciences (and
deaths [3]. this chapter) and how it relates to the use of the same term
To appreciate the scale of these statistics, consider that the and the closely related term “nutrition ecology” in human
3.4 million deaths attributed to overweight and obesity in nutrition.
2010 is 1432 times the number of airline fatalities in the
worst-ever year of commercial aviation disasters (1972) and
42 times the total number in 74 years of commercial aviation 4.2.1 Human Nutrition
history [7]. It is equivalent to 6800 jumbo jets fully laden with
500 passengers each – 18 jets for every day of the year. Adding In human nutrition, the first published use of either term of
childhood deaths due to undernutrition, and we are staring which we are aware was in a collection of essays titled The
in the face of what amounts to 12,800 fatal jumbo jet crashes Feeding Web: Issues in Nutritional Ecology [13], which exam-
a year, or 35 daily. Aviation-related losses would not be ined the impacts on health and ecological sustainability of
allowed to reach a small fraction of these numbers; in fact, the industrialization of the US and global food systems.
since 1978 they have steadily decreased, notwithstanding the Elaborating on this approach, the term “nutrition ecology”
steep increase in the numbers of flights [7]. was introduced in 1986, referring to an “interdisciplinary sci-
A question that is increasingly attracting attention is why entific discipline that incorporates the entire food chain as
have we not done a better job of preventing illness and deaths well as its interactions with health, the environment, society,
due to malnutrition? There are many views, but four themes and the economy” where the food chain encompasses “pro-
repeatedly emerge. First, nutritional behavior and its causes duction, harvesting, preservation, storage, transport, pro-
and consequences are highly complex [8, 9], and the domi- cessing, packaging, trade, distribution, preparation,
nant models of nutrition research and practice do not pay suf- composition, and consumption of foods, as well as disposal
ficient respect to its complexity [10–12]. Second, nutrition is of waste materials along the food path” [14]. Nutrition ecol-
an intrinsically interdisciplinary problem requiring expertise ogy is considered a new nutrition science [15], which differs
from many areas – e.g., chemistry, physiology, and psychol- from conventional human nutrition science in two key
ogy to economics, law, and politics – but insufficient attention respects. Firstly, it takes a broader view that extends beyond
is paid to this fact in the training of nutrition scientists. Third, nutritional biology to encompass also societal and ecological
a systems perspective is needed to bring together the diverse issues. Secondly, it emphasizes interdisciplinary systems sci-
parts of the complex multifaceted nutrition system and to ence as a framework for dealing with the broad scope of the
identify how they interact to determine the important out- subject [16].
comes. Finally, we need to evolve a food and nutrition system Nutrition ecology is considered to also be distinct from
that respects optimization goals beyond minimum cost and the field of “nutritional ecology” that has developed in the
maximum pleasure and profit, including human health, ecological sciences and anthropology [16]. We are, however,
equity, and planetary sustainability. Considerably less well- unaware of any explicit discussions on the similarities and
developed than the articulation of where we have gone wrong differences between the nutritional ecology frameworks in
in nutrition are concrete suggestions for how we can imple- these fields. Since “nutritional ecology” sensu the ecological
ment a systems-based interdisciplinary agenda in nutrition sciences has recently come to focus on humans [12, 17], as
science and practice to put the problem right. the closely related framework in anthropology has done for
In this chapter, we introduce a field from the natural sci- some time now (see below), it is worth briefly examining how
ences, called nutritional ecology, which we believe can con- this term is used in those two fields.
Nutritional Ecology and Human Health
41 4
4.2.2 Ecology and Anthropology The term “nutritional ecology” has been used in anthro-
pology in much the same way that it developed in ecological
An early use of the term “nutritional ecology” is Schneider sciences [32]. Jenike (2001) defined it as “…the interaction of
(1967) [18]. While based in the clinical and public health-­ diet, somatic maintenance, physical activity, and pathogenic
related field of nutritional immunology [19], this prescient agents as they relate to growth, body composition, develop-
paper advocates the use of experimental designs in epidemi- ment, and function in a constraining social, political and
ology derived from “an analysis of the problem in ecological natural environment” [32]. This definition was modified by
concepts that goes beyond classical concepts in the fields of Hockett and Haws (2003), who defined the approach as “…
nutrition and microbiology” [18]. As we discuss below, this the study of the relationship between essential nutrient intake
adumbrated a central defining feature of the ecological field and its effects on overall human health, including growth and
of nutritional ecology, namely, the importance of applying maintenance in individuals and general demographic trends
ecological and evolutionary theory to understand the nutri- in populations” [33]. Both definitions share, in common with
tional biology of animals [20]. the ecological sciences, an emphasis on the individual within
The earliest use of the word term “nutritional ecology” the context of the environment.
that we could locate in the ecological literature is a treatise on
grasshopper ecology, published in a 1962 volume of the
Memoirs of the Indian Museum [21]. Relevant subsequent 4.2.3 Nutritional Ecology and Human Health
uses include Von Goldschmidt-Rothschild and Lüps (1976)
[22] and Stanley Price (1978) [23]. The subjects of these pub- The origins of nutrition ecology (in human nutrition) and
lications could not have been more different from the context nutritional ecology (in the ecological sciences and anthropol-
in which Gussow (1978) [13] used the term in relation to ogy) thus differed, with the former being focused more on the
industrialized human environments. The study of Von broader human nutrition system and the latter on the individ-
Goldschmidt-­ Rothschild and Lüps (1976), for example, ual within that system. In the terms of ecological science, this
examined the extent to which domestic cats in Switzerland broadly reflects the difference between the sub-­fields of com-
prey on small game birds, by dissecting the gut contents of munity ecology (emphasis on community-level issues, such as
257 cats that had been shot while hunting [22]. Stanley Price’s food webs) and functional ecology (emphasis on the character-
study assessed the nutritional status of wild hartebeest [23]. istics of individuals that adapt them to their environments)
As in Von Goldschmidt-Rothschild and Lüps’ cat study, Price [34]. This difference is not, however, absolute, but more an issue
did this by dissecting out the gut contents of shot animals but of emphasis. Nutrition ecologists do not exclusively consider
went further by measuring the nutritional composition of the the social and environmental dimensions of nutrition, but also
eaten foods. He also performed digestion trials that com- the biological dimension [15]. Likewise, nutritional ecologists
pared the nutrient content of food eaten by captive hartebeest are aware of the importance of the biological characteristics of
and sheep with the nutrient content of the feces they pro- individual organisms in shaping the ecological communities
duced. Given how disparate Stanley Price’s study is from within which they exist [20, 35]. Issues of emphasis are, none-
Gussow’s book, which appeared in the same year, it is not theless, important because they influence the questions, theory,
surprising that these works did not refer to each other, and and methods that direct progress in a scientific field.
neither did Gussow refer to any of the earlier ecological stud- In the remainder of this chapter, we demonstrate using
ies nor Schneider’s (1967) paper [13, 18, 23]. This suggests our own work how the biological theory and methods from
that the term “nutritional ecology” was probably derived nutritional ecology can provide new insight into human
independently in nutritional immunology, human nutrition, nutrition and its links to health [12]. The perspective that we
and ecology. bring derives from almost three decades of research into the
Over subsequent years, “nutritional ecology” became nutritional ecology of non-human organisms, ranging from
established as a subfield of ecology in its own right, being slime molds, yeast, and insects in laboratory studies to giant
applied across animals in general, including insects [24], pandas, monkeys, gorillas, and orangutans in the wild [36].
mammals [25], birds [26], and fish [27], as well as plants [28]. We do not view this approach to be an alternative to nutrition
Nutritional ecology in this sense has been defined as “the sci- ecology, but rather a means to expand human nutrition sci-
ence of relating an animal to its environment via nutritional ence to integrate the interests and expertise of nutrition ecol-
interactions” [29]. These interactions involve behavioral and ogy with the biological theory and the comparative
physiological aspects of food and nutrient acquisition and perspective of nutritional ecology.
their relationship to the health, growth, and reproduction of
animals [30]. A strong emphasis is on the ways that individu-
als adapt to nutrition-related aspects of the environment, 4.3 The Importance of Appetite
which takes place across various timescales from short-term
homeostatic responses to environmental changes, through Among the most emphatic messages to emerge from our
developmental adaptation and Darwinian adaptation by studies of non-human animals is that appetite is paramount
natural selection [31]. for understanding foraging, feeding, and its impacts on the
 42 D. Raubenheimer and S. J. Simpson

animal and, ultimately, on the community of which it is a predicts that animals should have separate appetites for spe-
part. This might seem obvious, except that biological theory cific nutrients to help ensure that they eat the specific blend
combined with studies on the nutritional ecology of non-­ of nutrients that is appropriate for their particular needs at a
human animals has provided a more nuanced and powerful given time. Such “nutrient-specific appetites” are known to
concept of appetite than currently exists in human nutrition exist for many animals, including humans (see 7 Sect. 4.5).
 

science. Although the details of which nutrients are regulated by spe-

In this section, we summarize the biological background cific appetites are expected to differ with the ecological and
to the nutritional ecology view of appetite and, in the follow- evolutionary circumstances of different species, the univer-
4 ing section, introduce an approach for modeling and mea- sal importance of the macronutrients protein, carbohy-
suring appetite in this sense. Thereafter, we show how these drates, and fat means that most animals have separate
models can help to integrate appetite within the broader appetites to regulate either two or all three of these [36].
human nutrition system to help bridge the gap between the Some also have specific appetites for the minerals calcium
biological theory and methods of nutritional ecologists and [40] and sodium [41].
the integrative goals of nutrition ecology [15].

4.3.2 Appetites Interact

4.3.1 Multiple Appetites
Important as they are, the possession of nutrient-specific
To appreciate the subtleties of appetite, we need to step back appetites is not on its own sufficient to ensure that animals
and ask the question “what is appetite for?” This is a good satisfy their nutrient needs [42]. An added complexity is that
stage to point out that the “what for?” question is a hallmark most nutrients are not available separately in the environ-
of the evolutionary framework on which nutritional ecology ment, but come packaged in mixtures called foods. If a food
is based; it aims to understand biological traits partly through contains the same ratio of different nutrients as is needed by
knowledge of what they evolved to achieve [37]. The power the animal – for example, high protein relative to carbohy-
of this approach is that it provides an expectation of, firstly, drate and fat when reproducing – then the complex nature of
how the biological trait should be designed to achieve its foods is a benefit, because this enables the animal to satisfy its
evolved function and, secondly, how it should respond in requirements for all nutrients from one source. It is, however,
various circumstances. For example, it can help to under- seldom the case that the composition of foods exactly
stand how the human appetite works and how it might matches the mix of nutrients needed, and this complicates
respond to the industrialized food environments of which nutrition considerably, both for animals and for attempts by
Gussow (1978) wrote in the book that first used the term nutritional ecologists to understand animal nutrition.
“nutritional ecology” in the context of human nutrition [13]. Where possible, animals deal with this challenge through
The simple answer to the question “what is appetite for” is “complementary feeding,” in which specific combinations of
that it evolved as a “control center” that directs the animal to nutritionally imbalanced foods are mixed in the right pro-
meet its nutritional needs, in the same way that thirst directs portions to balance the diet overall. This requires that the
it to drink and the sensation of cold causes shivering and appetites for the different nutrients cooperate to ensure that
heat-seeking behavior. To achieve its purpose, however, each is eaten at a level that meets, but does not exceed, the
appetite should be considerably more complex than motiva- respective requirements. Many animals have been shown to
tions such as thirst or temperature-related discomfort, for balance their diets in this way, both in laboratory experi-
several reasons. First, thirst and temperature regulation have ments and in the wild [36], and so too do humans (see
simple endpoints (sufficient hydration and optimal tempera- 7 Sect. 4.5.1).
 

ture, respectively), whereas an animal’s nutrient needs are In reality, however, ecology is not always so obliging as to
complex, involving many nutrients, each required at its own provide combinations of complementary foods that can be
particular level. Second, the relative needs for different nutri- mixed to obtain a balanced diet. Rather, animals often find
ents change over time and with the circumstances of the ani- themselves in situations where the only foods available
mal; for example, female birds have elevated protein and restrict them to eating a diet that is imbalanced with respect
calcium requirements for producing eggs [38], whereas more to their nutrient needs. For example, many primates that
fat and carbohydrates are needed to fuel the costs of long- need both fruits, which are high in sugars and fats, and
distance migration [39]. Meeting multiple and changing protein-­rich leaves to balance their diet, endure periods of
nutritional needs in this way, in complex and changing envi- fruit scarcity in which they are forced to eat a leaf-rich diet
ronmental circumstances, is a substantial challenge. containing excess protein [43].
An animal could not deal with this challenge if it had In this situation, the appetites for protein and non-­protein
only a single appetite that, for example, caused a bird to eat energy enter into conflict, because the target intakes for both
the same diet regardless of whether reproducing or prepar- cannot be achieved simultaneously. Rather, the nutritional
ing for migration, any more than we would expect a motor options available to the animal are to eat the target level of
car to have only a single warning light that did not distin- protein and suffer a shortage of non-protein energy, to eat the
guish between an oil and gasoline shortage. Theory therefore target level of non-protein energy while overeating protein,
Nutritional Ecology and Human Health
43 4
or to settle on an intermediate outcome in which it has both ships explored to interpret the ways in which they interact to
a moderate excess of protein and a moderate shortage of influence important outcomes such as energy intake and
non-protein energy. Research has shown that different spe- health [44]. We now demonstrate how the nutritional ecol-
cies resolve this competition between appetites in different ogy ideas from the previous section can be modeled using
ways, which likely reflect the relative costs of under- or over- the simple geometry of GFN (. Fig. 4.1). Thereafter, we show
 

eating the two nutrients [36]. how these models have been applied to understand macro-
While such interactions between appetite systems are nutrient regulation and its consequences for energy intake in
complex, they are also extremely important for understand- humans.
ing how diet influences the behavior, the physiology, and the
health of animals. To help simplify the challenge, we have
invented a modeling approach called the Geometric 4.4.1 Model Selection
Framework for Nutrition (GFN). In the following section, we
introduce the basic concepts of GFN and show how they have The first step in constructing a GFN model is to select the
been applied to understand macronutrient regulation in nutrients that are relevant to the problem under investiga-
humans. tion. In so doing, special care should be taken to heed the
dictum attributed to Einstein that “things should be as simple
as possible … but no simpler”: we should include in the
4.4  rom Concepts to Models: Introduction
F model only those nutrients that we suspect play an important
to the Geometric Framework role in the problem, but ensure that all of the nutrients that
for Nutrition do so are included. A common problem in human nutrition
science is the tendency to attribute outcomes such as obesity
The value of the ecology- and evolution-inspired concepts to individual nutrients, usually fats or carbohydrates, without
from nutritional ecology is substantially enhanced if these regard for how they interact with other nutrients in exerting
concepts can be expressed in quantitative models. their influence [12, 45] (please see 7 Chap. 8).  

Quantitative models provide a framework within which the Since our example concerns obesity, we will focus on the
various relevant factors can be measured and their relation- energetic macronutrients protein, fat, and digestible carbo-

Nutrient space
a b
Food B

Food A
Non-protein energy (kJ)

Non-protein energy (kJ)

Intake target Intake target

Eat B

Eat C
A
ry
to
jec
tra
g

Food C
Eat B
int
Ea

Protein (kJ) Protein (kJ)

..      Fig. 4.1  Basic concepts in the Geometric Framework for Nutrition. the nutrients that each contains. As the animal eats, it ingests the
The “nutrient space” is the space formed by the two nutrient axes, in nutrients in the same ratio as they are present in the food it is eating,
this hypothetical model protein (horizontal) and combined fats and and its nutritional state thus changes along a trajectory identical to the
digestible carbohydrates (non-protein energy) [vertical]. An “intake rail for that food. The animal can therefore reach its intake target either
target” is plotted within the nutrient space, representing the amount by selecting a food that has the same ratio of nutrients as the intake
and balance of nutrients (in this case protein and non-­protein energy) target (i.e., a nutritionally balanced food) (food A, in a) or by switching
that are targeted by the animal’s regulatory systems. Foods are between foods that are individually imbalanced but together nutrition-
represented as lines, called “nutritional rails,” which originate at the ally complementary (foods B and C in b)
origin and project into the graph at angles that represent the ratio of
 44 D. Raubenheimer and S. J. Simpson

hydrates, although in different contexts we might be inter- food it is eating. Its nutritional state can therefore be viewed
ested in other nutrients (e.g., [46]). We will also initially as “moving” through the nutrient space at an angle equiva-
simplify the model by combining fats and carbohydrates into lent to the rail for the food it is eating and over a distance
a single category to address the question of how the human determined by how much of the food it eats. . Figure  4.1a
 

appetite for protein (P) interacts with non-protein energy shows that food A contains the same ratio of the nutrients as
(henceforth NPE) to drive energy intake (. Fig.  4.1). Our
  does the intake target (the rail passes through the intake tar-
reasons for doing this are that, firstly, in some contexts, fats get), and in the spatial metaphor of the model, the animal can
and carbohydrates can be regarded as interchangeable therefore “navigate” to the target by eating this food (feeding
4 sources of metabolic energy for humans [47] and, secondly, trajectory A in the figure). This food is thus nutritionally bal-
as we show in the next section, when all three macronutrients anced with respect to the animal’s requirements for protein
are considered in their own right, distinguishing fats and car- and non-protein energy.
bohydrates in the data that we present as an example does not Foods B and C, by contrast, do not pass through the
provide a better explanation for energy eaten than does con- intake target – they are nutritionally imbalanced with respect
sidering them combined. We note, however, that in many to P and NPE (. Fig. 4.1b). However, since food C contains
 

other contexts  – for example, appetite interactions in mice too much P relative to NPE (falls to the right of the target)
[48] and the causes of cardiovascular disease in humans and food B too much NPE relative to P (to the left of the tar-
[49] – it is important to distinguish fats and carbohydrates get), the two foods are nutritionally complementary and can
and even the different sub-categories of these nutrients. be combined in appropriate proportions to provide a bal-
Geometric models can readily be applied in this context. anced diet. Complementary feeding is shown in the nutrient
Having selected the nutrients of interest, the next step is space as a zigzag trajectory, where each leg represents an
to make a graph where each nutrient is represented on its amount eaten of the respective foods (. Fig. 4.1b).
 

own axis, as shown in . Fig. 4.1. Here, too, there is an impor-

 

tant decision to make, regarding the units in which to repre-

sent the different nutrients  – for example, whether mass 4.4.3 Negotiating a Compromise: When
(grams) or energy (kilojoules). In our model, we have chosen the Intake Target Cannot Be Reached
energy units, because the aim is to understand how different
blends of macronutrients influence energy intake. Animals can therefore reach their intake target by selecting
We have now constructed a nutrient space, which pro- balanced foods (e.g., . Fig. 4.1a) or mixing their intake from
 

vides the platform on which we model how the appetites for nutritionally complementary foods (. Fig.  4.1b). What
 

different macronutrients interact to influence energy intake options does the animal have when confined to a single
(. Fig. 4.1).
  nutritionally imbalanced food or non-complementary com-
bination of imbalanced foods? As discussed above, in this
case the target point cannot be reached for both nutrients,
4.4.2 Selecting an Intake Target: and the appetite systems need to negotiate a compromise that
Nutritionally Balanced minimizes the cost to the animal of its dietary predicament.
and Complementary Foods Such strategies are known as rules of compromise.
A distinguishing feature of GFN is that it enables us to
An important reference point in modeling appetite interac- model the various rules of compromise and thereby to under-
tions is the intake target, or the point in nutrient space that stand the strategies that animals have evolved to deal with
shows the amounts and balance of the nutrients that the dietary imbalance. . Figure 4.2 shows three examples, repre-
 

appetite systems will target under circumstances in which senting extreme responses chosen from a wide range of pos-
they are unconstrained by the quality or quantity of available sible strategies [36, 53]. In the blue strategy, protein wins over
food (. Fig.  4.1). Theory predicts, and studies have shown,
  entirely – the animal eats to the point on the nutritional rail
that in many cases the selected intake target provides a diet where its need for P is met, regardless of whether NPE is
that optimally satisfies the animal’s needs for the different under-eaten (on high P:NPE diets) or overeaten (on low
nutrients [50–52]. The animal is able to reach its intake target P:NPE diets). This pattern, known as protein prioritization,
through the appetites for the different nutrients working in has been observed in wild spider monkeys [54] and orang-
harmony to meet the respective intakes that are best for the utans [55]. The green strategy is the opposite, namely, priori-
animal. tization of non-protein energy, where P is over- or under-eaten
The way that the animal satisfies its nutrient needs is, of to meet the NPE target. This pattern is shown by wild moun-
course, by eating foods, but the important question is which tain gorillas, which overeat protein to obtain the target level
foods the animal can eat to reach its intake target. To exam- of fats and carbohydrates in periods when fruit shortage
ine this, we can plot in the model the composition of various commits these animals to a high-protein diet [56]. It is has
foods, as lines called nutritional rails, which project from the also been observed in several carnivores, including mink
origin into the nutrient space at an angle determined by the [57] and predatory beetles [52]. The red strategy represents
ratio of the nutrients that each contains. As the animal eats, it the situation where neither nutrient group dominates over
ingests the nutrients in the same ratio as is contained in the the other, but the appetite systems give equal weighting to
Nutritional Ecology and Human Health
45 4

a b Protein
prioritization

B
Food
NPE+
Non-protein energy (kJ)

Non-protein energy (kJ)

P–

Non-protein energy
NPE+

prioritization
P– P+
NPE–

C
Food
NPE–

P+

Equal
weighting

Protein (kJ) Protein (kJ)

..      Fig. 4.2  a Schematic showing geometric representation of cit of P on food B or a moderate excess of P and a deficit of NPE on food
possible regulatory responses to nutrient imbalance. When confined to C. b Testing different experimental groups, each on one of a range of
a single nutritionally imbalanced food (i.e., with a rail that doesn’t inter- foods varying in nutrient balance, provides a description of how the
sect the intake target), the animal needs to resolve a trade-off between animal resolves the trade-off between over- and under-ingesting
over-ingesting one nutrient and under-ingesting the other. By feeding nutrients when confined to imbalanced foods, termed a rule of
to the green point, it meets its target for non-protein energy (NPE, compromise (ROC). Three possibilities are illustrated: the blue symbols
comprising fats and carbohydrate combined) at the cost of suffering a represent absolute prioritization of protein (i.e., feeding to the target
shortage of protein of magnitude P- on low P:NPE diets (e.g., if coordinate for protein regardless of whether this involves over- or
restricted to food B) or a protein excess (P+) on high P:NPE diets under-eating NPE), the green symbols represent NPE prioritization, and
(food C). The converse would be true if the animal ate to the blue the red symbols represent an intermediate response in which the
points – it would meet its protein target, but to do so would have to regulatory systems assign equal weighting to excesses and deficits of
ingest an excess or deficit of NPE (NPE+ and NPE-, respectively). By the two nutrients (P– = NPE+ on food B and P+ = NPE- on food C).
feeding to either of the red points, the animal would meet its target for Many other configurations are possible
neither nutrient, but would ingest a moderate excess of NPE and a defi-

each: it eats to the point on the imbalanced nutritional rail Campbell et al. (2016) presented 63 Jamaican volunteers with
where the ingested excess of one nutrient exactly matches the 3 menus from which to select a diet over 3 days within a resi-
deficit of the other. This pattern has been observed in wild dential experimental facility [61, 66]. All 3 menus contained
rhesus macaque monkeys [58] and several species of general- the same 29 dishes, but the compositions of the dishes were
ist-feeding herbivorous insects [36]. manipulated using added protein and carbohydrate such that
all options on one menu had 10% of energy from protein, a
second had 15%, and a third had protein at 25%. Fat was held
4.5  he Geometry of Nutrition in Humans:
T constant at 30% for all dishes and menus. Since the human
Protein Leverage diet seldom contains less than 10% protein or more than 25%,
we reasoned that if an intake target exists, then it lies some-
How do humans regulate macronutrient intake, and can this where between these extremes and can be reached by com-
help to understand obesity? These questions have been posing a diet from the experimental menus through
addressed in several independent studies, including random- complementary feeding. The menu with 15% protein repre-
ized control trials [59–61], analyses of data compiled from the sented our best guess at what the composition of the target
literature [62], and survey data of human populations [63– diet is, because this is close to the mean intake levels found in
65]. Results of these studies have consistently highlighted the Western diets [67].
importance of appetite interactions in driving energy intake. Results are plotted in . Fig.  4.3. The three solid radial
 

lines are nutritional rails representing the compositions of

the experimental menus, and the blue-shading shows the
4.5.1 Do Humans Select an Intake Target? area that could potentially be reached by subjects in this
experiment. Despite the wide range of possibilities, it is strik-
A recent study has addressed this question, with striking ing that all subjects, whether male or female, clustered tightly
results. Following protocols developed by Gosby et al. (2010), around a line representing 14.7% protein, although males ate
 46 D. Raubenheimer and S. J. Simpson

10% P 15% P 5%P

20000
12000

P)
%

54 % P
17500

6.7
(1
10000

om
Fat + carbohydrate intake kJ/day

25% P

Fat + carbohydrate intake kJ/day

nd
15000

Ra
8000
12500
4
10000 6000

7500 4000

5000
2000

2500
0
0 2000 4000 6000 8000 10000 12000
0
0 1000 2000 3000 4000 5000 Protein intake kJ/day
Protein intake kJ/day

..      Fig. 4.4  Interaction of human appetite systems with dietary

..      Fig. 4.3  Daily protein and non-protein energy intakes self-­selected macronutrient ratios. Data are protein (x-axis) and non-protein (fat +
by 63 adult Jamaican volunteers, averaged for each subject over the carbohydrate, y-axis) ad libitum energy intakes by subjects restricted to
3-day experimental period. Red symbols are females, and blue symbols 1 of 138 experimental diets [62, 69]. The black dashed radials represent
are males. The solid radial lines are nutritional rails representing the the nutritional rails for the diets with the highest (54%) and lowest (5%)
compositions of the three experimental menus from which the diets proportional protein content. The area between these radials is the
could be freely selected (10, 15, and 25% protein by energy). The pale region of the nutrient space within which points for nutrient intakes are
blue region represents the range of diets that could theoretically be constrained to lie, with the pattern of actual intakes being determined
selected from these menus, and the dotted red line represents the by the ways that appetites for protein, fat, and carbohydrate interact.
expected outcome if the subjects mixed the diets randomly (16.7% P). The blue, red, and green lines represent the protein prioritization, NPE
The data show that subjects selected a diet of 14.7% protein, which prioritization, and equal weighting models from . Fig. 4.2. The analysis  

was significantly different from the random outcome. (Adapted from shows that humans maintain absolute protein intake relatively tightly,
Campbell et al. [61]. With permission from Creative Commons License) with non-protein energy intake varying more passively with dietary
macronutrient ratios. (Adapted from Raubenheimer and Simpson [12].
With permission from Annual Reviews)
more of the diet overall than females, which is not surprising
given their larger body size. What all of these studies in the compilation have in com-
One possible explanation for this pattern is that the sub- mon is that each experimental subject was restricted to one
jects did not distinguish between the three diets based on of a range of single diets, each with fixed P:NPE ratio, and
their macronutrient content, but simply ate equal amounts of allowed to eat as much of their respective diet as they wished.
each. It can be calculated that if this were the case, the intake The experiments therefore test how the human appetite sys-
points would align along the dashed radial line, representing tems interact to determine protein, fat, and carbohydrate
a diet with 16.7% protein. However, the actual intakes dif- intake as dietary macronutrient balance varies – i.e., the rule
fered with a high degree of statistical certainty from this line, of compromise for these nutrients. The result is shown in
showing that they represent macronutrient regulation to a . Fig.  4.4. Protein intake remained relatively stable over a
 

P:NPE intake target. An earlier experiment by Simpson et al. wide range of diet compositions, while the intake of fats and
(2003) showed similar results [68]. carbohydrates increased with decreasing dietary P:NPE ratio.
Humans thus show the protein prioritization pattern of mac-
ronutrient regulation (. Fig. 4.2).  

4.5.2  hat Is the P:NPE Rule of Compromise

W This analysis shows that information about the dynamics
in Humans? of human appetite systems is essential for understanding why
we eat the amounts of nutrients and energy that we do. The
Several studies, including randomized control trials [59, 60, main conclusion that it presents is by no means obvious: it
68], analyses of experimental data compiled from the litera- suggests that humans will overeat fats and carbohydrates not
ture [62], and observational studies using diet surveys [63], because they have a particularly strong drive to eat these
have addressed the question of how humans respond to nutrients, but because of a strong appetite for protein. On the
macronutrient-imbalanced diets. Since the results all tell the other hand, we should not interpret this to suggest that the
same story, we will present only the data of the literature human appetite is exclusively about protein. We know that
compilation of Gosby et  al. (2013), as expanded by this is not the case, because when allowed to select a diet
Raubenheimer et al. (2015) [62, 69]. from nutritionally complementary foods, humans regulate
Nutritional Ecology and Human Health
47 4
the intake of both P and NPE (. Fig. 4.3). Rather, in circum-
  onstrate in the context of the protein leverage hypothesis how
stances where it is possible, the appetites for different macro- it can provide an aid for understanding the biology-­
nutrients cooperate to select a balanced diet, but when limits environment interactions that influence health in industrial-
on available foods prevent this, protein regulation overrides ized food environments.
and fat and carbohydrate intakes follow more passively.
This phenomenon, where the appetite for protein influ-
ences the intake of other nutrients such as fats and carbohy- 4.6.1  he Geometry of Mixtures: Three
T
drates, has been termed protein leverage [47]. Components in Two Dimensions

As its name implies, the RMT is an approach for modeling

4.6 Beyond Appetites mixtures. The axes are therefore scaled as the proportional
(or %) contribution of each nutrient to the overall mixture,
Our discussion to this point illustrates the logical progres- rather than absolute amounts, as is the case in the GFN mod-
sion of research within the nutritional ecology framework. els of appetite interactions (e.g., kilojoules eaten per day, as in
We began by showing that evolutionary and ecological rea- . Figs.  4.3 and 4.4). The key difference between these two
 

soning predicts that animals should have separate appetites variants of nutritional geometry is thus that one is
for different nutrients and that these appetite systems should proportions-­based and the other is amounts-based. Beyond
interact to determine nutrient intakes. We then introduced that, they share much in common and are, in fact, comple-
nutritional geometry as an approach for measuring such mentary approaches for modeling nutrition.
appetite interactions and demonstrated how it has been As is the case for amounts-based geometric models, the
applied to humans. Results showed that the humans in our first step in building an RMT model is to decide which nutri-
study selected an intake target of approximately 15% energy ents are most relevant to the problem. Since we are extending
from protein, and when restricted to macronutrient-­ the analysis of how macronutrient appetites interact to influ-
imbalanced diets that prevented them from achieving this ence energy intake, we will include in our model the macro-
target, they showed the protein prioritization rule of compro- nutrients protein, fats, and carbohydrates expressed in energy
mise, in which fats and carbohydrates are passively over- or units. An important advantage of the RMT approach, how-
under-­eaten as the percentage of dietary protein varies. ever, is that it enables all three nutrients to be modeled in a
This is, principally, an examination of organismal (in this simple two-dimensional graph. Amounts-based geometry
case human) biology, which, as we commented above, is an can also cope with more than two nutrients, but generally only
important starting point for nutritional ecology research. by simplifying the model (e.g., combining two nutrients into a
The next step is to expand the model to understand how the single axis, as for fats and carbohydrates in . Figs. 4.3 and 4.4)
 

trait, in this case appetite interactions, engages with broader or else by plotting three two-dimensional graphs (protein vs.
aspects of the animal’s nutritional biology, including specific fat, protein vs. carbohydrates, and fat vs. carbohydrates).
nutrient requirements and the food environment that nutri- To illustrate how three components are represented in a
tion ecologists have emphasized in their writing. two-dimensional RMT, consider the black point in . Fig. 4.5a,
 

One hypothesis that addresses this is the protein leverage representing the macronutrient composition of a sample of
hypothesis (PLH) [47]. PLH proposes that the protein priori- rice. The percentage contribution of protein to total macro-
tization pattern of macronutrient regulation has interacted nutrient energy in the rice is 5% (x-axis) and of fat is 10%
with reductions in the P:NPE ratio of the human diet to drive (y-axis). Since % protein + % fat + % carbohydrate must add
fat and carbohydrate overconsumption and obesity. This up to 100% of macronutrient energy, it is easy to see that %
hypothesis can potentially provide a powerful bridge between carbohydrate = 100 – (%protein + %fat) = 100 – (5 + 10) = 85.
human biology, modern human environments, and health Geometrically, 85% carbohydrate is represented by a diago-
because, if true, it simplifies the search for the causes of the nal line that connects the same value on the x- and y-axes and
obesity epidemic. It does this by focusing attention on a very intersects the point representing the sample of rice. Any mix-
simple question about the role of environmental change in ture of macronutrients that comprises 85% of energy from
driving this epidemic: what is the cause of protein dilution in carbohydrates will fall on this line, which is plotted in the
the human diet that leads our appetite systems to overeat fats figure as the black dotted diagonal labeled “85.”
and carbohydrates? By the same logic, it can be seen at a glance that the peas
Simple questions are not, however, necessarily simple to in the plot comprise 25% of energy from protein, 5% from
answer, and this is no exception. Like human biology, mod- fat, and 70% from carbohydrate, and the steak comprises
ern industrialized human food environments are extremely 40% protein, 60% fat, and 0% carbohydrate.
complex, and the interactions between human biology and
modern environments potentially all the more so. To help
deal with this complexity, we have adopted from nutritional 4.6.2 A Hierarchy of Mixtures
ecology a form of nutritional geometry called the right-­
angled mixture triangle (RMT); [70]) (. Fig.  4.5). In the Just as the macronutrients combine in specific proportions in
 

remainder of this chapter, we introduce the RMT and dem- foods, so too do foods combine into meals, meals into diets,
 48 D. Raubenheimer and S. J. Simpson

a b
[0
100 ] 100 foods
95 95
meals
90 90
85 85
diets
80 80
75 75
70 70
[C [C
4 ar ar
65 65
60
steak bo m6 bo
hy 60 steak hy
55 dr 55 dr
at m7 at
e% e%
Fat % (kJ)

Fat % (kJ)
50 50 m5
45 kJ 45 kJ
] ]
40 40 m1
35 35 m4 d1
[7
30 0] 30
d2
25 25 m2
20 20 m3
[8
15 5] 15
10 rice 10 rice
5 peas 5
peas
0 0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Protein % (kJ) Protein % (kJ)

..      Fig. 4.5  a Right-angled mixture triangle [70] illustrating how contains 40% protein, 60% fat, and 0% carbohydrate. b Foods combine
components (in this case the macronutrients) combine into foods (rice, into meals (m1–m7), and meals combine into diets (d1 and d2). A meal
peas, and steak). Points represent the percentage contributed by each composed of two foods (e.g., peas and steak) is constrained to fall on the
component (protein, fat, and carbohydrate) to the sum of the three. Thus, line connecting those foods (e.g., m1 and m2), with the exact position
the macronutrient composition of rice is 5% protein and 10% fat, and along the line being determined by the proportion of the foods in the
since protein, fat, and carbohydrate sum to 100%, carbohydrate = 100 – meal. Adding a third food (e.g., rice) expands the set of possibilities to a
(5 + 10) = 85%. This value is represented by the negative dashed diagonal triangle (meals m1, m2, and m3 can be composed from the three foods,
joining 15% on the x- and y-axes, such that any mixture of macronutri- but m4–m7 cannot). By extension, diets d1 can be composed from meals
ents containing 85% of carbohydrate will fall on that line. Likewise, the m1 to m7, but d2 cannot. (Adapted from Raubenheimer and Simpson
peas contain 25% protein, 5% fat, and 70% carbohydrate, and the steak [12]. With permission from Annual Reviews)

and diets into dietary patterns. Recent work in nutritional strained to fall on the line connecting these foods, with the
ecology has emphasized the value of considering all of these exact position determined by the proportions of the two foods
levels for understanding the nutritional strategies of animals in the meals. Thus, meal compositions labeled m1 and m2 are
[71]. This is critically important in human nutrition, because attainable from peas and steak, but m3–m7 are not. If addi-
each level in the hierarchy engages in different ways with the tional foods are included in the diet, then the set of possible
complex organism-environment interface of humans in meal compositions expands to a space. For example, a meal
industrialized food environments [12]. consisting of peas, steak, and rice can take on any macronutri-
For example, nutrients, the base level in the mixture hier- ent composition that falls within the triangle formed by these
archy, interact with physiology, by engaging taste receptors, foods (e.g., m3), but no composition that falls outside of the
appetites systems, and numerous physiological pathways rel- triangle (m4–m7). By the same logic, meal m1–m7 could com-
evant to health (e.g., the insulin signaling system). It is not, bine into a weekly diet that falls within the polygon formed by
however, nutrients that we buy, but principally foods, and to connecting these meals (e.g., d1), but not outside of it (d2).
understand our shopping choices, we need to consider also
this level in the hierarchy. Although some foods are eaten
directly, the greatest portion of the human diet is eaten as 4.6.3 Dietary Macronutrient Balance
mixtures of foods, called meals. Meals, therefore, are impor-
tant levels of focus for understanding human eating choices. Distinguishing and interrelating different levels of the dietary
And yet neither foods nor meals are the primary link between mixture hierarchy in this way provides important benefits for
nutrition and health; for that we need to consider the long-­ examining the ways that human nutritional biology engages
term cumulative intakes of foods and meals, namely, diets. To with industrialized food environments. However, to realize
close the circle, diets impact health and disease principally the potential of this approach, we need to move beyond
via their primary components, the nutrients. describing mixtures such as foods, meals, and diets and
A powerful aspect of RMT plots is that they can model all examine how they link to human biology and to the food
levels in this hierarchy of mixtures, as illustrated in . Fig. 4.5b.   environments with which our biology interacts. An impor-
Consider, for example, a meal comprised of two foods, peas tant first step is to relate these compositional data to nutrient
and steak. The macronutrient composition of this meal is con- requirements.
Nutritional Ecology and Human Health
49 4
was a voluntary response of the subjects) to macronutrient
70 ratios of the diet (the experimentally fixed variable) [69].
65 The analysis shows that total energy intakes increased
60 (intake values grade from blue to red) as the percentage of
55 energy contributed to the diet by protein decreased (move-
50
ment from right to left on the protein axis). This result substan-
tiates the protein leverage effect shown in . Fig. 4.4, but takes
 
45
it further. First, it shows that the leveraging by protein of fat
40
and carbohydrate intake (. Fig. 4.4) translates into increased
Fat % (kJ)

35 total energy consumption, as predicted by the protein leverage

30 hypothesis. Second, energy intake changed as dietary protein
25 varied (along the x-axis), but remained relatively constant
[C
20 ar along the fat axis. This suggests that, for these data at least, the
bo
15
hy
dr main determinant of energy intake was the protein energy
at
10
e% ratio (x-axis), with little effect of the relative proportion of
KJ
[6
5% = fat:carbohydrate, and justifies our decision, discussed above, to
5 45
] %
] combine fat and carbohydrate into a single axis (. Fig.  4.4).
 

0
0 5 10 15 20 25 30 35 40 45 50 55 60 Finally, plotting the data in this way helps to integrate addi-
Protein % (kJ) tional factors into the model, such as energy balance.

..      Fig. 4.6  Macronutrient compositions of the 138 experimentally 4.6.5 Energy Balance
fixed diets plotted from . Fig. 4.4. The yellow polygon is an integrated
 

representation of Australian/New Zealand Acceptable Macronutrient

Distribution Range (AMDR; %P = 15–25%, %F = 20–35%, %C = 45–65%),
An important reference point for predicting the effects of
such that diet points falling within this polygon represent macronutri- protein leverage on obesity is Equilibrium Energy Intake
ent-balanced diets and those falling outside are macronutrient-imbal- (EEI), or the point at which energy intake matches energy
anced. (Adapted from Raubenheimer and Simpson [12]. With expenditure. Energy intakes that exceed EEI signify positive
permission from Annual Reviews) energy balance and risk of fat accumulation, while lower
intakes signify negative energy balance.
To illustrate, . Fig. 4.6 presents in RMT format the same
 
To incorporate the concept of energy balance into the
data as plotted in . Fig. 4.4, representing the compositions of
 
model relating macronutrient ratios to energy intake, we esti-
experimental diets compiled from the literature. As the figure mated the EEI (given body size, sex, and expected activity
shows, the data spanned a wide range of protein–fat–carbohy- levels under the experimental conditions) for the subjects
drate mixtures. To examine how these mixtures relate to pro- from the experiments represented in the analysis to be 8813
portional macronutrient requirements, we used for reference kJ/day [69]. This value can be incorporated into the model as
the Acceptable Macronutrient Distribution Ranges (AMDR) an EEI contour, represented in . Fig. 4.7a as the bold dashed
 

for Australia and New Zealand [72]. According to these rec- line. Intakes to the left of this line represent positive energy
ommendations, 15–25% of energy intake should come from balance, and intakes to the right represent negative energy
protein, 20–35% from fat, and 45–65% from carbohydrate. balance.
Delineating these individual ranges in . Fig. 4.6 enables  
We can now relate across the experimental population
us to identify the region representing diets that satisfy all dietary macronutrient balance (position in relation to the
three recommendations, plotted as yellow polygon. Any diet AMDR polygon) to energy intakes and energy balance, to
with a composition that falls within the yellow region is thus predict the compositions of diets that will cause human appe-
macronutrient-balanced with respect to the AMDR, and any tites to drive energy overconsumption. An interesting feature
diet that falls outside is macronutrient-imbalanced. of the model is that the EEI contour passes through the
AMDR region. Assuming the same applies more generally
within the relevant populations, this suggests that following
4.6.4  elationships Between Macronutrient
R the official New Zealand and Australian recommendations
Balance and Energy Intake for proportional macronutrient intakes would spontaneously
lead to balanced energy intake.
Central to the protein leverage hypothesis is the question of For comparison, we have also plotted in . Fig.  4.7a the
 

how energy intakes relate to dietary macronutrient ratios. US AMDR [73]. The recommendations for carbohydrate and
We already have shown that low dietary protein leverages the fat are the same as the Australian and the New Zealand
intake of excess fat and carbohydrate and now address the AMDR, but the range for protein is broader, spanning
implications for total energy intake. To do this, in . Fig. 4.7,   10–35% of energy intake. The model suggests that following
we have constructed a response surface onto the data from the low end of the protein range (10–15% of energy intake
. Fig.  4.6 that relates the ad libitum energy intakes (which
  from protein) would lead to energy overconsumption and
 50 D. Raubenheimer and S. J. Simpson

a b
Energy intake (kJ/day) Protein intake (kJ/day)
70 70

Ca
8813 kJ 1489 kJ

Ca
rb
65 65

r bo
oh

hy
yd

dr
ra
60 60

te

at
A A

1500

e%
%

1400
(k
55 55

(k
J
P

J
P

)
160
4

1800
0
50

5000

170
50

5500
6000

1900

2100

230 0
45 45

6500

4500

2600
M

2400
2500
40 40

2800
2200
Fat % (kJ)
Fat % (kJ)

35

2700
1150

1000
35
10 00

S
0

S
1100

30 30
0

9500
1050

1100
25 25
9000

1200
20 K

2000
20
00

00
0

75
8 50

70

1300
0
800

15 15 T
O

10 10

5 5
[6

[4
5%

5%
]

0 0
0 5 10 15 20 25 30 35 40 45 50 55 60 0 5 10 15 20 25 30 35 40 45 50 55 60

Protein % (kJ) Protein % (kJ)

..      Fig. 4.7  a Response surface showing ad libitum daily energy Australia/New Zealand AMDR, but a wider protein range (spanning
intakes associated with the experimental diet compositions plotted in 10–35%). b Response surface showing ad libitum protein intakes
. Figs. 4.4 and 4.6. The dashed contour represents estimated
  associated with the data in a. The dashed contour represents
equilibrium energy requirements (8813 kJ) for sex and weight approximate average protein requirements for the study population
assuming a physical activity level (PAL) of 1.5, which is commensurate (1489 kJ). The figure shows that protein intakes considerably higher
with activity levels in the experimental subjects. The data suggest that than estimated requirements are associated with diets having
energy equilibrium was achieved on diets with 15–20% protein, with macronutrient compositions equivalent to high-protein weight loss
energy balance being negative and positive for diets with higher and diets (A Atkins, P Protein Power, and S Sugar Busters). Conversely, low
lower % protein, respectively. The model is consistent with the protein intakes are likely to be associated with the macronutrient
association between weight loss and high-protein diets, such as the composition of the diets associated with exceptionally healthy and
Atkins (A), Protein Power (P), and Sugar Busters (S) diets: their long-lived human populations, the Mediterranean (M), Kitavan Islander
macronutrient compositions fall within the blue region of low ad (K), Tsimane (T), and traditional Okinawan (O) diets. (Adapted from
libitum energy intakes. The dotted polygon represents the AMDR for Raubenheimer et al. [69]. With permission from The Obesity Society)
the USA, which has the same ranges for fat and carbohydrate as the

positive energy balance. In contrast, the high end of the US carbohydrates results in protein overconsumption, albeit to a
range for protein (25–35%) corresponds with low energy smaller extent than low protein leads to fat and carbohydrate
intakes and negative energy balance (the blue region). overconsumption [12].
Indeed, the protein leverage effect can help to explain why To illustrate, in . Fig.  4.7b we have plotted the corre-
 

many popular high-protein weight loss diets including the sponding protein intake surface for the data shown in
Atkins, Paleo, and Sugar Busters, which are shown in the fig- . Figs.  4.6 and 4.7a. We have also calculated the Estimated
 

ure, fall within this region. Average Protein Requirements for the subjects in the experi-
mental trials to be 1489 kJ and plotted this as a contour equiv-
alent to the EEI contour in . Fig. 4.7a. Viewing the data in  

4.6.6 Beyond Energy: Protein Intake this way clearly shows the increase in absolute protein intakes
with increasing dietary % protein (left to right on the x-axis).
While the above analysis suggests a reason based on human It also shows that estimated dietary protein requirements are
appetite interactions (protein leverage) why high-protein met for diets with approximately 15–20% protein energy, and
diets are effective for weight loss (in the short term at least), at higher dietary protein densities, excess protein is ingested.
we caution that low energy intake is not the only effect of There is now strong evidence that excess protein intakes
consuming diets with high protein energy ratios. Another are associated with negative cardiometabolic profiles and
outcome is that compensation for the low levels of fats and accelerated aging, especially when coupled with low carbo-
Nutritional Ecology and Human Health
51 4
hydrate intakes [45, 74]. Consistent with this is the observa- tion of our diets. To address this, Brooks et al. (2010) calcu-
tion that the healthiest dietary patterns, including the lated the relationship between the concentration (g/100 g) of
Mediterranean, traditional Okinawan [75], Kitavan Islanders protein, fats, and carbohydrates and the cost (in US dol-
[76], and Tsimane [77] diets, are associated with low dietary lars/100 g) of 106 supermarket foods [79]. Results showed
protein densities and low protein intakes, as shown in that the cost of supermarket foods is positively related to
. Fig.  4.7b. This should caution against high-protein diets, their protein content (. Fig. 4.8). This suggests that economic
   

such as the Atkins, high-protein Paleo, and Sugar Busters considerations might be one factor that contributes toward
diets (. Fig.  4.7), except as therapeutic interventions for diluting dietary protein content in industrialized food envi-
 

weight loss. It also raises questions about the high end of the ronments, an influence that our model has shown is trans-
protein range sanctioned by the US AMDR. duced via the protein leverage effect into increased energy
In comparing . Fig. 4.7a, b, the alert reader might have intake. In this way, protein leverage might help to explain the
 

noted an apparent inconsistency. The Mediterranean, Kitavan well-established association between lower socioeconomic
Islander, traditional Okinawan, and Tsimane diets all have status and obesity [80].
low protein energy ratios (between 10% and 15%) We might likewise address the question of why the USDA
(. Fig.  4.7b) and under the model presented in . Fig.  4.7a AMDR spans such a wide range of dietary protein densities,
   

should thus be associated with excess energy intake, and yet encompassing both low-protein diets (10–15% protein),
obesity is not a problem within these societies. The reason for which our model suggests are likely to be associated with
this apparent inconsistency is that the parameters of such excess energy intake (. Fig.  4.7a), and the high end (25–  

models, including the shape of the surface relating energy 35%), associated with excess protein intake and premature
consumption-to-macronutrient ratios, are population-­ aging (. Fig. 4.7b). One possibility is that this reflects influ-
 

specific and might be influenced by differences in nutrient ence on research and government policy by the food indus-
and other aspects of the respective food environments. For try, rather than health considerations. For example, the sugar
example, the low-protein dietary patterns in . Fig. 4.7b are and affiliated industries selectively sponsor research that
 

associated with high fiber content compared with Westernized casts doubt on recommended upper limits to sugar intake,
diets to which the model in . Fig. 4.7a applies. High fiber is and the meat, dairy, and egg industries do the same for pro-
 

likely to induce satiety [78] at lower levels of protein (and tein [81, 82]. These industries also exert influence on dietary
energy) intakes than are low fiber diets [69], as has been guidelines through political lobbying [82].
demonstrated in mice [45]. The combination of low protein Several other possible facets of industrialized food envi-
and high fiber thus has the double health benefits of limiting ronments that might interact with human appetite systems to
protein intake while avoiding energy overconsumption. The influence health have been identified. These include the
extension to consider also fiber emphasizes the importance influx of low-protein processed foods into the human food
of matching the model to the context and also demonstrates
how these models can be built incrementally to incorporate
multiple food constituents. Equally important is their exten-
$US
sion to include broader components of the food environ- 100
ment, beyond diet composition.
0.8

80
I nteractions of Appetite with the Food
Fat + carbohydrate g/100g

4.6.7
Environment 60
1.2

1.4

To this point we have built a model that integrates human

1.6

appetite interactions with a range of factors relevant to the

1

40
1.8
0.6

relationships between diet and health, including the nutrient-­

food-­ meal-diet mixture hierarchy, dietary macronutrient
2.2
2

ratios, intakes of energy and protein, recommended dietary 20

macronutrient proportions and protein intakes, and energy
balance. The model demonstrates one advantage of doing 0
this: it helps to identify how these factors interrelate to 0 10 20 30 40
explain the links between diet, health and disease. Protein g/100g
Another advantage of building such a model is that it pro-
vides a context for identifying important aspects of our food
environment that might influence the relationships within ..      Fig. 4.8  Relationship between the concentration (g/100 g) of
the model. For example, among the most salient and influen- macronutrients (protein, fat, and non-structural carbohydrates) and the
cost ($US/100 g) of 106 supermarket foods. Cost increases from dark
tial aspects of industrialized food environments is econom- blue to red. The graph suggests that the cost of food increases with
ics, giving rise to the question of whether the cost of foods protein density but is unaffected by fat and carbohydrates. (Reprinted
might play a role in influencing the macronutrient composi- with permission from Raubenheimer et al. [17])
 52 D. Raubenheimer and S. J. Simpson

7.8
Ultra-processed
% protein

13.3
food quintiles

18.2
7.6 1
2
3
7.4 4
Non-protein energy (MJ)

7.2

4 7.0

PL2
8.
J)

9
M
6.8 gy(
er

NPE
en

PL1
6.6
8.
2

6.4
.7 .8 .9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 IT1 IT2
Protein energy (MJ)

..      Fig. 4.9  Relationship between ultra-processed food consumption

and protein leverage. The symbols represent protein and non-­protein
energy intakes for the lowest (green) to highest (red) quintiles of
ultra-processed food (UPF) consumption reported in the National Health PE
and Nutrition Examination Survey 2009–2010. The negatively sloped
diagonals represent daily total energy intakes (calculated as the sum of
X + Y), and the positive radials represent the dietary protein:non-protein ..      Fig. 4.10  Schematic showing the effect on protein leverage of an
energy ratio (X/Y). The dark vertical, horizontal, and diagonal lines increase in the protein coordinate of the intake target, as might come
represent alternative models to explain the data, as in . Figs. 4.2 and   about through decreased protein efficiency. The x-axis represents
4.4. The data show that increased inclusion of UPF in the diet corre- protein energy (PE) and the y-axis energy from c­ arbohydrates and fat
sponds with reduced dietary protein density (18.3–13.3%) and increased (NPE). The dashed radial shows the macronutrient composition of a
total energy intake (8.2–8.9 MJ), as predicted by the protein leverage food that has a lower PE:NPE ratio than intake target IT1. The arrow
hypothesis. (Reprinted with permission from Martinez Steele et al. [64]) labeled PL1 denotes the extent to which surplus intake of carbohy-
drate and fat is leveraged by the mismatch between the PE:NPE ratio of
the food relative to target IT1. For the same food, protein leverage is
supply (. Fig.  4.9) [64] and the reduction in plant protein
 
greatly exacerbated (PL2) for a small change in the protein coordinate
that may be associated with rising atmospheric carbon diox- of the intake target (IT1 increases to IT2). (Reprinted with permission
ide [17], both of which could potentially have the effect of from Raubenheimer et al. [17])
diluting the energy contribution of protein, thereby increas-
ing energy intake. sity and associated disease in recent decades. The broader
In addition to such influences on the compositions of message, however, is that a nutritional ecology perspective,
foods and diets, another interesting possibility is that envi- which emphasizes the interaction between biological traits
ronmental factors might interact directly with human and food environments, can provide a structured research
biology to influence the parameters of protein leverage. framework for generating and testing hypotheses regarding
For example, any factor that reduces protein efficiency the causes of health and disease in our radically altered
could exacerbate protein leverage, by increasing the intake industrialized food environments.
target of the protein appetite, thus requiring a stronger
compensatory response to protein dilution (. Fig.  4.10)  

[47]. Such environment-­ induced variation in protein 4.7 Conclusions

leverage might explain a number of poorly understood
correlations between obesity and environmental factors. Statistics such as those with which we opened this chapter
One example is the association of obesity with recent cul- leave no doubt that nutrition science ought to be doing a bet-
tural transitions from traditional high-protein diets to ter job of preventing premature deaths that are associated
Westernized diets rich in fats, oils, and simple carbohy- with malnutrition and chronic disease. The challenge, how-
drates [47]; another is and the vulnerability to later-life ever, is to understand how the diverse and complex set of
obesity of infants fed high-protein milk formulas [17]. In interacting causes drives the problem and to identify the key
both cases, high-protein diets are hypothesized to devel- control points that are amenable to intervention to improve
opmentally program low-protein efficiency, thus exacer- nutrition-related health. There is now widespread recogni-
bating protein leverage (. Fig. 4.10).   tion that success will require a systems-based approach,
We cite these examples to illustrate how an understand- which recognizes that relevant causal components are dis-
ing of the dynamics of human appetite systems might help to tributed across and between domains representing diverse
illuminate the factors that have driven the epidemic of obe- academic disciplines and societal sectors [8–12, 83]. The
Nutritional Ecology and Human Health
53 4
leadership, however, must come from nutrition science, 3. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C,
which at present is ill-equipped for the task. et al. Global, regional, and national prevalence of overweight and
obesity in children and adults during 1980–2013: a systematic
We have suggested in this chapter that a constructive analysis for the Global Burden of Disease Study 2013. Lancet.
branch for interdisciplinary engagement is with the basic 2014;384(9945):766–81.
biological sciences. Although nutrition science clearly has 4. Di Angelantonio E, Bhupathiraju SN, Wormser D, Gao P, Kaptoge S,
drawn heavily on chemistry, molecular biology, and physiol- de Gonzalez AB, et  al. Body-mass index and all-cause mortality:
ogy, its engagement with the core theory of biology – evolu- individual-participant-data meta-analysis of 239 prospective stud-
ies in four continents. Lancet. 2016;388(10046):776–86.
tionary and ecological theory – has been rudimentary. Such 5. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H,
theory can provide a powerful framework for identifying et al. A comparative risk assessment of burden of disease and injury
pivotal systems components and interactions, and in this way attributable to 67 risk factors and risk factor clusters in 21 regions,
direct and simplify the task, in much the same way that aero- 1990–2010: a systematic analysis for the Global Burden of Disease
dynamics theory can help to direct aviation research. Ecology Study 2010. Lancet. 2012;380(9859):2224–60.
6. Dangour AD, Mace G, Shankar B.  Food systems, nutrition, health
and evolution also provide a broad comparative perspective, and the environment. Lancet Planet Health. 2017;1:e8.
which helps to identify patterns and generalities across a 7. Network AS. Food systems, nutrition, health and the environment.
wide range of species and environments and, in this way, https://www.­aviation-safety.­net/statistics/, downloaded March 30
enrich the understanding of human-environment interac- 2017.
tions. Nutritional ecology is the branch of the natural sci- 8. Hummel E, Hoffmann I. Complexity of nutritional behavior: captur-
ing and depicting its interrelated factors in a cause-effect model.
ences that applies this approach in the context of nutrition. Ecol Food Nutr. 2016;55:241–57.
As an example, we have shown how biological theory 9. Bennett BJ, Hall KD, Hu FB, McCartney AL, Roberto C. Nutrition and
predicts that separate appetites would exist for particular the science of disease prevention: a systems approach to support
nutrients and that these appetites would interact to broker metabolic health. Ann N Y Acad Sci. 2015;1352:1–12.
beneficial outcomes across the range of varied food envi- 10. Allison DB, Bassaganya-Riera J, Burlingame B, Brown AW, le Coutre J,
Dickson SL, et al. Goals in nutrition science 2015-2020. Front Nutr.
ronments within which they evolved. We introduced nutri- 2015;2:26.
tional geometry as an approach for investigating appetite 11. Tapsell LC, Neale EP, Satija A, Hu FB.  Foods, nutrients, and dietary
interactions and examining how they are linked to broader patterns: interconnections and implications for dietary ­guidelines.
aspects of human biology and industrialized food environ- Adv Nutr. 2016;7(3):445–54.
ments. Our analysis suggests, somewhat counter-intui- 12. Raubenheimer D, Simpson SJ.  Nutritional ecology and human

health. Annu Rev Nutr. 2016;36:603–26.
tively, that the human propensity to overeat fats and 13. Gussow JD.  The feeding web: issues in nutritional ecology. Palo
carbohydrates is closely linked to our appetite for protein, Alto: Bull Publishing Company; 1978. p. 457.
via protein leverage. This, in turn, suggests a different focus 14. Leitzmann C.  Nutrition ecology: the contribution of vegetarian
for examining the causes of obesity, through drawing atten- diets. Am J Clin Nutr. 2003;78(3):657S–9S.
tion to the factors that influence dietary protein density. 15. Leitzmann C, Cannon G. Dimensions, domains and principles of the
new nutrition science. Public Health Nutr. 2005;8(6A):787–94.
Our analysis also cautions against the common tendency to 16. Schneider K, Hoffmann I. Nutrition ecology - a concept for systemic
assume that if “too little is bad, a lot must be good,” by high- nutrition research and integrative problem solving. Ecol Food Nutr.
lighting the dangers both of diets with too low and too high 2011;50(1):1–17.
protein energy density. It emphasizes the importance of 17. Raubenheimer D, Machovsky-Capuska GE, Gosby AK, Simpson

dietary balance. S. Nutritional ecology of obesity: from humans to companion ani-
mals. Brit J Nutr. 2014;113:S26–39.
In closing, we emphasize that our main goal is not to sug- 18. Schneider HA. Ecological ectocrines in experimental epidemiology.
gest that we have solved the problem of energy overconsump- A new class, the “pacifarins”, is delineated in the nutritional ecology
tion, obesity, and related diseases, but rather to introduce a of mouse salmonellosis. Science. 1967;158(3801):597–603.
biologically inspired approach that can help to structure 19. Beisel WR.  History of nutritional immunology  - introduction and
nutrition research. Beyond the macronutrients and their dif- overview. J Nutr. 1992;122(3):591–6.
20. Raubenheimer D, Simpson SJ, Mayntz D.  Nutrition, ecology and
ferent types and constituents, other dietary components such nutritional ecology: toward an integrated framework. Funct Ecol.
as fiber and micronutrients clearly are relevant to the prob- 2009;23(1):4–16.
lem, and likewise, many nutrient combinations are impor- 21. Misra SD.  Nutritional ecology of the clear-winged grasshopper,
tant for various other aspects of health. We suggest, however, Camnula pellucida (Scudder) (Orthoptera, Acrididae). Mem Indian
that these relationships are best examined in a framework Mus. 1962;14(3):87–172.
22. von Goldschmidt-Rothschild B, Lüps P. Nutritional ecology of “wild”
that is guided by biological theory and which examines the domestic cats (Felis silvestris f. catus L.) in the Canton of Bern (Swit-
interactions among nutrients rather than considering them zerland). Rev Suisse Zool. 1976;83(3):723–35.
separately. 23. Stanley Price MR.  The nutritional ecology of coke’s hartebeest

(Alcelaphus buselaphus cokei) in Kenya. J Appl Ecol. 1978;154(1):
33–49.
24. Scriber JM, Slansky F. The nutritional ecology of immature insects.
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 57 5

The Radial: Integrative

and Functional MNT
Kathie M. Swift, Elizabeth Redmond, and Diana Noland

5.1 Background – 58
5.2 Overview – 58
5.3 Core of the Radial: Personalized Nutrition Care – 58
5.4 Mind, Body, Spirit, Community, and Earth – 59
5.5 DNA Strands and Microbes – 59
5.6 Food, Environment, and Lifestyle – 59
5.7 Nutrition Physical Exam and Signs and Symptoms – 60
5.8 Biomarkers – 61
5.9 Laboratory Testing – 61
5.10 Metabolic Pathways and Networks – 64
5.11 Systems – 66
5.12 Gastrointestinal System – 67
5.13 Immune System: Defense and Repair – 67
5.14 Cardiovascular System: Cardiometabolic Comorbidities – 67
5.15 Endocrine System: Hormonal Health Influences – 67
5.16 Respiratory System: Lung and Sinus Illness – 67
5.17 Potential Triggers – 68
5.18 Stress – 69
5.19 Toxins and Toxicants – 69
5.20 Pathogens (See 7 Chap. 21) – 69
 

5.21 Food Allergies and Intolerances – 70

5.22 Conclusion – 70
References – 70
© Springer Nature Switzerland AG 2020
D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_5
 58 K. M. Swift et al.

5.1  Background dietitian or nutrition professional” [2]. The counseling com-

ponent of MNT has been described as a “supportive process
to set priorities, establish goals and create individualized
Radial (rā′dē-əl) action plans which acknowledge and foster responsibility for
radiates from or converges to a common center. self-care” [3]. The circular architecture of the Radial depicts a
American Heritage Medical Dictionary, 2007 person-centered process that allows for the evaluation of
complex interactions and interrelationships. The Radial pur-
posefully integrates the evidence-based Nutrition Care
As the field of integrative and functional nutrition took root, Process (NCP) for clinicians to apply an integrative and func-
a concrete model to help practitioners gain a deep under- tional methodology to provide high-quality nutrition care.
standing of this approach was needed. The ability to connect,
5 synthesize, and apply information coherently using an inte-
The radial is the core, five sphere, and four potential triggers.
The five primary spheres of influence in the Radial are as
grated, whole systems-based lens to nutrition care led to the follows:
development of the Integrative and Functional Medical 55 Food, lifestyle, and environment
Nutrition Therapy (IFMNT) Radial [1]. Recent updates to 55 Nutrition physical, signs, and systems
the IFMNT Radial (referred to as the Radial) were based on 55 Biomarkers
emerging data on nutritional science, systems biology medi- 55 Metabolic pathways and networks
cine, omics technologies, and the microbiome. 55 Systems (. Fig. 5.1)
 

5.2  Overview 5.3  Core of the Radial: Personalized

Nutrition Care
The Radial is a conceptual framework for critical thinking
and clinical investigation that graphically depicts the multi-­ Personalized nutrition care highlighting the NCP is featured at
dimensional facets of a systems-based nutrition assessment the core of the Radial. It is centrally positioned and shows the
in delivering medical nutrition therapy (MNT). The term four distinct, interrelated NCP steps including nutrition
medical nutrition therapy is defined as “nutritional diagnos- assessment, diagnosis, intervention, and monitoring/evalua-
tic, therapy, and counseling services for the purpose of dis- tion. Applying the NCP ensures that nutrition care is individu-
ease management, which are furnished by a registered alized and holistic using the highest quality information

..      Fig. 5.1  The Radial. (Courtesy

of Kathie Madonna Swift, Diana
Noland, Elizabeth Redmond)
The Radial: Integrative and Functional MNT
59 5
available to the clinician providing the service. A more detailed inflammation, oxidative stress, digestive and detoxification
description of the NCP can be explored elsewhere [4]. disturbances, metabolic chaos, neuro-endocrine-immune
A holistic approach to nutrition care embraces the assim- disruption, and nutritional depletion.
ilation of multiple components that influence one’s well-­
being. Health is viewed as a dynamic quality where mind,
body, and spirit are engaged in the fullness of life [5]. 5.6  Food, Environment, and Lifestyle

Food is the ideal starting point in an IFMNT assessment

5.4  Mind, Body, Spirit, Community, since it is a powerful determining factor in health and dis-
and Earth ease. Hippocrates is credited with the “food as medicine”
philosophy, although scholars debate the origin of this theme
The Radial core illustrates the intermingling of mind, body, since nutrition has been a central premise in ancient, tradi-
spirit, community, and earth and its association with person- tional forms of medicine [9, 10]. A modern, integrated con-
alized nutrition care, since all of these factors influence one’s cept of food as medicine emphasizes scientific understanding
health and healing. Mind, body, and spirit are viewed as of nutrition with lifestyle behaviors in relation to a person’s
wholeness versus distinct and separate physiological, psycho- ability to realize vital goals of healthy living. Food is valued as
logical, and spiritual units. The value of community and social an instrument for vibrant health and an essential tool to
networks as a component of health and wellness must be con- kindle healing by restoring nutritional integrity.
sidered since social contexts influence biological systems [6]. Changes in the human diet and food systems have altered
An appreciation of our intimate connection to the earth and crucial nutritional attributes that impact biological systems
the healing power of nature to foster one’s health is also valued including glycemic and insulinogenic load, carbohydrate
as an integrative concept of food and sustainable nutrition. quality, fiber content, fatty acid composition, macronutrient
balance, micronutrient density, phytonutrient richness,
sodium-potassium ratio, and acid-base balance [11]. A
5.5  DNA Strands and Microbes theme of healthful eating that considers these nutritional fac-
tors has been described with the strength of evidence sup-
The sequencing of the human genome and growing knowl- porting a plant-based diet with foods close to nature [12].
edge regarding genetic variation and biotechnological omics Other elements of diverse diets and healthy dietary patterns
advances is contributing to the development of personalized include limited refined starches, added sugars including
nutrition. The Radial depicts genetic influence by the strands fructose, avoidance of ultra-processed foods, and limited
of DNA that surround the core. Personalized nutrition is an intake of certain fats.
application of nutritional genomics and seeks to enhance Personalized nutrition extends beyond these general prin-
health through the understanding of “the functional interac- ciples of healthy eating and targets the underlying root causes
tion between bioactive food components with the genome at of system imbalances, is specific to the individual’s unique
the molecular, cellular, and systemic level in order to under- nutrient requirements, and is designed with biological com-
stand the role of nutrients in gene expression and… how diet patibility and lifestyle in mind [13]. It seeks to understand
can be used to prevent or treat disease” [7]. Diversity in the how diet and lifestyle-related modulators act together and co-
genetic profile among individuals impacts nutrient require- conspire to create the perfect storm of complex, chronic dis-
ments, metabolism, and response to dietary, nutritional, and ease. For example, personalized nutrition recognizes that
lifestyle interventions [8]. following general nutrition guidelines may result in high gly-
The microbiome revolution has established that micro- cemic responses in some individuals, accelerating metabolic
bial signatures vary between individuals far more than genet- decline and that there can be unique dietary responses
ics [9]. Dietary habits and lifestyle affect the gut microbiota because of biochemical uniqueness. Thus, consideration of
composition in dramatic ways. This vital influence must be personal variables including sex, age, genetics, biomarkers,
taken into account and is represented by the microbes in the lifestyle, and environmental factors must be taken into
graphic that, like the DNA strands, radiate to all five spheres account in tailoring a personalized nutrition prescription
of the Radial. The composition of the microbiome and its [14]. Food intolerances such as gluten, fructose, FODMAPs,
diverse activities are involved in most, if not all, of the bio- food chemicals, and histamine are other examples of the
logical processes, and thus, it is a key player in health and dietary discord that can impact the health of some individuals
disease at all stages of the life cycle [9]. while not affecting others. The age-old saying, “one person’s
The concept of “food as information” influencing genetic meat is another person’s poison,” is now viewed in light of the
expression, manipulating the microbiome and, consequently, scientific revelation that the multi-tasking, metabolically
supporting or hijacking the patient’s physiological systems is active microbes play a significant role in the unique interpre-
cardinal to the integrative and functional model. The Systems tation by the body of food as friend or foe [15].
sphere radiates from the core of the Radial and underscores To be effective, personalized nutrition care must integrate
the imbalances that are created by poor diet, unhealthy life- the scientific approach with cultural, emotional, ethical, spir-
style behaviors, and environmental exposures such as chronic itual, social, and sensual understandings of food [16]. The
 60 K. M. Swift et al.

science of nutrition and the art of dietary behavior change are physical exam (NPE). Universally, basic anthropometrics are
indispensable partners in personalized nutrition care that is measured: blood pressure, height, weight, and calculating
relational in nature. The heart of nutrition assessment lies in BMI.  For the IFMNT approach, the NPE can be expanded
a therapeutic relationship that values the patient’s story (see with tools that add more detailed information for assessing
7 Chap. 39). This means that the nutrition professional is able
  the nutritional and body composition status. These tool
to listen reflectively to the patient’s narrative, absorb what the options to consider collecting nutrition data are:
person is sharing, and understand their concerns. It must go 55 Tape measure: measures waist circumference
beyond root-cause analysis of medical history, anthropomet- 55 Bioelectric impedance analysis (BIA) (full body):
rics, symptomatology, testing, and other metrics and focus on measures several parameters described in 7 Chap. 22 on
 

the patient’s humanity and their desire to shape their well- Body Composition. One of the measurements most
5 being. This requires skills and competencies in addressing
health behaviors and engaging the patient in self-care man-
commonly appreciated is percentage of body fat/lean
mass and BMI.
agement of mind, body, and spirit. It implies attention of the 55 Fingertip Pulse Oximeter Blood Oxygen Saturation
patient on their personal health goals, increased self-aware- Monitor: measures oxygen saturation and pulse rate
ness, and commitment on ways to achieve and maintain opti- 55 Oral/axillary thermometer: measures body temperature
mal health. Shared decision-­making by both the clinician and 55 Calipers: measures body fat
patient is essential in the design of a nutrition intervention
plan that is truly personalized, actionable, practical, sustain- Signs and symptoms can be documented by patient ques-
able, and, ultimately, successful. tionnaires completed prior to the client visit, or upon arrival
Integrative health questionnaires can assist the clinician at the appointment. The medical symptoms questionnaire
in the personalized nutrition care process. Supportive tools (MSQ) commonly used in integrative and functional medi-
include food records, activity journals, circadian patterns, cine practice measures symptoms based on systems biology,
timeline of significant medical events, medication and dietary according to body systems. The practitioner’s assessment of
supplement lists, symptom appraisal forms, nutrition-­focused the questionnaire can be done quickly to easily see where the
physical findings, and biomarker results from both conven- system priorities are to consider for diagnosis and interven-
tional and functional laboratory testing. Individual health tion for the client. The systems and related symptoms often
risks of diet, physical activity, substance abuse, excess stress, included on the questionnaire are:
sleep deprivation, environmental toxins, pathogens, food 55 HEAD: headache, faintness, dizziness, insomnia
allergens, and intolerances must also be unearthed. Open- 55 EYES: Watery or itchy eyes; swollen, reddened/sticky
ended questions can reveal aspects of the patient’s story that eyelids; bags, dark circles; blurred or tunnel vision (does
may not have been revealed in specific data collection tools not include near or far-sightedness)
and techniques. These questions can help the clinician and 55 EARS: Itchy ears; earaches, ear infections; drainage from
patient as co-investigators in uncovering unique and deeply ear; ringing/hearing loss
personal themes that affect an individual’s health: 55 NOSE: Stuffy nose, sinus problems, hay fever, sneezing
55 Did something trigger a change in your health? attacks, excessive mucus
55 What makes you feel better? 55 MOUTH/THROAT: Chronic coughing; gagging/throat
55 What makes you feel worse? clearing; sore throat, hoarseness; swollen/discolored
55 Have you made any changes in your eating habits or tongue, gums, lips; canker sores
lifestyle because of your health? 55 HEART: Irregular/skipped beats, rapid/pounding beats,
55 What do you think would make the most difference in chest pain
your health and well-being? 55 SKIN: Acne; hives, rashes, dry skin; hair loss; flushing,
55 In your own words, tell me your story… hot flashes; excessive sweating
55 LUNGS: Chest congestion; asthma, bronchitis; shortness
The personalized nutrition care process, when delivered skill- of breath; difficulty breathing
fully, engages the patient in self-care to attain their highest 55 DIGESTIVE TRACT: Nausea, vomiting; diarrhea;
health potential. A thorough understanding of how the trilogy constipation; bloated feeling; belching, passing gas;
of food, environment, and lifestyle impact physiological sys- heartburn; intestinal/stomach pain
tems must be realized for the clinician to apply this in practice 55 JOINTS/MUSCLE: Pain or aches in joints, arthritis,
and support the patient with a truly personalized care plan. stiffness/limited movement, pain or aches in muscles,
feeling of weakness or tiredness
55 WEIGHT: Binge eating/drinking, craving certain foods,
5.7  Nutrition Physical Exam and Signs excessive weight, compulsive eating, water retention,
and Symptoms underweight
55 ENERGY/ACTIVITY: Fatigue/sluggishness; apathy,
Most patient encounters begin by hearing the patient’s story lethargy; hyperactivity; restless leg; jetlag
with appropriate history taking, identifying the signs and 55 MIND: Poor memory; confusion, poor comprehension;
symptoms with which they are presenting, and the nutrition poor concentration; poor physical coordination;
The Radial: Integrative and Functional MNT
61 5
difficulty making decisions; stuttering or stammering; serum amino acids can tell more about overall amino acid
slurred speech; learning disabilities status. Additionally, whole blood lead may not be the best
55 EMOTIONS: Mood swings; anxiety, fear, nervousness; way to assess lead levels, but it is the way public health orga-
anger, irritability, aggressiveness; depression nization and researchers check lead levels, and thus if you are
55 OTHER: Frequent illness; frequent or urgent urination; evaluating lead levels, it is best to check whole blood lead so
genital itch or discharge; bone pain comparisons can be made.
55 PAST SURGERIES AND DATES: See 7 Chap. 56 for a
  Beyond specimen selection, clinicians should be aware of
sample questionnaire. reference ranges and how they are set. While some biomark-
ers have medical decision points identifying what each level
means, such as levels of A1C, other markers do not have a
5.8  Biomarkers standard accepted reference range or decision point. For
many markers, the reference range is represented by what has
Nutrition-related biomarkers are biological indicators. While been noted within a “normal” population. A patient is con-
a nutrition assessment is essential to assess what nutrients the sidered abnormal if they are more than 2 standard deviations
diet is providing, an evaluation of biomarkers may provide a (>95.4%) from the mean within the population utilized to set
more detailed picture of what the client is actually digesting, the reference range. Researchers may correlate values with
absorbing, and utilizing. Diet assessments may not always disease status, but if comparisons are made to research stud-
coordinate with laboratory values of individual nutrients. ies, the laboratory technique and reference range population
This may be due to many factors, such as an individual hav- must be compared. For example, elevated alpha-­
ing a greater need for a nutrient than the RDA, poor-quality hydroxybutyrate has been associated with insulin resistance,
food or supplements, a genetic variation, impaired absorp- but the specific level is not established.
tion, exposure to a specific toxin whose detoxification Integrative and functional clinicians look at several areas
requires specific nutrients, etc. of laboratory assessments, including metabolism, inflamma-
tion and immune reactions, nutrition, nutrigenomics, diges-
tion and absorption, biotransformation, etc.
5.9  Laboratory Testing Metabolism: Metabolism includes energy metabolism
and metabolomics. Metabolomics accesses metabolite pro-
Most clinicians are familiar with conventional laboratory files to detect which biomarkers or biomarker patterns are
testing of standard markers. In addition to conventional lab associated with a disease in the hope of better defining a spe-
testing, integrative and functional clinicians also often utilize cific metabolic profile for each condition or disease. It has
specialty diagnostic laboratories, which are often early adopt- also been referred to as the specific metabolic “fingerprint”
ers of new testing. Functional medicine was an early adopter that is unique to each person and disease. In other words,
of the concept of utilizing organic acid measurements for metabolomics takes into account the impact of lifestyle fac-
assessment of biochemical pathways and metabolomics. tors like diet, movement, and the environment to illustrate
Functional medicine clinicians also incorporate a systems-­ overall health.
based interpretation of standard laboratory tests. Inflammation: Evaluation of inflammation can identify
There are two primary types of laboratory tests: indirect systemic inflammation, such as hsCRP, or it can be site-­
(also referred to as functional) or direct. specific, such as fecal calprotectin to evaluate gastrointestinal
A functional test is an evaluation of an analyte that is inflammation. Different specimen types can identify the type
dependent on the marker. For example, levels of methyl- of inflammation, lipid peroxides identify fatty acid mem-
malonic acid (MMA) measure functional need for vita- brane oxidation, and 8-hydroxy-2-deoxyguanosine evaluates
min B12. Vitamin B12 is a nutrient cofactor needed for oxidative damage to DNA.  Oxidative stress and inflamma-
the enzyme methylmalonyl-CoA mutase. It breaks down tion are key markers of nutrient deficiencies [18]. Nutrients
L-­methylmalonyl-CoA to succinyl-CoA, which then goes are the substrates for many immune reactions, such as fatty
into the Krebs cycle. If vitamin B12 is not available in ade- acids and immune cytokines. Nutrients can also modulate
quate amounts, the pathway will stall and MMA will build the immune system, for example, antioxidants tempering
up. Thus, elevated MMA levels in both urine and blood have immune responses to inflammation. While classic inflamma-
been correlated to vitamin B12 deficiency [17]. tion is short term, chronic “metaflammation” is a low-level
Direct laboratory testing identifies levels that are actually long-term inflammation that is associated with inflammation-­
there, such as serum 25-hydroxy vitamin D.  Though there related diseases. Chronic inflammation differs because there
has been significant disagreement on the “ideal” vitamin D is only a small rise in immune markers (i.e., a four- to sixfold
level, as the level needed for an individual may vary increase versus a several hundred-fold increase seen in acute
significantly, there is strong consensus on the specimen reactions) which can lead to systemic effects and is associated
­
selection of serum 25-hydroxy vitamin D. with a reduced metabolic rate [19].
Specimen selection should generally be based on what Testing can also identify the immune system’s reaction to
literature has identified. For example, urine amino acids can components in foods, such as proteins, toxins, and other bio-
identify what a person has eaten over the last few days, while active components. Functional medicine evaluates a patient’s
 62 K. M. Swift et al.

..      Table 5.1  Micronutrient laboratory assessment

Minerals IOM assessment [22–24] Possible functional or other testing options

Magnesium A serum magnesium concentration of less Serum/plasma magnesium concentration, red blood cell (RBC) mag-
than 0.75 mmol/liter (1.8 mg/dl) is thought nesium concentration, and urinary magnesium excretion appear to be
to indicate magnesium depletion. useful biomarkers of magnesium status in the general population [25].

Zinc Factorial analysis was used to set the Esti- Physical growth response to zinc supplementation [24].
mated Average Requirement (EAR). While both plasma and serum zinc concentrations are used as indicators
of zinc status, plasma zinc concentration is preferable because of the lack
of contamination of zinc from the erythrocyte [26].
5 Copper The primary criterion used to estimate Low serum copper. Serum copper and ceruloplasmin levels may fall 30%
the EAR for copper is a combination of in deficiency [27].
indicators, including plasma copper and An elevated homovanillate/vanilmandelate has been reported to identify
ceruloplasmin concentrations, erythrocyte copper need since the conversion of dihydroxyphenylalanine (DOPA) to
superoxide dismutase activity, and platelet epinephrine requires copper, though research is limited. Homovanillate
copper concentration in controlled human is the breakdown product of DOPA and vanilmandelate is the breakdown
depletion/repletion studies. product of epinephrine and nor-epinephrine. The ratio has been used as
a screening for Menkes [28].

Vitamins IOM assessment Possible functional or other testing options

Vitamin K Due to insufficient laboratory values to A direct measure of vitamin K is not of value as both serum and plasma
estimate levels, an Adequate Intake (AI) was phylloquinone reflect recent intakes (24 hours) and do not responds to
set based on representative dietary intake changes in dietary intake [24].
data from healthy individuals. Carboxylated Gla (Gla) or undercarboxylated osteocalcin (uc-OC) may be
used. A deficiency of vitamin K upregulates the level of serum under-
carboxylated osteocalcin (ucOC), and serum ucOC has been found to
correlate with fracture risk [29].

Folate The primary indicator used to estimate the Serum folate, without a concurrent vitamin B12 deficiency, is a useful
RDA for folate is erythrocyte (RBC) folate in biomarker for folate deficiency [30].
conjunction with plasma homocysteine and Formiminoglutamic acid (FIGLU) is an intermediate metabolite in
folate concentrations. L-histidine catabolism in the conversion of L-histidine to L-glutamic
acid. It may be an indicator of vitamin B12, folic acid deficiency, or liver
disease [31].
  Measurement of urinary FIGLU excretion after a histidine load has been
used as a marker of folate in those with adequate B12 levels [32].

B3 Niacin The most reliable and sensitive measures of An increase in urinary excretion of kynurenic acid and a decreased in
niacin status, also used to set the RDA, was quinolinic acid were found in pellagra that was corrected with niacin
urinary excretion of the two major methyl- supplementation [33].
ated metabolites, N1-methyl-nicotinamide Urinary branched chain keto acids (organic acids) positively identified
and its 2-pyridone derivative (N1-methyl- subjects with B vitamin-complex deficiency; those with the highest level
2-pyridone-5-carboxamide). of urine branched chain amino acids (BCAA) were more likely to be B
vitamin deficiency [34].

reaction to foods or environment. By definition, IgE reac- Nutrition: As noted, personalized nutrition is specific to
tions are true allergic reactions, while other reactions are the individual’s unique nutrient requirements. . Table  5.1  

food intolerances or sensitivities, measured with immuno- identifies examples of both laboratory markers used by the
globulins (IgG) or white cells, and have significantly less lit- IOM in setting recommended levels, and functional or other
erature support. IgG testing (ELISA) includes IgG1, IgG2, testing options. Though there is often controversy with the
IgG3, and IgG4. IgG testing is controversial, as limited evi- specific tests selected by the IOM, it is important to know the
dence from peer-reviewed research has found correlations technique and specimen used, and how other testing options
with migraines and IBS [20]. Some researchers believe IgG is compare to it.
identifying exposure, since “healthy” people can have ele- 55 Micronutrients are common enzyme cofactors.
vated levels. Leukocyte testing includes both the mediator Identifying inadequate levels of individual micronutri-
release and the leucocyte activation test. Though both evalu- ents may also identify possible blocks in biochemical
ate changes in white blood cells, they are different processes. pathways (. Table 5.2).
 

Both are also controversial with limited peer-reviewed litera-

ture, though, like IgG, many clinicians claim to find them Nutrigenomics: Nutrigenomics is the study of the interaction
helpful in clinical practice [21]. of nutrition and genes and has been shown to personalize
The Radial: Integrative and Functional MNT
63 5

..      Table 5.2  Functional nutrition approach to macronutrients

Protein Functional assessment goes beyond total protein evaluation and identifies individual amino acids and types of
protein (plant or animal). Plasma assessment of individual amino acids helps to identify overall level of protein
intake and processing. Plasma identifies longer term status and use. Urine identifies intake in the last 24 hours and
some metabolic issues. Both plasma and urine assessments are best done in a stable dietary intake. Blood amino
acids can be measured with a blood draw or from a finger stick.

Fat Functional assessment goes beyond evaluating standard blood lipids such as TAG, LDL, and HDL and includes
individual fatty acids, such as the polyunsaturated fats omega-3 and omega-6, as well as monounsaturated fats and
saturated fats. Specimen types include whole blood, plasma, or RBC and are available in blood draw or finger stick.
Fatty acids are measured as a percentage of total or as a concentration, and direct comparisons should not be made.
Further, the different methods of expressing fatty acids can lead to dissimilar correlations between blood lipids and
certain fatty acids [35].
Evaluation of fatty acids of varying carbon chain length and degree of saturation can help to identify dietary intake
and have been noted as biomarkers of various conditions. A review of individual fatty acids helps to evaluate
function of desaturase and elongase enzymes, which can impact treatment. For example, the conversion of
alpha-linolenic acid (ALA) to eicosapentaenoic acid (EPA) is not always efficient and supplementation with flax, high
in ALA, may not result in expected increases in EPA. Testing would aid in identifying those who are not making the
conversion.

Carbohydrates Conventional assessment of carbohydrates is generally the assessment of the body’s blood sugar response and
includes glucose and A1c. Functional medicine also evaluates additional early markers of biochemical disruption
using metabolomics, such as identifying alpha-hydroxybutyrate or impaired plasma levels of branched-chain amino
acids, which may identify risk of T2D and CVD [36]. The composition of the microbiome can also identify the impact
of carbohydrate and fiber intake. Plant-focused diets high in fiber are associated with greater microbial diversity and
higher levels of Prevotella over Bacteroides. Low levels of SCFAs (acetate, propionate, butyrate) in stool can identify
poor carbohydrate (fiber) intake or inadequate gut bacterial function [37]. Additionally, high-protein diets can
increase the level of bacterial products of protein breakdown, including the short-chain proteolytic fatty acids,
valerate, iso-butyrate, and iso-valerate [38, 39].

For comparison, the IOM Recommended Dietary Intake (RDI) for macronutrients in adults is 45–65% of their calories from carbohydrates,
20–35% from fat, and 10–35% from protein [40]

treatment. Test profiles are often buccal swabs and packaged samples, though breath tests can also identify levels of some
to evaluate a specific area such as weight loss, immune func- gut bacteria. The microbiome is a primary player in the
tion, nutrient absorption, etc. Previously, the US Food and immune system and is heavily impacted by diet, lifestyle, and
Drug Administration raised concerns about the validity of environment. There are many culture-independent tech-
the information and the potential for inappropriate medical niques in use, such as fluorescent in situ hybridization
actions, highlighting the need for practitioners to be aware of (FISH), polymerase chain reaction (PCR), next- and third-­
the literature of individual single nucleotide polymorphisms generation sequencing, etc. While each technique is valid,
(SNPs) [41]. the results are not comparable. Even laboratories that do the
Digestion and Absorption: Functional assessment of same stated process such as PCR assessment are generally not
digestion and absorption includes tests related to the gastro- comparable due to a lack of standardization. Evaluation of
intestinal tract and its function. Assessment of a patient’s microbiome levels with disease associations or conditions
digestion and absorption can be assessed in a variety of tests. needs to be done using comparable testing.
Two examples are pancreatic elastase 1 (PE1) and fecal fats. Intestinal permeability is another concern that functional
PE1 is a proteolytic enzyme that identifies the function of the clinicians evaluate in a full assessment. The intestine is lined
exocrine pancreas (not to be confused with the endocrine with a single layer of epithelial cells held together with tight
pancreas). The exocrine pancreas produces 3 types of junctions (TJ), which coordinate exchange between lumen
enzymes: amylase, protease, lipase. If it is impaired, digestion and tissues. Disruption of the intestinal barrier impairs func-
may be impaired. Exocrine pancreatic insufficiency is identi- tion and may increase the risk of specific disease. Zonulin is
fied with an elastase level < 200 μg/g stool [42]. Fecal fats are a physiologic modulator of intercellular intestinal tight junc-
used to evaluate fat malabsorption. The gold standard for fat tions. An increase in zonulin has been proposed to identify a
malabsorption is a 3-day quantitative determination of fecal “leaky gut” and has been related to autoimmune disease,
fat. It is cumbersome and takes significant dietary prepara- metabolic disorders, heart disease, and intestinal disease
tion, so a single fecal assessment is often done as an initial such as IBS, IBD, and non-celiac gluten [44, 45]. Unfortunately,
evaluation [43]. zonulin has been difficult to test accurately in commercially
Assessment of gut bacteria or the microbiome can aid available tests [46].
clinicians understanding of the impact of individual bacteria Detoxification (also known as biotransformation):
and overall diversity. Assessment is generally done with fecal Biotransformation refers to the process of transforming tox-
 64 K. M. Swift et al.

ins, hormones, etc. through the phases of detoxification. and symptoms, anthropometrics, diet assessment, and labo-
Functional clinicians can support the process by ensuring ratory evaluations, clinicians can take the next step of identi-
adequate nutritional status of detoxification pathways and fying key pathways that could be impaired. Several examples
identifying toxin levels when needed. There is no single test are listed below, including vitamin B12 and MMA, and
to evaluate detoxification phases. Phase I is generally done breakdown of fatty acids and BCAA.
with genetic SNP testing and phase II includes status of Vitamin B12 and Methylmalonic Acid (MMA): When
amino acid substrates and nutrient co-factors. Detoxification MMA levels are elevated, it may identify a need for vitamin
is heavily reliant on enzymes, such as cytochrome P450 oxi- B12 due to inadequate intake or increased need. If diet assess-
dase enzymes (CYP450) and nutrient status. Diet can signifi- ment identifies an adequate intake, there may be increased
cantly impact the ability to detoxify because it provides both needs due to other factors, such as decreased stomach acid or
5 needed nutrients and is a leading contributor of body toxins.
Testing for the presence of toxins is available from several
increased methylation issues. As seen in the simplified dia-
gram below, L-methylmalonyl-CoA (substrate) is converted
laboratories. The ability to compare toxin levels to popula- to succinyl-CoA (product) via the enzyme methylmalonyl-­
tion data, such as NHANES, allows clinicians to compare cli- CoA mutase. The enzyme requires a nutrient-cofactor, ade-
ent’s levels to the general population. nosylcobalamin (vitamin B12). If the enzyme function is
decreased, the L-methylmalonyl-CoA will build up and be
excreted as MMA. The enzyme may have decreased function
5.10  Metabolic Pathways and Networks due to a genetic SNP or decreased levels of its nutrient cofac-
tor, vitamin B12. As with most pathways, it is important to
Understanding biochemical pathways and how they function know that there are additional related pathways that can also
is essential in functional medicine. Biomarkers are not just be impacted. For example, converting homocysteine to
levels of individual analytes; they include markers of status methionine (methylation) may also be increased with a need
and pathway function. Individual nutrients often work as for B12 (. Fig. 5.2).
 

nutrient cofactors, and can impact the ability of a pathway to

flow smoothly. In order to fully evaluate a patient’s biochem- Fatty Acid Breakdown  Eicosanoids are signaling molecules
ical status, clinicians must know the key pathways and net- that result in a range of processes generally related to immune
works, such as methylation, conjugation, nutrient breakdown, and inflammation. They are derived from omega-3 and
urea cycle, etc., including substrates, products, enzymes, and omega-6 fatty acids, as seen in . Fig.  5.2. Diet provides the
 

cofactors. After a full evaluation of a patient’s history, signs fatty acids and nutrients support the breakdown pathways.

Propionyl-CoA
Methylmalonyl-CoA
Mutase
Krebs
L-Methylmalonyl-CoA Succinyl-CoA Cycle
AdoCbl
(adenosylcobalamin)

Methylmalonic aciduria
Cobalamin
(Vitamin B12)

MeCbl
(methylcobalamine)
Homocysteine + MTHF Methionine + THF

Methionine
Synthase

Homocystinuria

..      Fig. 5.2  Methylmalonic acid (MMA) pathway. (Courtesy of E. Redmond, PhD, RDN)
The Radial: Integrative and Functional MNT
65 5

Eicosanoids
Omega-3 family pg = prostaglandin tx = thromboxane Omega-6 family
pgi = prostacyclin It = leukotriene
a-linolenic acid = anti-inflammatory linoleic acid Corn, soybean,
Flax, soybeen, 18:3 ω-3 = more inflammatory 18:2 ω-6 sunflower, safflower
canola, walnut
D6 desaturase
Cofactors: vitamin, B2, B6, C, Mg; Enhanced
activity with insulin
Hemp, algae, stearidonic acid Y-linolenic acid Evening primrose Oil,
GMO-soy oil 18:4 ω-3 GLA 18:3 ω-6 borage oil
elongase
Cofactors: vitamin B3, B5, B6, C, and Biotin
eicosatetraenoic acid pge1 pgf1α dihomo y-linolenic acid
20:4 ω-3 txa1 DGLA 20:3 ω-6
blocks It4
D5 desaturase
pgd3 pge3 pgf3α pgd2 pge2 pgf2α
Fish, Krill, eicosapentaenoic acid pgi3 txa3 pgi2 txa2 Ita4 Itb4 arachidonic acid Meat, eggs,
main
seaweed EPA 20:5 ω-3 Ita5 ltb5 Itc5 ltd5 Itc4 ltd4 Ite4 AA 20:4 ω-6 dairy
Sprecher’s elongase
Shunt
docosapentaenoic acid docosatetraenoic acid
DPA 20:5 ω-3 22:4 ω-6
D4 desaturase
Fish, Krill,
docosahexaenoic acid docosapentaenoic acid
algae
DHA 22:6 ω-3 22:5 ω-6

..      Fig. 5.3  Eicosanoid pathway [47]. (Adapted with permission from: 7 https://commons.­wikimedia.­org/wiki/File:EFA_to_Eicosanoids.­svg)
 

Altered fatty acids have been associated with several metabolic are broken down to their keto-acids with transaminase
diseases, including diabetes, metabolic syndrome, hyperten- enzymes and the nutrient cofactor vitamin B6. If vitamin
sion, alcohol, radiation exposure, and others. The eicosanoid B6 is not in adequate supplies, the BCAA amino acids may
pathway is heavily reliant on elongase and desaturase enzymes, build up. The next step utilizes a dehydrogenase enzyme
which are dependent on adequate nutrient cofactors. Though a and its required nutrient cofactors, vitamins B1, B2, B3, B5,
conclusive list has not been developed the following are and lipoic acid (LA), which then flow into the Krebs cycle
thought to play a role in desaturase and elongase enzyme func- in the mitochondria. Identification of elevated keto-acids
tion, vitamins B2, B3, B5, B6, C, and biotin, and minerals zinc may signal a need for B-complex vitamins [34]. Thus, an
and magnesium. Additionally insulin is believed to impact impairment in the BCAA process has been proposed to
function [48–50] (. Fig. 5.3).
  impair basic mitochondrial function. Research has found
Furthermore, evaluations of specific monounsaturated that levels of BCAAs were higher in some individuals with
and saturated fatty acids can also identify functional impair- obesity and have been associated with worse metabolic
ments. The Δ9-desaturase enzyme or stearoyl-CoA desatu- health and future insulin resistance or type 2 diabetes mel-
rase (SCD) catalyzes the synthesis of monounsaturated fatty litus (T2DM). Insulin resistance may increase protein deg-
acids, primarily oleate (18:1) and palmitoleate (16:1), from radation since insulin normally suppresses it. In clients
saturated fatty acids, palmitate (16:0), and stearate (18:0). with metabolic issues, functional clinicians may evaluate
Stearic acid is correlated to cholesterol level and Δ9 may be plasma BCAAs as well as their keto acids to identify issues
impacted by insulin; thus, an evaluation may help to identify in the pathways (. Fig. 5.4 and . Table 5.3).
   

early biochemical function and possible increased risk [51, The evaluation of pathways and metabolites is continu-
52]. A decrease in insulin activity reduces the activity of ously being researched. Key resources include the following
desaturase enzymes that convert saturated to monounsatu- 55 The Scripps Center for Metabolomics: METLIN metabo-
rated fats, which can be identified by increases in blood satu- lites database 7 https://metlin.­scripps.­edu/index.­php
 

rated fat levels. 55 Expasy: omics scientific databases and tools 7 https://  

Branched-chain Amino Acids (BCAA) Breakdown: www.­expasy.­org/

Leucine, isoleucine, and valine are BCAAs. The BCAAs dif- 55 Canada’s Human Metabolome Database (HMDB) site
fer from other essential amino acids in that the liver lacks for the human metabolome markers: 7 http://www.­  

the enzymes to break them down or catabolize them. They hmdb.­ca/

 66 K. M. Swift et al.

..      Fig. 5.4  Krebs cycle.

(Courtesy of E. Redmond,
PhD, RDN) Leucine Valine Isoleucine

Branched chain amino acid transaminase (BCAT) + vitamin B6

Alpha-ketoisocaproate Alpha-ketoisovalerale Alpha-keto-beta-methylvalerate

5 Branched Chain keto-acid dehydrogenase (BCKDH) + vitamins B1, B2, B3, B5, LA

Krebs
Cycle

..      Table 5.3  Branched-chain amino acids (BCAA)

BCAA) Enzyme plus cofactors BCAA keto-acid Enzyme plus cofactors

Valine BCAA transaminase + vitamin B6 Alpha-ketoisovalerate Branched-chain keto-acid dehydrogenase +

B1, B2, B3, B5, LA
Leucine Alpha-ketoisocaproate

Isoleucine Alpha-keto-beta-methylvalerate

5.11  Systems Thirdly, simplicity reflects the application of systems biol-

ogy to manage the complexity of metabolism to create man-
The foundation of integrative and functional medicine is sys- ageable healthcare procedures that can be applied clinically.
tems biology [53]. There is a broad consensus as to the defini- Simplicity refers to prioritizing the systems that most impact
tion of systems biology. The biological systems described in the individual. Once systems of concern are ranked in impor-
IFMNT recognize that the whole human organism is com- tance, they enable a realistic analysis of “root” causes of a
prised of systems working together contributing to total chronic disease condition. Prioritizing and simplifying sys-
function. The systems included in assessment of the whole tems that need modulation increases the possibility of suc-
patient story are those where disease can be promoted with cessful outcomes for such patients. Prioritized systems
the individual’s identified pathophysiological symptoms and require practitioner skills in modulating the systems’ bio-
imbalances. In systems biology, of three primary principles, chemical networks, especially in the use of nutrients as cofac-
the first is diversity, where there is the appreciation of the tors and structural components. This knowledge is
complex molecular and genetic uniqueness of each individ- foundational for simplifying the development of effective
ual. The depth of grasping uniqueness has been enhanced interventions addressing “root causes” with food, dietary
with the discovery and identification of the human genome. supplementation, and lifestyle education. This knowledge
The second key characteristic of systems biology is the rec- depends on the principle that one disease can have multiple
ognition of the complexity of biological systems and the per- influences, with nutrient cofactors being primary when
turbations of those systems that can promote disease. In searching for “root causes.”
contrast to the reductionist medical acute-care model of Chronic diseases are diet- and lifestyle-related with the
quickly finding the diagnosis and applying a standard of care, influence of an individual’s unique genotype. Thirty years
a systems biology-based medicine and medical nutrition ther- ago, the Institute for Functional Medicine (IFM) was the first
apy applies a whole-systems approach to identification of “root to provide a framework, “The IFM Matrix,” for how to har-
causes” that is a better fit to treatment of chronic diseases. ness the complexity of chronic diseases into a manageable
The Radial: Integrative and Functional MNT
67 5
clinical tool that simplifies primary priorities needing meta- using the tools of nutrition physical exam, laboratory bio-
bolic correction (see 7 Chaps. 7 and 47). Later, IFMNT prac-
  markers of inflammation like C-reactive-protein-high sensi-
titioners implemented the conceptual diagram, The Radial tivity, sedimentation rate, differential with hearing the
(see . Fig.  5.1), to target the nutrition component in the
  patient’s history, and diagnosis/symptoms. Dietary history
practice of patient care. For a systems biology approach to be can reveal a diet of pro-inflammatory character that can be
effective, the uniqueness of each individual becomes “patient-­ modulated to improve the immune response for the individ-
centered care” [54], using tools like the Radial to “extract ual. Recent recognition of genomic polymorphisms that may
simplicity out of chaos” [53]. increase risk of inflammation includes people with HLA
Working knowledge of the following systems equips the DQ2 and DQ8 who have increased predisposition to celiac
IFMNT practitioner with advanced skills in “metabolic cor- disease-related inflammation (see 7 Chap. 49 Autoimmune).
 

rection” once an imbalance is identified (see 7 Chap. 7).

 

As we review the systems below, it is obvious that there is

interaction among all the systems to produce a personalized 5.14  Cardiovascular System:
phenotype, but at any time, there are usually two or three of Cardiometabolic Comorbidities
the systems raising a flag indicating dysfunction and needing
restoration back to wellness. According to the World Health Organization, heart and car-
diovascular diseases are the most common chronic diseases
worldwide. The bigger picture is the pathophysiology of the
5.12  Gastrointestinal System cardiometabolic system that underlays the trend toward the
high risk of cardio diseases for an individual.
Inflammation is foundational to the early stage develop-
»» All disease starts in the gut. –Hippocrates ment of atherosclerosis, along with contributing chronic
The gastrointestinal tract provides the largest interaction of infections, pro-inflammatory dietary choices, poor sleep,
the human with the environment primarily through ingested endocrine-disrupting chemical toxins, etc. Nutritional and
food, water, and beneficial fermented bacteria to promote a lifestyle interventions provide powerful change agents to
healthy gut ecology. The gut houses more than 70% of the modulate the cardiovascular system.
immune system in its lymphoid tissues. It is also the secretor
of many neurotransmitters and other life-giving metabolites
like the short-chain fatty acid butyric acid, the primary repair 5.15  Endocrine System: Hormonal Health
fuel for colonocytes (colon cells), which promotes increased Influences
energy and cell proliferation and may protect against colon
cancer. Key GI tract interventions are based on a whole foods The endocrine system’s response to our environment to mes-
low-antigen diet, with adequate prebiotics of soluble fiber sage cellular activity is important to consider when assessing
and fermented foods or supplemental probiotics. A common a patient. Two glands in jeopardy today are the adrenal and
thoughtful functional medicine approach to gut restoration pancreatic glands. The adrenal gland responds to stress and
is the 5R program [55]. It begins with removing the offender – lack of quality sleep-producing cortisol (stimulatory) eleva-
whatever is in excess or an a­ ntigen for an individual; then tions. The concerns for the hormones produced by the pan-
replacing digestive secretions/enzymatic activity and fiber if creas are the influence of insulin which, when in excess, is
indicated, repletion of insufficient or deficient nutrients; involved in promoting sarcopenic obesity (loss of muscle,
next, reinoculating to restore the balance of good bacteria, gain of body fat) and metabolic syndrome. The pancreas also
pre- and probiotics, adequate hydration; repairing the gut has an important influence by secretion of the digestive
barrier that may be compromised from long-standing insults enzymes: lipases, amylases, and proteases to digest the dietary
like antibiotics, antigen exposure, toxins, and emotional con- intake of the macronutrients fat, carbohydrate, and proteins.
flicts; and finally rebalancing. This type of protocol provides a Other important glandular systems are thyroid, parathyroid,
significant tool to provide treatment for an individual who is hippocampus, and pineal. All of the glandular hormones
experiencing gastrointestinal distress [56]. dance together, interacting to guide the human body to allo-
stasis – the best metabolic balance to survive (see 7 Chap. 47).
 

5.13  Immune System: Defense and Repair

5.16  Respiratory System: Lung
With chronic systemic inflammation being a common and Sinus Illness
denominator with all chronic diseases, it is important to
focus on the condition of a person’s immune system. This The oxygenation of the body is dependent on the respiratory
system, when perturbed, responds with inflammation that system exchange of oxygen from the air in the atmosphere
can lead to recoverable illness like flu and autoimmunity, as with the metabolic waste of carbon dioxide – a rhythm criti-
well as life-threatening cancer. The IFMNT practitioner can cal throughout life; going without for approximately 6 min or
assess if the immune system is a priority for an individual by more can result in death. The health of the sinus areas as the
 68 K. M. Swift et al.

..      Table 5.4  Genomic considerations for restrictive respiratory diseases

Condition Gene(s) Key nutrient considerations [57]

Asthma Alpha 1 antitrypsin Vitamins C, A, D

[Smoking increases risk] Zinc
Emphysema Biotin
Chronic obstructive pulmonary disease (COPD) Essential fatty acids

Cystic fibrosis Cystic fibrosis transmembrane conductance Vitamins C, A, D

regulator (CFTR) Zinc
Biotin
5 Essential fatty acids

Lung cancer [Smoking increases risk] Zinc

ROS1 Vitamins D, A, E
symptoms attributed to a respiratory Essential fatty acids
infection Immune support

Sarcoidosis Small groups of inflammatory cells to grow Vitamins D∗, A, E

in lungs Essential fatty acids
(∗Caution using vitamin D)

Idiopathic pulmonary fibrosis Scarring in the lungs Vitamins C, A, D

Zinc
Biotin
Essential fatty acids
Phospholipids

Granulomatosis with polyangiitis (GPA) Chronic inflammation of lungs, kidney, and Vitamins C, A, D
(“Wegener’s granulomatosis”) cells usually related to infection; a vasculitis; Zinc
rare multisystem autoimmune disease Biotin
Essential fatty acids
Phospholipids
Immune support

first air entry point is important as hair filters in the nose medicine is toward personalized medicine [58]. Often
protect from most particles being inhaled into the lungs. The referred to as “P4 medicine” (predictive, preventive, person-
lung has nutrient requirements of fats, oils, and proteins to alized, and participatory), the personalized paradigm for
maintain the structure of the lung barrier along with nutrient chronic disease healthcare is gaining support from practitio-
cofactors vitamin A, zinc, and vitamin C influencing lung ners of diagnostic medicine.
metabolism. As the exchange occurs, the oxygen entering the Biological systems are groupings of molecules, tissues,
bloodstream connects with the RBC heme to be carried and hormones, and organs that are affected by lifestyle choices
distributed to cells and tissues throughout the body. With and that work together to perform a common function to
many unique genomics that can affect the lung, knowledge of express as one whole human organism. Nutrients are basic
those increases the skill of the nutrition practitioner to inter- co-factors for all those systems that determine their function.
vene successfully for each individual (see 7 Chap. 52)   Common systems, such as the circulatory, respiratory, and
(. Table 5.4).
  nervous systems, need to be appreciated in the context of
Genotype-related risk of metabolic perturbation pathway their interactions. The concept of systems biology focuses on
systems and genes: interacting systems, in contrast to conventional acute-care
55 Methylation genomics: the genomic expression related medicine that generally considers systems as isolated entities
to B vitamins, phospholipids, and vitamin D. Genes: without appreciating their interrelationships.
MTHFR 677C/1298C, MMTR, MTR, etc.
55 Detoxification genomics: Glutathione-S-transferase
genes (GSTM1, GSTP1, GST), CYP, and COMT 5.17  Potential Triggers
55 Vitamin D receptor: VDR RXR. Vitamin D is dependent
on magnesium status for its function. Vitamin D is a The five spheres of the Radial can be impacted by genetics,
hormone and immune modulator in addition to the epigenetics, biochemical uniqueness, and microbial interac-
other roles in mineral metabolism and inflammation. tions and interplay. Imbalances can be triggered by chronic
stress, toxins, pathogens, food allergens and intolerances
Because of the recognition of the unique biochemical pheno- resulting in a disruption in cells, tissues, and organ systems.
type and genotype for each individual, the current trend in These potential biological triggers are illustrated in the exter-
The Radial: Integrative and Functional MNT
69 5
nal section of the Radial and can collude to harm health and
fuel chronic diseases such as obesity, diabetes, cardiovascu- Box 5.1  The ATSDR 2013 Substance Priority List [62]
lar, neurodegeneration, mental illness, autoimmune condi-
Arsenic
tions, allergies, asthma, and more. Evaluating the five spheres
Testing: Urine arsenic is the most reliable test for recent expo-
of influence and identifying pathological insults is essential sure to arsenic (within a few days prior). Tests of hair and fin-
in order to reestablish systems balance, foster metabolic gernails can measure exposure over the last 6–12 months. Most
integrity, and promote nutritional resilience. tests measure the total amount of arsenic in urine. This can
sometimes be misleading because there are non-harmful forms
of arsenic in fish and shellfish, which can give a high reading
even if you have not been exposed to a toxic form of arsenic.
5.18  Stress
Lead
Chronic stress is an antecedent to health issues and is repre- Testing: A blood test measures the amount and estimates recent
sented in the outside of the Radial. There have been many exposure. Lead in blood is rapidly taken up by red blood cells
and referred to as blood lead concentration (PbB) which is the
definitions of stress in the medical literature from Hans
most widely used and reliable biomarker for general clinical
Selye’s original description as “the nonspecific response of use, and reflects recent exposure, <30 days. Venous sampling of
the body to any demand made upon it” to R.S.  Lazarus blood is preferable to finger prick sampling. Urinary lead excre-
describing stress as “a circumstance external to a person, tion reflects, mainly, recent exposure.
which makes unusual or extraordinary demands on him, or
Mercury
threatens him in some way” [59]. The detrimental impact of
Testing: Blood or urine samples are used to test for exposure to
chronic stress has been well documented and causes major metallic mercury and to inorganic forms of mercury. Mercury in
disruptions in the neuro-endocrine-gastro-immune and whole blood or in hair from the scalp is measured to determine
musculoskeletal systems. Chronic adverse life experiences, exposure to methylmercury.
especially psychosocial stress, have been shown to induce
 olychlorinated biphenyls (PCB)
P
destructive changes to the microbiome [60].
Testing: There are more than 200 PCBs. Testing can identify if
The nutrition professional should assess the role stress PCB levels are elevated, which would indicate past exposure to
plays in a patient’s life by incorporating some questions in the above-normal levels of PCBs but cannot determine time and
health questionnaire that are specific to stress. This can be length of exposure.
done with a stress rating scale where the patient scores their
Benzene
chronic stress level (e.g., 1 = no stress to 5 = major stress) in
Testing: Measuring benzene in blood is a common test. How-
categories such as health, finances, relationships, and work. ever, since benzene disappears rapidly from the blood, it is
Referrals to clinical social workers, behavioral psychologists, only useful for recent exposures. Benzene is converted to the
integrative yoga therapists, or mind body skills groups should metabolite S-phenylmercapturic acid in urine, which is a sensi-
be made if the individual is unable to effectively manage tive indicator of benzene exposure. Since benzene is lipophilic,
it is preferentially distributed to lipid-rich tissues, so blood tests
chronic stress. In addition, some integrative nutrition profes-
should be lipid adjusted.
sionals have advanced training in behavioral therapies and
mind-body medicine and can apply those skills to a person-­ Cadmium
centered nutrition care process (see 7 Chap. 47).
  Testing: Cadmium can be measured in blood, urine, hair, or nails.
Blood shows your recent exposure to cadmium. Urine shows
both recent and past exposure and can reflect the amount
of cadmium in the body. However, urine test results can be
5.19  Toxins and Toxicants impacted by kidney function.

It can be difficult to know when a level of a toxin will have a

physiologic impact on a single person, as response to toxins is
individual. Nutritional interventions have been proposed as a This priority list is not a list of the most toxic substances, but
key prevention strategy. The impact of toxins is being identi- rather a prioritization of substances based on a combination
fied beyond just those with work-related exposures, and evi- of their frequency, toxicity, and potential for human expo-
dence suggests a significant impact in seemingly everyday sure. A biomarker of toxic exposure is a xenobiotic substance,
exposures [61]. Two primary references are the Centers for its metabolite(s), or the product of an interaction between a
Disease Control and Prevention’s (CDC) Agency for Toxic xenobiotic agent.
Substances and Disease Registry (ATSDR) ToxFacts sheets,
which address where toxins come from and how to best test
for them, and the National Health and Nutrition Examination 5.20  Pathogens (See 7   Chap. 21)
Survey (NHANES) Fourth Report evaluates toxins assessed
by NHANES from population studies, allowing the clinician Pathogens, by definition, are a bacterium, virus, fungus,
to make comparisons against population values [62, 63]. prion, or other microorganism that can cause disease.
55 . Table 5.1 lists a truncated list of the 7 Box 5.1 ATSDR
    Parasites are generally larger organisms like worms, ticks, or
2013 Substance Priority List. insects that can also cause disease. The concern for parasites
 70 K. M. Swift et al.

is often decided based on their level of virulence. Common 2. U.S.  Department of Health and Human Services: Final MNT regu-
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Parts 405, 410, 411, 414, and 415.
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known as “mad cow disease.” Pathogens can be difficult to education services and the ADA Nutrition Care Process for medical
nutrition therapy (MNT) services.
identify and treat. In 2016, the CDC debuted the MicrobeNet 4. “Nutrition Care Process.” Eatrightpro.Org, 2019, www.­eatrightpro.­
Pathogen database [64], which contains information on org/practice/practice-resources/nutrition-care-process. Accessed
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Adequate nutritional status helps to support the negative
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  PhD, 2018.
14. Magni P, Bier DM, Pecorelli S, Agostoni C, et al. Perspective: improv-
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approach to healthcare (also referred to as P4 medicine) [58]. K, et al. Food and health: individual, cultural, or scientific matters?
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It is a paradigm-shifting model for nutrition professionals to 17. Methylmalonic acidemia diagnosis by laboratory methods. Rep Bio-
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 73 6

The Power of Listening

and the Patient’s Voice:
“Please Hear Me”
Carolyn L. Larkin

6.1 Introduction: Solutions to Help Build Trust with Patients – 74

6.2  he Need for Improved Practitioner-­Patient Communication:

T
Practitioner Know Thyself! – 74

6.3  ehavioral Competency Soft Skills Improve the Practitioner-

B
Patient Experience – 75

6.4 Leading the Interdisciplinary Medical Team – 79

6.5  he Powerful Art of Listening: Learning to Adapt Practitioner

T
Behaviors to Meet the Needs of the Patient – 79

6.6 Telling the Patient’s Story – 79

6.7  aturally Occurring Patient Tribes:

N
The Power of Communities – 81

6.8 Conclusion – 82

References – 83

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_6
 74 C. L. Larkin

understand soft skills, practitioners need to learn how to use

Therapeutic Relationship multiple assessments, including those that measure personal
This means that the doctor (or practitioner) can imagine behaviors, team behaviors, emotional intelligence, resilience,
the inner experience of the patient and practices and empathy.
clinically sound medicine in a way that respects that This chapter is intended to demonstrate useful techniques
inner experience. In other words, patient-centeredness is for creating stronger trust relationships with patients that
a mindset expressed in professional behavior; and will become an integral part of patient therapy. A well-pre-
consulting skills are the translation tool between the pared practitioner who understands interpersonal skills and
mindset and the behavior [1]. who communicates sensitively and effectively with patients
of all personality types will improve their practitioner-patient
relationships. We encourage practitioners to be involved in a
holistic healing process encompassing mind-body-soul to
I ntroduction: Solutions to Help Build deliver personalized patient care and to encourage families to
6 6.1
become part of the healing process. We cannot continue to
Trust with Patients
confine the healing process inside of disconnected silos.
Everything related to the patient healing process should be
While growing research is focused on how to build a thera-
part of the same system. We need to define and improve con-
peutic practitioner-patient relationship, the current medical
nectivity of the totality of the health system.
paradigm has a less-than-complete understanding of how to
do so [1]. Ideally, practitioners should treat each patient as a
client and as such provide their clients superior customer
Trust impacts us 24/7, 365 days a year. It undergirds and
service. Superior customer service requires individualization
affects the quality of every relationship, every communi-
of patient care, which should be the focus for all practitio-
cation, every work project, every business venture, every
ners. It also demands a high level of engagement with the
effort in which we are engaged. It changes the quality of
patient, one that can lead to mutual trust. However, a high
every present moment and alters the trajectory and
level of engagement is only possible when the practitioner is
outcome of every future moment of our lives – both
trained in the best way to interact with the patient as an indi-
personally and professionally [4].
vidual [2, 3]. In the end, the practitioner’s goal should be to
foster excellent relationships with patients to deliver supe-
rior, customized personalized patient healthcare [3].
Teaching behavioral competencies, also referred to as soft
skills (see . Table 6.1 for list of soft skills), has been an impor-
6.2  he Need for Improved Practitioner-­
T
Patient Communication: Practitioner
 

tant part of leadership development in the corporate world

for many years [1, 2]. The development of leadership soft Know Thyself!
skills and the teaching of soft skills competencies is a missing
Educating practitioners to understand their behavior styles
element in healthcare training and education [1]. Providing
and to help them to improve communication skills is a miss-
this model of education to all types of medical practitioners
ing element of healthcare education curricula [2]. When
would improve patient interaction, communication, and
practitioners understand their preferred work behaviors,
engagement while increasing effectiveness in delivering per-
medical teams can come together and adapt their behaviors
sonalized patient care in a time-efficient manner [2].
to coworkers while meeting the needs of their patients [3].
Exploring the importance of understanding and using soft
This can help teams have a more cohesive, less stressful envi-
skills within medical practice will be our starting point. To
ronment while interacting with all types of patients with all
types of needs. If practitioners were to be taught new inter-
personal skills or soft skills for effectively communicating
with patients, the practice of medicine could significantly
..      Table 6.1  Description of hard skills and soft skills compe-
tencies improve. . Table 6.1 lists a set of useful soft skills, compared
 

with more commonly understood hard skills that are usually

Hard skills Soft skills acquired through education, training, and/or life experi-
ences. In this chapter, we focus on communication and
A degree or certificate program Communication skill
interpersonal skills.
Technology experience Interpersonal skill

Proficiency is a foreign language Teamwork

The most effective use of behavioral soft skills occurs
Machine operation knowledge Leadership when practitioners understand how to adapt their own
Coding ability Problem solving behavioral style to meet the needs of the patient.
The Power of Listening and the Patient’s Voice: “Please Hear Me”
75 6
understanding and acceptance of their emotional state. They
per|solog * want to hear information in simple words and will ask a lot of
Dominant Influencing
questions to help them understand the diagnosis. They may
• Fast • Sociable want to talk at length with the practitioner and may be
• Goal-oriented • Enthusiastic ­emotional. They don’t respond well when facing a practitio-
• Energetic • Optimistic
• Decisive D
Stronger
I • Imaginative
ner who is all business. They prefer a practitioner they con-
• Demanding • Influential sider a friend.

Steady Behavior (S)  Patients with this communication style

Cautious Steady will listen and take time to digest information. They limit con-
• Analytical • Supportive
• Reserved
C S
• Team-player
versation, are cooperative, and will want to know their progno-
Less strong
• Precise • Patient sis. Their focus when listening to the practitioner will be mainly
• Private • Reliable on how their health status will impact their family. They will
• Systematic • Loyal
want to protect and remove any risk to their loved ones and
want to put things in order, should their health be in danger.
..      Fig. 6.1  Four behavioral styles originally described by William They do not like conflict and are congenial and thoughtful.
M. Marston in his book Emotions of Normal People [5] and illustrated by
Persolog [6]. (Used with permission from Persolog.) Conscientious Behavior (C)  Patients with this style of com-
munication focus on accuracy of the diagnosis and will review
Starting in the mid-1920s, personality researchers began to all available data shared by the practitioner. They will conduct
develop descriptions of human personality types as they independent research to validate the data given by the practi-
relate to personal interactions. This work was brought into tioner. They want the diagnostic data numbers to be very clear.
focus by William M. Marston in his seminal book The Emo- If they have access to a computer during a hospitalization, they
tions of Normal People [5]. After being refined through fur- may check the information they receive from the practitioner
ther research, the description of behavioral styles has settled against online sources.
on terms denoted by the acronym “DISC,” standing for dom- For an example of two different behavioral styles and
inant, influencing, cautious, and steady [6]. The characteris- their interactions, consider a practitioner who is a dominant
tics of each behavioral style are shown in . Fig. 6.1 [5, 6].
  A-type personality, or DISC-style type D, working with a
patient who has a social-interactive style type I. The practi-
tioner will be direct and conclude the conversation in a short
Using skills related with human behavior in the health amount of time. The patient’s expectation of how the practi-
field is an effective way to create a stronger therapeutic tioner should communicate might include asking the patient
relationship between practitioners and patients. questions such as, “How are you feeling today? Have you
talked to your family about your situation? Do you have any
questions about what I said?” Many of these questions from
There are specific and identifiable styles of communication the practitioner will satisfy, reduce fear, and build trust and
between practitioners and patients that can be characterized confidence with the patient. Some practitioners naturally
using the DISC paradigm. What follows are examples of each connect with patients. For others, informal conversation is
style of either practitioner or patient behavior. These four not easy. Soft skills education will help practitioners under-
styles are commonly seen in healthcare settings and offer stand numerous communication styles.
some clues toward understanding behaviors of both the
patient and the practitioner:
The objective of learning to understand behavioral styles
Dominant Behavior (D)  This style of patient communication for better patient care is to increase engagement
is interested in receiving bottom-line information from the between caregivers and patients, to further build
practitioner. These patients prefer a brief conversation and lim- stronger relationships.
ited social interaction. They are not interested in a lot of data –
just enough to hear the news and what they will have to do with
the news. They may test the practitioner by asking direct ques-
tions while evaluating if the practitioner knows what they are 6.3  ehavioral Competency Soft Skills
B
doing. They have a need to control their environment and have Improve the Practitioner-Patient
a tendency to act as the authority figure. When unable to take Experience
control, they can be aggressive and demanding.
Time spent in the therapeutic encounter continues to be
Influential Behavior (I)  This type of patient seeks more reduced. Today, a major opportunity in healthcare presents
communication than in the dominant type above and may itself through teaching behavioral competency techniques
want hand-holding, reassurance, and their practitioner’s that will mitigate the patient’s frustration level when the
 76 C. L. Larkin

Using soft skills allows practitioners to consider how the

..      Table 6.2  The most important behavioral competencies
(soft skills)
patient is receiving a difficult diagnosis, for example, while
simultaneously allowing the patient to understand what the
Competencies Some critical behaviors practitioners medical expert is saying. If behavioral competency soft skills
need to strengthen are not in place, the patient receiving the medical diagnosis
may not be able to understand the important information
Leadership Remaining calm and effective in high-pres-
sure situations
the practitioner needs to deliver. Health practitioners fre-
Taking initiative – doing what needs to be quently convey diagnoses to their patients using medical
done without being asked to do so jargon or vocabulary that non-healthcare providers may be
Demonstrating high standards of ethical unfamiliar with, making it more difficult for patients to
conduct accept or process the information. If the medical practitioner
Dealing fairly with all people
Showing sensitivity and compassion for
does not consider how the patient is able to receive the infor-
mation, then the patient can experience confusion, fear,
6 people
worry, stress, and denial. The intent may be good on the part
Teamwork Treating coworkers with courtesy and respect
of the practitioner, but the message’s impact on the patient
Supporting decisions made by the team
Putting team goals before individual goals will be ineffective.
Helping coworkers when they are having
difficulty
Asking coworkers about their projects and In healthcare, practitioners would be more effective if
priorities
additional educational curriculum included competen-
Communica- Expressing thoughts, feelings in words cies focused on personalized patient communication.
tion Explaining the reasoning behind own
opinions
Listening to others without interrupting
Communicating in a clear, logical, and There are definite challenges and barriers between practi-
organized manner tioners, team members, and the patient; these challenges
Exhibiting an open mind when hearing and barriers are, in part, communication barriers.
people’s opinions Strengthening soft skills and enhancing communication
Focus on Placing a high priority on improving patient reduces conflict and initiates cooperation and collabora-
patient service tion. It turns disagreement into discussion, which leads to
Recognizing and rewarding people who creative solutions. Communication skills are sharpened to
deliver excellent patient service humanize the delivery of information to the patient and to
Encouraging employees to contact and listen
to patients
help the patient understand the practitioner more clearly.
Identifying and understanding the patient Besides words and body language, better communication
needs and service expectations also includes allowing the patient to be heard. This reduces
Appropriately communicating with patients patient fear, resistance, and shame in the clinical setting
to keep them informed on a regular basis [9–12].
Interpersonal Establishing effective relationships with The responsibility for effective communication rests with
skills coworkers the practitioner. Focusing on meeting the needs of the patient
Showing knowledge and respect for people’s through effective communication can help improve patient
responsibilities throughout the organization
Establishing trust with people at all levels
care, satisfaction, and outcomes. Enabling practitioners to
Taking time to establish relationships with learn and develop specific and critical behavioral competen-
people at all levels cies may significantly improve the level of engagement in
Demonstrating an appreciation of the value a patient interaction. In some ways, the healing process begins
diversity of people in the workforce when patients feel they have a voice in the conversation and
an audience for their story, one that listens, rather than
directs, how the conversation should go.
practitioner does not have enough time to listen. See The patient who believes their practitioner is listening to
. Table  6.2. Using interpersonal skills adapted to human
  them will begin to trust and be more willing to reveal infor-
behavior is an effective way to create stronger relationships mation. Information such as the possible root cause of their
between practitioners and patients [7, 8]. ailment, a trauma that could have initiated the beginning of
Behavioral competencies are identified in terms of both the disease, emotional upheaval, stress they live with, fears,
hard skills and soft skills. Soft skills are frequently used in the denial, and/or concern for their family’s reaction will be
business realm, but currently less so in medicine. Soft skills shared fully. A psychologist is not necessary to uncover such
are important competencies for practitioners to have, under- background. A trained, patient-focused team can do it when
stand, and use when caring for patients. Improving behav- it works in synergy. A term, situational communication, has
ioral competencies (listed in . Table  6.2) will improve the
  been developed to describe this type of teamwork [12]. Please
practitioner-­patient relationship. refer to the Case Study.
The Power of Listening and the Patient’s Voice: “Please Hear Me”
77 6
Case: Effective Communication to Build Strong and Trusting Patient Relationships: A Way to Personalized Patient Care

Optimal health depends on a robust practitioner–patient spontaneous because of prenatal rubella infection and others
relationship. This relationship involves the critical need for patients performed surgically after women were informed of the serious
and their families to have their often-unheard voices heard. risks of prenatal exposure. The storyteller states 1965 as the worst
Information shared in an open and safe environment contributes to year of her life and goes on to describe:
the formula that will effectively change the current model of the
practitioner–patient relationship. Paramount in this process is the »» “My one son was two years old at the time he contracted the
need to examine the importance of storytelling as a means to build disease (rubella). Unbeknownst to me, I was 1 ½ months
trust and the significance of identifying support communities when pregnant. During this time, primary doctors made house
striving toward optimal health. These communities have been iden- calls and the doctor came to my home to treat my son. A
tified as tribes and are a rich resource and support for the patient month later, again not knowing I was pregnant, I called my
and their families. As a new type of practitioner, it is critical to be doctor to inform him that I wasn't feeling good. I had a fever
armed with the communication resources to facilitate these and felt like I was getting the flu. He suggested I take some
trusting, healing connections. aspirin, a warm bath, and try to get some sleep. I did exactly
Below is a shared story; with changes in details and variations that, however I noticed that I had small bumps on parts of
in setting, thousands of people with similar life-altering my body, so I called once again to inform him and was told
experiences have told this type of life narrative. Important in this that I most likely contracted rubella. After the rash had
story is the focus on the conversation and allowing the storyteller cleared, I went into the office for a blood test. It was during
to speak uninterrupted so as to value their experience [14, 15]. that visit that I found out I was pregnant. Little did I know
The storyteller was first exposed to a family member’s serious that this event would change my life dramatically. My baby
health challenge when she was a young girl. She had a younger girl was born with multiple medical problems; problems that
brother 10 years her junior who was ill from birth, and she felt I was not aware could happen because of the rubella
compelled to help her mother care for him. He had been born with infection.”
a congenital urinary disorder that was not diagnosed until he was a
toddler and was eventually found to have an obstruction of the »» “At the time of her birth, she weighed in at 3 lbs. 11 oz. and
urethra, resulting in reflux with injury to the bladder and kidneys. was 21 inches in length.” When she reached 8 pounds, she
The obstruction was surgically removed, but recurred quickly. As a had her first open-heart surgery at Boston Children's
result, he underwent many surgical procedures over the following Hospital. At that time, neonatal care was just emerging. It
years. The mother became his nurse, changing catheters, while the was not until 1965 that the first American (neonatal)
sister was designated as her “little helper,” sterilizing the equipment intensive care unit (NICU) was opened in New
and assisting in other ways. The family members were not Haven, Connecticut and in 1975 the American Board of
specifically trained, but knew these interventions were necessary Pediatrics established sub-board certification for
and critical to save the child. They did the best they could to neonatology.”
understand the complex conversations and directions for
interventions the practitioners shared, including information »» “I had an appointment with the heart specialist to review her
regarding prognosis, what treatments he required, and what to prognosis and prepare for her surgery. With my baby in my
perform at home. The storyteller recalled her mother “doing arms, terrified and alone, the doctor entered the room and
everything she could possibly do to keep him alive,” in addition to introduced himself.”
answering the questions about her brother’s condition in a way the
family could understand. »» “The doctor was all business and spoke to me in terms I
What the storyteller remembers vividly is the frustration her didn't understand. The questions I asked were uninformed,
mother expressed in this situation, the isolation she experienced, too vague for the doctor to understand, and I was not
and feelings of being incapable of providing accurate information confident enough to continue to probe. I just listened… my
to family and friends. She describes these feelings as “palpable.” The anxiety was at an all-time high. After about 20 minutes of
storyteller discusses being involved throughout the remainder of listening to the doctor's information, he stood up and said
her childhood until she was a young adult and no longer living at his intern would be meeting with me to give me some
home, when she describes her support changing from direct printed information regarding my child's surgery. The
involvement to moral support. She describes her mother providing surgery was scheduled for the next day. The doctor left the
27 years of effective care for her brother until he died. room, while I sat crying, holding my baby in my arms,
As the only girl in the family of four children, she had an early wishing my resilient mother were with me.
education in “caretaking,” but believes this early education allowed
her to acquire many competencies that proved to be extremely
useful later in life. As the storyteller describes, “These skill sets were
»» “The next person to enter the room was the intern. He
introduced himself and handed me instructions and
ingrained in me and allowed me to face one of the most directions for the next day. I didn't hear much of what he
challenging health crisis I never expected to deal with again. A had to say, I was still in shock at the reality of what was
crisis that changed my life in ways I never expected, never thought happening. My heart was racing, tears were flowing; I felt
I could endure, nor survive.” like a baby trying to save my child. Then, the most
By the age of 27, the storyteller was the mother of four frightening words I ever heard came from the intern. He said,
children, all born within six years. She describes herself as a child ‘I'm sorry there is nothing that we can offer you to help you
raising children. During that time and before the development of with your child's additional health problem.’ Already
the rubella vaccine, a rubella epidemic swept the United States. confused, I said, ‘What additional health problem?” He
Over that short period, there were 12.5 million cases of rubella. answered, ‘Your child is deaf. Didn't your pediatrician inform
Around 20,000 children were affected with congenital rubella you about this?’ My reaction was filled with rage and
syndrome (CRS), which left more than 11,000 children deaf, 3,500 emotion, ‘You have the wrong chart. My child is NOT deaf!
blind, and 1,800 with mental retardation. There were 2,100 What kind of hospital is this? My child has a heart problem…
neonatal deaths and more than 11,000 abortions, some That's all. I need to speak to the doctor!’
 78 C. L. Larkin

»» “The doctor came back into the room. He tried to explain that Finally, the family was notified that the surgery was over, led to a
my daughter had both health challenges, while trying to conference room, and anxiously waited for the surgeon to enter.
reassure me that everything would be fine. At that point, it fell When he did arrive, the storyteller reported he looked at them, did
on my deaf ears. I went into total denial. I would not accept not say a word, sat down on a chair, and reviewed his paperwork.
the fact that my daughter was deaf. Even though her heart They waited until he finally said, “Oh, the surgery went well.” Aside
surgery was successful, I lost trust and confidence with the from the communication skills lacking on the part of the surgeon,
doctor, the hospital, and the staff. I was filled with fear for my the family burst into tears of relief. With each medical procedure
daughter's survival. I left the hospital and drove back home in the patient endured, she insisted the storyteller be by her side not
a rainstorm, with my tears flowing faster than the windshield only to interpret by signing but also to interpret the nuances of
wipers could wipe the rain away. As soon as I got home from what was being communicated – or poorly communicated.
the meeting I tried to prove to myself that my daughter was By telling her story, this storyteller was able to impart the
not deaf. I spent most of the rest of the day slamming cabinet nuanced richness of her life and life experiences and better able to
doors and hitting pots together intensely watching my project whom she is based on these experiences. If not allowed the
daughter's reaction, trying to prove that she was not deaf. I space to tell her story, an important element of care would be lost.
6 was in shock, ultimately ignorant about raising a deaf child. I
had zero exposure or experience with her health challenge.
The practice of medicine has improved and will continue to
improve, and medical practitioners are dedicated to providing
The worst nightmare had just begun, and I had no way out.” best-known solutions for their patients. Patients cannot expect
medical practitioners to excel in patient care when medical
The storyteller goes on to describe that 50 years later, her daughter, curriculum does not include what is currently unknown to them.
now a grown woman with multiple prior invasive heart procedures Unknown curriculum subjects such as storytelling and practitioner-
behind her, was facing another open-heart surgery. Due to the know-thyself training accompanied by important applicable
difficult and complex surgery she was facing, most of the extended self-assessments should be mandated in medical curriculum in
family members were present. When the surgeon spoke to the order for practitioners to have the tools to be successful while
family before entering the operating room, he was asked by the providing personalized patient care.
storyteller to take good care of their “little girl.” She reports he Trust needs to be established between the medical practitio-
replied, “I'll do my best, but this will not be easy,” words not ner, the patient, and the family members. Trust is inherent when
welcomed or comforting. The presurgical ritual was all too familiar communication is valued. Just as this storyteller describes,
for this mother as she accompanied her daughter into the OR and examples of poor communication can isolate patients and family
translated through sign language what was being communicated. members. When they are not heard, healing is not facilitated. As
Words of reassurance were signed to the daughter and received highlighted by this story, ineffective communication practices
with absolute trust in her mother. Everyone in the room was existed throughout the medical establishment; unfortunately, they
supportive and kind, and the storyteller reported feeling satisfied still exist. Education to teach practitioners to hear the stories is
with how events were proceeding at this point. paramount. As a new breed of practitioners, we need more focus
Although the surgery was technically a success, the storyteller on listening with our hearts, using better ways to acknowledge the
reported waiting for hours not knowing if there were complications patient’s voice, and finding solutions to capture the stories, in order
or even if her daughter had survived. Nothing from the surgeon. to realistically achieve personalized patient care.

Situational communication is a clear, concise, and focused outcomes. Developing soft skills competencies that focus on
communication strategy that maximizes the ability of a mini- communication skills needed by the practitioners will
mum amount of time to achieve successful results and effec- improve the patient’s experience and make the job of the
tive relationships [12]. Although it may be used in personal practitioner less frustrating and more rewarding.
settings, situational communication is mostly reserved for Experts in situational communication know how to
business and professional interactions, especially those that engage in robust and fruitful conversations that are tailored
are challenging, where the points of view, interests, or pre- to the individual patient. As previously noted (. Table 6.2),
 

ferred solutions of the communicators are different or in con- THere are other soft skills practitioners should develop that
flict. Leaders must be capable of planning for and executing impact the practitioner-­patient relationship in addition to
situational communication in order to be both successful and communication skills. All of these important skills promote a
effective. These interactions differ greatly from our mostly stronger trusting therapeutic relationship and improve the
effortless run-of-the-mill interpersonal interactions. biological function of the human body through mind-body
Situational communication represents purposeful, thoughtful interactions.
engagement. In the case of situational communication, there Behavioral competencies should be required as part of
is a planned payoff. These types of interactions are more for- medical curricula across all medical professions, and integra-
mal, structured, and well-planned, requiring significant tive and functional practitioners have been leading the way.
energy and focus [13]. When the interaction is personalized, patients can express
In most businesses, the organization strives to help its themselves in ways that lead practitioners to understand the
human talent develop necessary competencies in order to be patient’s status in a clear and concise manner. Behavioral
successful. In the healthcare industry, practitioners would competencies and communication skills are mandatory in
benefit by employing the same approach. This is accom- any industry; however, behavioral competencies and situa-
plished by adding educational curriculum that includes tional communication skills will enhance the development of
behavioral competencies focused on personalized patient the therapeutic relationships that leads to successful patient
communication with a desired effect of improved patient outcomes.
The Power of Listening and the Patient’s Voice: “Please Hear Me”
79 6
6.4 Leading the Interdisciplinary All of the major psychometric assessment tools in world-
Medical Team wide use employ the basic behaviors established by Dr. John
Geier, considered the leader in human assessment science
There are unique competencies that all members of the med- [16]. A combination of psychometric behavioral assessments
ical team bring to their specific roles. One important role is (. Table 6.3) can provide important data needed to properly
 

leadership. Many practitioners have not been schooled in train and prepare medical teams. Practitioners and interdis-
leadership competencies. However, leadership competencies ciplinary teams gain insight into their behaviors and the
are highly relevant when it comes to patient care. Members of effect on the patient, which allows the team to be of better
the entire medical team (such as dieticians, physical thera- service. Such assessments may include emotional intelli-
pists, psychologists, health coaches, pharmacists, nurses, gence, DISC profile, 360-degree assessments, and perfor-
doctors), referred to as an interdisciplinary team, need to mance evaluations, if appropriate. Behavioral evaluation
function together in relating to a patient. The interdisciplin- report results are directly available to each practitioner,
ary team has shared leadership responsibilities, starting with which opens the door for the practitioner to share results
understanding the principles of behavioral competency soft with the team to facilitate improved cohesiveness. Patients
skills in relationship to patients. may also be assessed, and this allows the practitioner to
Research states that the parts of the roles practitioners are understand his/her own behavioral style, to recognize the
highly competent to fill are usually roles that are personally patient’s style, and how to adapt his/her communication
motivating for them [13]. Excellent leaders understand that behavior to best address issues with the patient [18]. If medi-
some of their roles are not self-motivating and frequently ask cal practitioners are educated in soft skills assessments, like
for feedback from the interdisciplinary team in order to the ones mentioned in . Table 6.2, it would enable them to
 

gauge their own effectiveness. They seek out feedback on recognize how individual patients choose to hear informa-
their leadership style. They also self-evaluate their level of tion, resulting in improved communication between the
effectiveness. Ineffectiveness demands leadership changes. practitioner and patient. The most effective use of behavioral
Without the willingness to change, everything becomes soft skills occurs when practitioners understand how to adapt
static [13]. Competencies associated with corporate business their own behavioral style to meet the needs of the patient as
are transferable throughout many industries and can be discussed.
adapted to healthcare to improve patient care. Improving Obtaining practitioner behavioral assessments for each
patient care is the ultimate outcome healthcare should strive member of the interdisciplinary medical team enables a
to accomplish. team-building educational process. Tools, including train-
ing modules, can teach practitioner teams how to effec-
tively improve their communication within their medical
6.5  he Powerful Art of Listening: Learning
T team while understanding and respecting everyone’s
to Adapt Practitioner Behaviors to Meet behavioral style. Competencies within the team are
the Needs of the Patient strengthened and create more concise, positive outcomes
in the management of the difficult patient. In addition, for
The objective of learning to understand behavioral styles is to complicated patients, the combined process of tools and
increase engagement between caregivers and patients, ulti- training is not restricted to any particular disease or diag-
mately building stronger relationships. Effective communi- nosis. Any medical team can benefit from data-driven
cation occurs when both parties have a clear understanding assessments. These, combined with educational methodol-
of their own preferred communication style. To achieve that ogies, should be a necessary form of education for the
understanding, behavioral profiling tools can help and allow entire health industry.
the practitioner and patient to become a cohesive team. Once
practitioners are trained to understand their personal
­behavioral style, they can quickly assess the patient’s basic 6.6 Telling the Patient’s Story
style, enabling both parties to better work together.
Understanding the behaviors of their patients allows practi- For centuries, stories have been shared through the spoken
tioners to change their behaviors from expecting the patient word, interpersonal conversations, diaries, and the writing of
to listen and understand them, to practitioners listening and history. Storytelling has the potential to reveal emotion and
understanding the patient. More importantly, behavior psychological trauma. People remember stories. They repeat
assessment tools can assist interdisciplinary medical teams to them, often linking them to their own similar experiences.
understand their own preferred work behavior, so they can No matter what the story is, if it is told, millions of people in
also learn how to adapt their behaviors to meet the needs of many different languages around the world will have gone
the patients through stronger teamwork. Utilizing assess- through something similar. It is that sense of connection to
ment tools like those described below can reduce stress for community that says, “I’ve been there; I know what that is
the interdisciplinary team when dealing with very ill patients like.” Sharing stories can be an experience of enlightenment
and challenging situations. as emphasized in the Case Study.
 80 C. L. Larkin

..      Table 6.3  Psychometric behavioral assessments commonly used worldwide

Assessments What the tool evaluates Description of tools

H R Tools, Inc. The following tools can be located on the 7 HRToolsINC.­com

  See the following tools
7 http://
  link
HRToolsINC.­
com

Emotional Ability to characterize emotions in oneself and in others, The person takes the assessment and identifies what are
Intelligence ability to use feelings constructively and to understand and his/her strong skills and which are the ones he/she
analyze emotions and solve emotional problems, ability to needs to develop. Then work with a coach or participate
take responsibility for one’s emotions, attaining emotional in a training program that teaches them how to develop
growth and maturity each skill and work on that process

6 DISC Profile The DISC profile describes human behavior on the basis of
four behavioral styles, dominant (D), influencing (I), steady
There are many different programs where participants
take the assessment and then work in many different
(S), and cautious (C), and aims at a better understanding of training programs (also in coaching works perfectly) like
one’s own needs and those of others teamwork, leadership, communication, interpersonal
skills, and many others. The model adapts well for all
these methodologies because it is based on what is my
behavioral style, how I can identify other styles, and how
I can adapt to them [16]

360 This methodology consists in receiving feedback from After the 360 assessment is completed, the person
Assessments employee’s managers, peers, and direct reports. The receives the feedback and a consultant or coach helps
feedback is provided by them using an online tool that him to understand it and how to work in that, as well as
ensures the confidentiality of the feedback. The question- how to create a development plan
naire of the feedback is based on competencies and
behaviors that measure those competencies or soft skills

E4 Method The E4 method facilitates the connection through communi- A teaching methodology tool for practitioners to
cation and identifying teaching materials develop a standard of patient communication principles.
The E4 Method was developed by Butler and Keller [17]
in 1999 and is a commonly used tool

In many ways, social media holds the potential to be a process depends on this relationship. With shared experi-
healing vehicle. It provides humans an environment wherein ences through storytelling, synergy and mutual trust are cre-
they can tell their stories. Postings can quickly go viral; as ated. The practitioner needs to understand the patient’s
stories are shared, experiences connect us. In this era of feelings of fear, grief, or loss, and these feelings may be miti-
advanced communication technology, we have the freedom gated if received with the type of communication the patient
to share information and stories that instantly reach every needs. The practitioner and patient may then connect on
corner of the globe. another level where the patient feels understood, and, in
those moments of connection, the practitioner is truly serv-
ing the patient in a partnership leading to the best outcome.
When a patient shares their story, it helps the caregiver To facilitate the connection through communication,
to understand the patient’s journey and health chal- teaching materials are needed. The E4 Method developed by
lenges through the lens of the past and enlightens the Butler and Keller [17] is a commonly used tool for practitio-
present state of health. ners to develop a standard of patient communication princi-
ples. The E4 Method includes the following 4 Es:
55 Engagement – skills that support development of rapport
As stated by Hall and colleagues, medicine is an art whose with patients
magic and creative ability have long been recognized as resid- 55 Empathy – skills that help clinicians reflect concern for
ing in the interpersonal aspects of patient-practitioner rela- the patient’s condition
tionships [19]. In the healing encounter, sharing stories 55 Education – skills needed for discovering and developing
between practitioners and patients is one of the most impor- the patient’s understanding of his/her condition
tant parts of the healing process. When a patient shares a 55 Enlistment – skills that help in motivating and changing
story, it helps the caregiver to understand the patient’s jour- behavior
ney and health challenges through the lens of the past and
enlightens the present state of health. It is critical that the As the craft of storytelling expands, education in the field of
practitioner understand the patient’s stories so the two can storytelling is emerging and accessible [17]. Medical practi-
build a strong connection. Much of the psychological healing tioners need to be educated and trained through storytelling
The Power of Listening and the Patient’s Voice: “Please Hear Me”
81 6
curriculum, which teaches understanding of the process and team can be called upon to effectively help when other mem-
the uncovering of hidden meanings. Materials like the E4 bers are unavailable. There can be building of trust, safety,
Method, developed through evidence-based research, are and healing by wise use of team members’ time.
needed to build powerful relationships and would be a ben- Perceived barriers to training may also include the belief
eficial addition to the medical education curriculum. system that the practitioner is sacrificing time and energy
As highlighted by the E4 Method, communication when faced with coursework to develop communication
between the practitioner and patient is more effective when skills. Training must emphasize the payoff of improved
the practitioner allows the patient to construct a timeline of patient relationships, reduction in practitioner stress,
their story uninterrupted. A brief conversation with the improved effectiveness of time management, and healthier
patient is often not enough and may not be satisfactory for outcomes for patients and their caregivers. Training should
the patient in the moment. This storytelling process has be emphasized as a method to develop the skill to listen to
power to reveal traumas and triggers and provides a window and appreciate the patient’s story which will pay dividends by
into the current state of the patient’s physical and mental providing the needed context to the patient’s situation.
health. After the patient reveals significant psychological Practitioners need to understand that this education would
events and stressors by sharing life’s timeline, the practitioner enable personalized patient care with effective interventions
can pinpoint important information to help in the treatment and enhancement of their skills.
of the patient’s disease. The practitioner, indicating a degree We are overdue in providing the type of training neces-
of empathy for the situation, reflects the important events sary to change, improve, and close the gap between mediocre
back to the patient. communication skills and high-performance communica-
As a cohesive partnership develops between the practitio- tion skills. Connecting with the patient’s story is critical. If
ner and the patient, family members can be enlisted as part of practitioners are not trained in the necessary skills to connect
the team. This will serve to educate the patient and the family with patients, those stories will never be heard. Training
about the health condition in a safe and supportive environ- health practitioners to become proficient in storytelling and
ment. Enlisting the patient and family as a team will help story listening is a viable potential solution to the current
with motivating changes that need to be made. The team will healthcare crisis.
be in sync working together toward the accomplishment of
the best possible outcome. It is time for medical practitioners
to reap the rewards from the soft skill of listening…listening 6.7  aturally Occurring Patient Tribes:
N
to the stories waiting to be told, shared, understood, and The Power of Communities
accepted.
Articles and methodologies are available that build on
patient communities and patient support groups [21, 22].
It is time for medical practitioners to reap the rewards Naturally occurring patient tribes are forming throughout
from the soft skill of listening…listening to the stories the globe, and physicians, health practitioners, and health
waiting to be told, shared, understood, and accepted. communities are not necessarily included in them. This
model of patient support is becoming a powerful new way
for patients to share their specific experiences and deepen
Barriers to implementing therapeutic storytelling include their medical knowledge.
significant time constraints. The burden of the current A naturally occurring tribe can be formed anywhere,
healthcare paradigm with mandated abbreviated appoint- anytime, and in any location. The beginning of a tribe often
ment times puts practitioners in a time-crunch that is not occurs when patients are gathered in clinical settings while
conducive to meeting the needs for personalized patient care. waiting for treatment. In these situations, patient and care-
Practitioners expect patients to listen intently to what they giver tribes begin to form. What makes patient tribes dif-
have to say in this limited time, but the infrastructure of con- ferent is the conversation shared between patients with
ventional care does not afford the practitioner similar time to shared medical challenges. Such conversations can be
listen to the patient. By the act of listening with intention to highly valuable for the patient and may even be more infor-
the patient’s story and basing decisions on the shared conver- mative than a patient having a conversation with their
sation, some measure of relief of symptoms can be expected health practitioner.
[20]. This can have the effect of reducing symptomatic com- Naturally occurring patient tribes may be useful and
plaints, shortening the length of the disease course, improv- effective for patients because individuals dealing with similar
ing outcomes, and, in the long-term, reducing the burden of health challenges often find support in these informal con-
time with the patient. nections. There may be an unspoken acceptance to engage in
Another solution to the problem of implementing and difficult conversations, yet facing the difficult conversation is
retaining the personalization in a therapeutic encounter is to necessary and consoling. There is a level of trust that the tribe
depend on the contributions of the interdisciplinary health- environment creates. The trust is based on sharing informa-
care team members. With common training of each team tion and like experiences, such as fears, doubts, and chal-
member in the art of storytelling and listening, the entire lenges with practitioners.
 82 C. L. Larkin

Patients may seek out guidance from each other, learn They may apply to other professional settings, as well as per-
tips for managing their condition, and educate one another sonal relationships.
to understand the medical terminology associated with their When patients need information, the practitioner must
diagnoses. People may not feel free to ask questions of their give it in a clear and supportive manner. When patients need
medical team, yet have no hesitancy in asking the patients or support, the practitioner must let them know they will be
families of patients sitting nearby. There is power in this there for them [23]. In order to fulfill these needs and build a
shared experience. The tribe members are on the same jour- more effective practitioner-patient relationship, the practitio-
ney and perhaps have learned valuable things along the way. ner can learn effective listening. When using effective listen-
The tribe can help each other almost like a mentor helps a ing, the practitioner maximizes valuable time over the long
mentee understand specific situations and offers solutions term. Effective listening allows the dialogue between practi-
that may be found to be extremely effective. There are many tioner and patient to be focused, informative, and positive.
conversations about how relationships are built, how power- In challenging settings where there may be time con-
ful they are, and how they naturally create tribes of like minds straints or an undercurrent of psychological issues, the dia-
6 [14, 15]. This connection to the tribe is reinforced and logue can evolve and become more productive when the
strengthened as the relationship blossoms. practitioner attempts to understand the needs of the patient
Tribes also connect and form in other ways. In today’s and puts the patient first. By being sensitive about word choice
world of technology, shared experiences go viral, and power- learned through training sessions, practitioners can make
ful connections are achieved on an unprecedented scale headway toward fruitful communication and let the patient
never before seen. Social media is an easy-to-access “share know they understand where the patient is in the moment. It
button” that connects to the world of human experiences. is important for many patients to hear and understand this. In
This global technological connectivity vehicle allows millions addition, practitioners would do well to communicate with
of people who do not know each other the ability to com- patients’ families. Family members often deal with the shock
municate, share stories, reveal information, and connect of the illness of their family member and may put their feel-
both intellectually and emotionally because of the thread of ings aside in order to cope and manage the medical situation.
shared experiences. This situation can be acknowledged and validated. The practi-
tioner needs to realize the family members have their own
stories and can offer important insight into the history and
We want to encourage practitioners to be involved in a status of the patient. Stories reveal important ­information
holistic healing process for personalized patient care and indicative of their culture, family medical history, and genetic
very importantly for families who should be part of the information. Families share stories. Stories have power.
healing process. The tendency to organically form support groups or
tribes in medical office waiting rooms, social media, or other
social venues is an important part of patient healing that
This global phenomenon has informed many shared stories healthcare teams could tap. If practitioners can develop ways
containing private information and diverse conversations in to understand their patients’ tribes and reinforce information
every language. This global engagement between people is shared, positive clinical outcomes will be fostered and
powerful and has the ability to bond strangers together to enhance the practitioner’s effectiveness and efficiency.
become both a tribe of like minds and extended families. Evi- The time is overdue to identify and adjust the human fac-
dence has emerged in recent years that reveals how powerful tors that create barriers to build strong relationships. The differ-
relationships are [21, 22]. The relationships you have and the ences in human behaviors are vast, unique, diverse, and can be
tribe you spend time with and relate to are more powerful complicated. However, as human beings we strive to be under-
than even what you eat. stood, respected, and included. It will take a concentrated effort
to work to eliminate the barriers that separate us. The solution
is to first understand our own behaviors and behavioral limita-
6.8 Conclusion tions, and work to improve them. “Knowing thyself ” can be
daunting and frightening. It will however be enlightening.
In conclusion, we cannot expect health practitioners to have As practitioners, taking accountability for how we behave
skills that they have not been taught. Some health practitio- when we communicate to patients puts the onus of responsi-
ners have a level of intuitive empathy and are able to fill the bility where it should be – on ourselves! Honing communica-
gap between formal education and understanding how to tion skills is worth the effort. These skills will improve our
excel in patient communication, interaction, behavioral own lives, as well as the lives of others. When in the driver’s
styles, and skills. However, all healthcare practitioners seat, we hold the power to make or break relationships. The
should be given the opportunity to be trained to understand reward for taking responsibility and accountability for the
the human dynamic and the diversity of each human experi- effective way we communicate, listen, and respond to each
ence. This training will be an asset to practitioners, patients, other is a powerful reward for all of us humans. It will unite
medical teams, and organizations that employ them. us in our effort to change and build a powerful and healing
Communication skills are transferable and long-lasting. tribe of like minds.
The Power of Listening and the Patient’s Voice: “Please Hear Me”
83 6
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 85 II

Metabolic Characteristics
and Mechanisms of
Chronic Disease
Contents

Chapter 7 Metabolic Correction Therapy:

A Biochemical–Physiological Mechanistic
Explanation of Functional Medicine – 89
Michael J. Gonzalez

Chapter 8 The Nutrition Assessment of Metabolic

and Nutritional Balance – 99
Margaret Gasta

Chapter 9 IFMNT NIBLETS Nutrition Assessment Differential – 123

Robyn Johnson and Lauren Hand

Chapter 10 Nutritional Role of Fatty Acids – 135

Vishwanath M. Sardesai

Chapter 11 Lipidomics: Clinical Application – 151

Diana Noland

Chapter 12 Structure: From Organelle and Cell Membrane

to Tissue – 173
David Musnick, Larissa Severson, and Sarah Brennan

Chapter 13 Protective Mechanisms and Susceptibility to Xenobiotic

Exposure and Load – 191
Robert H. Verkerk

Chapter 14 Detoxification and Biotransformation – 205

Janet L. Black

Chapter 15 Drug–Nutrient Interactions – 213

Mary Demarest Litchford

Chapter 16 The Enterohepatic Circulation – 221

Robert C. Barton Jr.
 Chapter 17 A Nutritional Genomics Approach to Epigenetic
Influences on Chronic Disease – 235
Christy B. Williamson and Jessica M. Pizano

Chapter 18 Nutritional Influences on Methylation – 269

Jessica M. Pizano and Christy B. Williamson

Chapter 19 The Immune System: Our Body’s Homeland Security

Against Disease – 285
Aristo Vojdani, Elroy Vojdani, and Charlene Vojdani

Chapter 20 Nutritional Influences on Immunity and Infection – 303

Joel Noland and Diana Noland

Chapter 21 Body Composition – 323

Sue Ward and Diana Noland

Chapter 22 The Therapeutic Ketogenic Diet: Harnessing Glucose,

Insulin, and Ketone Metabolism – 335
Miriam Kalamian

Chapter 23 The GUT-Immune System – 367

Elizabeth Lipski

Chapter 24 Centrality of the GI Tract to Overall

Health and Functional Medicine Strategies
for GERD, IBS, and IBD – 379
Ronald L. Hoffman

Chapter 25 The Microbiome and Brain Health – 391

Sharon L. Norling

Chapter 26 The Role of Nutrition in Integrative Oncology – 407

Cynthia Henrich

Chapter 27 The Microenvironment of Chronic Disease – 437

Steven Gomberg

Chapter 28 Chronic Pain – 447

Jena Savadsky Griffith

Chapter 29 Nutrition and Behavioral Health/Mental Health/

Neurological Health – 473
Ruth Leyse Wallace
 87

Chapter 30 Neurodevelopmental Disorders in Children – 493

Mary Anne Morelli Haskell

Chapter 31 Nutritional Influences on Hormonal Health – 517

Filomena Trindade

Chapter 32 Nutritional Influences on Reproduction: A Functional

Approach – 533
Brandon Horn and Wendy Yu

Chapter 33 Lifestyle Patterns of Chronic Disease – 563

Sarah Harding Laidlaw

Chapter 34 Circadian Rhythm: Light-Dark Cycles – 577

Corey B. Schuler and Kate M. Hope

Chapter 35 Nutrition with Movement for Better Energy and

Health – 595
Peter Wilhelmsson

Chapter 36 Mental, Emotional, and Spiritual Imbalances – 613

Muffit L. Jensen
 89 7

Metabolic Correction Therapy:

A Biochemical–Physiological
Mechanistic Explanation
of Functional Medicine
Michael J. Gonzalez

7.1 Introducing Metabolic Correction – 90

7.2 I mplications of Subclinical Nutrient Deficiencies

(Nutritional Insufficiencies) – 90

7.3 Nutrient Requirements of Disease States – 90

7.4 Vitamins and Minerals and Hidden Hunger – 91

7.5 Why Metabolic Correction? – 92

7.5.1 I nferior Nutritional Value of Food and Low Availability
of Nutrient-Dense Foods – 92
7.5.2 Medication-Induced Nutrient Depletion, Adverse
Side Effects of Medication, and Iatrogenic Deaths – 92
7.5.3 To Compensate for the Increased Demand of Nutrients
due to the Disease State – 93
7.5.4 Biochemical Mechanism of Metabolic Correction: Molecular
Concentrations and Rate of Reactions – 93

7.6 B-Complex and Metabolism Briefing – 94

7.7 B-Complex and Metabolic Correction – 95

7.8  en Principles of the Concept of Metabolic Correction

T
in Disease Therapy – 95

7.9  eyond Metabolic Correction: Improving the Healthcare

B
Management Model – 96

7.10 Conclusion – 96

References – 97

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_7
 90 M. J. Gonzalez

7.1 Introducing Metabolic Correction a unique genetic or acquired dependency on supra-dietary

levels of one or more nutrients [1].
Metabolic correction (MC) is the utilization of a synergistic Clinical assessment of nutritional status has long been
combination of micronutrients and cofactors in their active exclusively focused on detection of absolute nutrient defi-
forms and proper doses to maximize the function of meta- ciencies by relying on clinical evidence of signs and symp-
bolic enzymes [1–3]. MC helps improve or rectify biochemi- toms of classic nutritional deficiency states (e.g., bleeding
cal disturbances that disrupt normal physiological processes gums with vitamin C deficiency or mouth redness and sores
and may originate degenerative diseases. MC is the fine-­ with b-vitamin deficiencies). Yet, relative nutrient deficien-
tuning of the cellular biochemistry by means of specific, tar- cies or insufficiencies due to disease are equally important, as
geted nutritional supplementation with the goal of improving is the detection of nutrient imbalances before clinical evi-
cellular, tissue, organ, system, and organism function [1–3]. dence of deficiency is present. At the point where altered cel-
Impaired or incomplete cellular biochemical reactions are lular function has evolved into clinical manifestations of
amended with MC. nutrient deficiency, cellular activity will have been compro-
MC is a functional biochemical/physiological concept mised for some time, and the compensatory responses that
that explains how improvements in cellular biochemistry might have allowed a temporary adjustment to the deficiency
7 help the body achieve metabolic or physiologic optimization would no longer be effective. Detection of subclinical changes
[1–3]. The MC concept provides the biochemical elucidation in cell processes early in the course of a nutrient deficiency,
of the utilization of nutrients for preventive and therapeutic when cell damage is minor and more reversible, can have a
purposes against disease. The MC concept becomes impor- considerable impact on the prevention and treatment of dis-
tant since our food is decreasing in nutritional value [4]; dis- ease. If subclinical deficiency is not corrected by providing
eases increase the demand for nutrients, and medications can the lacking nutrient, then prolonged marginalization of cel-
deplete nutrients [1]. These nutrient insufficiencies are caus- lular activity may not only increase vulnerability to disease,
ing enormous costs due to increased morbidity and mortal- but it may also exacerbate progression of existing disease and
ity. In summary, MC increases enzymatic function that interfere with effectiveness of treatment, since all drugs
enhances biological functions contributing to better health require some level of metabolic support to achieve their
and well-being. desired therapeutic effects.

»» Metabolic correction is a functional biochemical/ »» Detection of subclinical changes in cell processes

physiological concept that explains how early in the course of a nutrient deficiency, when cell
improvements in cellular biochemistry help the body damage is minor and more reversible, can have a
achieve metabolic or physiologic optimization. considerable impact on the prevention and treatment
of disease.
Michael J Gonzalez, DSc, NMD, PhD, FACN
University of Puerto Rico Medical Sciences Campus, Michael J Gonzalez, DSc, NMD, PhD, FACN
Schools of Public Health1, Department of Human University of Puerto Rico Medical Sciences Campus,
Development, Nutrition Program Schools of Public Health1, Department of Human
San Juan PR Development, Nutrition Program
San Juan PR

7.2 I mplications of Subclinical Nutrient

Deficiencies (Nutritional Insufficiencies) 7.3 Nutrient Requirements
of Disease States
A nutritional deficiency is defined as an inadequate supply of
essential nutrients (vitamins and minerals) in the diet, result- Diet and nutrition are important factors in the promotion
ing in malnutrition or disease. Tissue levels are low enough and maintenance of good health throughout the entire life
in one or more nutrients that pathology results primarily course. A change in metabolism occurs following injury,
from the nutritional deficiency and from secondary compli- stress, or infection, characterized by the need for increased
cations. Nutrient deficiency is described in medical pathol- macronutrients and enzymatic cofactors (micronutrients).
ogy textbooks; unfortunately, this is the start and end to The involvement of nutrients in cellular defense and repair
nutritional education for most physicians. A nutritional systems suggests that nutrient requirements are modified by
insufficiency is a subtle deficiency of a nutrient sufficient to pathology. In disease, nutrient-dependent activities are
affect health but not severe enough to cause classic index expanded to include effects that enhance cellular responsive-
deficiency symptoms. Problems here are more of a func- ness to treatment and accommodate accelerated rates of
tional/biochemical nature rather than pathologic, but they metabolic activity. Although specific nutrient requirements
may lead to the disease state. A nutrient dependency refers to for different diseases have not been established, they may be
Metabolic Correction Therapy: A Biochemical–Physiological Mechanistic Explanation of Functional Medicine
91 7
imputed from current knowledge of the chemical, physical, chemistry. Critical enzymes require vitamins and minerals as
and biological properties of each nutrient, the nature of the an integral part of their molecular structure and/or func-
disease, the physiology of tissues involved, the type of treat- tional mechanism of action. Enzymes play a critical role in
ment indicated, and the cellular activities targeted by the regulating and orchestrating the rates of the multitude of
treatment. biochemical reactions that take place in living organisms.
Vitamin deficiencies or coenzyme deficiency can lead to
serious health disorders because important biological pro-
7.4  itamins and Minerals and Hidden
V cesses break down when a lack of coenzymes prevents
Hunger enzymes from catalyzing essential chemical reactions [5].
Two well-known coenzyme vitamins are thiamin and niacin.
Vitamins fall into two general categories: water-soluble and Thiamin compounds serve as coenzymes for a variety of
fat-soluble. Water-soluble vitamins are found mainly in reactions involving cellular energy production, protein syn-
watery or starchy foods such as grains, fruits, and vegetables, thesis, and brain function. Thiamin deficiency causes a disor-
while fat-soluble vitamins are found mainly in fatty foods der known as beriberi, with symptoms such as irritability,
such as butter, nuts, olives, seafood, and organ meats. Only weakness, and even heart failure. Niacin is needed for numer-
water-soluble vitamins function as coenzymes, while cofac- ous reactions related to energy production and fatty-acid
tors can also be minerals and other micronutrients synthesis. Deficiency causes pellagra, which leads to demen-
(. Fig. 7.1).
  tia, skin problems, weight loss, and eventually death.
Vitamins, minerals, and other micronutrients play criti- Inadequate or insufficient dietary intakes of vitamins and
cal roles in a wide variety of highly complex and integrated minerals are widespread [4], most likely due to excessive
cellular processes in human biochemistry. The rate and consumption of calorie-rich, nutrient-poor, refined food.
extent of the enzymatic activity that determines these pro- Suboptimal intake of micronutrients often accompanies
cesses depend on the bioavailability of these micronutrients. caloric excess (hidden hunger). Hidden hunger (or occult
The healthy state where optimal (maximum) functioning, hunger) is a form of undernutrition in which a chronic lack
health, and well-being are achieved may be attained by meta- of vitamins and minerals has no visible warning signs.
bolic optimization therapy. Metabolic optimization is Hidden hunger refers to subclinical deficiencies or nutrient
achieved when we provide the metabolism the necessary insufficiencies from which our population suffers because of
components (form and dose) to reach full velocity and com- our excessive consumption of calorie-rich, nutrient-poor,
pletion of biochemical reactions to attain an optimal meta- refined food. This may be the basis of metabolic disruptions
bolic equilibrium. Thus, metabolic optimization therapy uses that underlie many pathological/disease states. Since we are
a combination of genetic makeup, diet, trauma, diseases, not eating enough of the proper nutrient-dense foods, what
infections, toxins, and environmental stressors, among oth- we end up eating contains insufficient vital nutrients and
ers, which will often elevate the demand of nutrients in order excessive calories. The Standard American Diet lacks essen-
to achieve this optimal metabolic equilibrium. It can be tial nutrients. This state of nutritional insufficiency is a pos-
argued that the true importance of vitamins in human bio- sible reason why millions walk around with headaches, body
chemistry is far from fully elucidated, simply because of the aches, digestive upset, skin problems, sinus problems, fre-
high complexity of cellular processes. What is commonly quent colds, and other signs and symptoms that may quickly
ignored and not fully appreciated is the essential role that disappear when you start taking necessary vitamins and
various vitamins and minerals play in functional human bio- minerals. Nutrition is enhanced through supplementation.

..      Fig. 7.1 Water-soluble
vitamins function as coenzymes

Substrate Active site

Coenzyme
factor
 92 M. J. Gonzalez

Hidden hunger can lead to mental impairment, poor health 7.5 Why Metabolic Correction?
and productivity, or even death.
These inadequate intakes may result in metabolic disrup- Metabolic correction therapy is indispensable because of these
tions [6]. Episodic shortages of micronutrients were com- specific issues:
mon during evolution. Natural selection favors short-term
survival at the expense of long-term health [6]. Short-term
survival was achieved by allocating scarce micronutrients by
7.5.1 Inferior Nutritional Value
nutritional triage [6]. As micronutrients become scarce, a tri-
age mechanism for allocating scarce micronutrients is acti-
of Food and Low Availability
vated. This triage (mechanism) means prioritization of of Nutrient-Dense Foods
relatively scarce nutrients to the most fundamental life-­
preserving functions. In metabolic reactions, enzymes We need to eat a wide variety of food to obtain the nutrients
involved in adenosine triphosphate (ATP) synthesis would we need. A big problem we face is that the nutritional values
be favored over deoxyribonucleic acid (DNA) repair of foods that people eat may be inferior to the listed values
enzymes, as well as over the production of immune system given in food tables. Foods today have less nutrient content
than foods 50  years ago. A study that assessed this issue
7 components and neurological chemicals [5]. When there is a
showed declines in protein (−6%), calcium (−16%), phos-
lack of synergistic components of the metabolic network, an
array of negative metabolic repercussions arise, eventually phorus (−9%), iron (−15%), riboflavin (−38%), and vita-
leading to loss of healthy physiological equilibrium and the min  C (−20%) [4]. There is a dilution effect, in which
development and progression of degenerative diseases. yield-­enhancing methods such as fertilization and irrigation
may decrease nutrient concentrations. Recent evidence sug-
gests that genetically based yield increases may have the
same result, a genetic dilution effect. Modern crops that
»» This triage (mechanism) means prioritization of grow larger and faster are not necessarily able to acquire all
relatively scarce nutrients to the most fundamental
the necessary nutrients, whether by synthesis or from the
life-preserving functions.
water and soil. Today’s foods are not as nutritious as those
Michael J Gonzalez, DSc, NMD, PhD, FACN eaten in the past. A report from the US and UK Government
University of Puerto Rico Medical Sciences Campus, statistics shows a decline in trace minerals of up to 76% in
Schools of Public Health1, Department of Human fruit and vegetables over the period from 1940 to 1991 [10,
Development, Nutrition program 11]. The nutritional decline findings alone give reason to eat
San Juan PR organic fruits and vegetables. In fact, for nearly all nutrients,
organic fruits and vegetables remain the most nutrient-
dense foods [12]. This information makes the updated
nutritional recommendations not so much current as reflec-
The triage theory of optimal nutrition states that the human tive of the need for an increase in fruits and vegetables in
body prioritizes the use of vitamins and minerals when it is order to get the same nutritional benefits as in the past. It is
getting an insufficient amount of them to be able to keep likely that Americans do not come close to the recommen-
functioning [6]. Triage means deciding which patient to dations to limit added sugars, refined carbohydrates, and
treat when faced with limited resources. When nutritional added fats and oils.
resources are limited, physiology (biological intelligence)
must decide which biological functions to prioritize to give
the total organism and the species the best chance to sur-
vive and reproduce. While short-term deficiencies or insuf- 7.5.2 Medication-Induced Nutrient
ficiencies are common, they are often not taken seriously by Depletion, Adverse Side Effects
mainstream medicine. Under such a limited scenario, the of Medication, and Iatrogenic Deaths
body will always direct nutrients toward short-term health
and survival capability and away from regulation and repair There are more than 100,000 deaths annually due to medi-
of cellular DNA and proteins, which ultimately optimize cation properly prescribed and taken as directed by the
health and increase longevity. Dr. Ames’s research shows health provider [13], resulting in extremely high incidence
how bodily insults accumulate over time as a result of vita- of serious and fatal adverse side effects in US hospitals  –
min and mineral insufficiencies and can lead directly to more frequently than is generally recognized. Fatal adverse
age-related diseases. The Triage hypothesis states that the side effects appear to be the fourth leading cause of death in
risk of degenerative diseases (those associated with aging, the USA [13]. If medication is necessary, providing meta-
including cancer, cognitive decline, and immune dysfunc- bolic correction principles may reduce medication require-
tion) can be decreased by ensuring adequate intake of ments, reduce adverse side effects, and improve treatment
micronutrients [5–9]. outcomes [14].
Metabolic Correction Therapy: A Biochemical–Physiological Mechanistic Explanation of Functional Medicine
93 7
7.5.3  o Compensate for the Increased
T higher genetic requirements for many micronutrients. This
Demand of Nutrients discussion seeks to provide a needed better understanding of
due to the Disease State the interrelationship between nutritional biochemistry and
the disease-pathological state.
The body’s nutritional demands increase in acute and chronic
illness [15]. These imbalances are mainly caused by either
deficiencies or insufficiencies of one or more nutrients. 7.5.4  iochemical Mechanism of Metabolic
B
Nutrients function in disease by mechanisms that differ sub- Correction: Molecular Concentrations
stantially from those of pharmacologic agents. Nutrients will and Rate of Reactions
modify nutrient fluxes and metabolic activities that are part
of cellular processes needed for physiological repair, correc- The majority of the chemical reactions in living organisms
tion, and/or balance, whereas drugs will bind to membrane are catalyzed by enzymes. The mechanisms of enzyme-­
receptors and modify their activity to alter cell responsive- catalyzed reactions involve [1] the formation of a complex
ness. Nutrient requirements in the presence of disease are between the enzyme and a substrate and [2] the breakdown
considerably higher than those that have been established to of this complex to form the products of the reaction. The
prevent the symptoms of the classic deficiency diseases. rate-determining step is usually the breakdown of the com-
These requirements can increase incrementally by as much as plex to form the products. Under conditions such that the
10 to more than 100 times the usual amounts (orthomolecu- concentration of the complex corresponds to equilibrium
lar medicine) [16]. At these levels of intake (some at pharma- with the enzyme and the substrate, the rate of the reaction is
cological doses), the roles for most nutrients are expanded to given by the Michaelis–Menten equation [21].
include functions that are not typically observed at normal A certain amount of energy, known as activation energy,
intakes. The higher requirements for nutrients in disease are is needed to initiate any chemical reaction. The fundamental
needed to support the accelerated rate of metabolic activity purpose of enzymes is to facilitate reactions by lowering the
that cellular systems demand in order to reduce the potential activation energy. Enzymes accomplish this by binding to
for permanent damage from the pathophysiological pro- reactant molecules and allowing them to interact in a more
cesses associated with the disease. energy-efficient manner. Reactant molecules bind to
Nutrient imbalances impose a metabolic burden on all enzymes at an intricately structured location known as an
organ systems, with the greatest burden on those systems active site, and the molecule involved in this binding process
responsible for achieving and maintaining metabolic equilib- is called the substrate. Coenzymes, some of which are vita-
rium. Long-term disruption of metabolic equilibrium will mins and some of which are synthesized directly from vita-
most often adversely impact the cardiovascular, pulmonary, mins, activate enzymes by helping the enzyme to bind to its
renal, gastrointestinal, neurological, and/or musculoskeletal substrate.
systems. In the absence of an adequate supply of nutrients to Cofactors (vitamins, minerals, and other compounds)
satisfy normal physiological requirements or adjust to work as enzyme assistants. Coenzymes activate enzymes pri-
increased metabolic demand, compensatory mechanisms marily by assisting the transfer of specific particles or com-
involving one or more of these systems must be initiated to pounds involved in the chemical reaction. For example, some
re-establish homeostasis. As with metabolic adjustments to coenzymes facilitate enzymatic reactions by carrying elec-
address short-term nutrient deficiencies, these compensa- trons and hydrogen ions from one atom to another, while
tory responses are important for correction of temporary others are involved in transporting the entire atoms or larger
imbalances, but if sustained over the long term, they may molecules. Explained another way, an enzyme might not be a
become maladaptive and contribute to the degenerative perfect fit for the intended substrate unless the active site is
changes responsible for development or worsening of chronic modified by the addition of a coenzyme (. Fig. 7.2).
 

diseases. For example, burns lead to loss of protein and The rate of an enzyme-catalyzed reaction is approxi-
essential nutrients [17]. Surgery increases the need for zinc, mately proportional to the concentration of the reactant,
vitamin C, and other nutrients involved in cellular tissue until concentrations that largely saturate the enzyme are
repair [18]. Broken bones need calcium, magnesium, and reached. The saturating concentration is larger for a defective
vitamin C for healing [19]. Infections challenge the immune enzyme with decreased combining power for the substrate
system and place high demands on nutritional resources than for the normal enzyme. For such a defective enzyme,
such as zinc, B-complex vitamins, and vitamin C [20]. The the catalyzed reaction could be made to take place at or near
same nutritional demand is present when exposed to its normal rate by an increase in the substrate concentration.
­chemical, physical, and emotional stress. This mechanism of action of gene mutation is only one of
People taking medications for chronic diseases are at several that lead to disadvantageous manifestations that
higher risk of interactions between these drugs and nutri- could be overcome by an increase in the concentration of
ents. There are thousands of conceivable genetic defects enzymatic cofactors. These binding problems may result in
(inborn or acquired), so it is likely that many people have metabolic inefficiency with the accumulation of metabolic
 94 M. J. Gonzalez

Cofactor
Non-active site of enzyme

7
Substrate Coenzyme

Active site of the

Enzyme

..      Fig. 7.2  Coenzymes bind to the reactant active site substrate of the enzyme, with cofactors as “helper molecules” that assist in biochemical
transformations

byproducts. In general, this is the Law of Mass Action: As the development and progression of diseases. Moreover,
vitamin and mineral concentration increases, enzyme effi- Motulsky has argued that many of the common degenerative
ciency increases. These considerations suggest a rationale for diseases are the result of the imbalance of nutritional intake
metabolic correction to provide the needed cofactors in the and genetically determined needs [23, 24].
amount needed to improve function. This increased enzyme Chromosome breaks lead to mutations that precede tis-
efficiency may allow a genetic defect to be overcome. This sue damage and disease. Many types of physiological impair-
biochemical activity follows the chemical Principle of Le ments due to inadequacy of vitamins and minerals can lead
Chatelier, which states that when stress is applied in an equi- to suboptimal organ system function, including poor drug
librium situation, it will move to the direction to minimize metabolism, insufficient neurotransmitter production, and
stress. In this case, there is an unfavorable equilibrium of impaired immune defenses. Chronic vitamin–mineral
active enzyme that, with the addition of the necessary nutri- undernutrition reduces immune competency and central
ents, will be moved toward a more physiologically favorable nervous system efficiency; it may increase morbidity, which
metabolic state [22]. may lead to degenerative diseases. This approach to optimize
Many human genetic diseases due to defective enzymes health by improving enzyme efficiency, and thereby metabo-
can be remedied or ameliorated by the administration of lism and physiology, is the basis of metabolic correction as a
high doses of the vitamin component of the corresponding therapeutic approach.
coenzyme (metabolic correction), which can partially restore
the enzymatic activity [5]. For several single-nucleotide poly-
morphisms in which the variant amino acid reduces coen- 7.6 B-Complex and Metabolism Briefing
zyme binding, enzymatic activity can be remedied by raising
cellular concentrations of the cofactor through high-dose The basic B-complex consists of a group of eight water-­
nutrient therapy (orthomolecular therapy). soluble compounds: thiamin (vitamin B1), riboflavin (vita-
Inadequate intakes of vitamins and minerals from food min B2), niacin (vitamin B3), pantothenic acid (vitamin B5),
can lead to DNA damage, mitochondrial decay, and other pyridoxine (vitamin B6), cobalamin (vitamin B12), folate
pathologies [3]. Ames suggests that evolutionary allocation (vitamin B9), and biotin (vitamin B7). Although each B vita-
of scarce micronutrients by enzyme triage is an explanation min is chemically distinct, they often work together in vari-
of why DNA damage is commonly found along with micro- ous biochemical functions throughout the body, from cellular
nutrient deficiency [3]. This particular situation favors the energy production to healthy red blood cell formation to
Metabolic Correction Therapy: A Biochemical–Physiological Mechanistic Explanation of Functional Medicine
95 7
healthy neurological function. Most B vitamins, with the 7.7 B-Complex and Metabolic Correction
exception of vitamin B12, are not stored in the body. They
must be acquired daily from the diet in order to maintain B-complex vitamins are essential for optimum metabolism.
optimal health. Michaelis developed a set of mathematical expressions to cal-
Supplementing with bioactive B vitamins (e.g., methyl culate enzyme activity in terms of reaction speed. The
folate) is important to everyone, especially individuals who Michaelis constant Km is defined as the substrate concentra-
may not be able to convert inactive or synthetic vitamins to tion at half the maximum velocity. For practical purposes,
their active forms in the liver because of compromised liver Km is the concentration of substrate that permits the enzyme
function, poorly functioning enzymes, digestive distur- to achieve half of its maximum activity.
bances, genetics, or age. Dietary supplements containing An example of metabolic correction is that high-dose B
these active cofactors have enhanced bioavailability, ensuring vitamins can counteract a poor Km. As many as one-third of
the body gets the nutrients it needs. mutations in a gene result in the corresponding enzyme hav-
Every process that goes on inside our bodies requires ing an increased Km (decreased binding affinity) for a coen-
energy, specifically metabolic energy. When the body does zyme, causing a lower rate of reaction [5, 7]. About 50
not have enough energy to function properly, different com- different human genetic diseases are due to a poorer-binding
ponents of the body may malfunction in their own ways. For affinity of the mutant enzyme for its coenzyme. This can be
example, if the brain does not have enough energy, cognitive corrected by feeding high-dose B vitamins, which raise levels
processes, such as memory and focus, may become impaired. of the corresponding coenzyme; many polymorphisms also
The body converts fats, sugars, and proteins into ATP that is result in a lowered affinity of enzyme for coenzyme [5, 7] and
then used for energy. However, there are other factors thus may be, in part, remediable.
involved that can affect how well our body can make this To summarize, metabolic correction has three important
conversion into the ATP molecules. The thyroid hormones biological actions:
are essential in maintaining and regulating the body’s metab- 1. Optimizes cellular function by improving enzymatic
olism. The thyroid gland makes the hormone T4 (thyroxine). efficiency
T4 converts to T3 (triiodothyronine) and RT3 (reverse T3, 2. Produces a pharmacological effect to correct abnormal
rT3). T3 turns on the ATP (energy), while RT3 is a way to get cell function due to biochemical disarray occasioned by
rid of any unneeded T4, thus reducing energy output. This the disease process
happens because the adrenal glands are too weak to handle 3. Provides a compensatory response to nutrient imbal-
the stress of the body’s normal metabolic energy and force a ances in order to re-establish physiological homeostasis
downregulation of energy production.
Triiodothyronine (T3) is the most active thyroid hor- An optimum intake of micronutrients and metabolites – which
mone. Approximately 85% of circulating T3 is produced by varies with age, environmental factors, and genetics – should
mono-deiodination of thyroxine (T4) in tissues such as the tune up metabolism and markedly increase health at a modest
liver, muscle, and kidney. Production of these thyroid hor- cost, particularly for the poor, obese, and elderly [7].
mones is controlled by TSH (thyroid-stimulating hormone),
which is released by the pituitary gland in the brain. The pitu-
itary takes its orders from the hypothalamus. The adrenal
glands, located on top of each kidney, help the body deal with 7.8  en Principles of the Concept
T
stress. If the metabolic activity is excessive, the adrenals per- of Metabolic Correction in Disease
ceive this as a stress. In response to this stress, the hypothala- Therapy
mus will signal the pituitary to produce less TSH, thus
producing decreased T4 and thyroid activity. This metabolic 1. Metabolic correctors, along with proper nutrition,
control activity utilizes various enzymes whose main cofac- should come first in medical treatment. Knowledge of
tors are B-complex vitamins. the safe and effective use of nutrient combination,
Lack of B vitamins may lead to hypothyroidism because enzymes, hormones, and other naturally occurring
the thyroid gland cannot make enough T4 [25]. molecules in their bioactive forms is essential to ensure
Hypothyroidism is a condition in which an underactive thy- an effective outcome. However, some patients may
roid gland produces less than optimal amounts of thyroid need more acute treatment for their particular condi-
hormone. A lack of the thyroid hormones can lead to fatigue, tion, for which pharmacological therapy is recom-
constipation, hoarse voice, puffy face, unexplained weight mended.
gain, pain and stiffness in the joints, muscle weakness, sensi- 2. Metabolic correctors have a low risk of toxicity.
tivity to cold, elevated cholesterol levels, brittle nails, and Pharmacological drugs often carry a risk of negative
depression. Hypothyroidism has also been linked to other side effects and, in a chronic condition, should be the
health issues, such as heart disease, infertility, autoimmunity, second choice if there is a metabolic correction alterna-
and obesity. tive available.
 96 M. J. Gonzalez

3. Detect nutrient deficiencies: Some laboratory tests might be 7.9  eyond Metabolic Correction:
B
useful in identifying the nutritional needs of some Improving the Healthcare
patients. These tests could be of special importance to Management Model
patients who present genetotrophic diseases or genetic
polymorphism associated with specific conditions. Metabolic correction should be a fundamental consideration
However, some laboratory tests do not necessarily reflect of a complete healthcare plan, and the fundamental root causes
nutrient and enzyme levels within specific organs or of the prevalent conditions must be identified and addressed to
tissues, particularly in the nervous system. The need for achieve optimal therapeutic results. Unfortunately, medical
laboratory testing for nutrients varies among individuals. guidelines often do not assess these root causes of disease in
For many patients, therapeutic trial and dose titration is each individual case. Therefore, comprehensive laboratory
often the most practical therapy approach, especially when testing is mandatory to identify etiological factors and monitor
utilizing synergistic metabolic correction formulations. progress toward the desired outcomes. This approach allows
4. Biochemical individuality is a central precept of meta- for correlating objective laboratory tests with functional evalu-
bolic correction. Hence, the search for optimal nutrient ations and patient signs and symptoms. We know that a certain
combination doses is a practical issue. Doses of combination of nutrients can improve physiological function.
7 nutrients and their combinations above the recom- However, giving the necessary nutrients will have limited
mended daily allowances are often effective. Many results if environmental contaminants such as pesticides,
patients tolerate optimal doses and respond well; heavy metals, medications, or an undetected chronic infection
however, dose titration is indicated in otherwise are affecting the patient. Therefore, to achieve metabolic cor-
unresponsive cases. rection and the best physiological function possible, it is neces-
5. Recommended daily allowances (RDA) for diseased sary to correct the underlying cause of the problem. This
individuals. RDAs for nutrients are intended for involves providing the necessary nutrients for repair, correc-
normal, healthy people. By definition, diseased patients tion, and improved enzymatic activity, which must include
are not normal or healthy and not likely to be ade- removing the contaminants present [29].
quately served by obtaining just the recommended daily
allowances. Practically every person is deficient or
insufficient in a nutrient at some level due to an
insufficient diet among other limiting factors (genetics, »» Metabolic correction should be a fundamental
medication, toxins, etc.). consideration of a complete healthcare plan, and
6. Environmental pollution of air, water, and food is an the fundamental root causes of the prevalent
increasing problem and more common than is generally conditions must be identified and addressed in
recognized, posing a very important risk factor for order to achieve optimal therapeutic results.
mitochondrial damage and related diseases such as cancer
Michael J. Gonzalez, DSc, NMD, PhD, FACN
and neurometabolic disorders [26, 27]. Diagnostic search
University of Puerto Rico Medical Sciences Campus,
for toxic pollutants and treatment is necessary to identify
Schools of Public Health1, Department of human
these factors and design a proper treatment approach.
Development, Nutrition Program
7. Monitor and update metabolic correction over time.
San Juan PR
Optimal health is a lifetime challenge. Biochemical needs
change, and our metabolic correction prescriptions need
to change based upon follow-up, repeated testing, and
therapeutic trials to permit fine-tuning of each prescrip- To improve outcomes beyond current standards, it is neces-
tion and to provide the best possible health outcome. sary to improve our health models to include detection of all
8. Nutrient-related disorders are always treatable, and significant underlying causes of disease. In addition to a
deficiencies and insufficiencies are curable. Most comprehensive medical history and a complete physical
diseases encounter some nutrient-related disruption. To examination, there should be comprehensive laboratory test-
ignore their existence is malpractice. ing that includes whole-genome sequencing, inflammation,
9. Nutrigenomics and pharmacogenomics. Genetic and immune testing, heavy metals, xenobiotics, nutrient, food
hereditary disorders are often responsive to metabolic intolerance/sensitivities, and metabolic panels for a complete
correction because it takes advantage of nutrigenomics patient assessment.
and pharmacogenomics [28].
10. Inspire active role-taking responsibility for your health.
Inspire patients to understand that health is not merely 7.10 Conclusion
the absence of disease, but the positive attainment of
optimal function and well-being. This requires an To encourage the most efficient metabolism, we need basic
individual to take an active role in necessary lifestyle macronutrients required for fuel: fat, protein, and carbohy-
changes, and it requires a commitment to continuous drate. But we also need about 15 vitamins that are coenzymes
education along with a responsible attitude about health. and about 15 minerals that are required for enzyme function.
Metabolic Correction Therapy: A Biochemical–Physiological Mechanistic Explanation of Functional Medicine
97 7
We also need two essential fatty acids (omega-3 and omega- 5. Ames BN, Elson-Schwab I, Silver EA.  High-dose vitamin therapy
­6) and seven or eight essential amino acids. In addition, other stimulates variant enzymes with decreased coenzyme-binding
affinity (increased Km): relevance to genetic disease and polymor-
important nutrients  – such as coenzyme Q10, acetyl-L-­ phisms. Am J Clin Nutr. 2002;75:616–58.
carnitine, and lipoic acid  – must also be considered in our 6. Ames BN. Low micronutrient intake may accelerate the degenera-
quest for physiological optimization. Virtually every meta- tive diseases of aging through allocation of scarce micronutrients
bolic pathway requires micronutrients. by triage. Proc Natl Acad Sci U S A. 2006;103:17589–94.
What determines the optimal concentration of a nutrient 7. Ames BN. The metabolic tune-up: metabolic harmony and disease
prevention. J Nutr. 2003;133(5 Suppl 1):1544S–8S.
is its physiological functionality. While most people function 8. Ames BN.  A role for supplements in optimizing health: the meta-
below 100% efficiency, they nevertheless do not present any bolic tune-up. Arch Biochem Biophys. 2004;423:227–34.
detectable disease or significant symptoms. Yet, we can 9. Ames BN, Suh JH, Liu J. Enzymes lose binding affinity for coenzymes
improve their functionality if we supply them with the needed and substrates with age: a strategy for remediation. In: Rodriguez
micronutrient substances in optimum concentrations. Certain JKR, Kaput J, editors. Nutrigenomics: discovering the path to per-
sonalized nutrition. Hoboken: Wiley; 2006. p. 277–93.
individuals have a greater need than that supplied by the diet 10. Worthington V. Nutritional quality of organic versus conventional fruits,
(even if a good dietary regime is followed). This could be vegetables, and grains. J Altern Compliment Med. 2001;7:161–73.
caused by an array of variables (digestive problems, malab- 11. Leape LL. Institute of medicine medical error figures are not exag-
sorption, food sensitivities, metabolic dysfunction, low levels gerated. JAMA. 2000;284:95–7.
of neurotransmitter precursors, etc.). This lack of needed 12. The Organic Center. State of science review: nutritional superiority
of organic foods. 2008. Retrieved: https://www.­organic-center.­org/
micronutrient cofactors manifests insidiously and is difficult reportfiles/NutrientContentReport.­pdf. Accessed 29 Jul 2017.
to identify. Some vague symptoms may be present, such as 13. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reac-
lethargy, irritability, insomnia, and difficulty in concentrating. tions in hospitalized patients: a meta-analysis of prospective stud-
This also affects the body’s ability to resist disease and infec- ies. JAMA. 1998;279:1200–5.
tion, its ability to recover from exercise, surgery, or disease, 14. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, et al. Metabolic cor-
rection in the management of diabetic peripheral neuropathy:
and the ability of the brain to function at an optimal level. improving clinical results beyond symptom control. Curr Clin Phar-
Detecting and treating disease at its earliest stages of cellular macol. 2011;6:260–73.
biochemical abnormality, rather than waiting for clear clinical 15. Richardson RA, Davidson HIM.  Nutritional demands in acute and
symptoms, is cost-effective and of benefit to the patient. chronic illness. Proc Nutr Soc. 2003;62:777–81.
Nutrient deficiency diseases are the end product of a 16. Williams RJ, Kalita DK, editors. A physician’s handbook on orthomo-
lecular medicine. Oxford: Pergamon Press; 1978.
long and complex series of nutrient depletion reactions. We 17. Prins A.  Nutritional management of the burn patient. S Afr J Clin
need to abandon outdated paradigms framing nutrient Nutr. 2009;22:9–15.
intake as needed merely to prevent deficiencies and expand 18. Rahm DH, Labovitz JM. Perioperative nutrition and the use of nutri-
them to include preventing chronic degenerative diseases tional supplements. Clin Podiatr Med Surg. 2007;24:245–59.
and achieving optimal health. Metabolic correction provides 19. Kakar S, Einhorn T.  Importance of nutrition in fracture healing. In:
Holick M, Dawson-Hughes B, editors. Nutrition and bone health.
the biochemical–physiological explanation of how to achieve Totowa: Humana Press, Inc; 2004. p. 85–103.
this state of metabolic harmony and health. Metabolic cor- 20. Bendich A. Antioxidant vitamins and human immune responses. Vit
rection therapy used as a comprehensive model can provide Horm. 1996;52:35–62.
a systematic, rational, evidence-based, proactive, individual- 21. Pauling L.  Orthomolecular psychiatry. Varying the concentrations
ized, and integrated decision-making process. That process of substances normally present in the human body may control
mental disease. Science. 1968;160:265–71.
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standing metabolic correction for its potential to elevate our Med. 1981;3:12–22.
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1987;45:1108–13.
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 99 8

The Nutrition Assessment

of Metabolic and Nutritional
Balance
Margaret Gasta

8.1 Introduction – 101

8.2 The Microbiome – 101

8.3 Fiber – 102

8.4 Iodine – 103

8.5 B Vitamins – 104

8.5.1 T hiamine (Vitamin B1) – 107
8.5.2 Riboflavin (Vitamin B2) – 107
8.5.3 Niacin (Vitamin B3) – 107
8.5.4 Pantothenic Acid (B5) – 107
8.5.5 Vitamin B6 – 107
8.5.6 Folate (Vitamin B9) – 108
8.5.7 Vitamin B12 – 108

8.6 Fat-Soluble Vitamins – 109

8.6.1  itamin D and Vitamin K – 109
V
8.6.2 Vitamin A and Vitamin D – 109
8.6.3 Tocopherols and Tocotrienols – 110

8.7 Minerals – 110

8.7.1  alcium and Magnesium – 110
C
8.7.2 Sodium-to-Potassium Ratio and Hypertension – 112
8.7.3 Zinc and Copper – 112
8.7.4 Assessing Zinc Status – 114
8.7.5 Copper-to-Zinc Ratio in Cancer – 114

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_8
8.8 Fatty Acids and Phospholipids – 114
8.8.1 F atty Acid and Phospholipid Balance – 114
8.8.2 Gamma-Linolenic Acid – 116
8.8.3 Conjugated Linoleic Acid – 116
8.8.4 Phospholipids – 117
8.8.5 Short-Chain Fatty Acids – 117
8.8.6 Increasing Beneficial Fatty Acids – 118
8.8.7 Assessing Erythrocyte Fatty Acid Profiles – 118
8.8.8 Hydrogenated Oils – 119
8.8.9 Overall Diet and Macronutrient Distribution – 119

8.9 Summary – 119

References – 120
The Nutrition Assessment of Metabolic and Nutritional Balance
101 8
8.1 Introduction
The key considerations for nutritional balance are
The field of integrative and functional nutrition is expected, as follows:
by its very nature, to be progressive and on the cutting edge 55 The microbiome: use of probiotics and foods in
of new concepts in nutrition. Patients in desperate need of different gastrointestinal conditions
healing seek out reliable, valid, and progressive solutions 55 Fiber: appropriate needs for different diagnoses
from their nutritionist. The constant barrage of changing 55 Iodine: finding the right balance and removing
nutritional recommendations should teach integrative and antagonistic toxic halogens
functional nutrition practitioners to hold the principle of 55 B vitamins: appropriate amounts and forms based
nutritional balance at the core while new findings continue to on biochemical individuality
come forth. 55 Mineral balance: sodium, potassium, zinc, copper,
Fad diets and supplements will come and go through the magnesium, calcium iron
decades, and it is important to always question the long-term 55 Vitamin D status: associated requirement for
consequences of every proposed new nutritional concept. magnesium
Concurrently, nutritionists must keep an open mind for 55 Fat-soluble vitamins: individual requirements
something that may help a patient with a puzzling condition. 55 Omega-6 and Omega-3 fatty acids: ratios,
What may seem extreme and/or inappropriate for one per- adequate gamma-linolenic acid (GLA), and
son may be lifesaving for another. Many human genetic dis- specialized proresolving mediators (SPM)
eases, due to defective enzymes, may be ameliorated by high 55 Micronutrient and macronutrient ratios in
doses of specific nutrients required as cofactors for the different disease processes
enzyme to partially restore activity of that enzyme [1]. Over
the lifespan, metabolic and biochemical needs change and
nutritional balance should be periodically reassessed and 8.2 The Microbiome
rebalanced [1]. Furthermore, detecting and addressing dis-
ease at its earliest stage of biochemical imbalance, rather than One of the core principles of Integrative and Functional
waiting for the condition to progress to a diagnosed disease, Medicine Nutrition Therapy (IFMNT) is biochemical indi-
is a cost effective and physiologically beneficial approach for viduality, and recommendations for the feeding and care of
the patient. individual microbiome are no exception. Although we are far
“Biochemical individuality,” first proposed by Roger from fully understanding the microbiome, certain research-­
J.  Williams in 1947, refers to differing metabolic needs for guided patterns have begun to emerge. For instance, the con-
optimal physiological function and infers that nutritional ditions of obesity, type II diabetes, and nonalcoholic liver
balance for one person may require different amounts of disease are associated with a higher abundance of the phylum
nutrients than for another person [1]. One of the founda- Firmicutes compared with Bacteroides [4]. In certain disease
tional principles of integrative and functional nutrition is to states, we might find that overgrowth or subclinical bowel
recognize each person’s unique nutritional needs. If practi- infections of normally occurring commensal bacteria, such
tioners rely on nutritional studies as a guide to establishing as the Klebsiella microbes, may be associated with autoim-
optimal nutrient intake for individuals, as opposed to using mune diseases such as Sjogren’s syndrome, ankylosing spon-
individualized nutrient assessment, this may pose challenges. dylitis, rheumatoid arthritis, or Crohn’s disease [5].
For instance, many nutrition studies fail to show a benefit of Research suggests that changing the diet to one that is
supplementation due to flawed study design, as investigators plant-based and high in fiber is a rapid, effective way to cause
often fail to establish baseline nutrient status of study partici- a beneficial change in our intestinal microbiome [6].
pants to accurately measure outcomes [2]. Testing and retest- Conversely, for those with irritable bowel syndrome (IBS),
ing may be one of the most helpful tools to keep clients’ small intestinal bacterial overgrowth (SIBO), or inflamma-
nutritional status in balance and provide metabolic correc- tory bowel disease (IBD), this approach may not be appropri-
tion. Integrative and functional nutritionists have a vast array ate. Foods high in certain types of fiber such as highly
of tools to choose from in this regard. fermentable oligosaccharides, monosaccharides, disaccha-
To assess nutritional imbalance, a clinician can use a rides, and polyols (FODMAPs) may result in rapid gas pro-
nutritional physical exam, conventional and integrative labo- duction and discomfort for those with IBS and possibly those
ratory testing, as well as signs and symptoms. When imbal- with SIBO or IBD [7]. Additionally, therapeutic diets for
ance is found, such as a zinc deficiency, calling for diet change autoimmune disease may consist of grain-free, nut-free,
and supplement intervention, one must then pay attention to dairy-free, egg-­free, and legume-free diets which would
the balance of other nutrients that may be negatively affected, make it almost impossible to successfully implement a solely
such as copper status. Another example of this is the critical plant-based diet. However, many plant foods can be incorpo-
role that magnesium plays in the synthesis and metabolism rated into an autoimmune diet to promote a healthy microbi-
of vitamin D and parathyroid hormone [3]. ome. Diets need to be individualized in every circumstance.
 102 M. G. Gasta

Stool cultures may show that certain strains of beneficial over 50 [9]. The amount of fiber recommended for children
bacteria, such as Bifidobacterium, are low, and a specific sup- is the child’s age plus 5 grams per day; an 8-year-old child, for
plemental probiotic strain might be indicated. Recurrent instance, is recommended to consume 13 grams of fiber per
infections such as H. pylori or Strep pyogenes may also indi- day. However, Americans average 15 grams of fiber per day,
cate specific strains of probiotics to be used. which is very low, and only 3% of the population meets the
recommendations for fiber intake [9, 12].
Most plant foods are a mix of soluble and insoluble fiber
8.3 Fiber [13]. Some key sources of insoluble fiber include wheat bran,
psyllium, quinoa, nuts–seeds, pine nuts, and flaxseed. Key
Fiber intake is critical for gut ecology because of its role as sources of soluble fiber include beans, oats and oat bran,
fuel for the microbiome [8]. Many food sources of fiber con- psyllium, barley, prunes, figs, pears, leafy greens, cauliflower,
tain a mix of both soluble and insoluble fiber. Soluble fiber broccoli, flaxseed, acorn squash, and potatoes. Cozma-Petrut
becomes gel-like and is fermented by friendly bacteria in the and colleagues suggest a new classification of fiber that
colon to make short-chain fatty acids (SCFA). Insoluble fiber includes solubility, fermentability, viscosity, and gel forma-
is not only indigestible but also important for stool bulking tion [13]. Examples of these categories include insoluble
and better gut motility. Eating a wide variety of plant foods poorly fermented (wheat bran), soluble, nonviscous readily
ensures a wide variety of the different types of fibers includ- fermented (inulin), soluble, viscous gel-forming readily fer-
ing pectin, gum, mucilage, cellulose, hemicellulose, lignin, mented (beta-glucans), soluble viscous–gel-forming low or
8 and soluble fiber. The peels of fruits and vegetables are high non-fermentability (psyllium) [13].
in fiber, although all peels may not be edible or palatable. Several studies suggest that the best tolerated and most
Beneficial bacteria ferment soluble fiber, which produces effective fiber for IBS are those with low fermentability, such
short-chain fatty acids (SCFA) that, in turn, serve as a fuel as psyllium [13]. For IBS, soluble fiber was found to be better
source to colonocytes [8]. The fermentation of soluble dietary tolerated and possibly helpful compared with insoluble fiber
fiber by the microbiota produces SCFA that promote such as wheat bran, which may worsen symptoms [7]. For
increased gut cellular proliferation and differentiation, lower IBS, an intake of 20–30 grams per day of soluble viscous
intestinal pH which makes the gut more resistant to patho- fibers with low rate of fermentation, such as psyllium and
gens, and regulates inflammation. Fiber improves the health ground flax seeds, starting with a low dose and slowly
of the gut barrier by promoting tight junctions and increas- increasing is recommended, at a rate of not more than 5
ing the production of mucins that play a role in forming grams per week [7]. Psyllium husks and powder should
mucus to protect the gut barrier [8]. always be mixed in plenty of fluid.
Butyrate, a SCFA produced by fermentation of fiber, may A novel concept regarding fiber intake for those with
decrease the risk of colon cancer by inducing apoptosis in chronic idiopathic constipation is that these individuals may
tumor cells [9]. The 2011 Colorectal Cancer Report found have worsening symptoms when consuming a high-fiber
evidence that for every 10 grams per day increase in fiber diet. Ho et al. [14] conducted a prospective longitudinal case
intake, there was a 10% decrease in colorectal cancer risk study on subjects with chronic idiopathic constipation that
[9]. Fiber aids healthy elimination of toxins through the showed marked improvement in constipation and bloating
enterohepatic circulatory system with higher elevation of in subjects who consumed a low-fiber or no-fiber diet com-
SCFAs while adding bulk to the stool to assist motility pared with those who stayed on a high-fiber diet. The authors
through the gut [8]. In general, consuming a variety of point out that most individuals who visit medical practitio-
dietary fiber helps promote diversity of gut microbiota, ners for chronic constipation are already consuming a very
which supports a more robust state of health [8]. A 2017 high-fiber diet to self-treat their constipation [14]. Those
report of the gut microbiome of the Hadza hunter–gatherers who improve on a low-fiber diet may have bacteria that are
of Tanzania who average 100–150 gm of fiber/day showed fermenting the fiber which may contribute to bloating and
much greater microbiota diversity when compared with constipation [14]. Fiber creates bulk in the stool that can
Americans who consume only about 15 grams of fiber per make it more difficult to expel and can result in straining and
day [10]. Fiber intake from legumes, fruits, vegetables, and fissures [14]. Fiber can slow peristalsis and result in a buildup
nuts had a protective effect against CVD events, and cereal of gas that becomes difficult to expel [14].
fiber was associated with a lower risk of stroke and ischemic When adding fiber supplements to the diet, nutritionists
stroke [11]. Fiber intake is inversely associated with cardio- need to use caution and start with low amounts and increase
vascular disease, body weight, type II diabetes, some can- water intake so as not to cause constipation or a bezoar
cers, and chronic diseases [12]. (intestinal blockage of a solid mass of indigestible material
The recommended amount of fiber in the UK is 30 grams that accumulates in the digestive tract). In addition, if clients
per day, while it is 14 grams for every 1000 calories in the complain of severe constipation or of not having had a bowel
United States [12]. The Institute of Medicine recommends 38 movement for days or weeks, do not recommend fiber sup-
grams per day for men aged 50 and younger and 30 grams for plements until the constipation has resolved. It may be pru-
males over 50. For women, the recommendation is 25 grams dent to recommend they visit a physician to uncover the
daily for those 50 and younger and 21 grams daily for those cause of the protracted constipation. In this author’s clinical
The Nutrition Assessment of Metabolic and Nutritional Balance
103 8
experience, prunes, magnesium, vitamin C, flaxseed oil, or g­ eneral population, 220–250 mcg/day during pregnancy, and
the herbal blend triphala, and aloe vera juice can be helpful in 250–290 mcg/day of iodine during lactation [15]. The WHO
these cases, although caution is recommended for the use of uses median spot urinary iodine concentrations of 100 mcg/L
aloe vera juice. At times, a physician-prescribed laxative is to represent an intake of 150 mcg/day and 100–190 mcg/L
needed to clear a blockage. The nutritionist can follow this per day to define adequate intake for a nonpregnant popula-
intervention with constipation prevention techniques (e.g., tion [15]. Excessive iodine intake is classified by the WHO as
diet, 5-HTP, magnesium, etc.). In addition, referral to an the median urinary iodine excretion >300 mcg/L for general
integrative or naturopathic practitioner may help to manage population and >500 mcg/L for pregnant women [16].
lifelong constipation issues with other interventions such as To assess iodine status, a clinician may use clinical mani-
homeopathics, herbals, acupuncture, and the like. festations such as thyroid size, combined with detailed his-
Notwithstanding all the benefits of fiber, the nutritionist tory focused on the dietary iodine intake and a history of
may find it challenging to help patients consume a wide frequent or current infection, and laboratory testing for
variety of fiber when certain gastrointestinal conditions serum thyroglobulin, thyroid-stimulating hormone (TSH),
exist. Judicious use of different fibers will be required for dif- and urinary iodine [15]. Urinary iodine reflects recent iodine
ferent gastrointestinal disease states and symptomatology. intake within days, whereas thyroglobulin represents iodine
Determining the cause of a person’s distress may be helpful intake over a period of months, and thyroid size assessment
in determining which type of fibers will be tolerated. An represents iodine intake for a period of years [15]. Either spot
example is someone with severe IBS.  Certain fermentable urine or 24-hour urine collection iodine testing may be used.
fiber products may worsen the symptoms. Instead of Spot urinary iodine is more useful for assessing populations
improving the person’s health, these products may cause rather than the individual patient, as anything less than 10
increased distress and worsen their constipation or diarrhea. urine samples in an individual is considered misleading due
Those with celiac disease (CD) might be made worse with oat to diurnal variations [16]. Urine iodine levels also vary
fiber and certainly with wheat bran. Standard high-fiber greatly in and between individuals based on the amount of
foods often recommended such as beans, oats, apples, pears, iodine consumed in a day and the level of fluids ingested by
plums, cashews, and pistachios might worsen constipation in the individual [15]. Expressing the ratio of urinary iodine to
someone with IBS, SIBO, or aggravate cases of IBD. In addi- creatinine may be especially useful when estimating 24-hour
tion, healthy high-fiber seeds such as chia seeds, hemp seeds, urinary iodine [15].
and flax seeds might be damaging to sensitive individuals. Those at risk with iodine-deficient diets include vegans
Being familiar with FODMAPs, SIBO diets, the specific car- and people who avoid dairy or iodized salt, as well as athletes
bohydrate diet, and a low-residue diet is essential in helping who experience excessive sweating [15]. Alternatively, people
patients with certain GI conditions to recover. Combing the who consume kelp may have excessive iodine intakes [15].
market for suitable fiber supplements can be an arduous task Goiter is thought to be an adaptation to chronic iodine defi-
but highly recommended, as one size does not fit all. ciency as low iodine intake leads to reduced thyroid hormone
In summary, dietary fiber is a critical component to production, which stimulates TSH production from the pitu-
maintaining balance and diversity in gut ecology. Fiber can itary gland. Goiter results as increased TSH increases iodine
help normalize gut transit time, promote mucus production, uptake, which stimulates thyroid growth [15]. In adults,
and strengthen the gut barrier. Promoting the proper intake the thyroid may develop nodules as it enlarges [15]. For
of fiber and water is crucial to improving the health of our those with overt hypothyroidism due to iodine deficiency,
clients. For those with IBS or chronic constipation, instead of Niwattisaiwong et  al. recommend initiating levothyroxine
using highly fermentable fiber grains, flax seeds, chia seeds, treatment along with iodine supplementation by using
or fermentable fiber supplements, clinicians may simply want iodized salt or a multivitamin containing approximately 150
to recommend a diet that uses FODMAP-compliant fruits, mcg of iodine [15]. When urine iodine has normalized and
vegetables, and increasing water intake. For these individu- goiter has decreased, consider decreasing the thyroid treat-
als, adding Bifidobacter probiotic supplements with the fiber ment, but reassessing thyroid status in 4–6 weeks after stop-
may also be essential. If psyllium is to be added, start with ping levothyroxine [15]. While mild gestational iodine
very low doses; this author recommends 1–2 grams/day to deficiency does not result in cretinism (severe mental retar-
start and slowly build up depending on individual tolerance. dation and other neurologic or physical defects), children
The herbal blend called triphala, as well as supplemental born to mothers with mild gestational iodine deficiency were
magnesium citrate, can be helpful with chronic constipation. found to have reductions in spelling, grammar, and English
literacy performance [15].
In the recent past, high-dose supplemental iodine between
8.4 Iodine 12 mg and 50 mg (12,000 mcg– 50,000 mcg) was a common
recommendation in the integrative and functional medicine
Iodine is an essential element needed for thyroid hormone community for preventing breast cancer and helping with
synthesis and fetal neurodevelopment [15]. The World subclinical or overt hypothyroidism. While adequate amounts
Health Organization (WHO) and the US Institutes of of iodine are required for healthy thyroid function, a need for
Medicine recommend 90–150 mcg/day of iodine for the caution exists if using supplemental iodine. The American
 104 M. G. Gasta

Thyroid Association (ATA) recently released a statement

..      Table 8.1  Tolerable upper intake levels for chronic iodine
advising against the use of >500 mcg of iodine daily through ingestion
dietary supplements [16]. Excessive amounts of iodine can be
an environmental factor linked to the development of auto- Age Male Female Pregnancy Lactation
immune thyroiditis and can cause hypothyroidism, hyper-
thyroidism, cancers, and autoimmune thyroid disease [17]. Birth to 200 mcg 200 mcg
1 year
This can especially be a concern for autoimmune-­prone indi-
viduals who are at risk of developing thyroid autoantibodies 1–3 years 300 mcg 300 mcg
[17]. Iodine causes cytokine and chemokine-mediated lym- 9–13 600 mcg 600 mcg
phocyte infiltration in autoimmune-­prone individuals, which
is a key element in the production of thyroid autoantibodies 14–18 900 mcg 900 mcg 900 mcg 900 mcg
[17]. Excess iodine is also thought to produce oxidative ≥19 1100 mcg 1100 mcg 1100 mcg 1100 mcg
stress-related injury to thyrocytes, and active lipid peroxida-
tion can occur after high-­dose iodine administration [17]. Based on data from Institute of Medicine (US) Panel on
Excessive iodine, an example of poor nutritional balance, Micronutrients [18]
can easily occur and is becoming a more common concern Note: The American Thyroid Association recently advised against
due to high levels of salt iodization, iodine in supplements, consuming >500 mcg of iodine daily in supplements [16]
and regular consumption of iodine-rich foods [17]. Iodine
8 toxicity has been reported due to overconsumption of sea-
weed in Asian countries [17]. Drinking water can also be a
source of iodine excess in places such as Somalia, Saharawi, fluoride. Chlorine is present in swimming pools and chlori-
and Europe and can occur from the use of water purification nated drinking water [20].
systems that contain iodine [17]. In Western countries, dairy Current recommendations point to iodine supplementa-
can be a source of excessive iodine from the animal feed and tion between 300 and 500 mcg per day with diet and lifestyle
equipment-cleaning products used in the dairy industry changes to support healthy thyroid function. If the patient
[17]. Iodized salt may contain excessive or deficient amounts has autoimmune thyroiditis, it is best to limit iodine to
of iodine as diligent monitoring of iodine levels in salt does iodized salt and dietary intake and steer clear of supplemen-
not always occur [17]. Multivitamin supplements testing in tal iodine. Some autoimmune patients seem to do better
the United States had ranges for iodine between 11 and 610 eliminating iodized salt, but every patient is different, and
mcg, and 15 brands had higher iodine levels than what was individual needs should be assessed.
listed on the label [17]. Pharmaceutical products are another
source of excessive iodine as Amiodarone contains 37%
iodine; one tablet can contain several hundred times the rec- 8.5 B Vitamins
ommended dose [17]. Contrast agents used for diagnostic
radiology can contain hundreds of thousands of times the The concept of nutritional balance is important with dosing
recommended daily amounts for iodine in one single dose. of B vitamin supplements. The B vitamins consist of eight
Transdermal antiseptic cleaners can also be a source of excess water-soluble vitamins interacting together as coenzymes for
iodine for patients and healthcare workers [17]. It can take a variety of catabolic and anabolic enzyme reactions [21].
more than 1 month for the iodine levels in the body to nor- Collectively, B vitamins have effects in proper brain function,
malize following exposure [17] (See . Table 8.1)
  energy production, DNA and RNA synthesis and repair,
To protect thyroid health, one lifestyle recommendation genomic and non-genomic methylation, and the synthesis of
integrative and functional clinicians make is to limit expo- numerous neurochemicals and signaling molecules [21].
sure to the halogens consisting of fluoride, chlorine, and bro- Although water-soluble and generally regarded as nontoxic,
mine. Iodine is a halogen as well, and excessive exposure to over-supplementation of a complex of B vitamins or isolated
fluoride, chlorine, and bromine may result in the thyroid B vitamins such as B6 or folate is a concern. Conversely,
absorbing and storing these halogens, and thus displacing underdosing by adhering strictly to RDA levels for certain B
iodine. Halogens have the potential to interfere with the pro- vitamins may leave some portions of the population at risk
duction of thyroid hormone, iodine metabolism, and may for insufficiency [21] (See . Table 8.2).
 

contribute to hypothyroidism or thyroid hormone derange- Homocysteine, a potentially toxic amino acid, is thought
ment. For example, excessive ingestion of fluoride, even in to accumulate when vitamins B12, folate, B6, and/or trimeth-
the presence of adequate dietary iodine intake, may induce ylglycine (TMG) are insufficient. Elevated homocysteine is
thyroid disturbances by interfering with enzymes such as theorized to increase oxidative stress, inhibit methylation
deiodinases that are required for metabolizing thyroxine into reactions, increase damage to DNA and dysregulation of its
its derivative forms [19]. Fluoride may also interfere with repair, promote atherosclerosis [28], and direct and indirect
iodide transport and displace iodide resulting in accumula- neurotoxicity, leading to cell death and apoptosis [21]. These
tion in the thyroid [19]. Halogens are found in flame retar- processes are thought to lead to the detrimental health condi-
dants, dioxins, pesticides, polychlorinated biphenyls, and tions seen with elevated homocysteine including accumula-
The Nutrition Assessment of Metabolic and Nutritional Balance
105 8

..      Table 8.2  Tolerable upper limits of B vitamins

B Vitamin RDA Upper limit Additional comments

B1 thiamine RDA for adults [17] Not established as Common dose of 50–100 mg for adults unless under special
no adverse effects medical conditions exist such as alcoholism, malabsorption, the
Male 1.2 mg have been found elderly, HIV/AIDS, or after bariatric surgery [22].
Females 1.1 mg with daily doses of
50 mg [22]
Pregnancy 1.4 mg
and lactation

B2 riboflavin Adults 19–50 years [23] Studies have not Essential component of the two coenzymes FMN and FAD that
shown adverse play major roles in energy production, cellular function, growth
Males 1.3 mg effects from high and development, and metabolism of fats, drugs, and steroids
Females 1.1 mg riboflavin intakes of [23]. FAD is required for the conversion of tryptophan to niacin
400 mg/day and [23]. FMN is required for the conversion of vitamin B6 to
Pregnancy 1.4 mg there is no coenzyme pyridoxal 5′-phosphate [23]. Also used in the
established UL [23] metabolism of homocysteine. Clinically it may be helpful in
Lactation 1.6 mg higher doses with prevention of migraine headaches [24]. People
at risk for deficiency include vegetarians, athletes, pregnant and
lactating women and their infants, vegan and dairy-free diet
followers, infantile Brown–Vialetto–Van Laere syndrome [23].

B3 niacin RDA for adults [25]: 35 mg [25] Temporary flushing of the skin may occur at doses of 100 mg [21].
 16 mg males Nausea, vomiting, diarrhea, and very rarely liver damage have
 14 mg females occurred at extended doses of 1 gram of more [21]. Doses of up
 18 mg pregnancy to 250 mg have been used in Parkinson’s disease [21].
 17 mg lactation

B5 pantothenic Adequate intake for Not established [25] Essential coenzyme in the mitochondria for formation of
acid adults [25]: adenosine triphosphate (ATP) along with thiamine, riboflavin
 5 mg and niacin [21].
 6 mg pregnant
 7 mg lactation

B6 pyridoxine RDA for adults [25]: 100 mg [25] 50–100 mg [16]. Essential in the metabolism of homocysteine.
(pyridoxal-5′-  1.3 mg Doses over 100 mg have been known to cause neurosensory
phosphate)  1.7 mg 51+ years issues [21].
 1.9 mg pregnancy
 2.0 mg lactation

B9 Folate RDA for adults [25]: 1000 mcg [25] 1000 mcg is the daily upper limit; however, 200–400 mcg is often
 400 mcg recommended as research is unclear about supplemental folic
 600 mcg pregnancy acid and cancer [21]. Exceptions include the use of certain
 500 mcg lactation medications and higher levels than the upper limit may be
indicated in some cases of high homocysteine [21]. High doses of
folate can exacerbate the effects of B12 deficiency [21]. Folate is
essential in the metabolism of homocysteine [24].

B12 RDA for adults [25]: Not established [25] Dependent on the individual physiological needs and conditions
 2.4 mcg involving absorption [24]. Essential in the metabolism of
 2.6 mcg pregnancy homocysteine.
 2.8 mcg lactation

Inositol No RDA set Not established Inositol can be synthesized in the body from glucose. Found in the
germ and bran of grains, beans, nuts, seeds, and citrus fruit [26].

Biotin Adequate intake for Not established [25] Biotin, thiamine, and B12 interrelate in the citric acid cycle [16].
adults [25]: Biotin can be deficient genetically susceptible individuals or with
 30 mcg dysbiosis. Biotin is formed by gut microbiota [27].
 35 mcg lactation

tion of beta-amyloid, hyper-phosphorylation of tau, brain B12, vitamin B6 and vitamin B2 [29]. Plasma homocysteine
tissue atrophy, compromised cerebrovascular circulation, levels were categorized by the 2009 US National Academy
cardiovascular disease, and compromised cognitive function of Clinical Biochemistry Laboratory Medicine Practice
and dementia [21]. Elevated plasma homocysteine levels can Guidelines on Emerging Biomarkers of Cardiovascular
be due to renal insufficiency, deficiencies of folate, vitamin Disease and Stroke as (umol/L): desirable <10, intermediate
 106 M. G. Gasta

>10 to <15, high >15, very high >30 [29]. For biomarkers for essential in maintaining optimal physiological and neuro-
B vitamin assessment, see . Table 8.3.   logical function [21].
Elevated homocysteine and low levels of vitamins B12, Deficiency of even one B vitamin will negatively affect the
B6, and folate have also been associated with bone loss and ability to generate energy in the cell [21]. For example, the
structural deterioration of bone tissue [35]. Deficiency of status of folate, B6, and B12 is dependent on levels of flavo-
vitamin B12 is associated with lower blood levels of osteocal- proteins derived from riboflavin. Riboflavin is also essential
cin and alkaline phosphatase and may point to the activity of to homocysteine metabolism [21]. Niacin, vitamin B3, serves
osteoblasts and bone metabolism being affected by vitamin as a necessary cofactor in the folate–tetrahydrobiopterin and
B12 status [35]. methionine cycles [21]. Prolonged elevated folate status is
While it is pertinent to address elevated homocysteine associated with protected cognitive function only in those
levels, the homocysteine hypothesis has resulted in limited with normal B12 status, whereas high folate status exacer-
B-vitamin research in other conditions with nutritional sup- bated the detrimental effects of low B12 status [21].
plementation research focused mainly on folic acid and vita- Supplementation with folic acid also contributed to ribofla-
min B12, only occasionally including vitamin B6 [3]. This has vin deficiency in participants in one study [21].
resulted in virtually ignoring the importance and intercon- The active forms of thiamine, riboflavin, niacin, and pan-
nectivity of the role of the entire spectrum of B vitamins as tothenic acid are essential coenzymes in the mitochondria to

8 ..      Table 8.3  Biomarkers to assess B vitamin status

B1 B2 B3 B6 Folate B12

Whole blood thiamine Riboflavin Most reliable: Direct RBC folate is consid- Serum B 12 marker.
pyrophosphate (TPP) status is not urinary excretion of measurement: ered to be the most Subclinical deficiency:
available at labcorp. routinely niacin’s two major plasma robust marker for  <200 pmol/L.
NL 66.5–200 nmol/L. measured. methylated pyridoxal long-term folate status.  Low is 150–
Retrieved from Please refer metabolites, 5’phosphate RBC folate for 249 pmol/L.
7 https://www.
  to Riboflavin N1-methyl-­ (P5P) >20 populations should be Acute deficiency is
labcorp.com/ Fact Sheet for nicotinamide and nmol/L [31]. around 1000– <149 pmol/L. This marker
test-­menu/36661/ Health N1-methyl-­2- This is affected 1300 nmol/L. Woolf has limited diagnostic
vitamin-­bsub1-­sub- Professionals pyridone-5-­ by inflamma- et al. used >140 ng/mL ability. Serum B12 does
whole-blood# on for more carboxamide [30]. tion markers [31]. WHO recom- not represent cellular B12
2/17/2019. information Levels in adults: and albumin mends <906 nmol/L levels [33].
Urinary amino acids [23].  Normal niacin concentration (>400 μg/L) in women Severe B12 deficiency
test or organic acids Urinary status is >17.5 [32]. of reproductive age to has been documented
test can also be organic acids micromol/day of Functional prevent neural tube with normal or high
helpful test can be these two biomarkers defects [29]. serum levels of B12 [33].
helpful metabolites [30]. may be better Evaluate homocysteine Plasma homocysteine is
 Low niacin assessed by and MMA. If homocys- high at >13 μmol/L, can
status: Excretion integrative teine is high and MMA be used along with
rates between testing is normal, this the most specific test for
5.8 and 17.5 phenomenon may functional B12 deficiency
micromol/day reflect a folate which is elevated serum
[30]. deficiency [33]. methylmalonic acid at
 Deficient niacin Urinary FIGLU >260–350 nmol/L,
status: urinary-­ normal: not detected. (118 pmol/L), or
excretion rates Elevated levels can 0.80 μmol/L [33].
are less than 5.8 represent folate Reduced kidney function
micromol/day deficiency [34]. This may affect the clearance
[30] case can be assessed of both homocysteine
through organic acids and MMA, thus resulting
testing in higher levels. Another
marker to consider in
these cases is holo-­
transcobalamin (holo-TC)
[33]
Normal holo-TC level is
20–125 pmol/L. Below
20 pmol/L would be
correlate with B12
deficiency [33]

Note: Iron deficiency should always be taken into account when assessing folate and B12 status. Iron deficiency causes microcytosis, whereas
anemia of folate and B12 can cause macrocytosis [33]. Iron-deficiency anemia can mask macrocytosis and megaloblastic anemia from B12 [33].
The Nutrition Assessment of Metabolic and Nutritional Balance
107 8
make adenosine triphosphate (ATP), the cell’s energy cur- a modulator of blood pressure, specifically in individuals
rency. Acetyl CoA provides the main substrate for this cycle with the MTHFR 677TT genotype, and can reduce systolic
and relies on pantothenic acid [21]. Thiamine, biotin, and BP by 5–13 mmHg in these genetically at-risk adults [38].
B12 also interrelate in the citric acid cycle and electron trans-
port chain. B vitamins have a fundamental impact on brain
function and are actively transported across the blood–brain 8.5.3 Niacin (Vitamin B3)
barrier with the concentration of methyltetrahydrofolate,
biotin, and pantothenic acid found in the brain at levels much Niacin-derived nucleotides, such as nicotinamide adenine
higher than plasma [21]. B vitamins can generally be con- dinucleotide (NAD) and NAD phosphate (NADP), are criti-
sumed in amounts much higher than the RDA and may be cal for enzymes involved in every aspect of peripheral and
necessary for optimal health. To date, only vitamins B6, B12, brain cell function [21]. Niacin receptors are found in
and folate have an established upper daily limit. immune cells and adipose tissue as well. Niacin plays a role in
neuromodulation of inflammatory cascades and antiathero-
genic lipolysis in adipose tissue. People with Parkinson’s dis-
8.5.1 Thiamine (Vitamin B1) ease are often low in niacin. One study found this population
to benefit from 250  mg niacin supplementation, which
Thiamine plays a role in the synthesis of fatty acids, steroids, resulted in attenuation of the disturbed sleep architecture
nucleic acids, and aromatic acid precursors and in the syn- associated with Parkinson’s disease [21].
thesis of neurotransmitters and bioactive compounds essen-
tial for brain function [21]. Thiamine also plays a
neuromodulatory role in the acetylcholine neurotransmitter 8.5.4 Pantothenic Acid (B5)
system and can relieve fatigue associated with hypothyroid-
ism [36]. Thiamine can be deficient in grain-free diets and Pantothenic acid is required for the synthesis of coenzyme A
depleted with high intake of alcohol [37]. In a study enrolling (CoA). CoA plays a role in oxidative metabolism and con-
young women with adequate thiamine stores but given 50 mg tributes to the structure and function of the brain via its role
of thiamine or placebo for 2 months, the thiamine-­ in the synthesis of cholesterol, amino acids, phospholipids
supplemented group reported improved mood as assessed by (PLs), and fatty acids. Through the action of CoA, panto-
the Profile of Mood States. The thiamine-treated group also thenic acid also helps with the synthesis of neurotransmitters
demonstrated improved attention evidenced by faster and steroid hormones [21].
decision-­making on reaction time tasks [21]. Thiamine plays
a role in glucose metabolism. Between 17% and 79% of obese
patients examined for bariatric surgery were found to be 8.5.5 Vitamin B6
deficient in thiamine, and this may suggest a connection
between thiamine status, blood sugar regulation, and obesity. Vitamin B6 plays an essential role in the folate cycle and
In conditions of fatigue, neurological conditions, or hypothy- amino acid metabolism and is a rate-limiting cofactor in the
roidism, higher supplemental doses of thiamine (50–100 mg) synthesis of neurotransmitters including dopamine, sero-
may be beneficial [19, 25]. Alcoholism and bariatric surgery tonin, GABA, noradrenaline, and the hormone melatonin
will likely require far higher doses delivered under medical [21]. Neurotransmitter synthesis is especially sensitive to B6
supervision. deficiency. Even a mild deficiency can result in downregula-
tion of GABA and serotonin synthesis. When GABA is
unable to participate in its inhibitory role on neural activity,
8.5.2 Riboflavin (Vitamin B2) disordered sleep, behavior changes, cardiovascular function,
and loss of hypothalamus–pituitary control of hormone
Riboflavin is required for the synthesis of two flavoprotein secretion can result.
coenzymes, FMN and FAD, which are rate-limiting factors in Low B6 status has been found in oral contraceptive users,
most cellular enzymatic processes [21]. The flavoproteins are smokers, and people with celiac disease, alcoholism, and dia-
required for the synthesis, conversion, and recycling of nia- betes [32]. B6 deficiency usually does not occur in isolation,
cin, folate, B6, the synthesis of heme proteins, nitric oxide but rather, with other B-vitamin deficiencies. Assessing B6
synthesis, P450 enzymes, and proteins involved in electron status can be difficult. Pyridoxal phosphate (PLP), the active
transfer and oxygen transport and storage. The flavoproteins form of B6, is often used to assess vitamin B6 by laboratory
are also involved in fatty acid metabolism in brain lipids, the testing. PLP testing appears to be accurate in healthy indi-
absorption and utilization of iron, and the regulation of thy- viduals and has been found to reflect the vitamin B6 content
roid hormones. For many reasons, riboflavin deficiency in the liver and correlate with vitamin B6 dietary intake [32].
would negatively impact brain function. Clinically, higher However, plasma PLP levels can be affected by albumin con-
doses of riboflavin at 400  mg are helpful with preventing centration, alkaline phosphatase activity, inflammation, and
migraine headaches [24]. Recent randomized controlled tri- alcohol consumption [32]. Also of concern, low plasma PLP
als have demonstrated that riboflavin may play a novel role as has been found with inflammation such as rheumatoid
 108 M. G. Gasta

arthritis, inflammatory bowel disease, cardiovascular dis- higher doses of folate [39]. Caution is advised in using high
ease, diabetes, deep vein thrombosis, and cancer [32]. Plasma doses of folic acid in combination with antifolate medica-
PLP shows an inverse relationship with markers of inflam- tions, such as methotrexate, prescribed for conditions such
mation such as C-reactive protein and other markers of acute as rheumatoid arthritis, psoriasis, cancer, bacterial infec-
phase reactants [32]. tions, and malaria [21]. In addition, supplemental folate
The activated form of B6, pyridoxal-5′-phosphate is may confer protection against cancer at lower doses but
downregulated during times of inflammation and therefore may cause increased risk of cancer at higher doses, but
may contribute to dementia and cognitive decline due to the there is no consensus on blood levels of folate that may
essential role it plays in brain glucose regulation, immune cause harm.
function, and gene transcription–expression [21]. Vitamin As many patients turn to vitamins and supplements to
B6 can be over-supplemented and cause sensory neuropathy enhance energy, relieve fatigue, or generally feel better, it is
that is usually reversible. Evidence from case studies suggests important to understand the connection between the B vita-
that this can happen with as little as 100  mg per day [19]. mins and psychiatric symptomatology. Vitamins B6, B8, and
Keeping the total amount of B6 to 50–100 mg per day is rec- B12 have been shown not only to reduce psychiatric symp-
ommended [21]. If higher doses need to be used, consider toms but also shorten the duration of illness [39]. However,
this as a short-term intervention of 2–3 months, and a lower when patients lack a specific genetic enzyme which converts
dose of around 50  mg should be recommended after this folate–folic acid to its most usable form, L-methylfolate, the
time period. There are, however, clinical trials that have used neuroprotective, and neuropsychiatric benefits are lost.
8 B6 doses as high as 750 mg over several years with no reports L-methylfolate allows for the synthesis of the three major
of neuropathy [21]. Individuals with certain single nucleo- neurochemicals—serotonin, norepinephrine, and dopa-
tide polymorphisms in the CBS genes and MTHFR will have mine—across the blood–brain barrier [39]. Exploring the
different requirements for vitamin B6. Please refer to conversion of folate–folic acid into L-methylfolate and the
7 Chap. 18 for this discussion.
  various polymorphisms of the MTHFR gene while examin-
ing the B vitamins associated with the treatment of psychiat-
ric symptoms allows integrative and functional practitioners
8.5.6 Folate (Vitamin B9) to treat patients with the appropriate B vitamins [39]. For an
in-­depth analysis of how to assess folate status, please see
Folate and B12 are linked due to their complementary roles . Table 8.2 for biomarker assessment. For a detailed discus-
 

in the folate and methionine cycles [21]. If B12 is deficient, sion, see Nutragenomics in 7 Chap. 17.
 

folate can become trapped as methyltetrahydrofolate, result-

ing in a functional folate deficiency [21]. Requirements for
folate may also differ based on genetics. Either an actual or 8.5.7 Vitamin B12
functional deficiency of folate may hamper DNA stability
and repair as well as gene expression and transcription. This, Vitamin B12 is protective against neurological deterioration,
in turn, affects neuronal differentiation and repair, which and deficiency of B12 is associated with peripheral neuropa-
promotes hippocampal atrophy and demyelination. thy, cognitive impairment, and neurodegenerative disease
Ultimately, this compromises the integrity of membrane [33]. Causes of B12 deficiency are largely related to absorp-
phospholipids resulting in the impaired action potential of tion in the GI tract, lack of intrinsic factor, or dietary defi-
the neuron [21]. ciency such as with vegan diets [33]. Autoimmune pernicious
A lack of folate may result in decreased synthesis of pro- anemia, intestinal surgery such as bariatric surgery, and
teins and nucleotides required for DNA and RNA synthesis. chronic gastritis from H. pylori infections all decrease the
This can have negative ramifications for rapidly dividing tis- release of intrinsic factor which can result in B12 malabsorp-
sues, such as fetal development, and can lead to megaloblas- tion. Undiagnosed celiac disease can also result in malab-
tic anemia and neuronal dysfunction [21]. Additionally, the sorption of B12 [33]. Some medications interfere with
folate cycle needs to function effectively to synthesize and absorption and metabolism of B12, including metformin.
recycle tetrahydrobiopterin, which is an essential cofactor for Metformin decreases serum B12, but in some studies, it was
enzymes that convert amino acids to monoamine neu- shown to decrease plasma methylmalonic acid (MMA) and
rotransmitters such as serotonin, melatonin, dopamine, nor- increase intracellular B12, although there are conflicting
adrenaline, adrenaline, and nitric oxide [21]. reports [33]. Metformin may alter B12 homeostasis and tis-
The upper daily limit for folic acid is set at 1000 mcg/day. sue distribution, but the clinical consequences remain to be
This upper level is related to folate’s ability to mask vitamin determined. Proton pump inhibitors and other medications
B12 deficiency, resulting in irreversible damage [21]. that reduce the production of hydrochloric acid are also asso-
Detrimental effects of high doses of folic acid are related to ciated with B12 deficiency [33]. B12 deficiency can be masked
high levels of unmetabolized folic acid on normal folate by folate supplementation and can cause severe neuropathy
metabolism and immune function [21]. and neurodegeneration. An effective test for B12 sufficiency
The use of folate comes with caveats. Individuals with is MMA in blood or urine. Refer to . Table  8.2 for assess-
 

MTHFR single nucleotide polymorphisms often require ment of B12 levels.

The Nutrition Assessment of Metabolic and Nutritional Balance
109 8
Doses of vitamin B12 that far exceed the RDA are [42]. Long-term, three-year supplementation with menaqui-
commonly used in the integrative and functional nutrition none (K2) of 180 mcg in 120 healthy postmenopausal women
realm. Anecdotally, nutrition practitioners have found resulted in decreased arterial stiffness [40].
that genetically susceptible individuals with catechol-O-­ Vitamin K2 includes several different vitamers, of which
methyltransferase (COMT) single nucleotide polymorphisms MK7 is the most well-known. One study found that plasma
have a decreased ability to metabolize catecholamines, and concentrations of albumin and vitamin K1 were significant
supplementation with the methylcobalamin form of vitamin predictors of hip fracture in the general population, whereas
B12 may aggravate symptoms of anxiety and insomnia. Some MK7 was not [42]. To promote a decreased risk of bone frac-
of these individuals do better with hydroxocobalamin or ture while protecting from vascular calcification, it is likely
adenosylcobalamin. To counter untoward effects when prudent to include both vitamin K1 and vitamin K2, specifi-
beginning B12 supplementation, start with a lower dose, cally MK 4 and MK 7, when recommending calcium and
such as 500 mcg, and slowly titrate dose upward. vitamin D [42].
The take-home message with B vitamins is to supplement
all the B vitamins (not just one) because they work synergis-
tically, even if the exact mechanisms has not been fully eluci- 8.6.2 Vitamin A and Vitamin D
dated in research.
Vitamins A and D are important synergistic partners due to
their shared binding of the nuclear retinoid X receptors
8.6 Fat-Soluble Vitamins (RXR), resulting in synergistic effects of one vitamin with the
other. In nature, vitamins A and D are found together in bal-
Fat-soluble vitamins are at risk of deficiency with certain ance such as in cod liver oil, egg yolk, and organ meats.
states of malabsorption and malnutrition. When used in Vitamins A and D function in many systems throughout the
supplemental form, these vitamins need to stay in balance body beyond the eyes and bones. Furthermore, vitamins A
with each other, notably vitamin K1–K2 and vitamin D and and D are important as immune and hormone modulators as
vitamin D and vitamin A.  Vitamin E is best provided in a well as affecting structural forms such as bones, cell mem-
natural full-spectrum combination as delta, beta, gamma, branes, tissues, etc.
d-alpha tocopherols and the four tocotrienols, the way it is The effects of vitamins A and D supplementation on bone
found in food. mineral density have been controversial. Observational
studies have reported an association between higher serum
retinol concentration and risk of bone fracture; another
8.6.1 Vitamin D and Vitamin K study reported that high retinol concentration in the pres-
ence of vitamin D deficiency can increase the risk of osteo-
One of the risks of using supplemental vitamin D is the porosis in menopausal women [42]; another recent study
increased gastrointestinal absorption of calcium that results found that higher intake of vitamin A, when combined with
in high serum levels of calcium and increased vascular cal- sufficient intake of vitamin D, can promote increased bone
cification [40]. Theoretically, if vitamin D supplementation density [43]. In a Korean population, a higher dietary vita-
is balanced with supplementation of vitamin K1 and K2 in min A intake does not appear to negatively affect bone min-
the forms of menaquinone-4 (MK 4) and menaquinone-7 eral density when 25 (OH) D levels are moderate at
(MK 7), this will decrease the likelihood of soft tissue calci- 50–75 nmol/L [43].
fication and of bone fracture [40]. In addition, a few vitamin When assessing an individual’s vitamins A and D status,
K-dependent small proteins act to inhibit soft tissue calcifi- it is beneficial to get a baseline of blood vitamin A retinol and
cation and include osteocalcin (bone Gla protein), matrix vitamin D 25–OH, vitamin D1, 25-OH, and PTH, at mini-
Gla protein (MGP), and possibly Gla-rich protein (GRP) mum, to develop more targeted interventions and improve
[41]. The role of these proteins has been elucidated in stud- outcomes. If genomic information is available for vitamin D
ies monitoring the effects of treatment with oral anticoagu- receptor and BCMO1 genes, genomic differences that influ-
lants that are known vitamin K antagonists (VKA). ence the ability to establish balance between vitamin A and
With regard to VKA, all vitamin K-dependent calcifica- vitamin D might come to light. This highlights the fact that
tion inhibitors will remain uncarboxylated and inactive [41]. there are unique requirements for individuals to maintain
Compared with controls, subjects taking anticoagulants had nutrient balance.
significantly higher calcification of arteries and the aortic Serum retinol and serum 25(OH)D can both be tested
valve [41]. Despite previous publications that reported vita- to ensure safe and adequate levels are maintained. Normal
min K1 had no effect on bone mineral density, in a recent levels of serum vitamin A range from 50 to 200 mcg/dL or
study, vitamin K1 deficiency was the strongest predictor of 1.75–6.98 micromol/L [6]. Interestingly, in nature, vita-
vertebral fractures and vascular calcification in chronic kid- mins A and D are found together such as in egg yolk, liver,
ney disease. In postmenopausal women, 5 mg of vitamin K1 and butter. Overall, keeping the vitamin D level adequate
protected postmenopausal women from bone fractures, appears to be protective to bones when supplementing
despite having no positive effect on bone mineral density vitamin A.
 110 M. G. Gasta

8.6.3 Tocopherols and Tocotrienols to 1:1. Supplemental calcium continues to be controversial as

it may be associated with an increased risk for myocardial
Vitamin E is a family of fat-soluble antioxidants that mainly infarction, stroke, and cardiovascular mortality and an
refers to alpha tocopherol, but naturally includes several increased risk for kidney stones and soft tissue calcification
tocopherols and tocotrienols [40]. Vegetable oils contain [46] and more recently continues to be controversial as it may
higher amounts of tocopherols, while tocotrienols are found be associated with an increased risk for myocardial infarction,
in palm oil [44]. Both tocopherols and tocotrienols have four stroke, and cardiovascular mortality and an increased risk for
homologues consisting of alpha, beta, gamma, and delta [44]. kidney stones and soft tissue calcification [46]. There is grow-
Gamma-tocopherol is known mainly for its beneficial func- ing evidence for the need for calcium supplementation to be
tion in maintaining cardiovascular health, whereas the toco- in tandem and balanced with magnesium. Integrative and
trienols have shown more diverse application and protection functional nutritionists often see clients with malabsorption,
against cancer, cardiovascular disease, neurodegeneration, and part of the dietary intervention may include eliminating
oxidative stress, fertility, and immune regulation [44]. dairy products, often without recommending supplemental
Tocotrienols exert different effects. Delta- and gamma-­ calcium or calcium-rich foods. This may have unintended
tocotrienols were more potent in cancer studies, while alpha-­ harmful consequences (See . Tables 8.4 and 8.5).
 

tocotrienols are more effective with neuroprotection. In a trial, Using celiac disease (CD) as an example, calcium malab-
subjects supplemented with gamma- and delta-­tocotrienols sorption and insufficient intakes of calcium may result in
hypocalcemia, which produces a compensatory increase in
8 showed a significant reduction in triglycerides and very low-
serum levels of parathyroid hormone. This, in turn, leads to
density lipoprotein with no change in total cholesterol, LDL
and HDL cholesterol, whereas the other homologues, alpha increased bone turnover and ultimately bone loss, with bone
and gamma, did not show any effect on lipid profiles [44]. resorption being faster than new bone formation [47]. It is
In preclinical cancer studies, tocotrienols have been possible that the malabsorption of calcium is the main con-
shown to have antiproliferative, antiangiogenic, proapop- tributing factor to secondary hyperparathyroidism seen in
totic, and immune-enhancing properties [44]. The first CD [48, 49]. In addition, whenever parathyroid hormone is
clinical trial of tocotrienols involved a five-year, placebo- elevated, there is rapid conversion of 25 OH vitamin D to 1,
controlled, double-blinded study. Participants showed
decreased number of deaths and incidence of recurrence in ..      Table 8.4  High calcium foods to recommend to patients on
the tocotrienol group. Gamma-tocopherol showed increased dairy-free diets
apoptosis in a study on pancreatic ductal neoplasia.
Tocopherols and tocotrienols have neuroprotective prop- 1 cup okra, cooked 150 mg
erties and were shown to reduce glutamate toxicity, and sub- 1 cup spinach, cooked 350 mg
sequent damage to neurons and astrocytes and the use of
1 cup kale, cooked 94 mg
vitamin E for the management of Alzheimer’s disease is a
topic of interest [45]. In a two-year study, daily supplementa- 1 cup broccoli, raw 42 mg
tion of 400 mg of tocotrienol-rich fraction (TRF) resulted in 1 cup collard greens, cooked 150 mg
statistically significant reduction in white matter lesions,
compared with placebo group [44]. 1 cup turnip greens, boiled 190 mg
At this writing, there is no general consensus on recommen- 1 cup bok choy, raw 74 mg
dations for vitamin E intake as it is dependent on age, lifestyle,
3 oz canned sardines with bones 325 mg
fat malabsorption, individual differences in vitamin E metabo-
lism, and interaction with pharmaceuticals, such as blood thin- 3 oz canned salmon with bones 190 mg
ners and statins [40]. Vitamin E may become a prooxidant when ½ cup firm tofu made with calcium sulfate 253 mg
administered at high levels, but this effect may be mitigated by
1 cup calcium-fortified milk alternative 300 mg
the coadministration of other antioxidants, such as vitamin C
[40]. There is recent speculation that supplemental tocotrienol Calcium-fortified juice 261 mg
(T3) exerts more benefit than supplemental tocopherol and ½ cup soy beans and white beans 80–90 mg
tocopherols should be solely obtained through food sources.
Luna bar 350 mg

Power bar 300 mg

8.7 Minerals
1 cup calcium-fortified cereal 250–300 mg
8.7.1 Calcium and Magnesium 2 tablespoons of Tahini or sesame seeds 120–180 mg

Calcium and magnesium are important nutrient partners that Based on data from National Institutes for Health Calcium Fact
require balance, as elevation of one can cause suppression of Sheet for Health Professionals retrieved on 8/14/2017 from
the other. Integrative and functional medicine clinicians rec- 7  https://ods.od.nih.gov/factsheets/Calcium-HealthProfes-
sional/
ommend supplementing calcium–magnesium at a ratio of 2:1
The Nutrition Assessment of Metabolic and Nutritional Balance
111 8
may lead to a greater risk of metabolic syndrome, type 2 dia-
..      Table 8.5  Recommended daily allowances (RDAs) for
calcium intake
betes, cardiovascular disease, skeletal disorders, chronic
obstructive pulmonary disease, depression, decreased cogni-
Age Male Female Pregnant Lactating tion, and vitamin D deficiency [3]. Magnesium plays a criti-
cal synergistic role in the synthesis and metabolism of
0–6 monthsa 200 mg 200 mg parathyroid hormone (PTH), vitamin D-binding protein
7–12 months a 600 mg 600 mg (VDBP), and three major enzymes that determine 25-OH
vitamin D concentrations [3]. Magnesium deficiency leads
1–3 years 700 mg 700 mg
to decreased levels of 1, 25 (OH)2 D, the active form of
4–8 years 1000 mg 1000 mg vitamin  D, and subsequent impaired PTH response [3].
9–13 years 1300 mg 1300 mg Additionally, a specific form of vitamin D-resistant rickets
that is magnesium-­dependent exists and only responds to
14–18 years 1300 mg 1300 mg 1300 mg 1300 mg
vitamin D therapy when magnesium is concurrently admin-
19–50 years 1000 mg 1000 mg 1000 mg 1000 mg istered [3]. Readers will note other nutrients besides calcium,
51–70 years 1200 g 1200 mg
magnesium, and vitamin D that play a role in bone density
include protein, vitamin K, zinc, copper, and boron.
aAI (adequate intake) National Institutes for Health Calcium Fact Two small clinical studies on magnesium-deficient
Sheet for Health Professionals retrieved on 8/14/2017 from patients show that magnesium administered alone is not
7  https://ods.od.nih.gov/factsheets/Calcium-HealthProfes- enough to raise vitamin D levels and that administration of
sional/ vitamin D3 combined with magnesium infusion resulted in a
substantial increase in both 25(OH)D and 1, 25 (OH)2 com-
25 OH vitamin D (the active form of vitamin D) to enhance pared with the infusion of magnesium alone. A recent
calcium absorption [48]. Clinically, you may see a low 25 OH NHANES study found that a high intake of magnesium was
and an elevated 1, 25 OH. Regarding CD, 75% of untreated independently and significantly associated with a reduced
adult CD patients with overt malabsorption, and about half risk of vitamin D deficiency [3]. Although more studies will
of those with subclinical CD presenting with minimal symp- elucidate the relationship between magnesium and vitamin D
toms or asymptomatic CD patients will have bone loss. In status, it may be prudent for clinicians to correct both vitamin
2000, the British Society of Gastroenterology published D status and magnesium status concurrently. If clinicians
guidelines for treating osteoporosis in CD that includes a experience vitamin D-resistant patients, the patient may be
daily calcium intake of 1500 mg and vitamin D supplementa- deficient in magnesium as well. Supplementing with vitamin
tion [47]. Malabsorption of other micronutrients may also D and calcium in the presence of suboptimal magnesium
contribute to altered bone metabolism and increased pro-­ intake may be affecting health through interactions between
inflammatory cytokines that enhance osteoclastogenesis and the three nutrients that have not yet been fully explained [3].
bone resorption [49]. Since 1977, the United States has increased both dietary
In cases where malabsorption is suspected, it may be pru- calcium and magnesium intake, but dietary calcium intake
dent to request the patient have a parathyroid hormone test. It has increased at a rate of 2–2.5 times that of dietary magne-
may be possible that secondary hyperparathyroidism may occur sium [3]. Some US studies have shown that since 2000, the
with low, normal, or high serum calcium levels. High serum calcium-to-magnesium ratio has increased ≥3 times and
calcium levels may be the result of long-term calcium malab- coincides with increasing rates of type 2 diabetes and colorec-
sorption resulting in secondary hyperparathyroidism. Have cli- tal cancer [3]. High dietary calcium-to-magnesium ratio has
ents work with a physician to see if they are a candidate for been proposed as an explanation for the striking variation in
calcium and vitamin D supplementation. Clinically, it may be incidence of postmenopausal breast cancer associated with
safe to assume that individuals at risk for calcium and vitamin D geographic location [50], the lowest calcium intakes being in
malabsorption include those with CD, inflammatory bowel dis- Asia where the incidence of breast cancer is much lower
ease, bariatric surgery (gastric bypass surgery) and other GI compared to North America and northern Europe [50]. An
surgeries, eating disorders, and the presence of gastrointestinal imbalance of the calcium–magnesium intake may lead to
pathogens [49]. Seeing a pattern of low normal serum protein, irregularities in DNA repair, cell proliferation, differentia-
low normal albumin, low ferritin, or other markers of iron sta- tion, and carcinogenesis [50].
tus, elevated MCV (suggesting deficiencies of folate and vitamin Reduced magnesium intake may be due to increased
B12) and low normal serum calcium might suggest a pattern of intake of refined and processed foods, softening of hard
malabsorption. Various medications, such as steroids, proton water, chronic alcohol ingestion, and gastrointestinal disor-
pump inhibitors, and loop diuretics, also increase the need for ders causing malabsorption and certain medications. In
calcium supplementation [49]. The overarching recommenda- addition, calcium supplementation may accentuate the prob-
tion is to dose calcium based on individual needs rather than lem of reduced magnesium intake [50]. Subclinical dietary
blanket recommendations for the general population. magnesium deficiency was shown to increase calcium reten-
Magnesium is often left undiscussed in treating bone tion, and once calcium is high, magnesium absorption can be
health and cardiovascular disease. Low magnesium status significantly depressed. Moderate alcohol consumption is
 112 M. G. Gasta

associated with breast cancer and alcohol exacerbates mag- The joint effect of high sodium and low potassium intakes
nesium deficiency [50]. may have a greater effect on hypertension than elevated
Higher self-reported dietary and supplemental magne- sodium intakes or low potassium intakes alone [53]. In a
sium intakes were associated with lower levels of coronary Korean study by Park et  al., dietary intake of both sodium
artery calcification, which is a sensitive, discriminating mea- and potassium was evaluated, and the authors showed that an
sure of subclinical cardiovascular disease [51]. Huang et al. increased ratio of sodium to potassium was correlated with
found that consumption of moderate amount of calcium and increased prevalence of hypertension [53].
an adequate amount of magnesium with maintenance of Study subjects who had a lower prevalence of hyperten-
calcium-to-magnesium ratio of 2.0–2.5 are important for sion had a Na–K ratio of 1.21:1, and with increased preva-
reducing cardiovascular risks in older patients with diabetes lence of hypertension, there was a Na–K ratio of 2.56:1 [56].
[52]. Individuals who consume 1000–1200 mg of calcium per Additionally, blood pressure results had almost a linear dose
day need to increase their magnesium intake to maintain the response to increasing ratio of Na–K [53].The blood pressure
calcium-to-magnesium ratio of 2.0–2.5 [52]. lowering effects of potassium were greatest in those with the
Traditional advice is to maintain calcium-to-magnesium highest intake of sodium, and the ratio of Na–K had a greater
ratios for optimal health [3], and the authors of a 2007 effect on the risk of cardiovascular disease than sodium or
colorectal neoplasia study suggested the optimal dietary potassium alone [53]. Recommending a diet high in fresh
calcium-­to-magnesium ratio be <2.8. It is thought that fruits and vegetables, including low-fat dairy products, and
calcium-­to-magnesium ratios >2.6–2.8 can have detrimental consuming a whole-food diet, is likely the most effective
8 health effects, and it has also been questioned if a calcium-to-­ approach for lowering the Na–K ratio [53]. Caution is advised
magnesium ratio of <2.0 may also be detrimental [3]. More when looking at sodium-to-potassium ratios as great vari-
research is needed to establish a beneficial ratio. ability in sodium sensitivity exists between different ethnic
groups [53].

8.7.2 Sodium-to-Potassium Ratio

and Hypertension 8.7.3 Zinc and Copper

The effect of sodium-to-potassium (Na–K) ratio on hyper- Zinc and copper are another example of nutrient partners
tension is perhaps more important than looking separately that need to be metabolically balanced. Excessive elevation of
at the effect of individual sodium or potassium intake on either one can suppress the other, much like the relationships
hypertension. Inconsistencies have been found in observa- described above.
tional studies around the world showing a relationship Zinc is used clinically in supplement form to facilitate
between high sodium intake and hypertension, as well as wound healing; decrease skin inflammation; support
high Na–K ratios and hypertension [53]. The mechanisms of immune function, tissue growth, and maintenance of thy-
sodium and potassium on blood pressure are multiple. In roid function; promote GI tract healing; protect against such
salt-­sensitive individuals, sodium intake results in sodium ocular diseases as macular degeneration; and promote tes-
and water retention and extracellular volume expansion. The tosterone balance. Zinc supplementation can induce copper
extracellular volume expansion results in release of sub- deficiency that may result in serious neurological condi-
stances that increase heart and blood vessel contraction and tions, hematological abnormalities, and possibly thyroid
affect the renin–aldosterone system [53]. Potassium abnormalities; therefore, zinc needs to be balanced with
increases urinary sodium excretion, which lowers serum copper [57, 58]. High tissue–copper levels may be associated
sodium levels, and is thought to induce vascular smooth with inflammation and certain disease states, such as cancer.
muscle relaxation or widening of the blood vessels to lower “The RDA recommendations for zinc and copper intake are
blood pressure [53]. in a ratio of 9:1 [59]”. When working with medical condi-
Potassium is an electrolyte needed for normal cellular tions, it is important to measure a baseline blood test for
function and is easily excreted by healthy functioning kid- both nutrients to determine if supplementation of either is
neys rather than stored in the body [54]. Therefore, humans needed. (See . Table 8.6 Assessing zinc and copper status.)
 

need a constant supply of potassium through the diet. Measuring the serum copper to zinc ratio is a helpful
Adequate intake of fruits and vegetables is a major source of parameter in states of disease and inflammation. The normal
potassium [54]. The average potassium consumption is at plasma zinc to serum copper ratio in children and adults is
54% of the US recommended intake [54]. Low potassium 1:1 [64]. The increment of this ratio of the opposite (copper–
intake is also correlated with central obesity and metabolic zinc) above 2.0 in the elderly usually reflects an inflammatory
syndrome [54]. A caveat is high potassium intake which is response or decreased zinc status [65]. High serum copper to
contraindicated in renal disease because of poor excretion zinc ratio has been associated with cardiovascular death,
and potential for elevated levels. malignancy, and all-cause mortality in the elderly [65].
Potassium supplementation has consistently been shown During the acute phase of various diseases, systemic mecha-
to lower blood pressure, and low dietary potassium is associ- nisms decrease zinc and increase copper. Using the ratio of
ated with an increased risk of developing hypertension [55]. serum copper to zinc may be more predictive of inflamma-
The Nutrition Assessment of Metabolic and Nutritional Balance
113 8
Copper deficiency impairs oxidative phosphorylation,
..      Table 8.6  Summary of copper and zinc assessment
cellular antioxidant defense, collagen and elastin biosynthe-
Copper reference ranges Zinc reference ranges sis, production of several metalloenzymes such as copper–
zinc superoxide dismutase, and affects levels of
Serum free copper: Normal serum zinc: selenium-dependent glutathione peroxidase [64]. Copper
1.6–2.4 μmol/L or 10–15 μg/dL [60] 60–120 μg/dl [62]
Total copper: Plasma zinc is deficient if
deficiency impairs blood coagulation, has adverse effects on
10–22 μmol/L or 63.7–140.12 μg/ below: blood pressure and heart function, affects cholesterol and
dL [60] 60 μg/dL [63] glucose regulation, contributes to neurodegeneration, causes
Serum ceruloplasmin: Alkaline phosphatase anemia, affects cross-linking of connective tissue, and causes
2.83–5.50 μmol/L or 18–35 μg/dL (ALP) normal range: mineralization of the bone, ultimately leading to osteoporo-
[60] 45–115 units/liter (U/L)
<20 mg/dL ceruloplasmin signifies [62]
sis [66]. Copper deficiency results in optic neuropathy [67].
Wilson’s disease along with Kayser– <45 U/L ALP indicates Anemia that is refractory to iron supplementation is a clas-
Fleischer rings [61]. zinc and/or magnesium sic, well-documented sign of chronic copper deficiency [68].
Wilson’s disease is a genetic defect deficiency [62] One study in frail elderly men found decreased hematocrit
in copper excretion. ∗ For reference in and serum iron levels in subjects who had an elevated serum
24-hour urine copper: assessing low ALP,
0.3–0.8 μmol or 20–50 μg [60] normal serum magne-
copper to zinc ratio [68]. Additional symptoms of copper
<40 mcg/day [61] sium: deficiency include leukopenia, neutropenia, decreased
>100 mcg/day occurs in Wilson’s 1.3–2.5 mEq/L [62] superoxide dismutase, decreased ceruloplasmin, increased
disease [61] plasma cholesterol and LDL–HDL ratio, and abnormal car-
Liver copper: diac function [64].
0.3–0.8 μmol/g of tissue or
20–50 μg/g of tissue [60]
Copper intoxication rarely occurs in humans, as it is
excreted in the bile [64]. However, elevated copper levels are
associated with infections, inflammation, Wilson’s disease,
trauma, systemic lupus erythematosus (SLE), and autism
tion than using other inflammatory biomarkers such as CRP [64]. Both zinc and molybdenum deficiency may be a risk
and ESR [65]. Nutritional factors such as increased copper factor for copper toxicity. Due to its role as a cofactor, copper
intake and decreased zinc intake are not thought to be the toxicity has been associated with such neurological diseases
cause of an elevated copper-to-zinc ratio during states of as amyotrophic lateral sclerosis, Alzheimer’s disease, and
inflammation, but rather, other systemic mechanisms may be Creutzfeldt–Jakob disease [64]. Physiological factors inde-
the cause. Zinc is carried on albumin, and copper is carried pendent of copper intake can affect copper levels. Plasma
on ceruloplasmin (Cp). Synthesis of these proteins and the copper levels are higher in women than men due to estrogen
regulation of serum copper and zinc occurs mainly at the [59]. Infection, inflammation, and estrogen levels increase
hepatic level. plasma copper. Corticosteroid and adrenocorticotropic hor-
During oxidative stress, the albumin-bound zinc in the mone lower copper concentrations.
plasma decreases while labile zinc relocates to peripheral tis- Copper is bound to the protein ceruloplasmin that is
sues [65]. This labile zinc induces the antioxidant metallo- regulated by homeostatic mechanisms [59]. High serum cop-
thionein (MT). Infections and inflammatory conditions per concentration with elevated copper-to-ceruloplasmin
which induce oxidative stress cause copper–ceruloplasmin ratio is indicative of copper excess [59]. In Wilson’s disease, a
levels to rise. During inflammation and aging, the cytokines condition of copper excess, free copper is elevated, and ceru-
interleukin (IL) 6, IL-1 beta, tumor necrosis factor-alpha, loplasmin is lowered [59]. Ceruloplasmin is an acute phase
and interferon gamma (IFN-gamma) are known to suppress reactant and may be raised in response to hepatic inflamma-
the synthesis of albumin (i.e., bound to zinc) and increase the tion, pregnancy, estrogen use, or infection [61]. Falsely low
synthesis of ceruloplasmin. This mechanism may be protec- ceruloplasmin levels may occur with any protein deficiency
tive in response to oxidative stress, infection, and low-grade state including nephrotic syndrome, malabsorption, protein-­
inflammation. Impaired insulin action also decreases the losing enteropathy, and malnutritions [61].
synthesis of albumin, which may, in turn, decrease plasma A review of methods of assessment of copper status in
levels of zinc. humans suggests that serum copper seems to be the most
Following inflammatory stimuli, zinc is redistributed accurate biomarker to assess copper status in humans, reflect-
from the plasma to the liver, thymus, and marrow. This may ing changes in status in both depleted and replete individuals
be a mechanism to restrict zinc from being used by invading [69]. Measuring copper levels may be elusive, but low plasma
pathogens, protect the liver and tissues from oxidative stress or serum levels of copper indicate depletion. Hair and uri-
by producing MT, and manufacture lymphocytes to protect nary copper are not useful indicators of copper status [59].
against invading pathogens [65]. Increased levels of copper Total ceruloplasmin protein level is related to copper status,
in the serum may help the antimicrobial function of macro- but deficiency reflects changes in highly depleted individuals
phages. Very low or undetectable levels of zinc are found in only [69]. One of the first signs of copper deficiency is a drop
infected tissue, whereas copper accumulates at sites of infec- in ceruloplasmin. Ceruloplasmin accounts for 90% of total
tion where macrophages are present in high amounts [65]. plasma copper [70]. Ceruloplasmin and serum copper are
 114 M. G. Gasta

acute phase reactants and can rise in response to inflamma- repleted, the serum zinc increased, as did alkaline phospha-
tion, even in states of copper deficiency [66]. tase. Other studies in Guatemalan children have shown an
The dosing range for copper in adults is 2–10  mg/day association between serum zinc and alkaline phosphatase
with monitoring of zinc status during supplementation [59]. [72]. However, it was noted in children and adolescents
In states of copper deficiency, typically 2 mg/day of copper depending on age, serum alkaline phosphatase levels have a
will reverse the hematological abnormalities in the early wide variation and therefore should be interpreted cautiously.
stages [58].

8.7.5 Copper-to-Zinc Ratio in Cancer

8.7.4 Assessing Zinc Status
Functional medicine experience-based practice recommen-
Symptoms of severe zinc deficiency include hypogonadism, dation in serum copper-to-zinc ratio is 1:1 for optimal health,
dwarfism, growth-retarded infants and children, dermati- although this author could not find research to corroborate at
tis, diarrhea, alopecia, and loss of appetite [64]. More mod- this time. When serum copper-to-zinc ratio is being assessed
erate zinc deficiency can result in decreased immune during cancer treatment, serum zinc is used. Numerous
function, increased mortality due to infections, and brain studies have found an association between elevated copper-
damage in a fetus when the pregnant mother is zinc defi- to-zinc ratio and disease severity. Inducing copper deficiency
cient [64]. Zinc-­repletion dosing ranges anywhere from to prevent angiogenesis in cancer has been proposed as an
8 5  mg/day to 50  mg/day with monitoring of copper status adjunctive treatment for cancer [70]. Currently, it is uncer-
during supplementation [59]. tain if enough research exists to put this into clinical practice.
There is currently no specific sensitive biochemical or A phase II trial of advanced kidney cancer looked at inducing
functional indicator of zinc status [71]. Accurate measures of copper deficiency by using TM, a novel antiangiogenic agent,
plasma zinc are complicated by the body’s homeostatic con- to chelate copper, with the goal of lowering ceruloplasmin
trol of zinc levels and factors affecting zinc status that are level to 5–15 mg/dl for 90 days [70]. This resulted in disease
unrelated to nutritional status [71]. Plasma zinc is bound to its stabilization rather than a reduction in disease burden. The
carrier protein albumin; therefore, anything that alters albu- authors proposed that this may only be useful for a patient
min levels will alter plasma zinc levels [59]. There is no func- with minimal disease.
tional reserve of zinc in the body, and the body’s zinc levels are Diez et al. reported on the ratio of serum copper to zinc
maintained by conservation and tissue redistribution [71]. in diagnosis of lung cancer and found ratios of 2.34 ± 0.78 in
Cessation of growth in children is an example of severe the lung cancer cohort, 1.62 ± 0.23 in patients with benign
zinc deficiency [71]. When dietary zinc intake is low, fecal pulmonary lesions, 1.43 ± 0.29 in patients with benign lung
zinc excretion may be reduced by 60%, coupled with diseases, and 0.188 (not significant) in healthy subjects [73].
increased intestinal zinc absorption. In mild zinc deficiency, A cutoff value of Cu–Zn ratio of 1.72 resulted in sensitivity of
plasma zinc can be maintained at the expense of zinc from 89%, specificity of 84%, positive predictive value of 7%, and
other tissues [71]. Therefore, plasma zinc is not a reliable negative predictive value of 92% between lung cancer patients
measurement of zinc intake or whole-body zinc status [71]. and healthy subjects [73]. Lung cancer patients with pretreat-
Plasma zinc levels in mildly zinc-deficient growth-retarded ment Cu–Zn concentrations equal to or above 2.25 had
children who responded to zinc supplementation were not 24-month survival rates of less than 5%. By contrast, pre-
significantly different from normally developed children, treatment Cu–Zn levels below 1.72 were associated with
before or after zinc supplementation [71]. 24-month survival rate of 70% [73].
Decreased plasma zinc levels may result from stress, infec- Functional medicine doctors working in oncology typi-
tion, inflammation, use of estrogen, oral contraceptives, and cally strive for a serum Cu–Zn ratio of 1.0, although this
corticosteroids. Plasma zinc levels are known to fall 15–20% author could not find adequate studies supporting this ratio.
after a meal [71]. Increased zinc levels may occur from fasting Serum Cu–Zn ratio should be interpreted cautiously in
or red blood cell hemolysis [59]. A better alternative to plasma cases of suspected malignancy that are accompanied by
zinc levels might be red blood cell zinc levels, as RBCs contain infections, liver diseases, use of oral contraceptives, or other
zinc-dependent proteins. RBCs turn over every 120  days; conditions known to affect copper.
hence, RBC zinc status would reflect whole-body zinc status
over a longer period of time than plasma zinc and is not prone
to recent changes in whole-­body zinc status [59]. 8.8 Fatty Acids and Phospholipids
Zinc-containing enzymes are another possible marker for
zinc status, and alkaline phosphatase has been studied as a 8.8.1 Fatty Acid and Phospholipid Balance
biomarker for zinc status. In a study in Guatemalan children,
low serum zinc was associated with low serum albumin and A balanced ratio of omega-6 to omega-3 fatty acids is impor-
low serum alkaline phosphatase [72]. When assessing ALP, it tant for overall health related to its impact on inflammation,
is important to differentiate if low alkaline phosphatase is immune balance, obesity, depression, and cardiovascular dis-
due to zinc or magnesium deficiency [62]. When zinc was ease. See also 7 Chaps. 10 and 11. Omega-6 and omega-3
 
The Nutrition Assessment of Metabolic and Nutritional Balance
115 8
fatty acids cannot interconvert into one another; they are available in foods and an increased risk for changing the
metabolically and functionally distinct and have important, physiological state of the body to a more inflammatory, ath-
opposing physiological effects [74]. Alpha-Linolenic acid erogenic state. The balance of omega-6 to omega-3 can affect
(omega-3) and linoleic acid (omega-6) are the two essential gene expression, prostaglandin, and leukotriene metabolism
fatty acids that must be obtained through the diet; they can- and interleukin-1 production [74]. Modern agriculture and
not be endogenously formed by humans and other mammals aquaculture have changed the omega-3 fatty acid content for
due to a lack of enzymes for desaturation [74, 75]. the worse in many foods by replacing them with omega-6
The balance of omega-6 compared with omega-3 fatty fats.
acids influences the metabolic pathway of each of these fatty Depression is associated with low plasma phospholipid
acids [76]. Omega-6 and omega-3 fatty acids produce differ- and erythrocyte levels of EPA and DHA [75]. It is possible
ent eicosanoid products that result in different effects on that omega-3 fatty acids aid in mitigating depression by
inflammation. The need for balance between the eicosanoid decreasing inflammation systemically. Evidence points to
families is critical for metabolism involving inflammation, utilizing supplemental omega-3 fatty acids for therapeutic
resolving inflammation, structural composition, hormones, intervention of depression as a monotherapy or in addition
and immune functions. The nutritionist should be aware of to antidepressant medications, although results have been
the balance of the eicosanoids, their downstream metabo- mixed [75]. It has yet to be determined what blood levels of
lites, and the functions of such prostaglandins as PG1, PG2, EPA and DHA might be associated with improvement in
PG3, and specialized proresolving mediators (SPM). depression. Therapeutic levels of omega-3 depend on diet,
In the past three decades, because of public health pre- genetic variation in omega-3 fatty acid metabolism, and the
scriptions for low-fat diets, the intake of overall fat in the rate of absorption and incorporation into biologic systems
Western diet has decreased. However, proinflammatory [75]. In both short- and long-term studies, a fixed daily
omega-6 fatty acid consumption has increased, while dose of omega-3 results in a large variation of individual
omega-3 fatty acid consumption has decreased [74]. The omega-3 blood levels, possibly due to genetic polymor-
ratio of omega-6–omega-3, historically, was 1:1–4:1, and phisms and dietary intake. In a study on supplemental
today it is reported to be around 20:1. This change in con- omega-3 fatty acids and depression, researchers found that
sumption correlates with the rising epidemic of obesity and participants whose depression remitted had higher baseline
inflammatory disorders [74]. Arachidonic acid (AA), an omega-3 levels than those whose depression did not go into
omega-6 fatty acid, is a critical fatty acid for cell membrane remission [75].
structure and resolution of inflammation as it promotes spe- RBC levels are less sensitive to recent intake of omega-3
cialized SPM. However, when it is out of balance, excessive compared with plasma levels and may provide a more reli-
AA can become pro-inflammatory. As with all molecules and able estimate of omega-3 levels over time [75]. A level of
metabolites throughout metabolism, altered metabolic bal- 5–6% of omega-3 in RBC may be a reasonable target to pro-
ance can promote dysfunction. vide a therapeutic level. However, those who experienced
AA is used as a substrate to make eicosanoids such as remission of depression had levels of omega-3 in RBC at 8%
prostaglandin E2 and leukotriene B4 [74]. These cytokines, with the highest probability of remission at 9–10% [75]. This
when in excess, are pro-inflammatory and more potent finding is similar to results of a review on omega-3s to
mediators of thrombosis and inflammation than cytokines improve cardiovascular outcomes [75]. Overall, looking at
derived from omega-3 PUFAs. Eicosanoids from AA are bio- individual RBC levels to obtain therapeutic efficacy might be
logically active in small amounts, and when present in large a better way to dose supplemental omega-3 than providing a
amounts, they contribute to the formation of thrombus and fixed dose for everyone.
atheromas, allergic and inflammatory disorders, and prolif- Omega-3 fatty acid-enriched diets improve inflammatory
eration of cells [74]. status of metabolic dysfunction and reduction in adipose tis-
EPA and DHA, both omega-3 essential fats, suppress the sue if kept in balance with other essential fats [76].
production of proinflammatory cytokines IL-1B, Il-6, and Supplementation with omega-3 fatty acids and certain doses
TNF alpha [75]. EPA inhibits AA synthesis from linoleic acid of omega −6 fatty acids was shown to help with decreasing
and competes with AA for enzymatic conversion, resulting in body fat mass and hip circumference loss [76]. Dietary inter-
reducing AA conversion to pro-inflammatory molecules ventions optimizing the ratio of omega-6 to omega-3 have
[75]. The ingestion of fish or fish oil results in the EPA and shown significant reduction in low-density cholesterol as
DHA partially replacing omega-6 in the cell membranes of well. Omega-6 versus omega-3 essential fats have different
platelets, erythrocytes, neutrophils, monocytes, and liver influences on body fat mass through mechanisms of adipo-
cells [74]. In humans, the cerebral cortex, retina, testis, and genesis, lipid homeostasis, brain–gut–adipose tissue axis,
sperm are particularly rich in DHA, and DHA is abundant in and systemic inflammation [74]. In summary, lowering
the brain’s structural lipids [74]. omega-6 and increasing omega-3 may decrease the risk for
During evolution, omega-3 fatty acids were found in weight gain and associated inflammation.
almost all foods consumed including meat, fish, wild plants, Testing RBC fatty acid profiles is helpful to clinicians
nuts, and berries [74]. The dietary and agricultural changes when assessing fatty acid balance and is important because
over the last 100–150  years have resulted in less omega-3 AA and DHA both have critical but different biological func-
 116 M. G. Gasta

tions. There may be instances where omega-3 fatty acid levels tional inflammation may promote cancer, cardiovascular
are too high compared with levels of arachidonic acid (AA), disease, autoimmune disease, and the loss of organ function
which may have untoward consequences. The eicosanoids [80]. The nutritional balance between GLA, DGLA, and AA
produced from AA are important for immunity and immune and their metabolites may be key to maintaining a healthy
response and serve as mediators and regulators of inflamma- balance of inflammation in the body.
tion [77]. AA is critical for infant growth, brain development, Deficiency of fatty acids is often due to dietary insuffi-
and health. Too much DHA may suppress benefits provided ciency, but excessive supplementation of flax or fish oils leads
by AA [77]. DHA controls signaling membranes in the pho- to omega-3 fatty acid dominance [81]. Potential laboratory
toreceptor, brain, and nervous system, whereas AA has a role findings will reveal high omega-3 fatty acids with low AA
in the vasculature and certain aspects of immunity [77]. fatty acids and elevated EPA–DGLA ratio as well as depressed
Animal studies have provided evidence that both preformed AA–EPA ratios. This imbalance will produce a lowering of
DHA and AA are required for optimal cognitive function class 2 eicosanoid signals, which may lead to blunting of
[77]. More about omega-3 dominance is found in the section immune responses [81]. Supplementing omega-3 fatty acids
on gamma-linolenic acid. in an individual with a deficiency of n-6 fatty acids can fur-
ther exacerbate clinical outcomes by competing for desatu-
rase enzymes. Adding GLA-rich evening primrose oil may
8.8.2 Gamma-Linolenic Acid improve the clinical outcome in these individuals [81]. A diet
low in LA can be corrected by supplementing with LA-rich
8 Gamma-linolenic acid (GLA) and its downstream metabolite oils and/or correcting for malabsorption.
di-homo-gamma-linolenic acid (DGLA) are two omega-6 Another risk of omega-3-dominant conditions is lipid
fatty acids important to any discussion of fatty acids (please peroxidation of cell membranes and increased risk of oxida-
see 7 Chaps. 10 and 11). They are often grouped into the “too tive damage in the body that may give way to serious health
 

much omega-6 statements” without addressing their critical conditions, including heart and neurological diseases. In
importance in nutritional therapy. GLA is not present in the general, it is recommended to supplement with antioxidant
human diet and is formed from the essential fatty acid cis-­ nutrients when using omega-3 fatty acids to protect against
linoleic acid [78]. It is often supplemented in the form of bor- lipid peroxidation and monitor fatty acid profiles and anti-
age oil, evening primrose oil (EPO), or black currant seed oil. oxidant nutrients [81].
As a metabolite of the essential fatty acid linoleic acid (LA), To prevent an imbalance in fatty acids, consider supple-
GLA, in turn, produces DGLA. DGLA is available as a sub- menting the full range. When GLA, DGLA, EPA, and DHA
strate to produce AA or be directed to form the prostaglan- are given together, the overproduction of pro-inflammatory
din 1 series (PG1) metabolites. The balance needed between cytokines IL-6 and TNFα is suppressed [78]. The combina-
the prostaglandin groups is another critical consideration tion of GLA, EPA, and DHA in supplemental form would
when assessing an individual’s fatty acid balance. For exam- likely induce a powerful combination of anti-inflammatory
ple, autoimmune and skin conditions are dependent on ade- and necessary inflammatory metabolites [79]. Common
quate PG1 molecules. Most of the PGs, TXs, and LTs are genetic and epigenetic variations affect the rate of conversion
proinflammatory. AA products generally enhance inflamma- of long-chain PUFAs and their metabolites and are strongly
tion as the precursor of 2-series PGs and thromboxanes related to ethnicity, suggesting that “one size fits all” dietary
(TXs) and 4-series leukotrienes (LTs) [79]. Therefore, the and supplement recommendations for fatty acids may not be
balance of AA to DGLA in the body may be a critical factor appropriate, with laboratory testing critical [79].
in regulating inflammatory processes [78].
GLA metabolism in humans is complex as all the cellular
compartments metabolize GLA differently [79]. This differ- 8.8.3 Conjugated Linoleic Acid
ence is due to differential expression of PUFA-metabolizing
enzymes. GLA supplementation can lead to increased DGLA Conjugated linoleic acid (CLA) is another fatty acid that may
levels in certain inflammatory cells but can increase both have anti-inflammatory and anti-cancer benefits. CLAs are a
DGLA and AA in circulating lipids [79]. The impact of AA series of isomers of LA and chemically do not belong to the
accumulation in the body remains controversial. When GLA omega-6 family; however, they can originate from the endog-
is given with omega-3 fatty acids, the conversion of DGLA enous biohydrogenation of LA by gastrointestinal tract bac-
(from GLA) to AA is inhibited, and the accumulation of teria [82]. CLAs have demonstrated a benefit in inflammatory
serum AA appears to be prevented [79]. bowel disease (IBD) and colon cancer and may serve as an
Inflammation is the immune system’s response to infec- agonist for peroxisome proliferator-activated receptor
tion and injury and facilitates the removal of the cause of the gamma (PPARγ) [83]. PPARs are nuclear receptors for
inflammation (the offending agent) and the restoration of tis- endogenous lipid molecules such as prostaglandins or
sue structures and physiological function [80]. Inflammatory hydroxyl-containing PUFAs [83]. Their main biological
prostaglandins derived from AA play a key role in necessary function is to sense intracellular nutrient concentrations and
inflammation. Therefore, our goal is not to eliminate inflam- regulate gene expression involved in maintaining metabolic
mation but, rather, keep it in check. Persistent and dysfunc- and tissue homeostasis. When CLA is used in conjunction
The Nutrition Assessment of Metabolic and Nutritional Balance
117 8
with omega-3 fatty acids, it may prevent or ameliorate IBD in phage phagocytic capacity were significantly improved with
animal models [83]. In addition to activating PPAR γ, CLA soy PC supplementation. PLs (purified extract of PPC from
can also modulate the production of AA metabolites, which soybeans) have shown a beneficial effect with viral hepatitis
may reduce the production of inflammatory lipid mediators. and alcohol-induced liver damage. PLs have also been dem-
Several CLA isomers are found naturally in milk, cheese, and onstrated to reduce total liver lipid, liver TG, and total cho-
ruminant products [83]. Grass-fed beef and fatty milk prod- lesterol [84].
ucts from grass-fed beef are good dietary sources of CLA. Chronic alcohol ingestion depletes PL in brain cell mem-
branes and depletes antioxidant systems from the cell mem-
branes which, in turn, promotes lipid peroxidation in the
8.8.4 Phospholipids brain and other cells such as enterocytes [84].

Any discussion on fatty acids must include a discussion on

the importance of phospholipids. Phospholipids (PLs) are 8.8.5 Short-Chain Fatty Acids
amphiphilic lipids (containing both hydrophilic and hydro-
phobic properties) found in all animal and plant cell mem- Short-chain fatty acids (SCFA) are the major metabolic prod-
branes [84]. PLs are arranged as lipid bilayers with the ucts formed by anaerobic bacterial fermentation of soluble
hydrophilic regions reaching toward the outer surface of the fiber in the gastrointestinal tract and may be the link between
cell membrane and the hydrophobic properties reaching microbiota and host tissues [85]. SCFA include acetate (C2),
toward the inner membrane compartment. PLs can be glyc- propionate (C3), and butyrate (C4) [85]. Acetate is utilized for
erophospholipids (GPLs) found in most cell membranes or lipogenesis in the liver and as a fuel source once it enters the
sphingophospholipids (i.e., sphingomyelin or SPM), com- peripheral circulation; propionate is also used in the liver as
monly found in high quantities in the brain and neural tis- a substrate for hepatic gluconeogenesis; butyrate is primarily
sues [84]. Cell membranes are also composed of glycolipids used as a fuel source for the colonocytes [86]. Besides serving
and cholesterol and proteins. as a fuel source for the intestinal epithelial cells, SCFA also
GPLs can be extracted from soybeans, egg yolk, milk, or modulate electrolyte and water absorption in the GI tract and
marine organisms such as fish, roe, or krill [84]. GPLs can regulate the inflammatory process in the GI tract [85]. The
have different fatty acid compositions. Soybean PL consists concentration of SCFA in the GI tract and blood may predis-
of GPLs with a high content of unsaturated FA such as LA pose to or prevent illnesses such as inflammatory bowel dis-
(n-6 FA); egg yolks have mainly phosphatidylcholine (PC) as ease (IBD), cancer, and diabetes [85]. SCFA modulate
their source of PL and contain unsaturated FA, mainly oleic different processes such as cell proliferation and differentia-
acid; milk GPLs have both PC and phosphatidylethanol- tion, hormone secretion of leptin and peptide YY, and
amine (PE) as their main PL classes in addition to SPM, and immune and inflammatory responses and serve as an energy
the FA content consists of both unsaturated and saturated; source for colonocytes, the liver, and muscle [85]. SCFA lev-
marine GPL is mainly composed of PC and binds the unsatu- els have been found to be lower with increasing age in
rated eicosapentaenoic acid (EPA) and docosahexaenoic acid humans, dogs, and mice [86].
(DHA) [84]. Consuming dietary GPLs with a specific FA Butyrate is the most widely studied SCFA and is predom-
composition may alter the FA composition of membrane PLs inantly produced by Faecalibacterium prausnitzii (F. praus-
and affect cellular function such as signaling, transport, and nitzii). Butyrate serves as an energy source for colonocytes
activity of membrane enzymes. The possibility for modulat- and exerting an anti-inflammatory effect in the colon [87].
ing cell function from specific PLs could contribute to health Studies reported benefit when butyrate was administered for
benefits [84]. IBD-related lesions and symptoms [87]. A study by Zhang
A number of possible clinical applications of using phos- et  al. in rats found that oral administration of butyrate
pholipids exists. They involve reducing inflammation; improv- resulted in increased percentage of butyric acid, fecal con-
ing lipid profile; increasing production of cytoprotective centration of butyric acid, and overall total SCFA [87].
mucosal PGE2 in the GI tract, which may help with ulcerative Studies in mice have suggested that the obese microbiota,
colitis or the side effects of using NSAIDs; and improving cog- which has a higher ratio of Firmicutes to Bacteroidetes com-
nitive function, visual function, and memory [84]. pared with lean microbiota, produce a higher amount of
Phosphatidylserine (PS), the best studied GPL for brain SCFA compared with leaner counterparts, potentially con-
performance, may be especially protective against age-related tributing to obesity [86].
cognitive decline. PS has been shown to revitalize memory, The reasons for higher SCFA in obese individuals may be
learning, concentration, and vocabulary skills and assist with due in part to lower colonic absorption of SCFA, reduced
managing stress hormones and depression [84]. PS also stim- colonic transit time, or increased SCFA production due to
ulates acetylcholine synthesis, which triggers the release of differences in dietary intake [86]. The ratio of Firmicutes to
neurotransmitters. Changes in the composition of cell mem- Bacteroidetes in humans is not always higher in obese indi-
branes with age include an increased cholesterol–PL ratio, viduals; thus, the higher SCFA theory in obese individuals is
which may reduce the immunological function of lympho- not a consistent finding [86]. A study by Rahat-Rozenbloom
cytes. In a study on rats, lymphocyte number and macro- et  al. comparing obese versus lean subjects suggested that
 118 M. G. Gasta

SCFA production was higher in obese individuals, but this and is representative of longer-term dietary intake rather
was not due to decreased absorption of SCFA or differences than recent dietary intake as is represented in plasma profiles
in dietary intake. Rather, this may be due to the differences in of fatty acids [81]. Fatty acid analysis can also help pinpoint
the microbiome with the obese microbiome being higher in certain key vitamin and mineral needs. Laboratory profiles of
Firmicutes than the lean microbiome [86]. Further research fatty acids include more than 40 analytes that may be evalu-
will be critical in finding the important relationships. ated using patterns within families rather than assessing each
Increasing the production of SCFA is largely accom- individual fatty acid [81]. Individual variability of intake,
plished by eating a whole-foods diet high in plant foods and digestion, absorption, and degradation can produce different
fiber. Butter is a natural food source of butyrate. Butter from fatty acid profiles and support the notion of not using a “one-­
grass-fed cows would provide the additional benefit of the size-­fits-all” approach to recommending supplemental fatty
anti-inflammatory effects of the fatty acid CLA. In cases such acids [81]. The assessments of patterns include general fatty
as IBD, a high-fiber diet may not be tolerated during an exac- acid deficiency, omega-3 deficiency or excess, omega-6 defi-
erbation of the illness, and this is where the oral or enema ciency or excess, hydrogenated oil toxicity, micronutrient
administration of butyrate might be of benefit. Working with deficiency, metabolic and genetic disorders, and fatty acid
an experienced integrative and functional medicine practi- ratios and indices [81].
tioner in the use of butyrate is recommended. RBC fatty acid profiles can indicate certain micronutrient
deficiencies. For example, when biotin is deficient, the ratio
of vaccenic acid to palmitoleic acid is significantly lower.
8 8.8.6 Increasing Beneficial Fatty Acids Vaccenic acid has large effects on membrane fluidity and
inhibition of tumor growth in cell culture [81]. B12 defi-
Increasing omega-3 fatty acid intake might include eating ciency is associated with abnormal fatty acid synthesis that
grass-fed beef (also high in CLA), wild-caught fish, eggs results in odd-chain fatty acids building up in the lipids of the
from free-range chickens with omega-3 fatty acids in their nervous system. This results in altered myelin integrity and
feed, and supplementing with omega-3 fatty acids. demyelination, leading to impaired nervous system func-
Simopoulos et al. recommend lowering omega-6 by chang- tioning [81]. Moreover, this may in part explain the neuropa-
ing vegetable oils from corn, sunflower, safflower, cotton- thy associated with cobalamin deficiency [81].
seed, and soybean oils to oils that are high in omega-3, such To further elucidate this metabolic process, the produc-
as flax, perilla, chia, rapeseed, and oils that are high in mono- tion of fatty acids with odd numbers of carbon atoms is initi-
unsaturated fats such as olive oil, macadamia nut oil, hazel- ated by propionic acid [81]. Propionic acid requires B12 to be
nut oil, and increasing fish intake to two to three times per converted into succinate; therefore, a deficiency of vitamin
week while decreasing meat intake [74]. Processed foods are B12 results in the accumulation of propionate and a build-up
notoriously high in omega-6; therefore, consuming a whole- of odd-numbered fatty acids [81]. In animal studies of biotin
food, unprocessed diet is also an important factor in balanc- deficiency, abnormalities from the accumulation of propio-
ing the ratio of omega-6–omega-3 fatty acids. Increasing nate have been shown to occur. These abnormalities result in
GLA involves supplementing with a good source of GLA, the buildup of odd-chain fatty acids in the plasma phospho-
such as evening primrose oil, black currant seed oil, or bor- lipids, plasma, and liver in experimental animals [81]. Gut
age oil. Increasing CLA can be done through supplemental bacteria in ruminants also produce high amounts of propio-
sources that include a variety of isomers or eating grass-fed nate. Consequently, eating animal and dairy products may
beef and whole-fat dairy products from grass-fed beef, such result in accumulation of odd-numbered fatty acids [81].
as butter, yogurt, cheese, or milk, and enhancing the micro- Zinc may be the best-known nutritional deficiency that
biome through diet to support the endogenous biohydration can show up in a RBC fatty acid analysis. The desaturase
of LA.  Increasing phospholipids such as choline can occur enzymes needed for the conversion of fatty acid substrates
through eating sunflower seeds, egg yolks, fish, and milk. into products rely on zinc. The delta-6-desaturase enzyme
Sunflower or soy lecithin are both sources of phospholipids that converts LA to DGLA will be under-functioning in
(sunflower lecithin is typically recommended over soy leci- zinc deficiency; thus, an elevated ration of LA–DGLA is a
thin) and dietary supplementation of phosphatidylserine sensitive marker for zinc deficiency [81]. In cases where
and phosphatidylcholine. LA-rich foods are restricted and extra flaxseed oil is used,
the ALA–zinc ratio may also be elevated as that pathway
requires zinc [81].
8.8.7  ssessing Erythrocyte Fatty Acid
A Essential fatty acid deficiency will show up as an elevation
Profiles in mead acid [81]. The production of mead acid rises as EFA
intake falls. Mead acid is an omega-9 PUFA produced by
Because a “one-size-fits-all” approach to fatty acid supple- repeated desaturation of nonessential fatty acids. Mead acid
mentation is not optimal for balancing fatty acid nutritional cannot participate in eicosanoid formation but mimics mem-
status, testing erythrocyte fatty acid profiles is a helpful tool brane fluidity action of PUFAs derived from EFA.
as a part of nutritional assessment. Assessing fatty acid pro- When supplemental fatty acids are used, they must be
files in packed erythrocytes is the most common procedure kept from air and light to keep oxidation low. In addition,
The Nutrition Assessment of Metabolic and Nutritional Balance
119 8
these supplements often contain vitamin E to help prevent on an individual basis. Specific conditions such as chronic
oxidative damage to the fatty acids [81]. Erythrocyte fatty kidney disease will benefit from a controlled protein intake,
acid follow-up testing is recommended to be done after and epilepsy can benefit from a very low-carbohydrate, high-­
90 days of starting interventions [81]. fat ketogenic diet. For years, the field of nutrition has been
bombarded with claims of various adjustments in macronu-
trient ratios having benefit. Nutritionists need to take into
8.8.8 Hydrogenated Oils account individual disease states and give the patient the
most sustainable, realistic plan to improve health.
Hydrogenated oils are harmful fats also known as trans-fatty While the ketogenic diet (low-carbohydrate, high-fat) is
acids. Hopefully, trans-fatty acids will be less of a concern in showing promise for various conditions including epilepsy,
the United States due to the phasing out of these fats in the cancer, weight loss, type 2 diabetes, metabolic syndrome,
food manufacturing industry. Trans-fatty acids are harmful dementia, and neurological diseases [90], the ketogenic diet
because, although listed as unsaturated fats, they behave like can be difficult for the average person to sustain. The guid-
saturated fats and lead to higher cholesterol levels, and they ance of a ketogenic-trained nutritionist can assist in compli-
mimic unsaturated fats by binding to desaturase enzymes ance. This dietary regimen can be a critical intervention to
and interfering with the normal production of necessary sub- produce a successful outcome. It is important that a keto-
stances [81]. Trans-fatty acids have been shown to contribute genic or modified ketogenic diet regimen be developed for
to the risk of heart disease and cancer [81]. Trans-fatty acids the individual and their medical condition. In this author’s
are found in margarine, hydrogenated peanut butter, baked opinion, intermittent fasting (IF) and time-restricted feeding
goods, desserts, snack foods, and crackers [81]. The main (TRF) may prove to have as important cardiometabolic and
trans-fatty acid type found in hydrogenated foods is C-18 neurological benefits as the ketogenic diet and may be appro-
trans-fatty acids including elaidic acid, trans-vaccenic, and priate for those who cannot sustain a ketogenic diet.
trans-petroselinic, followed by palmitelaidic acid. Time-restricted feeding (TRF) may be a feasible alterna-
Milk products and beef can contain some naturally occur- tive to calorie restriction, ketogenic diet, and intermittent
ring trans-fatty acids (elaidic acid) formed from the bacteria in fasting when compliance with more restrictive eating regimes
the gastrointestinal tract of ruminant animals [81]. Naturally is not likely or not recommended. TRF is an eating pattern
occurring trans-fatty acids are not a health concern [81]. based around circadian rhythms that occurs within a limited
time span (usually 8–12  hours), with a span of 4  hours in
between meals with no attention paid to calorie intake [91].
8.8.9  verall Diet and Macronutrient
O In one study, eight overweight participants consumed their
Distribution entire caloric intake within a 10–11-hour window. These par-
ticipants consumed 20% less calories (due to eliminating
Diet is the core treatment for many diseases, including obe- alcohol and late-night snacks) and lost 4% body weight in
sity, hypertension, hyperglycemia, and dyslipidemia. Many 16  weeks that they sustained for 1 year. The participants
interventions are beneficial, including replacing harmful reported improved sleep and elevated alertness during the
fats with health-promoting fats; increasing fiber; increasing day [91]. TRF can impart other benefits as well. Prolonged
phytonutrient content such as flavonoids, polyphenols, and overnight fasting (>13 hours) correlated with reduced risk of
antioxidants from plant-based foods; reducing salt; and breast cancer [91]. TRF is still being investigated, and more
restricting calories [88]. The Mediterranean diet is one of studies are needed to validate its effectiveness.
the most studied diets and recommends high consumption
of extra virgin olive oil, fruits, vegetables, nuts, seeds,
legumes, cereals, moderate fish, poultry, dairy, and red wine Correcting nutritional imbalances by designing individual-
and lower consumption of eggs, red meat, processed meat, ized food and dietary supplementation recommendations
and processed foods. The Mediterranean diet improves are the cornerstone of functional nutrition.
blood pressure, lipid profiles, insulin sensitivity, CRP, oxida-
tive stress, atherosclerotic disease, and cognitive function
[88]. The Mediterranean, pescetarian, vegetarian, or vegan 8.9 Summary
diets also offer environmental benefits with decreased
greenhouse gas emissions [88]. People who eat an organic, Nutrient intake is a contributing factor to living with or with-
Mediterranean diet may contribute to a reduction in global out disease. Correcting nutritional imbalances by designing
environmental impact [88]. In terms of lowering of HbA1C, individualized food and dietary supplementation recom-
a systematic review found that a low carbohydrate mendations are the cornerstone of integrative and functional
Mediterranean diet and low-fat vegan diet were possibly the nutrition. When using supplements, always keep balance in
most effective [89]. mind. Retest lab parameters to ensure clients are staying in
To reemphasize, a one-size-fits-all diet or macronutrient balance. Adjust dietary macronutrient ratios according to
recommendation is not plausible. The percentage of calories individual needs instead of using a one-size-fits-all approach
from carbohydrate, fat, and protein needs to be determined (See 7 Box 8.1).
 
 120 M. G. Gasta

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69. Harvey L, Ashton K, Hooper L, Casgrain A, Fairweather-Tait S. Meth- 85. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflam-
ods of assessment of copper status in humans: a systematic review. mation by short chain fatty acids. Nutrients. 2011;3(10):858–76.
Am J Clin Nutr. 2009;89:2009S–20024S. 86. Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence
70. Goodman VL, Brewer GJ, Merajver SD. Copper deficiency as an anti- for greater production of colonic short-chain fatty acids in over-
cancer strategy. Endocr Relat Cancer. 2004;11(2):255–63. weight than lean humans. Int J Obes. 2014;38(12):1525–31.
71. Lee R, Neiman D. Nutritional assessment. 6th ed. New York: McGraw- 87. Zhang M, Zhou Q, Dorfman RG, Huang X, Fan T, Zhang H, et  al.
Hill; 2013. Butyrate inhibits interleukin-17 and generates Tregs to ameliorate
72. Bui VQ, Marcinkevage J, Ramakrishnan U, Flores-Ayala RC, Ramirez- colorectal colitis in rats. BMC Gastroenterol. 2016;16(1):84.
Zea M, Villalpando S, et al. Associations among dietary zinc intakes 88. Wade AT, Davis CR, Dyer KA, Hodgson JM, Woodman RJ, Keage HA,
and biomarkers of zinc status before and after a zinc supplemen- et al. A mediterranean diet to improve cardiovascular and cognitive
tation program in Guatemalan schoolchildren. Food Nutr Bull. health: protocol for a randomised controlled intervention study.
2013;34(2):143–50. Nutrients. 2017;9(2)
73. Diez M, Cerdan F, Arroyo M, Balibrea L. Use of the copper/zinc ratio 89. Dussaillant C, Echeverria G, Urquiaga I, Velasco N, Rigotti A.  Cur-
in the diagnosis of lung cancer. Cancer. 1989;63(4):726–30. rent evidence on health benefits of the mediterranean diet. Revista
74. Simopoulos AP.  An increase in the Omega-6/Omega-3 fatty
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acid ratio increases the risk for obesity. Nutrients. 2016; 90. Boison D. New insights into the mechanisms of the ketogenic diet.
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75. Carney RM, Steinmeyer BC, Freedland KE, Rubin EH, Rich MW, Har- 91. Longo VD, Panda S. Fasting, circadian rhythms, and time-restricted
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 123 9

IFMNT NIBLETS Nutrition

Assessment Differential
Robyn Johnson and Lauren Hand

9.1 Introduction – 124

9.2 N: Nutrient Deficiencies/Insufficiencies – 124

9.3 I: Inflammation/Immunity – 125

9.4  : Biochemical Individuality and Genetic/Epigenetic

B
Influences on Chronic Disease – 127

9.5 L: Lifestyle Factors – 127

9.6 E: Energy – 128

9.7 T: Toxic Load – 129

9.8 S: Stress and Sleep – 129

9.9 Sleep – 130

9.10 Conclusion – 131

References – 131

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_9
 124 R. Johnson and L. Hand

9.1 Introduction 9.2 N: Nutrient Deficiencies/Insufficiencies

An integrative assessment and diagnosis of each individual is Medical history/current condition/diagnosis  When assess-
fundamental to identifying root causes for an appropriate ing an individual patient, the patient’s medical history and cur-
intervention. Because of the complexity of human metabo- rent condition or diagnosis can guide initial considerations,
lism and the diverse influences, the NIBLETS assessment was based on evidenced nutrient foundations for that condition or
developed as a way to assess factors that are affecting nutrient diagnosis. For example, for a patient presenting with a diagno-
metabolism. The NIBLETS model is named for its seven sis of heart disease, nutritional-­ metabolic concerns would
components: focus on lipid metabolism, vitamin D, and inflammation. If a
55 Nutrient deficiencies/insufficiencies patient presented with type 2 diabetes mellitus, one would con-
55 Inflammation/immunity sider carbohydrate metabolism, vitamin D, and nutrients
55 Biochemical individuality (genetic/epigenetic influences required for glucose/insulin metabolism. Each health condi-
on chronic disease) tion will have nutrient-related considerations that have shown
55 Lifestyle factors particularly strong associations or causal relationships. The
55 Energy assessment investigation can begin with these considerations.
55 Toxic load
55 Stress and sleep Dietary intake  The foundation of any person’s nutritional
sufficiency is his/her dietary intake to meet individual bio-
Historically, nutrition assessment focused on evidence-­based chemical nutrient needs, which are influenced by genetics and
research, nutrient requirements of populations, and dietary environmental stressors. The Standard American Diet, consist-
9 intake. IFMNT expands this population-focused nutrition ing of mostly nutrient-poor processed and fast foods, has left
assessment by assessing the individual and their unique the majority of the public overfed and undernourished. While
nutrition status at the time of the assessment. The individual’s over 70% of US adults are considered clinically overweight or
nutrition status becomes the foundation on which interven- obese, theoretically consuming more calories than needed,
tions are based, within the safety of evidence-­based medicine they are still not consuming adequate amounts of essential
and clinical expertise. Many of the tools that IFMNT practi- nutrients. Three-quarters of Americans consume less than the
tioners have found useful in performing a NIBLETS assess- recommended intake of vegetables and fruits, and that is when
ment are included in this textbook, with further description fried potatoes and refined juices are included in these counts
of each of the NIBLETS categories. [1]. The majority of Americans are not even reaching the esti-
One of the most beneficial tools used by the IFMNT mated average requirement or adequate intake of potassium,
practitioner when assessing nutrient status is laboratory fiber, choline, magnesium, calcium, and vitamins A, D, E, and
testing of various components of the body: blood, saliva, C [1]. Meanwhile, these standards for nutrient consumption
urine, breath, stool, and others. Integrative laboratory test- are currently based on average needs for our population to
ing can reveal the deeper, unseen, and otherwise unidenti- remain in a disease-free state. For many individuals, nutrient
fied issues that linger underneath the surface. However, a needs may actually be much higher for optimal function, driv-
practitioner can begin a differential nutrition assessment ing the chasm between need and intake even wider.
through the NIBLETS lens prior to receiving any test Reliance on convenience foods and the dissipation of the
results, immediately after hearing a patient’s story. Whereas family dinner table is certainly a lifestyle factor affecting our
the patient’s story will cover their medical history, this part nutrient status. Within the span of less than 30 years starting
of the assessment considers the current modifiable factors in the late 1970s, Americans’ consumption of food prepared
and clinical imbalances that influence an individual’s outside the home, as a percentage of total calories consumed,
health. To treat a person rather than a condition requires a nearly doubled [2]. This has a direct correlation with decline
thorough assessment of external factors negatively impact- in diet quality [3]. However, even within the home, the stan-
ing that person’s health. Regardless of the advances in phar- dard American way of eating is heavy in refined grains and
maceutical and nutraceutical support the medical added sugars and increasingly lacking in whole, nutrient-­
community is able to make, patients will find themselves in dense foods. The current hurried lifestyle pattern in the USA
a similar position once again if interventions are not made leaves very little time for the food preparation involved in
to change the patterns that helped cause the problem in the cooking tasty meals containing nutrient-dense foods such as
first place. In order to inform these changes, a thorough quality proteins and vegetables. In 2014, the average
assessment and diagnosis must first be made. In this sec- American spent roughly half an hour each day on preparing
tion we will outline the seven components of the NIBLETS food and cleaning up. However, between those who used any
model and discuss the benefit of using the integrative restaurant foods on a regular basis and those who did not,
NIBLETS assessment for determining an individual’s nutri- there was a 30-minute discrepancy in daily time spent on
tion and metabolic status. food preparation [4]. Considering our currently overworked,
IFMNT NIBLETS Nutrition Assessment Differential
125 9
under-rested, hurried lifestyles, it is no wonder why these macronutrient deficiencies can cause immune dysfunction,
convenience foods are highly sought after. For this reason, increasing the likelihood of inappropriate inflammation or
intervening to improve diet quality will undoubtedly require infection. Therefore, since the relationship between nutrient
directives on addressing these time and budget constraints status and immunity is bidirectional, assessing a patient for
(see 7 Chap. 2).
  both is crucial to determining an appropriate and effective
In addition to the typical dietary patterns of the Standard intervention.
American Dieter, those who follow restrictive diets such as Acute immune response requires many different nutri-
vegetarianism and veganism are at risk for further nutrient ents for both initiation and resolution. Adequate nutrition is
deficiencies. While many factors may lead a person to this needed for both adaptive and innate immune responses.
dietary pattern including moral, religious, or even health-­ Undernutrition is recognized worldwide as a major contribu-
based motivations, it is still worth noting the increased risk. tor to poor survival in developing countries. However, even
In addition to the aforementioned nutritional deficiencies for in populations of adequate food access, hospitals are screen-
those with a Western-style diet, those who avoid animal ing for malnutrition because of its association with increased
products are at further risk of inadequate intakes of protein, complications and mortality [5]. In the case of starvation,
omega-3 fatty acids, vitamin B12, iron, zinc, vitamin K2, and immune function can be impaired quickly because of the
iodine. While a nutritionally adequate diet can still be lack of nutritional reserve within immune cells.
achieved, special attention should be given to those adopting Undernutrition is known to alter both innate and adaptive
this dietary pattern to address the higher risk. immune responses, including T-cell proliferation and func-
tion [6]. However, micronutrient status has been one vastly
Laboratory testing  Lab testing is a valuable component of a overlooked area, particularly in acute settings, though two-
nutrition assessment, as it can provide insight and information thirds of patients hospitalized in an infectious disease clinic
that is hard to identify through symptoms alone (i.e., infec- were found to be deficient in at least one nutrient [7]. Vitamin
tions, nutrient deficiencies, hormonal imbalances, etc.). While A, vitamin D, vitamin E, zinc, omega-3 fatty acids, and
there are many different forms of testing – such as micronutri- omega-6 fatty acids are among the most-studied nutrients
ents, stool, urine, and saliva – not all are equal, nor do they test active in the immune response, though many other nutrients
the same things. For example, a urine organic acid test is valu- play integral parts in the optimal function of the immune
able to assess a patient’s methylation function, while a compre- system. Therefore, a complete nutritional assessment would
hensive stool analysis is valuable to assess a patient’s gut health include looking for macro- and micronutrient deficiencies.
and microbiome status. Both tests are valuable, but both might However, the relationship between inflammation and
not be necessary for every patient. During a nutrition assess- nutrition is rather complex and can lead to a cyclical issue.
ment, the practitioner can gather information and use clinical While malnutrition certainly increases susceptibility to ill-
judgment to determine which laboratory testing would pro- ness, inflammation can in turn promote nutrient deficien-
vide additional data necessary for that patient. cies. Many immune or inflammatory processes drive
There is no “perfect” method of testing for nutrients. consumption of certain nutrients, such as in the case of con-
Many forms of testing are currently available, including ditionally essential amino acids. Other inflammatory condi-
serum, red blood cell (RBC), lymphocyte, stool, urine, and tions, such as in the case of infection, can also indirectly
hair. Labs are a tool to be used in conjunction with the rest of cause nutrient deficiencies by increasing intestinal permea-
the nutrition assessment. If laboratory testing is ordered, bility or anorexia. Therefore, using an integrative assessment
even if it isn’t direct nutrient testing, the results can provide can help pinpoint the root cause of the issue so it can most
guidance to the practitioner on what dietary, lifestyle, or effectively be addressed.
supplement changes need to be made. Prolonged inflammation contributes to the progression
IFMNT practitioners look beyond population guidelines. of many chronic diseases, such as types 1 and 2 diabetes mel-
Instead, they look at the individual and work with each indi- litus, cardiovascular disease, Alzheimer’s, psoriasis, lupus,
vidual to optimize the body. Identification of an individual’s and more. Modifiable lifestyle factors including diet, smok-
current nutrient status via laboratory testing can provide ing, and exercise have profound impacts on these levels of
answers and guidance for a proper intervention for the patient. inflammation. While acute inflammation is necessary for
healing, chronic, low levels of inflammation appear to be
major players in chronic disease etiology. Immune dysregu-
9.3 I: Inflammation/Immunity lation and oxidative stress are closely related to inflammation
in the body, with common etiology and positive feedback
The inflammatory and immune responses to injury and loops, compounding the detrimental impacts. For many, this
infection are essential for host defense and survival. However, inflammation may go undetected for years, leading it to be
these responses carry a significant metabolic burden, driving termed the “silent killer” by scientific and media reports.
the need for certain nutrients. Furthermore, both micro- and Regardless of a symptom manifestation, chronic inflamma-
 126 R. Johnson and L. Hand

tion poses a damaging impact, increasing risk of chronic dis- ously, omega-3 fatty acids have a large anti-inflammatory
ease and mortality. Western lifestyle behaviors such as poor effect because of their eicosanoid metabolites and down-
diet, inactivity, and smoking are often underlying root causes stream resolvins and protectins, which have an inflammation-­
of this inflammation. resolving impact. Furthermore, negative attributes of the
Diet is a major player in this underlying inflammation. Western lifestyle may act synergistically to either counteract
Red meat consumption, for instance, has shown to stimulate or compound the inflammation. Mice exposed to cigarette
the production of the prooxidant trimethylamine-N-oxide smoke have shown increased oxidation levels when fed a
(TMAO) 3.7 times more than chicken in rat models [8]. high-refined-carbohydrate diet [16] and protection from the
Excess consumption alone can be a stimulant for inflamma- oxidative damage when given omega-3 fatty acids [17].
tion. Hyperinsulinemia caused by excess carbohydrates and Beyond the direct influence on inflammation, lifestyle
calories has a pro-inflammatory effect. High-carbohydrate factors also influence our immune system through various
diets have been associated with a greater likelihood of having mechanisms. Generally speaking, obesity preferences Th1
an elevated hs-CRP in postmenopausal women [9]. and Th17 dominance over Th2, promoting inflammation.
Furthermore, excess adiposity, particularly in regard to white Visceral adiposity, in particular, appears to contribute to this
and/or visceral adipose tissue, contributes to the circulation immune and inflammatory dysregulation because of the
of pro-­inflammatory adipokines such as leptin and is associ- macrophage infiltration of the adipocytes. These macro-
ated with increased levels of interleukin-6 and tumor necro- phages promote the Th1 dominance through the release of
sis factor alpha [10]. IL-6 and IL-1 and TNF-alpha [18]. Furthermore, the health
Immune responses to both acute and chronic inflamma- of the gastrointestinal system is a major factor in determin-
tory responses involve complex molecular signaling. One ing the health of our immune system. It is known as our first
9 major pathway at play involves the eicosanoids, which are line of defense against pathogens. Unfortunately, the Western
derived from polyunsaturated fatty acids. The relative produc- style of living with stress, poor diet, and toxin exposure has
tion of anti-inflammatory prostaglandin eicosanoid (PGE)-1 led to the rise in intestinal permeability, impacting the integ-
or PGE-3 versus pro-inflammatory PGE-2 directly modulates rity of the gut lining. This leads to a greater susceptibility of
the inflammatory state. Because PGE-3 is derived from pathogens to escape defenses of the gut and enter circulation.
omega-6 fatty acids and PGE-2 from omega-3 fatty acids, bal- Diet, by promotion of a healthy microbiome, affects adaptive
ancing fatty acid intake is crucial to creating an optimal envi- immunity. A healthy diet rich in fiber leads to a rise in benefi-
ronment. These two fatty acids and their subsequent cial bacteria that produce metabolites acting as ligands on
metabolites compete for space within the cellular membrane, aryl hydrocarbon receptors (AHR) found in the mucosa of
cleavage from the cell by phospholipase A2, and further the intestinal lining. The activation of AHR promotes the dif-
metabolism by delta-5 and -6 desaturases. While current ferentiation of T cells into T-regs. Nutrients such as vitamins
dietary guidelines for Americans recommend increasing A and D also have direct impact on the adaptive immune
intake of all polyunsaturated fatty acids, evidence suggests that system. Vitamin A is needed for stability of Th1 response, in
increasing omega-6s without increasing omega-3s increases such a way that a deficiency has been shown to stimulate
the risk of CVD events, further confirming how critical the Th1  in allergic diseases. Synergistically, vitamin D when
appropriate ratio is for balancing inflammation. In fact, having binding to a vitamin D receptor heterodimerizes with vita-
a higher omega-6/omega-3 ratio in the diet has shown associa- min A receptor RXR, promoting T-cell differentiation to
tion with a higher level of CRP [11]. Though determining an T-regs and inhibiting IgE synthesis [18].
optimal ratio for PUFAs is difficult, experts suggest a range Considering the complexities of the relationship between
between 1:1 and 4:1 in omega-6 to omega-3 FAs [12]. Because inflammation and nutrition, a deeper, integrative assessment
of the omega-6 fatty acids in cheap oils such as corn, soybean, of an individual is necessary for determining nutrient status.
and cottonseed used in processed and restaurant foods, the First of all, the discovery of chronic inflammation in most
Western diet has an estimated 20:1 ratio, leaving its consumers cases should indicate a greater nutrient need, due to its
with cells primed for propagating inflammation. impact on malabsorption in the gut. However, determining
Conversely, diet can be used therapeutically to reduce adequate status can also prove difficult. For instance, several
chronic inflammation. Those who followed a Mediterranean nutrient laboratory values are known to be altered in inflam-
or Paleolithic pattern of dieting have been found to have matory conditions, mostly because of changes in acute-phase
lower levels of hs-CRP [13]. Similarly, those who had higher reactants. Vitamin A is a one example of this. Serum levels of
scores on the Alternative Healthy Eating Index or were able vitamin A do not accurately reflect liver stores during an
to improve their scores over a 6-year period had lower levels inflammatory response. Therefore, assessment of vitamins
of IL-6 [14]. This is likely related to the high antioxidant and without knowledge of inflammatory status could lead to
fiber intake found within these dietary patterns. Antioxidants inappropriate supplementation. Conversely, ferritin, the
work to quench free radicals, halting the propagation of lipid storage form of iron, is elevated during times of inflamma-
peroxidation. Having a higher intake of foods rich in antioxi- tion, potentially masking a deficiency. For this reason, an
dants relative to those devoid of antioxidants alone is associ- integrative assessment demands looking at the inflammatory
ated with a lower C-reactive protein level, as well as a decrease and immune status in conjunction with nutrient status to
in systolic and diastolic blood pressure [15]. As noted previ- determine the patient need (. Table 9.1).
 
IFMNT NIBLETS Nutrition Assessment Differential
127 9
other body system, practitioners must not solely treat the
..      Table 9.1  Assessment for inflammatory/immune status
genes but must also consider the many additional factors that
Assessment Markers of inflammation/immune status influence gene expression. Environment, food, water, stress,
category gut health, and toxin load can act on various genes both
directly and indirectly and alter gene expression. The degree
Biomarkers Hs-CRP, fibrinogen, myeloperoxidase, WBC, to which any lifestyle factors influence disease states may
Physical exam Large waist circumference, excess adiposity, depend on an individual’s genetic makeup.
edema Genetic information provides additional answers to the
Symptoms Chronic pain/aches, bloating, swelling, question of “why?” Gene expression can be altered by SNPs,
weight gain nutrient insufficiency or toxicity, toxin overload, and many
other factors. Aberrant genes do not, in and of themselves,
cause disease. It is now recognized that human genotypes are
transformed into human phenotypes as a consequence of
9.4  : Biochemical Individuality
B environment and lifestyle factors that determine health or
and Genetic/Epigenetic Influences disease patterns. The topic of epigenetics and genomics is
on Chronic Disease covered in this textbook in 7 Chaps. 17 and 18.
 

The combination of certain genetic polymorphisms and

IFMNT skills start with the medical condition or symptoms, epigenetic factors may require nutrient support beyond the
and then an assessment is completed using the NIBLETS dif- recommended daily allowance (RDA) if genetic polymor-
ferential. The evidence gathered is the baseline to consider phisms are present and the nutrition assessment or lab results
corrective interventions where nutritional injuries/altered indicate need for nutrient therapy. In these cases, modifica-
nutrition status have been identified. With technological and tions in diet and supplementation can be made. However, just
scientific discoveries of the past few decades, the tools of because an individual has certain genetic SNPs does not nec-
assessment have expanded tremendously. Biochemist Roger essarily mean any intervention is necessary. As with the other
Williams was the first to gain recognition for the term “bio- components of IFMNT, genetics is one tool in the toolbox for
chemical individuality” after he published his book the health provider to utilize but should be considered with
Biochemical Individuality in 1965. He led a movement toward the rest of the information gathered in an assessment.
understanding the origin of disease through the concept of
biochemical individuality, which he defines as “the anatomi-
cal and physiological variations among people and how they 9.5 L: Lifestyle Factors
relate to their individual responses to the environment.” He
then related this individuality to differing nutritional needs One key component of an integrative assessment is taking
for optimal wellness. Another breakthrough in healthcare the time to hear a patient’s story. In order to truly assess root
came with the recognition that nutritional status and needs causes of any health needs, including nutritional deficiencies,
can be influenced by genetics. This is another important a practitioner must also consider influencing lifestyle factors.
component in biochemical individuality and has received a Sleep and stress are two major lifestyle factors influencing
significant amount of attention and research over the past nutrient balance covered later in this chapter; however, other
several decades. It is well recognized that genetics affect dis- factors such as relationships, activity, and even substance
ease risk and are influenced by environment, lifestyle, and abuse should also be evaluated for their nutritional impact.
nutritional factors. Relationships are a major part of an individual’s health
Before nutrigenomic data was available, inherited or dis- and well-being. Often, a community or intimate relation-
ease tendencies within a family were gleaned assembling a ships can have a direct influence on diet choices. On a very
“family history,” which would hint at metabolic tendencies practical level, positive relationships can allow for easier
that should be considered for an individual. With the discov- implementation of nutritional interventions, particularly in
ery of the Human Genome in 2008, the research on nutrige- the case of caregiver support. Spouses committed to health
nomics has grown, and so has the availability of genetic changes can promote reciprocal behavior in their partners
testing and analysis (see 7 Chaps. 17 and 18). Genetic testing
  [19]. While they can provide a great support particularly in a
can be extremely valuable information for individualizing or battle against chronic disease, stressed relationships can also
personalizing assessment, as it gives the provider an under- prevent adequate nourishment and be a burden to one’s
standing of molecular-level interactions between nutrients health. One study showed that men who became divorced or
and the patient’s genome. If a patient is not responding to widowed consumed fewer vegetables [20]. Even beyond diet
lifestyle and diet changes, genetic data can provide more choices, induced stress, potentially from a relational cause,
explanations as to why or provide more information on the can alter digestive, lipid, glycemic, and inflammatory
next intervention to make. Genetic and epigenetic informa- responses to meals [21]. Considering these relational influ-
tion is an extremely valuable component of the patient’s story. ences on a patient’s dietary choices and metabolism allows
Though genetics are not modifiable, lifestyle habits can for more practical and effective interventions for improving
modify gene expression through epigenetics. As with any nutritional status.
 128 R. Johnson and L. Hand

Physical activity is an integral part of an individual’s 9.6 E: Energy

nutritional status. Physical activity has a long-established
role in body composition and nutrient metabolism. However, When assessing the nutrition status of an individual, the
physical activity is less considered in the context of its influ- energy systems of the human metabolism must be consid-
ence on nutrient status. Prolonged exercise, because of its ered. This starts at the most basic level of energy production,
metabolic demand, can lend to greater nutrient needs, par- within the mitochondria, and expands to a larger assessment
ticularly in the case of electrolytes. For instance, plasma of the entire organism’s energy balance, which determines an
magnesium is depleted following intensive exercise, yet gen- individual’s body composition. Nutrient sufficiency is needed
erally rebounds within hours [22]. Therefore, assessment of at every level of energy production, greatly influencing meta-
magnesium status and supplementation interventions should bolic pathways and determining phenotypes.
also consider exercise timing. Evidence shows intensive Starting at the cellular level, an integrative practitioner
exercise can promote intestinal permeability and, therefore, considers the nutrient cofactors and structural components
could influence nutrient status indirectly as well, potentially of the mitochondria and cell membrane, where the molecu-
warranting gut-healing protocols [23, 24]. Furthermore, lar production of the energy unit of ATP occurs. The practi-
both excessive exercise and sedentary lifestyles can induce tioner needs to have working knowledge of the primary
oxidative stress, potentially driving the need for antioxidant biochemical systems involved in energy production, such as
nutrients. the citric acid or Kreb’s cycle, gluconeogenesis, management
Substance abuse is another lifestyle factor likely to influ- of glucose and insulin, and energy fuel sources found in fats.
ence nutritional status. Alcoholism gives way to susceptibility Emerging evidence supports supplementing key nutrients to
to multiple nutrient deficiencies via primary or secondary improve outcomes in conditions of mitochondrial dysfunc-
9 pathways of malnutrition. While many alcoholics simply have tion such as Alzheimer’s and Parkinson’s diseases [30]. In
inadequate diets by the preference of alcohol over other food fact, a recent trial suggests using serum folate and red cell
and drinks, alcohol can also interfere with the absorption and hemoglobin content levels as a predictive marker of amyloid
metabolism of nutrients. The most widely recognized nutrient plaque burden [31]. One of the most-studied nutrients
deficiency common in alcoholics is thiamine. Alcohol inhibits involved in mitochondrial function is coenzyme Q10
absorption of thiamine, and severe deficiencies can lead to (CoQ10). CoQ10 is required for ATP production via the
Wernicke-Korsakoff ’s syndrome [25]. Though less recog- electron transport chain and also has a powerful antioxidant
nized, many other deficiencies are common in alcoholics. function [32]. Deficiencies in CoQ10 caused by metabolic
Folate deficiency has been found in 80% of hospitalized alco- disorders or statin medications can result in mitochondrial
holics and may be of particular interest due to its role in the dysfunction and reactive oxygen species [32]. Assessment
hepatic methylation cycle and the observed influence of folate and repletion of the status of this antioxidant can reduce
deficiency on progression of liver disease in animal models inflammatory markers [33] and even reduce the atherogenic
[26]. Because of the impact of liver disease on production of lipoprotein (a) [34].
bile and vitamin carrier proteins (see 7 Chap. 16), alcoholics
 
Beyond the molecular level, further assessment of a
are also at risk for depletion of fat-soluble vitamins; however, patient’s phenotype indicates how those energy systems con-
current recommendations suggest using caution with replac- tribute to chronic disease when energy metabolism is altered.
ing any of them without initially testing an individual’s blood Increased body fat, particularly within visceral adipose tissue
levels [25]. In regards to vitamin A, fatty liver from alcoholism (VAT), and the body shape that ensues give clinical evidence
prevents the conversion of beta-­carotene to retinol and pro- that energy is altered in an inflammatory and unhealthful
motes the excretion of vitamin A from the liver. Therefore, direction. Though very basic in their assessment, anthropo-
alcoholism can promote functional deficiencies of vitamin A metrics can provide a global scale view of energy balance.
while maintaining serum levels. Understandably, then, cor- These assessments include height, weight, body mass index
recting the deficiency proves difficult and is cautioned for fear (BMI), and circumferences including arm, waist, and hip. In
of toxicity [27]. This highlights the need for monitoring blood addition to general energy balance, these measurements have
levels of the fat-soluble vitamins periodically when interven- also been indicative of cardiometabolic risk factors, includ-
ing to replete. Deficiencies in vitamin C and B12, magnesium, ing insulin resistance, inflammation, and triglyceride level in
and zinc have also been reported in alcoholics, but their direct certain populations [35]. Body composition analysis,
relationship with alcohol consumption is less understood obtained through a number of techniques such as skin folds,
[25]. Additionally, cigarette smoking appears to directly bioelectrical impedance analysis (BIA), and dual-energy
impact antioxidant levels independent of dietary intake. The X-ray absorptiometry (DXA), can provide a more complete
evidence is so compelling in this regard that smokers have look at body structure beyond a height-to-weight compari-
higher requirements for vitamin C [28]. Additionally, levels of son, including distribution of weight among fat and lean tis-
provitamin A carotenoids may also be compromised in smok- sues and distribution of water in relation to the cell. Because
ers [29]. Identifying these modifiable lifestyle factors should body weight can be deceiving in regard to health status, a
be a first-line approach to addressing the nutritional deficien- body composition analysis providing breakdown of mass will
cies at the root cause. assess excess adiposity or inadequate muscle mass even in an
IFMNT NIBLETS Nutrition Assessment Differential
129 9
otherwise “healthy”-weight individual. In fact, BMI alone eliminated. Many of the toxins can be identified through
has shown inaccuracy in predicting cardiometabolic risk in various available testing modalities that can quantify and
healthy-weight, overweight, and obese individuals [36]. reveal the impact of residual tissue toxins from past expo-
Depending on the body composition test taken, more data sures on a person’s health.
may also be available suggestive of a global nutritional
­balance. Endogenous toxins  Optimizing management and detoxifi-
While the assessments at this level tend to lack specificity, cation of endogenous toxins such as hormonal metabolites,
they lay the foundation to help direct and prioritize the sub- excess stress toxins, and elimination organ processes is directly
sequent steps of the integrative assessment, even in investi- related to nutrients, food, and lifestyle.
gating nutrient sufficiency. For instance, obesity alone All sources of toxins contribute to the total toxin load,
warrants a deeper look into key nutrients such as vitamin D, which can benefit by interventions with food, dietary supple-
whereas wasting or low muscle mass would trigger an inves- ments, and other naturopathic interventions that enhance
tigation of the slew of nutrients associated with undernutri- the body’s detoxification pathways (see 7 Chap. 13). Dietary
 

tion. In body composition assessments that evaluate interventions utilizing genetic information, individual nutri-
hydration status, such as BIA, an imbalance in intracellular tion requirements, and other lifestyle factors can be used to
vs. extracellular water could suggest evaluating electrolytes. prevent, mitigate, and improve chronic disease affected by
Additionally, the BIA also includes a phase angle, a marker of toxin exposure.
cell membrane integrity indicative of status of minerals such When it comes to total toxin load for an individual, many
as magnesium [37, 38], and has also been shown to be pre- factors will contribute. Those factors will include some of the
dictive of severity of certain conditions such as psoriasis [39] more obvious toxin exposures such as cigarette smoke, alco-
and chronic obstructive pulmonary disease [40]. By includ- hol, and various drugs, but it will also include car exhaust,
ing this deeper assessment of metabolism and considering heavy metals, paint fumes, Teflon, aluminum cookware,
the underlying nutrients driving their functions, an integra- mold, dry-cleaned clothes, pet dander, pesticides, nail polish,
tive approach expands on the conventional assessment of hair dyes, perfumes, fertilizers, plastics, etc.
energy balance for a more complete analysis. Exposure to polycyclic aromatic hydrocarbons (PAHs)
has been shown to impair the immune system through epi-
genetic modifications [44]. Toxin exposure affects methyla-
9.7 T: Toxic Load tion and enzymatic activity, which then influences compound
and nutrient production [45]. During an assessment and/or
Just as many nutrients function as cofactors and substrates with laboratory testing, the practitioner can get information
for gene function, many toxins act as inhibitors or inducers on the patient’s total toxin load and begin to recognize its
as they impact function and metabolism detrimentally. Both implications. If the patient has a high toxin load combined
past and present environmental exposures can have an with a poor nutrition quality of life and possibly even genetic
impact on gene expression [41–43] and disease risk as well as polymorphisms, then their system will not be working opti-
a buildup of endogenous toxins overloading an individual’s mally, increasing their risk for disease.
metabolism.

Environmental/exogenous toxins  These toxins affect people 9.8 S: Stress and Sleep
in different ways, due to differences in body chemistry and
effects from the food they eat, genetics, and lifestyle choices. We use the word “stress” in everyday life, yet the meaning is
These toxins include pesticides, air pollutants, heavy metals, ambiguous. Stress can be traumatic, or it can be eustress
excessive medications, and various toxins in our food and (good stress), simply reflecting the daily grind of life. The role
water supply, as well as the air we breathe. We’ve recently of stress in health is well established, yet all too often over-
become aware that the “toxic” effects of electromagnetic fre- looked by practitioners. Stress has many different triggers
quencies (EMF) on the metabolic pathways may add to a per- with many different manifestations. Therefore, identifying
son’s total toxin load. Excessive amounts of toxins can impact presence of points of stress can be difficult.
gene expression and affect many biochemical pathways. If an Psychoneuroimmunology is a term used to describe the
individual has ineffective and inefficient detoxification pro- impact of mental attitudes on the body’s resistance to disease,
cesses for reasons such as genetic SNPs, poor nutrient status, or especially with respect to the links among and between the
organ dysfunction or removal, or the toxin load is too high for mind, the brain, and the immune system. The central ner-
the body to combat, disease may arise. Laboratory testing can vous system and the immune system have constant commu-
help identify levels of some specific toxins, such as heavy met- nication [46]. Research on the brain-immune system
als, and can aid in intervention development. connection has emerged over the last decade [46–48], giving
Though past environmental exposures cannot be pre- practitioners more evidence to give appropriate attention to
vented, current xenobiotic/exogenous toxins in an individu- the beliefs and feelings of the patient. Cognitive states such as
al’s environment can be identified and further exposure perceived control of a situation, of one’s health, view of self,
 130 R. Johnson and L. Hand

and views of the future have been linked with immune and status, but nutrition intake and status also affect the abil-
responses. During an assessment, the conversation about ity to establish proper sleep hygiene. For some individuals,
psychological stressors can be initiated through initial paper- it’s difficult to know which is the root cause of the problem
work or the flow of the discussion, but for the provider, it’s a and which should be addressed first or most aggressively. A
component that cannot be overlooked. 1999 study conducted at the University of Chicago con-
While short-term/acute stress can be healthy and impor- cluded that restricting sleep to just 4 hours per night for 7
tant for our health (e.g., exercise), chronic/long-term stress is days led to increased insulin sensitivity and characteristics of
another factor increasing risk for development of chronic diabetes [54]. Additionally, research shows sleep deprivation
disease. After an acute stress response, the main stress hor- increases various inflammatory markers including IL-6 and
mone, cortisol, lowers again, and the body can return to a CRP-hs [55]. Research by Van Cauter shows that individuals
balanced state. However, in times of chronic stress, cortisol who are sleep-deprived have an increased appetite, which
remains elevated, which has many negative effects on the aligns with other findings that have identified the relation-
body [49]. During times of stress, the adrenal glands are ship between short sleep duration and increased intake of
working harder to produce cortisol. In this case, they also unhealthy food with more sedentary habits [56, 57]. Leptin
need additional nutrient support. Nutrients such as magne- has been proposed as one possible mechanism linked to the
sium, potassium, and sodium are in higher demand when the increasing rates of obesity. Various studies have indicated a
body is under stress. rise in leptin levels after sleep deprivation [58, 59]. This is
The brain first perceives a stressor and determines what is promising as we know the cravings for unhealthy food are
threatening. It then determines the behavioral and physiolog- strong and in an environment dominated by processed food,
ical responses to the stressor. Physiologically, the sympathetic it’s difficult to practice willpower, especially when sleep-
9 and parasympathetic systems, hypothalamic-pituitary-adre- deprived or stressed. The current research on the neurologi-
nal (HPA) axis, immune system, metabolic hormones, and cal connection between sleep, food consumption, and obesity
molecular processes within all organs adjust to combat the is promising and will, like many other factors in reaching
response [50]. That is, these organs activate to achieve stabil- health, require lifestyle changes. A review by Dashti et  al.
ity. These adjustments are manageable in the short term, but [60] concluded that short sleep duration is associated with
when they are overused or imbalanced for too long, the body higher total caloric intake, higher total fat intake, protein
can become overloaded. This overload or imbalance can intake, lower intake of fruits and vegetables, and diets of
affect systemic physiology via neuroendocrine, autonomic, lower quality. Dashti also concluded that behavior and meal
immune, and metabolic mediators. Nutritionally, this over- timing may also be impacted by sleep. Even changing the
load requires more nutrient support [51]. Studies have shown timing of meals and/or altering the ratios of macronutrients
nutrient therapy such as with B vitamins has a beneficial in those meal times can be a starting place for some people
effect on perceived stress, mild psychiatric symptoms, and and start the process of reaching better alignment with their
aspects of everyday mood to support those under chronic natural circadian rhythm. Evidence points to the fact that
stress [52]. eating behaviors deviate from the traditional three meals per
day to more frequent energy-dense and highly palatable
snacks throughout the day and at night. The mechanisms
9.9 Sleep behind these findings linking sleep and dietary intake are
likely multifactorial but are important to consider during a
Having a properly functioning circadian rhythm is critical to nutrition assessment.
healthy hormonal balance, metabolism function, memory When it comes to sleep and nutrition, some nutrients
and mental performance, optimal cellular energy produc- have been studied more than others. Caffeine, for example,
tion, and the immune system. In fact, one study showed has plenty of literature showing an inverse relationship [61].
people with chronic insomnia have a three times greater risk Not surprisingly, the function of caffeine is evidenced to dis-
of dying from any cause [53]. rupt sleep quality and quantity. Conversely, vitamin D has
The modern world sends mixed messages to the brain also been shown to promote circadian rhythm at a cellular
about whether it’s day or night, and the line between sleep level [62].
and awake can easily be blurred. When the body receives Light exposure is the primary regulator of circadian
mixed messages, insomnia and fatigue are inevitable results. rhythm. Too much light after sunset affects melatonin pro-
In contrast, when the right messages are sent, healthy sleep duction [63]. The blue light spectrum from many artificial
patterns result. light sources such as TVs, cell phones, and computers
Sleep is essential to health and even if nutrition is optimal enters the eye and feeds a signal to the brain that “it’s day-
but sleep is poor, one’s health status will quickly decline. In time.” The combination of poor sunlight during the day and
our modern world and fast-paced society, there are many excessive blue light at night has major implications on cir-
expectations to do more, which for some people means trad- cadian rhythm. Many other factors also contribute to circa-
ing sleep for productivity. This is common for college stu- dian rhythm, including activity, stress, micronutrient
dents, parents of newborns, and many people with status, and transition activities before bed, but each client
demanding careers. Sleep hygiene affects nutrition intake will have different levels of readiness on where to start.
IFMNT NIBLETS Nutrition Assessment Differential
131 9
Bringing awareness to the importance of sleep is step one systemic oxidative stress, TMAO formation and inflammation in rats,
and can begin during an assessment when collecting infor- and dietary fat content modulates these effects. Food Funct.
2016;7(9):3760–71. https://doi.org/10.1039/c6fo00462h.
mation on their habits. 9. Alves BC, Silva TR, Spritzer PM.  Sedentary lifestyle and high-­
Gut motility is mediated by specific genes expressed in carbohydrate intake are associated with low-grade chronic inflam-
intestinal epithelial cells and in the enteric neurons, which mation in post-menopause: a cross-sectional study. Rev Bras Ginecol
help control circadian rhythm [64]. Colonic motility is faster Obstet. 2016;38(7):317–24. https://doi.org/10.1055/s-0036-1584582.
in the morning and slower at night [65]. Disruption of the 10. Asghar A, Sheikh N.  Role of immune cells in obesity induced low
grade inflammation and insulin resistance. Cell Immunol.
circadian cycle can provoke changes in gut motility. Circadian 2017;315:18–26. https://doi.org/10.1016/j.cellimm.2017.03.001.
rhythm shifts that occur with traveling, night shifts, or other 11. Julia C, Meunier N, Touvier M, Ahluwalia N, Sapin V, Papet I, Cano N,
sleep disruptions can lead to gut symptoms, including bloat- Hercberg S, Galan P, Kesse-Guyot E.  Dietary patterns and risk of
ing, abdominal pain, diarrhea, or constipation [64] (see elevated C-reactive protein concentrations 12 years later. Br J Nutr.
7 Chap. 35).
 
2013;110(4):747–54. https://doi.org/10.1017/S0007114512005636.
12. Yehuda S, Rabinovitz S, Mostofsky DI. Modulation of learning and
neuronal membrane composition in the rat by essential fatty acid
preparation: time-course analysis. Neurochem Res. 1998;23(5):
9.10 Conclusion 627–34.
13. Whalen KA, McCullough ML, Flanders WD, Hartman TJ, Judd S, Bos-
tick RM.  Paleolithic and mediterranean diet pattern scores are
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tive practitioner. In order to intervene at the root cause of any balance in adults. J Nutr. 2016;146(6):1217–26. https://doi.
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metabolic processes that ultimately determine one’s health. Kivimaki M.  Long-term adherence to healthy dietary guidelines
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Cangussu SD, Talvani A, Bezerra FS.  The administration of a high
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 135 10

Nutritional Role of Fatty Acids

Vishwanath M. Sardesai

10.1 Introduction – 136

10.2 Saturated Fatty Acids – 137

10.2.1 S hort-Chain Saturated Fatty Acids (SCFA): C1–C6 [6, 7] – 137
10.2.2 Medium Chain Triglycerides (MCT): C6–C12 with an Aliphatic
Tail [12] – 137
10.2.3 Long-Chain C13–C21 and Very-Long-Chain
Fatty Acids C22 or More – 138

10.3 Monounsaturated Fatty Acids – 139

10.4 Polyunsaturated Fatty Acids – 139

10.4.1  iosynthesis – 139
B
10.4.2 Functions – 140
10.4.3 Deficiency – 143
10.4.4 Requirements – 144
10.4.5 W3 Fatty Acids and Health – 144
10.4.6 Food Sources – 146

10.5 Trans-Fatty Acids – 146

10.6 Conjugated Fatty Acids – 147

10.7 Conclusions – 147

References – 148

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_10
 136 V. M. Sardesai

10.1  Introduction The double bond locations are designated by the number of
carbon atoms from the carboxyl side or from the methyl side.
Fatty acids are key components of lipids. They are important Fatty acids are abbreviated in the Δ system by listing the
dietary sources of energy and have roles in modulating acute total carbon number and the position of the double bonds.
and prolonged inflammation [1] and as key components of cell Palmitic acid (which contains no double bond) is abbreviated
membrane structure [2]. They are called acids because of the as C16:0 or C16:Δ0, and palmitoleic acid which contains one
organic acid group (COOH) that they contain. They are chains double bond is C16:1 or C16:1 Δ9. The number after the Δ in
of covalently linked carbon atoms bearing hydrogen atoms. The this classification system signifies the position of double
naturally occurring fatty acids are, for the most part, unbranched bond relative to the carboxyl end. In palmitoleic acid, the
and acyclic, but complex structures with branched or cyclic double bond is in the ninth carbon atom from the carboxyl
chains also occasionally occur. They have the basic formula group. It is between carbon atoms 9 and 10 from the carboxyl
CH3(CH2)n·COOH where n can be any number from 2 to 24. carbon as number one. In the W numbering system, palmi-
The bulk of the fatty acids in the human body have 16, 18, or 20 toleic acid is abbreviated as C16:1, W7. This signifies that the
carbon atoms, but there are some with longer chains that occur fatty acid has 16 carbons and one double bond which is
principally in the lipids of the nervous system. One method of located 7 carbon atoms away from the W carbon counting
fatty acid classification is according to their chain length. Those the W carbon as number 1. In other words, the double bond
containing 2–4 carbon atoms are called short-chain fatty acids, is between carbon 7 and 8 counting from the W end as shown
while those with 6–10 and 12–24 carbon atoms are called here:
medium-chain and long-chain fatty acids, respectively. In most
cases, naturally occurring fatty acids contain an even number of CH3 - CH2 - CH2 - CH2 - CH2 - CH = CH - ( CH2 )7 COOH
carbon atoms. Fatty acids are also classified as saturated with no Palmitoleic acid
double bonds, monounsaturated with one double bond, and
10 polyunsaturated fatty acids (PUFA) with two or more double . Table  10.1 lists unsaturated fatty acids of importance in
 

bonds. Depending on the number of double bonds from 2, 3, 4, human nutrition using the W numbering system.
5, and 6, they are called dienoic, trienoic, tetraenoic, pentanoic, Other relevant information is the stereochemical config-
and hexaenoic, respectively. The carbon atoms of fatty acids uration of each double bond. Fatty acids that contain double
may be numbered either with the carboxyl carbon as number 1 bonds can exist in two geometric isomeric forms. These
(Δ numbering system) or from the terminal methyl (CH3) forms are known as cis and trans isomerism. When a double
group carbon as number 1 (W or n numbering system). bond occurs along the length of a carbon chain, the pair of
the hydrogen atoms on the participating carbon atom may lie
∆ numbering system (carboxyl side) on the same side of the double bond; in this case, they are
described as cis or they may be on opposite sides of the dou-
16 4 3 2 1 ble bond, in which case they are described as trans. Double
CH3 (CH2)11 CH2 CH2 CH2 COOH bonds in naturally occurring fatty acids are of the cis configu-
1 13 14 15 16 ration. Thus, oleic acid is the cis form and elaidic acid is its
trans form [3]:

..      Table 10.1  Unsaturated fatty acids of importance in human nutrition

Common name Systematic name Structural formula

Palmitoleic Hexadecenoic (W7) CH3(CH2)5CH = CH(CH2)7COOH

Oleic Octadecenoic (W8) CH3(CH2)7CH = CH(CH2)7COOH

Linoleic Octadecadienoic (W6,9) CH3(CH2)4CH = CHCH2CH = CH(CH2)7COOH

Linolenic Octadecatrienoic (W3,6,9) CH3CH2CH = CHCH2CH = CHCH2CH = CH(CH2)7COOH

γ-Linolenic Octadecatrienoic (W6,9,12) CH3(CH2)4CH = CHCH2CH = CHCH2CH = CH(CH2)4COOH

Dihomo-γ-linolenic Eicosatrienoic (W3,6,9) CH3CH2CH = CHCH2CH = CHCH2CH = CH(CH2)9COOH

Arachidonic Eicosatetraenoic (W6,9,12,15) CH3(CH2)4CH = CHCH2CH = CHCH2CH = CHCH2CH = CH(CH2)3COOH

Eicosapentaenoic (W3,6,9,12,15) CH3CH2(CH = CHCH2)5CH2CH2COOH

Docosahexaenoic (W3,6,9,12,15,18) CH3(CH2CH = CH)6CH2CH2COOH

Vaccenic Octadecenoic (W7) CH3(CH2)5CH = CH(CH2)9COOH

Nervonic Tetracosenoic (W9) CH3(CH2)7CH = CH(CH2)13COOH

Nutritional Role of Fatty Acids
137 10
H C (CH2)7 CH3 CH3 (CH2)7 C H 10.2.1  Short-Chain Saturated Fatty Acids
H C (CH2)7COOH H C (CH2)7COOH (SCFA): C1–C6 [6, 7]
cis trans
Understanding the role of SCFAs is important for nutritional
oleic acid elaidic acid
modulation of the gut ecology. The short-chain fatty acid
substrates result from fermentation between resistant
When unsaturated and PUFA are hydrogenated to make starches and soluble fibers, and beneficial species and
margarine and shortening, anywhere from 5% to 70% of the amounts of microflora present in the colon. The SCFAs are
double bonds occur in trans form. The trans-fatty acids [4] produced, primarily acetate, propionate, and butyrate, as end
account for 5–8% of the fat in the American diet. products. The SCFAs produced are the primary energy
When double bonds of the unsaturated fatty acids are sources for colonocytes and are particularly important for
conjugated, that is, the double bonds occur without an inter- colon health. These SCFAs have anticarcinogenic properties,
vening carbon atom not part of a double bond, they are called inhibit the growth and proliferation of tumor cell lines
conjugated fatty acids. Conjugated linoleic acid (CLA) occurs in  vitro, induce differentiation of tumor cells, and possess
naturally in meat and milk food products derived from rumi- anti-inflammatory properties [8]. Maintaining a life-long
nant sources (e.g., beef, lamb, dairy) because of the process of colon of healthy cells depend on continual production of
bacterial isomerization of linoleic acid (present in food stuff SCFAs [8, 9] (. Fig. 10.1).
 

for these animals) in the rumen. CLA is higher in grass-fed 55 Acetic acid (C2) does not occur in natural fats
ruminant sources compared with grain-fed [5]. and oils, but vinegar contains approximately
Fatty acids occur primarily as esters of glycerol when 5% of acetic acid.
they are being used for energy storage and utilization. Esters 55 Propionic Acid (C3)
of one, two, or three fatty acid residues are called monoglyc- 55 Butyric acid (C4) is also uncommon in natural food fats
erides, diglycerides, and triglycerides, respectively. Mono- except for milk, butterfat, and breastmilk. A primary
and diglycerides occur only in minor amounts and largely as endogenous source of butyric acid for its important role
metabolic intermediates in the biosynthesis and degradation as a primary fuel for colonocyte repair is from the
of glycerol-containing lipids. The bulk of the fatty acids in healthy colonic microbiome when dietary fiber is
the human body exist as triglycerides in which all three fermented in the colon [11].
hydroxyl groups on the glycerol are esterified with a fatty
acid. Most triglyceride molecules contain two or more dif-
ferent fatty acid moieties (i.e., the fatty acids within triglyc- 10.2.2  Medium Chain Triglycerides (MCT):
erides are not often repeated) and have the general
C6–C12 with an Aliphatic Tail [12]
composition as follows:

CH2 O COF1 Straight-chain MCFAs are as follows:

55 Caproic acid C6
CH O COF2 55 Caprylic acid C8 (n-octanoic acid or fatty acid C8, goat
milk, coconut oil, palm oil)
CH2 O COF3
55 Capric acid C10
55 Lauric acid C12
where F1COOH, F2COOH, and F3COOH are fatty acid
chains that may or may not all be the same. MCTs do not require bile salts for digestion. The MCTs are
Triglycerides account for about 90% of the fat in our food absorbed directly into the portal vein and then transported
and more than 90% of the fat in the body. rapidly to cells and the liver for β-oxidation. Thus, thermo-
There are five categories of fatty acids based on the degree genesis is increased. Because of the ability to be absorbed
of saturation and types of double bonds. They are saturated, without requiring emulsification from bile, MCT oils are
monounsaturated, polyunsaturated, trans, and conjugated commonly used in enteral feedings, liver disease diets, weight
fatty acids. loss, and others. Patients who have malnutrition, malabsorp-
tion, or particular fatty-acid metabolism disorders benefit
from inclusion of MCTs in their diet as they do not require
10.2  Saturated Fatty Acids energy for absorption, use, or storage. More recently, the
MCT oils are universally used in ketogenic diets of all types
When discussing saturated fats and their nutritional influ- as they evidence beneficial contributions to brain/nerve
ences on human metabolism, it is important to differentiate metabolism [12]. Substantial amounts of saturated fatty acids
between the three main saturated fat categories: short chain, are found in certain vegetable products such as coconut and
medium chain, and long chain. palm oil.
 138 V. M. Sardesai

Lipolysis AMPK activity

Adipogenesis Insulin sensitivity
Inflammation Lipid accumulation
Leptin

Inflammation
FA

AMPK activity
Satiety
Insulin sensitivity
Lipid accumulation
Acetate
Propionate
Butyrate

Intestinal
glucogenesis PYY
Sympathetic activity GPR41/43
GLP-1

10 Acetate, propionate, butyrate Faeces

Undigested foods

..      Fig. 10.1  SCFA and interorgan crosstalk [10]. SCFA and interorgan reach the circulation and can also directly affect the peripheral adipose
crosstalk fermentation of indigestible foods in the distal intestine results tissue, liver, and muscle substrate metabolism and function. In addition,
in the production of SCFA. The ratio of acetate to propionate to butyr- circulating acetate might be taken up by the brain and regulate satiety
ate in the ileum, caecum, and colon is ~3:1:1. Butyrate and propionate via a central homeostatic mechanism. Whether metabolic effects are
are generally metabolized in the colon and liver and, therefore, mainly mainly explained by direct effects of SCFA or indirectly via gut-derived
affect local gut and liver function. In the distal gut, SCFA bind to GPR41 signaling molecules remain unclear. Solid lines indicate direct SCFA
and GPR43, which leads to the production of the gut hormones PYY and effects, and dashed lines indicate indirect SCFA effects. Abbreviations:
GLP-1 and affect satiety and glucose homeostasis. Furthermore, propio- AMPK adenosine monophosphate-activated protein kinase, FA fatty
nate and butyrate might induce intestinal gluconeogenesis and sym- acid, GLP-1 glucagon-like peptide-1, GPR G-protein coupled receptor,
pathetic activity, thereby improving glucose and energy homeostasis. PYY peptide YY, SCFA short-chain fatty acid. (Reprinted from Canfora
Small amounts of propionate and butyrate and high amounts of acetate et al. [6]. With permission from Springer Nature)

10.2.3  Long-Chain C13–C21 and Very-Long-

Chain Fatty Acids C22 or More ..      Table 10.2  Examples of long-chain and very-long-chain
saturated fatty acids

These fatty acids are the most abundant in animal and human Common name Chemical structure C:D
fats, accounting for 30–40% of the fatty acids in adipose tis-
sue. Substantial amounts of longer-chain saturated fatty acids Myristic acid CH3(CH2)12COOH 14:0
are found in meat and certain heat- and oxygen-processed Palmitic acid CH3(CH2)14COOH 16:0
oils that are used in hydrogenated shortenings and marga-
Stearic acid CH3(CH2)16COOH 18:0
rines (. Table 10.2).
 

The saturated fatty acids are not only a source of body fuel Arachidic acid CH3(CH2)18COOH 20:0
but also are structural components of cell membranes. Behenic acid CH3(CH2)20COOH 22:0
Various saturated fatty acids are also associated with proteins
and are necessary for their normal function [14]. They are Lignoceric acid CH3(CH2)22COOH 24:0
synthesized as needed by the body to provide an adequate Cerotic acid CH3(CH2)24COOH 26:0
level required for their physical and structural functions.
Saturated fatty acids vary in the degree of cholesterol Based on data from Ref. [13]
influence. For example, stearic acid (C18) has little or no effect
Nutritional Role of Fatty Acids
139 10
on serum cholesterol, while lauric (C12) and palmitic (C16) growth and function of all tissues. These fatty acids must be
dramatically increase cholesterol concentrations. Because supplied by a dietary source [15, 16] and are called essential
palmitic acid is more abundant than lauric and myristic fatty acids (EFA).
acids, it may be the primary fatty acid affecting cholesterol
concentrations. Saturated fatty acids containing 10 carbons
or less have not been shown to have any effect on cholesterol 10.4.1  Biosynthesis
levels.
There is no dietary requirement for saturated fatty acids The liver is the site of most of the PUFA metabolism that
because they can be synthesized endogenously. The average transforms dietary 18-carbon EFA into long-chain PUFA
American diet provides approximately 15% of calories in the with 20 or 22 carbons. The mammalian tissues contain four
form of saturated fat. The saturated fatty acid intake ranges series of PUFA. The precursors of the two of these groups are
from 21 to 34  g per day in men and 15 to 21  g per day in the MUFA palmitoleic and oleic acids, which can be synthe-
women. sized from saturated fatty acids. The precursors for the other
two are necessarily derived from dietary source: LA and
ALA. A complex series of desaturation and elongation reac-
10.3  Monounsaturated Fatty Acids tions acting in concert transform the precursors to their
higher polyunsaturated derivatives. These four precursors
The liver is the main organ responsible for the endogenous are alternatively desaturated (two hydrogens are removed to
synthesis of monounsaturated fatty acids (MUFA). create a double bond) and chain elongated (addition of two
Monounsaturation at the Δ9 position is the rule, and in carbons). The desaturations are catalyzed by ∆6, ∆5, and ∆4
humans the double bond cannot be introduced between car- desaturases, and the two carbon additions are catalyzed by
bon 1 and 6 starting from the W carbon of the fatty acids. elongases to form the principal PUFA found in tissues
Therefore, there are only two saturated fatty acids available (. Fig. 10.2).
 

for desaturation: Palmitic to palmitoleic acid and stearic to The same enzymes catalyze the equivalent steps in the
oleic acid. On the one hand, MUFA with double bonds W7, W9, W6, and W3 fatty acid pathways, and there is com-
occurring before the Δ9 position are not synthesized to a sig- petition among substrates for these enzymes. The critical
nificant extent by animals and humans because the required enzyme ∆6 desaturase displays highest affinity for the
desaturase is absent and trace amounts found in animal tis- most highly unsaturated C18 substrate. The order of prefer-
sue lipids probably arise from the diet. Plants, on the other ence is ALA>LA  >  oleic acid>palmitoleic acid (provided
hand, can introduce double bonds between Δ9 and the termi- the substrate concentrations are equal). In the presence of
nal methyl group. either of the two EFA, little desaturation of oleate occurs.
Plant sources rich in MUFA include olive oil (about 75%). ALA effectively inhibits the desaturation of LA (at equal
High oleic acid variety sunflower oil contains as much as concentrations). In the absence of the members of the W6
80–85% MUFA. Canola oil has about 58% MUFA. It is also and W3 families, however, oleate is desaturated and mem-
found in red meat, whole milk products, olives, and avoca- bers of the W9 family, particularly C20:3, W9, appear in the
dos. Oleic acid accounts for about 90% of dietary MUFA. The tissues [17].
MUFA, including oleic and nervonic acid (C24:1, Δ9), are In the desaturation process, additional double bonds are
important in membrane structural lipids, particularly ner- inserted between the preexisting double bonds and the car-
vous tissue myelin. Other MUFA, such as palmitoleic acid, boxyl group, and the chain elongation always proceeds by the
are present in minor amounts in the diet. MUFA neither addition of two carbon units to the carboxyl terminus of the
elevate nor lower the level of serum cholesterol; thus, a high-­ fatty acid chain. Therefore, the position of the double bond
fat diet is not necessarily associated with a high level of serum counting from the methyl (W) end of the precursor fatty acid
cholesterol in the population. Inhabitants in Mediterranean remains unaltered through all transformations. All products
countries consume large amounts of olive oil but tend to have of oleic acid possess the W9 configuration of oleate itself and
low levels of serum cholesterol. The average American con- are recognized as members of the W9 family. Nervonic acid
sumes MUFA which makes up about 50% of total fat and C18:1, W9, a component of nerve tissue lipid, is derived by
provides 20% of the calories in the diet. chain elongation of oleate. Vaccenic acid C18:1 W7 that occurs
in small amounts in tissue lipids is formed by chain elonga-
tion of palmitoleic acid. Similarly, LA and ALA give rise to
10.4  Polyunsaturated Fatty Acids W6 and W3 families of PUFA. No interconversion between
these families occurs. In addition to desaturases, there is
Humans are not able to introduce double bonds closer to the competition of the substrates for chain elongase enzymes and
methyl group than the W9 position. Thus, two broad classes for the acetyl transferases involved in the formation of phos-
of biologically active polyunsaturated fatty acids (PUFA)  – pholipids (which require PUFA). Lower members of the fam-
the W6 linoleic acid (LA) C18:2, W6, and the W3 linolenic ily may also be able to compete with some of the products for
acid also called α-linolenic acid (ALA) C18:3, W3 – cannot be enzyme sites and the expression of its family. Long-chain
synthesized by humans. These are required for normal highly unsaturated fatty acids can be shortened by two car-
 140 V. M. Sardesai

..      Fig. 10.2  Biosynthesis of

polyunsaturated fatty acids. Palmitic Stearic
(Courtesy of Vishwanath C 16:0 C 18:0
M. Sardesai, PhD)
∆9 desaturase

Palmitoleic Oleic Linoleic α–Linolenic

C 16:1, W7 C 18:1, W9 C 18:2, W6 C 18:3, W3

∆6 desaturase

C 16:2, W7 C 18:2, W9 γ–Linolenic C 18:4,

C 18:3, W6 W3

elongase

C 18:2, W7 C 20:2, W9 Dihomo-γ-Linolenic C 20:4,

C 20:3, W6 W3

∆5 desaturase

C 18:3, W7 C 20:3, W9 Arachidonic Eicosapentaenoic

Mead C 20:4, W6 C 20:5, W3

elongase
10
C 20:3, W7 C 22:3, W9 Docosatetraenoic C 22:5, W3
C 22:4, W6

∆4 desaturase

C 22:5, W6 Decosahexaenoic
C 22:6, W3

bons, a phenomenon called retroconversion. Because of the DHA [18]. This better conversion efficiency in young women
competition, retroconversion, etc., each family has charac- compared with men appears to be related to the effects of
teristic end products that accumulate in tissue lipids, while estrogen.
intermediates are usually found in much smaller, often trace The data from experimental animals suggest that ∆6
amounts. Thus, for oleate and palmitoleate, the major PUFA desaturase is sensitive to several factors. Those that tend to
are the trienes C20:3, W7, and C20:3, W9, respectively. For increase the enzyme activity include a high-protein diet,
linoleate, the major PUFA are arachidonic acid (AA) with insulin, and EFA deficiency, whereas fasting, zinc deficiency,
four double bonds (tetraene) and some dihomo-gamma-­ aging, glucagon, glucocorticoids, and diabetes are known to
linolenic acid (DHGL/DGLA). For linolenate, eicosapentae- decrease its activity. Reduction in the activity of ∆6 desatu-
noic acid (EPA) and docosahexaenoic acid (DHA) are the rase can limit the availability of DHGL and AA, which are
main end products. The 22-carbon hexanoic acid is the most required for normal physiologic functions. Although a good
unsaturated fatty acid commonly found in the lipids of higher deal of AA is acquired from foods of animal origin such as
animals. meat and dairy products, little or no DHGL/DGLA is found
∆6 desaturase is considered one of the rate-limiting in a normal diet.
enzymes in the metabolic pathway. A typical western diet
tends to be much higher in W6 than in W3 fatty acids.
Although ALA is the preferred substrate for ∆6 desaturase, 10.4.2  Functions
the excess of dietary LA compared with ALA results in
greater formation of AA than EPA. The capacity for conver- After ingestion, LA and ALA are distributed between adipose
sion of ALA to DHA is higher in women than men. Studies tissue triglycerides, other tissue stores, and tissue structural
of ALA metabolism in healthy young men indicated that lipids. A proportion of LA and ALA provides energy, and
approximately 8% of ALA is converted to EPA and 0.4% is these are oxidized more rapidly than the saturated and
converted to DHA. In healthy young women, approximately MUFA. In contrast, long-chain PUFA derived from EFA are
21% of ALA is converted to EPA and 9% is converted to less rapidly oxidized. These acids when present preformed in
Nutritional Role of Fatty Acids
141 10
the diet are incorporated into structural lipids about 20 times cells. This may cause a change in membrane fluidity leading
more efficiently than after synthesis from dietary LA and to alteration of activity of enzymes, receptor expression, and
ALA. PUFA are the major components of structural lipids of intercellular signaling, which in turn can influence lympho-
membranes of cells, mitochondria, and nuclei, and they play cyte responsiveness. Patients with acquired immune defi-
a major and vital role in the properties of most biomem- ciency syndrome (AIDS) exhibit significant reductions of 20
branes. In the phospholipids, the saturated fatty acids prefer- and 22 carbon fatty acids derived from EFA. EPA and DHA
entially occupy the carbon 1 position and PUFA occupy are thought to be anti-inflammatory nutrients with protec-
carbon 2 of the glycerol moiety, although MFUA can also tive effects in inflammatory diseases including asthma and
take the carbon 2 position. allergies [20].
Structure of phospholipids: Infection is a common clinical problem in patients under-
going fat-free hyperalimentation. Certain PUFA are known
1CH
2 O - COR to be effective in killing those viruses that have a lipid com-
ponent in the envelope. Recent study has shown that W3 fatty
R CO-O 2CH
acids from fish oil can prevent wound infection and can
Essential Fatty Acid 3CH O P O nitrogenous compound improve early wound healing. Combinations of W3 fatty
2
acids with arginine are much more effective in preventing
OH infections than either one alone [21]. The combinations can
RCOOH is the fatty acid
reduce the incidence of adult respiratory distress syndrome
and shorten the hospital stay in surgical patients. Other stud-
The physical properties (such as fluidity) of phospholipids ies have shown that W3 fatty acids could help the body fight
are in large part determined by the chain length and the lung infections common to inflammatory diseases such as
degree of unsaturation of their component fatty acids. The chronic obstructive pulmonary disease.
physical properties, in turn, affect the phospholipid’s ability
to perform the structural function, for example, the mainte- 10.4.2.3  Gene Expression
nance of normal activities of membrane-bound enzymes Cell culture and animal studies suggest that PUFA can mod-
such as adenylyl cyclase and Na/K ATPase. Several cellular ulate the expression of a number of genes including those
functions which include secretion, signal transmission, and involved in fatty acid metabolism and inflammation [22].
susceptibility to microorganism invasion depend on mem- These PUFA may regulate gene expression by acting like ste-
brane fluidity. The highly unsaturated fatty acids EPA and roid hormones [23].
DHA are particularly concentrated where there is a require-
ment for rapid activity at the cellular level, such as may be 10.4.2.4  Cholesterol
required in transport mechanism in the brain, its synaptic PUFA of both the W6 (LA) and W3 (ALA) family tend to
junctions, and the retina, where only the long-chain PUFA lower plasma cholesterol levels, including the low-density
derived from EFA are found. Other biological functions of lipoprotein (LDL) cholesterol fraction, possibly by increasing
EFA include stimulation of growth, maintenance of skin and the activity of LDL receptors. Many epidemiologic and con-
hair growth, regulation of cholesterol metabolism, lipotropic trolled interventional studies have shown the antiatherogenic
activity, maintenance of reproductive performance, and effect of both ALA and its long-chain fatty acids. W3 acids
other physiologic and pharmacologic effects. A few specific have unique triglyceride-lowering properties not shared by
functions are given below. W6 fatty acids. PUFA, although effective in lowering both
total and LDL cholesterol, have a tendency to lower high-­
10.4.2.1  Skin density lipoprotein (HDL) cholesterol, which is protective
One essential function of LA is to maintain the integrity of against coronary heart disease (CHD).
the epidermal water barrier in the skin. The physical struc-
ture of water barrier is ascribed to sheets of stacked bilayers 10.4.2.5  Eicosanoids
that fill intercellular spaces of the uppermost layer of the epi- DHGL/DGLA, AA, and EPA are the precursors of biologi-
dermis. These lipid bilayers contain large amounts of sphin- cally potent metabolites. These include prostaglandins,
golipids which contain LA-rich ceramides. In EFA deficiency, thromboxanes, prostacyclins, lipoxins, and other related
LA is replaced by oleic acid which results in severe water loss compounds. They participate in many physiological and
from the skin. pathological processes. Eicosanoids are compounds with
diverse physiological and pathological properties. They are
10.4.2.2  Immunity and Infection derived from 20 carbon PUFA (e.g., DHGL/DGLA, AA, and
There is significant reduction in immune response in EFA EPA). The precursor fatty acids are normally not found in the
deficiency. The data from animal studies have shown that free state to an appreciable extent in the cell, but occur as
these PUFA have powerful anti-inflammatory and immuno- esterified components of phospholipids, preferentially
modulatory activities in a wide array of diseases (e.g., auto- located in the carbon-2 position of glycerol (of the mem-
immunity, arthritis, and infection) [19]. PUFA may cause brane phospholipid). In humans, the tissue phospholipid
change in the membrane fatty acid composition of lymphoid content of AA is much higher than that of DHGL/DGLA and
 142 V. M. Sardesai

..      Fig. 10.3  Formation of

eicosanoids. The pathway is
for arachidonic acid (ArA in the Membrane phospholipids
figure). With DHGL/DGLA as the Corticosteroid
precursor, the PGs, TXs, and PGIs Phospholipase A2
will be of 1 series and LTs of the 3
series; with EPA as the precursor, 5-Lipoxygenase LTA
ArA HPETE LTA4 LTB4
the PGs, TXs, and PGIs will be of Hydrolase
3 series and LTs of 5 series. (Cour- Cyclooxygenase
tesy of Vishwanath M. Sardesai, NSAID LTC4 synthetase
PhD) Aspirin Prostaglandin
PGG2 synthetase
LTC4
Peroxidase

PGH2 γ-glutamyl transpeptidase

TX synthetase PGI synthetase

LTD4
TXA2 Isomerase PGI2
Aminopeptidase

PGs of the “2” series

LTE4

10
EPA. Therefore, eicosanoids derived from AA dominate over In platelets, the principal product is TXA2 which is
those from other 2 precursors [24]. All cells except erythro- formed by the action of TX synthetase on PGH2 [25]. TXA2
cytes are able to produce one or more types of eicosanoids. stimulates platelet aggregation and is also a potent vasocon-
They are not stored within cells but are synthesized as strictor. The product formed from PGH1 is TXA1, but is not
required and rapidly inactivated. Classic eicosanoids include of much significance because PGH1 is a poor substrate for the
prostaglandins (PG), thromboxanes (TX), prostacyclins enzyme. TXA3 formed from PGH3 is less potent as a
(PGI), and leukotrienes (LT). vasoconstrictor than TXA2 and has little platelet aggregating
Perturbation of the cell membrane by mechanical, ability.
trauma, clinical, or other stimuli activates phospholipase A2, In endothelial cells, PGH2 is converted to PGI2 by the
a membrane-bound enzyme that is found in virtually every action of prostacyclin synthetase. It has an action dramati-
cell type and organ in the body, and liberates the precursor cally opposite of TXA2. It inhibits platelet aggregation and is
fatty acid from phospholipids. This step appears to be rate-­ a powerful vasodilator. PGH1 does not have the Δ5 double
limiting because the free fatty acid is readily converted to bond and therefore cannot be converted to PGI1. PGI3
PGs and other eicosanoids. The synthesis is carried out by a formed from PGH3 has actions similar to those of PGI2.
membrane-bound PG synthetase complex which has two Arachidonic acid can be converted to LTB4, and cysteine-­
components: the cyclooxygenase component converts fatty containing LTC4, LTD4, and LTE4 by the action of
acid to PGG, and the peroxidase component quickly converts 5-­lipoxygenase followed by other enzymes. LTB4 is a potent
PGG to PGH (. Fig. 10.3).
  chemotactic agent attracting neutrophils and macrophages
The enzyme cyclooxygenase converts AA to PGH2. and causing aggregation at sites of infection or injury. LTB3
During this process, two double bonds of the precursor fatty produced from DHGL/DGLA has action similar to LTB4 and
acid are lost, and the product has two double bonds (if the is equally potent in its biological activity. The LTE5 formed
precursor is AA). The subscripts 1, 2, and 3 refer to the dou- from EPA is 10- to 100-fold less active than LTB4. The cyste-
ble bonds of the product. If the precursors were DHGL/ inyl LTs are potent vasoconstrictors and bronchoconstric-
DGLA and EPA, the products would be PGH1 and PGH3, tors. They increase permeability in postcapillary venules and
respectively. Once formed, PGH is acted upon by a series of stimulate mucus secretion.
enzymes to produce PGs, TXs, and PGIs. PGH is converted In addition to these classical eicosanoids, there are others
to several PGs by individual isomerases which are found in produced by different pathways. The products include lipox-
all tissues, but some cells are highly selective in the metabo- ins and others with different properties.
lism of PGH. Sometimes it becomes necessary to decrease or eliminate
PGs play important roles in several aspects of human the formation of inflammatory eicosanoids. A number of
physiology. They regulate a wide variety of processes includ- compounds are known to interact at one or more of the many
ing stomach secretion, uterus contraction, reproduction, steps involved in the formation of eicosanoids. The steroidal
blood pressure control, central nervous system, and inflam- anti-inflammatory agents, corticosteroids, inhibit phospho-
mation. lipase A2 and block the release of PUFA from membrane
Nutritional Role of Fatty Acids
143 10
phospholipids. This prevents the formation of all eicosanoids. free-living healthy adults contain about 10% of total fatty
Several synthetic corticosteroids have been developed and acids as LA, biochemical and clinical signs of deficiency do
are used clinically. Drugs blocking prostanoid synthesis are not appear during dietary fat restriction or malabsorption
usually preferred over the more powerful steroids because when they are accompanied by an energy deficit. In this situ-
of their undesirable systemic effects. The nonsteroidal anti-­ ation, release of LA and small amounts of AA from adipose
inflammatory drugs (NSAIDs) such as aspirin and ibuprofen tissue reserves may prevent development of EFA deficiency.
are potent inhibitors of cyclooxygenase. These drugs block Young, especially low-birth weight infants have limited body
the synthesis of PGG and hence of PGs, TXs, and PGIs. The stores of EPA and are more susceptible to deficiency. Cow’s
NSAIDs have been used to reduce inflammation, pain, and milk has only 25% of the LA contained in human milk, but
fever as well as platelet stickiness in an effort to reduce the when ingested in normal amounts, it has enough LA to pre-
risk of CHD. Aspirin (low doses) is one of the most important vent deficiency. Babies fed formula low in LA, such as a skim
and cost-effective drugs for arthritis and for the secondary milk formula, can develop deficiency [28].
prevention of CHD. It reduces the rate of arterial thrombotic In human infants, the deficiency signs include dermatitis,
events in high risk patients by at least 25%. Recent avail- rough and scaly skin, unsatisfactory growth, and impaired
able research data of aspirin’s use for primary prevention water balance. The skin symptoms and water loss are both
for high-risk CVD patients is showing a modest benefit. examples of a general derangement of membrane structure
Recommendations are that future aspirin studies consider and consequent function [29]. Erythrocytes become more
the extent of benefit–risk for healthy individuals that possibly fragile and susceptible to osmotic hemolysis. There is ele-
can be partially counterbalanced by the risks [26, 27]. vated triene/tetraene ratio above 0.2. The most common
Dietary intake determines to a great extent the fatty acid cause of EFA deficiency in humans of all ages is the long-­
composition of phospholipids in the plasma and cell mem- term intake of fat-free parenteral nutrition (PN). It is com-
branes. The eicosanoids derived from AA are, in general, monly administered as a continuous infusion of a
pro-inflammatory, while those derived from DHGL/DGLA glucose-containing solution, which results in a constant ele-
and EPA are less inflammatory or anti-inflammatory. EPA vation of serum insulin. This depresses the release of fat from
can be increased by consuming fish regularly or taking fish adipose stores, which in normal adults have a little more than
oil supplements. DHGL/DGLA can be increased by taking 1000 g of EFA, enough to otherwise sustain dietary needs for
borage oil, which is rich in gamma linolenic acid. It increases more than 6 months. Because of the block in the release of
DHGL/DGLA which forms PGE1, a potent antagonist to EFA, continuous fat-free PN seems to provide optimal condi-
inflammatory PGE2. There are several dietary constituents tions for the development of deficiency [30]. In these patients,
that can modulate the accumulation of PUFA in tissues and/ plasma-free fatty acids are derived from glucose and these do
or control the eicosanoid production. not include EFA.  Glucose-free PN containing only amino
acids and fat does not produce EFA deficiency.
10.4.2.6  Specific Role of W3 Fatty Acids Studies in infants maintained on long-term fat-free PN
ALA is not known to have any specific functions other than showed development of clinical signs together with bio-
to serve as a precursor of EPA and DHA.  Biological struc- chemical evidence of deficiency (high triene/tetraene ratio).
tures involved in fast movement or signal transmission Some premature infants developed very rapid clinical signs
appear to have a requirement for the highly unsaturated fatty and biochemical changes in plasma starting on the second
acid DHA. This measure is important for visual and neuro- and third day of life. Limited stores of EFA characteristic of
logical development. In several species, including humans, the premature state and high caloric expenditure might have
the retinal rod outer segment disk membrane in which rho- been responsible for the early development of deficiency. In
dopsin rests, the major phospholipid contains 40–60% of the the neonate, signs of deficiency may become apparent in
total fatty acid as DHA.  The retina conserves and recycles 5–10 days on fat-free PN, whereas in adults, the biochemical
DHA even when fatty acid intake is low. It is required for evidence of deficiency may be seen by the end of 2 weeks
normal development and function of the retina. The phos- after initiation of PN and by the end of 7 weeks; all patients
pholipids of the brain gray matter contain high proportion of exhibit clinical signs of deficiency. Manifestations of defi-
DHA, suggesting it may be important in central nervous sys- ciency in these patients include alopecia, brittle nails, derma-
tem function. Brain DHA content may be particularly impor- titis, increased capillary fragility, indolent wound healing,
tant because animal studies have shown that depletion of and increased susceptibility to infection. Administration of
DHA in the brain can result in learning deficits. diets containing LA reverses both clinical and biochemical
abnormalities. To correct or prevent the deficiency when oral
intake is denied, LA must be provided intravenously. The
10.4.3  Deficiency minimum LA dose to prevent deficiency state is about 5% of
the total calories for adults and 2% for pediatric patients.
Animal experiments have shown that the young are more Deficiency is accelerated by the increased metabolic demands
susceptible to EFA deficiency than adults. Deficiency in associated with growth and hypermetabolism following
humans is rare because most diets contain adequate EFA to injury, sepsis, or stress. These patients should receive 500 ml
meet the daily requirement. Because adipose tissue lipids in of 10% lipid emulsion 2–3 times per week.
 144 V. M. Sardesai

The first case involving ALA deficiency was described in milk is present as LA and ALA and 1% as long-chain PUFA
1982. A young girl was maintained on PN-containing saf- derived from these acids amounting to about 6% of total
flower oil emulsion rich in LA and poor in ALA.  After 3 energy as EFA and its metabolites. The fat stored during nor-
months, she developed visual problems and sensory neu- mal pregnancy is utilized during lactation at the rate of about
ropathy [31]. Serum analysis revealed very low levels of ALA 300 calories per day. Between 3 and 5 g of EFA are secreted in
and PUFA derived from it. PN was then changed to include milk per day [35]. An additional 1% and 2% of energy in the
soybean oil, which contains both LA and ALA.  Within form of EFA is recommended during the first 3 months of
3 months, all the symptoms of deficiency were resolved. Since lactation, and an additional 2% and 4% of the energy above
then several other cases involving ALA deficiency have been the basic requirements is recommended thereafter. The ade-
reported [32, 33]. quate intake for LA is set at 13 g per day and for ALA 1.3 g
W3 PUFA are low in children with attention-deficit per day. For infants, the adequate level for LA is 4.4 g per day,
hyperactivity disorder (ADHD) compared with other chil- and ALA is 0.5 g per day based on the average amount of LA
dren. Patients with Zellweger syndrome have lower levels of provided by human milk. Human milk contains long-chain
DHA in the brain, retina, and erythrocytes. Recent studies fatty acids including AA and DHA. Normal growth of infants
show a correlation between low levels of DHA and certain depends on an adequate supply of EFA.  The formula milk
behavioral and neurological conditions associated with should have EFA, including AA and DHA similar to those
aging, such as dementia, depression, memory loss, and visual found in human milk.
problems.

10.4.5  W3 Fatty Acids and Health

10.4.4  Requirements
The tissues of the body require W3 PUFA for their proper
10 The exact requirement of EFA in humans is not clearly functioning just as they need W6 PUFA.  The importance
defined [34]. Clinical signs of EFA deficiency are generally of W3 PUFA is their likely role in the prevention of many
found only in patients on PN and without a source of chronic diseases, now rampant in our society [36]. These
PUFA.  The plasma triene/tetraene ratio is below 0.2 when especially include CHD and even cancer. EPA and DHA
dietary EFA are adequate and is increased above 0.2 in rela- have been assumed to reduce the risk of CHD and stroke
tion to the degree of deficiency. The optimum dietary LA by a multitude of mechanisms by preventing arrhythmias,
required to give a ratio of less than 0.2 and to prevent symp- reducing atherosclerosis, decreasing platelet aggregation,
toms of EFA deficiency is 1–2% of total calories. It has been lowering plasma triglyceride concentrations, decreasing pro-­
suggested that those functions dependent on eicosanoid inflammatory eicosanoids, and decreasing blood pressure in
formation may show an optimum response with dietary LA hypertensive individuals.
at higher levels perhaps as high as 6–10% of total calories. Many epidemiologic studies have used fish and fish oil
An absolute amount required is not yet known, but because intake as surrogates for W3 fatty acids intake because of their
no ill effects have been reported up to this level, the ten- high content of EPA and DHA found in fish. People who fol-
dency is to consider it as optimal. The average daily intake of low a Mediterranean diet are less likely to develop heart dis-
LA by adults in most industrialized western countries is ease. The diet emphasizes foods that are rich in W3 fatty
about 10  g. The recommended adequate intake is 17  g for acids. Alaska natives who get high amounts of W3 fatty acids
young men and 12  g for young women. The quantitative from eating daily fish also tend to have lower incidence of
requirement for ALA in humans is not known. Biochemical heart disease. The ratio of LA/ALA is important in the diet
changes of W3 fatty acid deficiency include a decrease in because LA and ALA compete for the same desaturase
plasma and tissue DHA concentrations. There are no enzyme [37]. Thus, high ratio can inhibit conversion of ALA
accepted cut-off concentrations of plasma or tissue DHA to DHA, while a low ratio inhibits conversion of LA to AA.
below which functions attributed to W3 fatty acids, such as Clinical and epidemiological studies have addressed the
visual or neural functions, are impaired. However, on the W6/W3 fatty acid ratio with respect to the beneficial effects
basis of its derived products found in the blood of patients on the risk of certain diseases associated with W3 fatty acids,
maintained on PN, it has been suggested that ALA require- including EPA and DHA [38]. Low rates of heart disease in
ment should be between 0.2% and 0.3% of total calories. The Japan compared with the United States have been attributed,
recommended adequate intake is 1.6 and 1.2 g per day for in part, to a total W6/W3 fatty acid ratio of 4:1 with about 5%
men and women, respectively. energy as LA, 0.6% energy from ALA, and 2% energy from
In pregnancy, the accumulation of EFA is estimated to be EPA + DHA in Japan, compared with intakes of 6% energy
about 620 g, which includes the demand for uterine, placenta, from LA, 0.7% energy from ALA, and less than 0.1% from
mammary gland, and fetal growth and the increased mater- EPA plus DHA in the United States. Similarly, an inverse
nal blood volume. To meet these needs, 4.3% of the accepted association between the dietary total W6/W3 fatty acid ratio
calorie intake in the form of EFA is recommended during and cardiovascular disease, cancer, and all-cause mortality as
pregnancy. Approximately 4–5% of total energy in human well as between fish intake and CHD mortality has been
Nutritional Role of Fatty Acids
145 10
reported. Based on studies in animals, children, and adults, a ing at least a moderate part of the diet significantly lowers the
reasonable LA/ALA ratio of 5:1 to 10:1 has been recom- risk of prostate cancer. EPA and DHA have been shown to
mended for adults. suppress neoplastic transformation, inhibit cell growth and
Two recent studies show that people who eat substantial proliferation, induce apoptosis, and inhibit angiogenesis by
amounts of fish are greatly protected from sudden unex- suppressing omega-3-derived eicosanoid products.
pected death caused by severely abnormal heart rhythms Several studies have reported a negative relationship
[39]. In the Physicians’ Health Study, 22,000 men were between PUFA intake and risk of diabetes. Fish intake has
divided in four groups based on the concentrations of W3 specifically been reported to have a negative association.
fatty acids in blood. The men in the highest quartile had 81% Rheumatoid arthritis (RA) is an autosomal disease that
lower risk of sudden death than those in the lowest quartile causes inflammation of joints. Fish oils have been found to
during a 17-year period of observation [40]. In the Nurses’ reduce symptoms of RA, including joint pain and morning
Health Study, investigators used dietary information gath- stiffness. People with RA who take ALA may be able to
ered in five interviews between 1980 and 1994 to estimate the reduce their dose of anti-inflammatory drugs. Fish oil also
fish intake of 85,000 female nurses. Those who ate fish once a may help people with osteoarthritis. One study in rats has
week had a 30% lower risk of heart attack or death than those suggested that diets containing omega-3 fatty acids lead to
who never ate fish, and those who ate fish 5 times a week had lower levels of fat accumulation compared with diets con-
a 34% lower risk. The data also indicated that similar to the taining other fatty acids.
mortality from CHD, all-cause mortality was lowest among Population studies in Chicago have reported that people
groups of women who ate the most fish [41]. 65 and older who ate fish at least once weekly were 60% less
Results of these studies indicate that even in people with likely to develop Alzheimer’s disease than those who never or
no history of CHD, high blood W3 fatty acid levels can lower rarely ate fish [48]. Depression is associated with lower levels
their risk of CHD death. The link to arrhythmias is the most of W3 fatty acids in RBC membranes. Countries with the
substantiated [42], but fish oils also have other heart-friendly highest rates of depression ate the least amount of fish while
effects, such as lowering the levels of triglycerides in blood, those with the lowest rates of depression ate the most fish [49,
reducing inflammation, slowing coronary artery thickening, 50]. W3 fatty acids may also protect the eyes. In one study, it
and reducing the tendency of blood to clot. has been reported that those who ate fish twice a week had a
It has been proposed that omega-3 index be used as a bio- 36% lower risk of macular degeneration, the leading cause of
marker for cardiovascular disease risk [43]. The index is blindness in old age [51].
defined as the amount of EPA + DHA in red blood cell (RBC) There are also data suggesting W3 fatty acids may be help-
membranes expressed as the percent of total RBC membrane ful for a raft of other ills such as hypertension, aggression,
fatty acids. The EPA + DHA content of RBCs correlates with attention deficit disorder, autoimmune diseases, and several
that of cardiac muscle cell, and several observational studies other diseases [52, 53]. Fish and fish oil thus qualify as func-
indicate that a lower omega-3 index is associated with tional foods.
increased risk of CHD mortality [44]. The proposed zones Fish such as salmon and tuna are considered as optimal
being used are high risk <4%, intermediate risk 4–8%, and dietary sources of omega-3 fatty acids. The acceptable daily
low risk >8%. Supplementation with fish oil capsules for a intake of these fatty acids is 1.6  g for men and 1.1  g for
few months increases the omega-3 index. women, although more may be recommended for certain
The American Heart Association recommends that conditions such as heart disease and arthritis. Fish contain
healthy adults, especially those at higher risk for heart dis- mercury and other unsafe pollutants which may limit the
ease, eat a variety of fish, preferably oily fish such as salmon, amount of fish that should be consumed, particularly for
mackerel, and sardines, at least twice a week [45]. The asso- children and women who are pregnant or breastfeeding.
ciation also recommends increasing the intake of ALA-rich Mercury is a known toxin for the human nervous system and
foods such as walnuts, flax seeds, and canola and soybean oil. is linked to learning and behavioral problems in children
In September 2004, the US Food and Drug Administration [54]. In adults, mercury can cause memory loss and other
(FDA) allowed the following “qualified” health claim for cer- health problems. For those who do not eat fish, a fish oil
tain foods containing fish oils: “Supportive but not conclusive supplement may be considered. The best fish oil supplements
research shows that consumption of EPA and DHA W3 fatty contain 1 g per capsule, which provides 440 mg of W3 fatty
acids may reduce the risk of coronary heart disease” [46]. The acids. The most common fish oil capsules in the USA provide
FDA action marks the second time the agency has allowed a 180 mg of EPA and 120 mg of DHA. The recommended dos-
qualified health claim for a conventional food product: early age is 1–2 capsules a day for adults. Large doses may exert a
the same year, the agency granted a claim linking walnuts and dose-related effect on lowering bleeding time.
certain other nuts to a reduction in heart disease risk. With the increasing popularity of the vegetable diet and
Oily fish and fish oil consumption have been associated mounting focus on mercury and other contaminants in sea-
with protection against the development of some types of food, flaxseed oil which contains ALA has become a safer
cancer, such as colorectal, mammary, and prostate cancer choice. We can make EPA and DHA from ALA, but the
[47]. A study has shown that consumption of fish constitut- process is slow. Researchers at Dow AgroSciences inserted
 146 V. M. Sardesai

the algae genes required to make DHA into canola seeds. The
..      Table 10.4  Selected food sources of EPA and DHA content
enzyme that these genes produce allows the canola plant to in grams
synthesize the DHA from ALA [55]. Such plants produce
canola oil that is enriched with DHA. Monsanto genetically Source Serving size (ounce) EPA (g) DHA (g)
engineered a soybean plant to produce W3-derived products
in soybean oil. Herring 3 1.06 0.75

Salmon 3 0.86 0.62

Sardines 3 0.45 0.74

10.4.6  Food Sources
Crab 3 0.24 0.10
The most prevalent source of W6 fatty acids is LA. It is pres- Oysters 3 0.75 0.93
ent in almost all vegetable oils such as safflower oil, corn oil,
Tuna 3 0.40 0.44
sunflower oil, and soybean oil. Common fatty acids found in
most land plants are generally not elongated above the Trout 3 0.45 0.74
18-carbon level. Borage seed oil is the richest source of Mackerel 3 0.43 0.59
γ-linolenic acid (GLA) among vegetable oils. It contains 24%
of GLA.  Black currant is the next with 17% and evening Shrimp 3 0.07 0.10
primrose contains 8% of GLA. This fatty acid is an intermedi- Flounder 3 0.24 0.25
ate in the conversion of LA to AA. Dietary meat, poultry, and
eggs provide small amounts of AA. The W6 PUFA intake in
the USA ranges from 12 to 17 g per day in men and 9–11 g
per day in women. It accounts for 5–7% of total energy intake 10.5  Trans-Fatty Acids
10 in diets of adults. Most W6 PUFA (80–90%) are consumed in
the form of LA.  Others such as AA and GLA are in small Due to fermentation in ruminant animals such as cows, small
amounts in the diets. amounts of trans-fatty acids exist naturally in meat and dairy
The major sources of W3 fatty acids as ALA include veg- products. This was the source of trans-fatty acids in diets of
etable oils such as soybean, canola, and flaxseed oil. Flaxseed humans until the beginning of the last century.
is the rich source containing 50–60% ALA. . Table  10.3   After the introduction of Crisco in 1911, partially hydro-
shows the linolenic acid content of some foods. genated fat was used to make margarine and numerous other
Leafy vegetables, such as spinach, kale, and romaine let- products, including crackers, cookies, and other baked goods
tuce, contain small amounts. Fish oils provide a mixture of and fried snacks such as potato chips. Food manufacturers
EPA and DHA, and fatty fish are the major dietary sources of started using partially hydrogenated fats because of their
EPA and DHA. . Table 10.4 shows the content of EPA and
  favorable properties, such as longer shelf life, stability during
DHA in some types of fish. frying, and palatability. Consumers preferred these products
The intake of total omega-3 fatty acids in the United (usually considered to be “cholesterol-free” and high in
States is about 1.6 g per day (0.7% of energy intake), and of PUFA) to lower cholesterol intake, theoretically reducing the
this, ALA accounts for 1.4 g/day and only 0.1–0.2 g/day of risk of CHD. The consumption of these products continued
EPA and DHA. to increase steadily [56].
Trans-fatty acids account for 3–8% of the fat in the
American diet or 8.3–13.5  g per day. However, the intake
may be much higher for persons consuming large amounts of
..      Table 10.3  Selected food sources of ALA commercially baked products and fried foods. A medium-
Source Serving size Content in grams
size helping of French fries contains 5–6 g, a doughnut con-
tains 2 g, and an ounce of crackers 2 g of trans-fatty acids.
Canola oil 1 tablespoon 1.30 Prior to 1980, there was generally no concern about the
Walnut oil 1 tablespoon 1.40
trend toward increased consumption of hydrogenated fat in
the US diet, especially because it displaced fat relatively high
Flaxseed oil 1 tablespoon 7.48 in saturated fat. In the 1980s, studies showed hypercholester-
Soybean oil 1 tablespoon 0.90 olemic effects of trans-fatty acids in rabbits. Several studies in
humans reported that a diet enriched with trans-fatty acids
Flaxseed ground 1 tablespoon 7.48
caused blood LDL cholesterol to increase and HDL choles-
Walnuts 1 ounce 2.60 terol to decrease, resulting in less favorable total cholesterol/
Chia seeds 1 ounce 4.90 HDL ratio to increase [57]. Two studies also showed a rise in
plasma lipoprotein(a) with relatively high consumption of
Soybeans 1 ounce 0.47
trans-fatty acids. Similar to LDL, the concentration of
Hickory nuts 1 ounce 0.29 lipoprotein(a) in plasma is directly associated with increased
risk for CHD.
Nutritional Role of Fatty Acids
147 10
On a per calorie basis, trans-fatty acids currently appear drop in fat mass of about 0.2 lb. each week (i.e., about 1 lb. a
to increase the risk of CHD more than any other macronutri- month) compared with those given a placebo. Some studies
ent at low levels of consumption (1–3% of energy intake). indicate CLA has potent beneficial effects as antitumor, anti-­
The major evidence came from the Nurses’ Health Study obesity, antiatherogenic, and antidiabetic activities. The mol-
(NHS)  – a cohort study that has been following approxi- ecules have been shown to modulate immune function
mately 120,000 female nurses since its inception in 1976. mainly in animals and in in vitro studies [63].
Researchers analyzed data from 900 coronary events from Small amounts of CLA are present in all diets. It is usually
the NHS population during 14 years of follow-up and deter- found in beef and dairy products. The best sources of CLA
mined that a nurse’s CHD risk roughly doubled for each 2% are from grass-fed cattle and its products. The average intake
increase in trans-fat calories consumed (instead of carbohy- in the USA is in the range of 151 to 212 mg/day. CLA is mar-
drate calories). By contrast, it took a more than 15% increase keted in dietary supplement form for its anticancer benefit,
in saturated fat calories (instead of carbohydrate calories) to for which there is some evidence, but no known mechanism,
produce a similar increase in risk. Trans-fatty acids behaved and as a body building aid. Despite the many claims made,
similar to saturated fatty acids by increasing plasma LDL good evidence of human health benefits remains scarce.
cholesterol, but unlike saturated fat, it had the additional
effect of lowering plasma HDL cholesterol levels [58]. Other
adverse effects reported were on growth and development, 10.7  Conclusions
inhibition of conversion of LA and ALA to AA and DHA,
respectively, possible association with Alzheimer’s disease, Fatty acids are integral components of the lipid macronutri-
and increase in weight gain [59]. ents that have four major physiological roles. First, fatty
In recent years, a series of studies has provided unequivo- acids are fuel molecules stored as triacylglycerols, or triglyc-
cal evidence that trans-fat adversely affects health [60]. In erides, that have a neutral charge mainly stored in adipose
2003, Denmark became the first country to ban trans-fat. tissue in adipocyte cells. The triacylglycerols are oxidized
Many other countries followed suit. In the United States, and able to provide energy needs of the cells or tissues.
New York City passed such a ban in restaurants in 2006 and Second, fatty acids function as the base unit of phospholip-
California did the same in 2008. ids and glycolipids, colluding with cholesterol responsible
The US Food and Drug Administration addressed this for modulating cell membrane fluidity (see 7 Chap. 22).  

issue by requiring disclosure of the trans-fat content in food These amphipathic molecules are important components of
in Nutrition Labels, beginning in 2006. On March 16, 2015, all the biological bilayer membranes that allow for highly
the FDA took further action that will significantly reduce the selective permeability barriers. Membrane processes such as
use of partially hydrogenated oils, the major source of artifi- transport and cell sensing depend of the fluidity of the
cial trans-fat in the food supply [61]. The FDA is providing membrane modulated by cholesterol (see 7 Chap. 12).  

the companies 3 years to either reformulate products without Dietary intake of fats and cholesterol are primary determi-
partially hydrogenated oils and/or petition FDA to permit nants of the structure and composition of the membranes
specific uses. Food companies have already been working to affecting their function. Third, fatty acids by a covalent
remove partially hydrogenated oils from processed foods, attachment can modify proteins to position the location of
and FDA anticipates that many may eliminate them ahead of the protein on the membrane structure. Specific proteins
the three-year compliance date. This action is expected to involved with mediating membrane functions such as
reduce cardiovascular disease risk. The Centers for Disease energy transduction, transport, and cell-sensing communi-
Control and Prevention estimates that this action could pre- cation. The fourth role of fatty acids is their synthesis to
vent as many as 20,000 coronary events and 7000 deaths derivatives that serve as hormones and intracellular messen-
from coronary causes each year in the USA. gers. Fatty acids and their role in human metabolism are
presented in this chapter to provide the science and princi-
ples for which the nutrition practitioner can guide disease
10.6  Conjugated Fatty Acids management for assessment of an individual’s fatty acid
status and develop therapeutic interventions toward restor-
Conjugated linoleic acid (CLA) represents a collective term ing optimal function (see 7 Chap. 11).
 

for a group of geometric and positional isomers of LA that

contain a conjugated double bond system instead of the iso- Acknowledgments  I wish to gratefully acknowledge the secre-
lated double bonds. It has attracted a fair amount of attention tarial assistance of Cindy Luiz in the preparation of this manu-
and has been reported to have different biological effects in script. I also wish to thank Amie Dozier, Associate Director,
health-related disorders [62]. Medical Education Support Group of the School, for preparing
CLA is beneficial in lowering body fat while preserving the illustrations and Cynthia Washell, Practice Administrator,
muscle tissue. Individuals who took 3.2 g CLA per day had a Department of Surgery, for providing support.
 148 V. M. Sardesai

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American Oil Chemists’ Society; 1983. p. 247–66.
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triglyceride feeding. Am J Clin Nutr. 1977;30(10):1670–6.
acid profiles and antioxidant content in grass-fed and grain-
31. Holman RT, Johnson SB, Hatch TF.  A case of human linolenic acid
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1982;35(3):617–23.
6. Canfora E, Jocken J, Blaak E. Short-chain fatty acids in control of body
32. Bjerve KS. Alpha-linolenic acid deficiency in adult women. Nutr Rev.
weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11:577–91.
1987;45(1):15–9.
7. Greer JB, O’Keefe SJ.  Microbial induction of immunity, inflamma-
33. Bjerve KS. n-3 fatty acid deficiency in man. J Intern Med Suppl.
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1989;731:171–5.
8. Scheppach W. Effects of short chain fatty acids on gut morphology
34. Flock MR, Harris WS, Kris-Etherton PM.  Long-chain omega-3

and function. Gut. 1994;35(1 Suppl):S35–8.
fatty acids: time to establish a dietary reference intake. Nutr Rev.
9. Andoh A, Tsujikawa T, Fujiyama Y.  Role of dietary fiber and short-­
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35. Hansen AE, Haggard ME, Boelsche AN, Adam DJ, Wiese HF. Essential
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Figure 2. SCFA and interorgan crosstalk.
acid deficiency. J Nutr. 1958;66(4):565–76.
36. Simopoulos AP. Essential fatty acids in health and chronic disease.
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991–3.
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38. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid
an adverse metabolic profile when compared to olive oil. J Am Coll
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14. Vallim T, Salter AM.  Regulation of hepatic gene expression by
sudden death. N Engl J Med. 2002;346(15):1113–8.
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41. Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM,
16. Holman RT, George O.  Burr and the discovery of essential fatty
Hunter D, Manson JE. Fish and omega-3 fatty acid intake and risk of
acids. J Nutr. 1988;118(5):535–40.
coronary heart disease in women. JAMA. 2002;287(14):1815–21.
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Biochem. 1992;3(4):154–66.
Choo BH. Omega-3 fatty acids: a comprehensive review of their role
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nutritional and biological implications. Curr Opin Clin Nutr Metab
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Care. 2004;7(2):137–44.
ease. Am J Clin Nutr. 2008;87(6):1997S–2002S.
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smart/fats/fish-and-omega-3-fatty-acids.
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acids. Adv Nutr. 2012;3(2):127–34.
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24. Sardesai VM. Eicosanoids. In: Introduction to clinical nutrition, vol.
Aggarwal N, Schneider J.  Consumption of fish and n-3 fatty acids
xxix. 3rd ed. Boca Raton: Taylor & Francis/CRC Press; 2012. p. 674.
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Nutr Biochem. 1992;3(11):562–79.
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long-term health. N Engl J Med. 2014;370(19):1773–5.
 151 11

Lipidomics: Clinical Application

Diana Noland

11.1 Introduction – 153

11.2 History of Dietary Fat – 153

11.2.1  uman History – 153
H
11.2.2 The Nutrition Transition of Oils and Fats in the
Early 20th Century – 154

11.3 The Lipidome and Clinical Application – 154

11.3.1 Clinical Imbalances – 155

11.4  utritional Influences on Body Composition

N
and Function – 156
11.4.1 Structure and Functions of the Cell Membrane – 156

11.5  he Eicosanoid Cascade: Acute and Chronic Tissue

T
Inflammation Management – 158
11.5.1 F atty Acid Elongation (See . Fig. 11.4) – 159
 

11.5.2 Fatty Acid Desaturation (See . Fig. 11.4) – 159

 

11.6 Metabolic Stressors – 160

11.7 Tools of the Trade for Lipid Therapy – 160

11.7.1 L aboratory Principles – 163
11.7.2 Structural Integrity – 163
11.7.3 Defense and Repair – 163

11.8  ey Nutrient Cofactors and Foods Influencing the Eicosanoid

K
Metabolism – 163
11.8.1 L ipids – 163
11.8.2 Sterols – 164
11.8.3 Minerals – 164
11.8.4 Methyl Nutrients – 164
11.8.5 Phytonutrients: Protective Support for Lipid Structures – 165

11.9  ey Lifestyle Factors Influencing the Risk of Lipid

K
Damage – 165
11.9.1 Sleep [74] (See 7 Chap. 35) – 165
 

11.9.2 Stress (See 7 Chap. 47) – 165

 

11.9.3 Movement (See 7 Chaps. 36 and 54) – 165

 

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_11
11.10 C
 hronic Disease and Impaired Lipid Metabolism
(See Tables . 11.3 and 11.4) – 166
 

11.10.1  eart Disease/Cardiovascular Association with the Lipidome – 166

H
11.10.2 Oncology – 166
11.10.3 Neurological – 166
11.10.4 Respiratory – 167
11.10.5 Autoimmune – 167

11.11 Case Reviews – 168

11.12 Conclusion – 170

References – 170
Lipidomics: Clinical Application
153 11
Learning Objectives
..      Table 11.1  Integrative and functional medicine principles
1. The Lipidome and Clinical Application
2. Nutritional Influences on Composition and Function Focuses on patient/client-centered approach
3. Tools of the Trade for Lipid Therapy
4. Case Reviews Acknowledges biochemical uniqueness of each individual

Patient practitioner partnership

Appropriately uses conventional and complementary treatments

11.1  Introduction
Considers genetic, environmental, and lifestyle factors
The main global healthcare concern of the twenty-first cen- Seeks balance between mind, body, and spirit
tury is chronic disease. Public health leaders around the
Acknowledges all body systems are interconnected by physi-
world are working to quell the unsustainable widespread ological and metabolic factors
changing phenotype of populations. In the United States,
more than two-thirds of the citizens are currently overweight Identifies health as a positive vitality
or obese, and the trend is increasing. In 2012, there began an Uses natural, effective, less invasive interventions, when possible
unprecedented decline in U.S. lifespan. Much of the trend
toward chronic disease is due to dysfunction in the underly-
ing mechanisms of cell signaling and the messages that oper- personal genetics determine the type and amount of fats that
ate at the organelle and cell membrane sites. This is where the may benefit an individual.
DNA is expressed and put into action as body systems read The goal of this chapter is to help the nutrition-trained
the environment and determine how to respond to survive. professional understand the molecular structure of an
IFMNT is a person-centered approach with each indi- individual’s cellular membranes and how those structures
vidual assessed, and interventions developed, as personalized affect the efficiency and proper functioning of metabolism.
therapy based on the nutrition and medical data that is gath- With that knowledge, one has the clinical skills in medi-
ered during a comprehensive evaluation. For population of cal nutrition therapy for assessment and intervention. The
persons with the same diagnosis, there will be an equal num- practitioner must have working knowledge of foods and
ber of uniquely designed protocols. Each disease has many supplements, which support the body’s metabolic plasticity.
causes, thus this chapter does not give a recipe for diagnosis This approach is viewed through the lens of systems biology,
and intervention rather provides principles and tools to draw which is the science of all systems interacting and influenc-
from to form the best protocol to restore wellness. ing each other to produce the phenotype of an individual; it
In this chapter, we first examine the structure of the cell is often referred to as integrative and/or functional medicine
membrane, which is comprised of different regions of micro- (see . Table 11.1).
 

domains referred to as membrane rafts with varying percent

lipids (e.g., fats, phospholipids, steroids), which are mainly
formed from the food fats and oils we eat [1]. The structure 11.2  History of Dietary Fat
of membranes determines the function of the “control
tower” of our systems where communication and cell signal- It can be enlightening to think back on historical diets and
ing occurs. Second, we assess function and how well the events that led to the current recommendations about fat.
body can manage all its systems to enable them to produce a Around the 1950s, recommendations to Americans concern-
healthy organism. The evidence that the lipids we eat create ing fat were promoted by publications from Gofman [3] and
the composition of our lipid structures and control our func- Keys (1953) [4], in which the dogma was propagated that
tion is mounting in recognition of the metabolic plasticity of “saturated fat and cholesterol were bad.” A connection was
human metabolism [2, 3] (see 7 Chap. 10). At the time of
 
made with respect to the rise of heart disease and epidemio-
this publication, there is public and scientific interest in the logic correlations between dietary saturated fat, cholesterol
comparison of the effects of high carbohydrate, low fat diets and heart disease. Not much has changed in the last 70 years
to those with low carbohydrates and high fat. The main in recommendations to reduce total fat, saturated fat, and
thrust of this latter diet protocol is exchange of carbohy- cholesterol-rich foods. Until the 1940s in the United States,
drates for fats. Nutrition professionals need to be aware of heart disease and cancer were minor contributors to mortal-
the metabolic implications of this dietary change and the ity statistics, but they have continued to grow to the number-
science behind what is often referred to as paleo or ketogenic one and -two causes of death in industrialized countries.
(keto) diets (see 7 Chap. 23).
 

This chapter addresses emerging evidence about fatty

acid metabolism and outdated misinformation that is still 11.2.1  Human History
accepted dogma regarding dietary fat. Understandably, the
public and even nutrition professionals are confused about Fats used for dietary ingestion were “all natural” (not pro-
dietary fats. We are on the brink of a new understanding of cessed) prior to ~1900. Lipids, oils, and fats commonly used
the science of lipids, food processing, and how one’s unique were:
 154 D. Noland

55 Fat or oil-rich foods Horrobin [6] proposed an ideal ω6:ω3 ratio of 4:1, and most
55Meat fatty-acid scientists agree optimum ratio somewhere with the
55Poultry and skin range of 1:1 to 5:1 ratios [7, 8].
55Fish, shellfish, roe Chronic diseases are characterized as long-latency life-
55Egg yolk style and diet-related. Chronic diseases all have inflamma-
55Olives, olive oil tory pathophysiology promoted by injury, infection, or
55Other plants: nuts, seeds, avocado biological stressors (e.g., chronic inflammation, high visceral
55Essential and/or medicinal oils adiposity, emotional stress). For example, an acute infection
55 Cooking oils may either be resolved by a healthy immune system or sur-
55Butter, ghee vive and continue as a subclinical infection that is often not
55Lard recognized but continues to wear on the immune system.
55Tallow Lipids that participate in eicosanoid metabolism are largely
55Coconut oil responsible for control of inflammation and the ability of the
55Olive oil, foot-pressed metabolic resolution of an inflammatory event.
The healthy human body is equipped with defense fea-
The nutrition transition to the standard American diet tures from conception throughout life to interact with the
(SAD) [5] at the beginning of the twentieth century paral- environment to protect it from infection and injury. All of
leled the increase in the onset and progression of chronic the barriers’ defensive functions are a reflection of their lipid-­
human diseases as the food supply changed in quality and dominant structure. Much of the defense starts with the
quantity, giving rise to obesity and a mismatch of gene–diet lipid-rich skin barrier and microbiome at all body orifices to
interactions. Cooking oils intolerant to heat, processed foods protect from pathogens entering and infecting or causing
containing trans fats, and damaged oils have become com- injury.
monplace. There is currently a debate regarding the impact
of the increase in omega-6 on human health [6] and newer
processing methods in the food oil industry that are allow- 11.3  The Lipidome and Clinical Application
11 ing “damaged” oils and “new-to-nature” forms of oils into
the food supply (e.g., hydrogenated vegetable oils, high heat The application of lipidomics in clinical practice is an impor-
processing of vegetable oils, changing proportion of linoleic tant new tool for the healthcare practitioner due to expand-
acid, and monounsaturated fats to “high oleic” vegetable ing knowledge of the structural and functional properties of
oils). Issues that need to be addressed include the influence fat. Dietary fat is a key topic in government food policy,
of ingested food oils on the structure and function of cellular research, public media, and in the homes of families prepar-
health and how these food oil changes have contributed to ing food during a period of dramatic change in thinking
the epidemic of chronic disease? about how we incorporate fat into diets. Many people feel
confused about the amount and types of fat to eat. Is satu-
rated fat bad? Is a low-fat diet good? Dietitians and health-
11.2.2  The Nutrition Transition of Oils and care professionals are beginning to learn about the emerging
Fats in the Early 20th Century science of lipidomics and how that applies to the science of
lipid metabolism and the use of dietary and food supplement
Processed oils: to maintain health.
55 Heat-processed vegetable oil Lipids are highly diverse molecules that are as important
55 High heated commercial oil used for deep frying for life as proteins and genes [2] with critical roles in mem-
55 Hydrogenation of vegetable oils brane structure, cell signaling, energy storage, inflammation
55 Charred red meats or high-temp-oil deep frying produce regulation, and as base units for constructing messenger hor-
trans fats or acrylamides mones. Maintaining lipid balance and homeostasis is within
a practitioner’s capability when they are skilled at recogniz-
Specialty foods available after 1950: ing lipid imbalances and their relationship to disease pathol-
55 Natural: nitrogen-packed seed/nut oils, refrigerated ogy. One of the profound roles of lipid metabolism involves
55Sunflower, safflower, flax (refrigerated), avocado oil, metabolic regulation of inflammation. It is essential to
flax–safflower oil 4:1, macadamia oil understand how to modulate lipid metabolism considering
55 Processed: that the global epidemic of chronic disease in healthcare
55Deep frying with vegetable oils reflects prolonged and unresolved inflammation. All the
55Hydrogenated or partially hydrogenated vegetable oils “ingredients” of lipids (fatty acids, phospholipids, sterols,
sphingolipids) and the associated enzymes and nutrient
The ratio between the types of fats has changed dramatically cofactors affect the control and resolution of inflammation.
during the past 70–100  years with a three-fold increase in Knowledge of lipid modulation by dietary and lifestyle
dietary levels of the omega-6 (n-6) 18 carbon (C18), polyun- changes is a powerful addition to the toolbox of the IFMNT
saturated fatty acids (PUFA), linoleic acid (LA; 18:2n-6) [5]. practitioner.
Lipidomics: Clinical Application
155 11
The two functions of the lipids that can be modulated by Each individual is unique. IFMNT is a person-centered
nutrition therapy are membrane structure and inflammation approach with each individual assessed, and interventions
control. develop as personalized therapy based on the nutrition and
55 Membrane structure: the membrane is at least 50–75% medical data that are gathered in the initial interview. For a
lipids with embedded protein structures forming recep- population with the same diagnosis, there will be that many
tors, channels, and other structures [6] “You are what different protocols recommended. For one disease, there
you eat.” What fats and oils and sterols you eat become are many causes. That is why this chapter does not include
the structural composition of your membranes and specific interventions for a diagnosis but provides princi-
influence their function of cell signaling, communica- ples to consider and draw from in forming the best regula-
tion, and transport. tion of structure and inflammation control to restore
55 Inflammation control: The lipid eicosanoid molecules wellness.
play a key role in our survival. They are the primary
metabolites teaming with the immune system to man-
age the immune response and control inflammation. 11.3.1  Clinical Imbalances
Dysregulated lipid metabolism and nutrient status are
thought to play a major role in the pathophysiology of The conceptual diagram below (see . Fig.  11.1) provides a  

every chronic disease. Since chronic prolonged inflam- guide to hearing the patient’s whole story, so that an assess-
mation is present in every chronic disease, the eico- ment can be as comprehensive as possible to narrow down
sanoids become priority in supporting their metabolic root causes of the patient’s condition. In seeking root causes
function. And the most effective way of modulating the of the etiology of a disease condition, one must investigate
eicosanoid cascade is nutrition lipid therapy guiding the health and structural integrity of the cell membrane. All
dietary intake of fats and oils and nutrient cofactors. cells in the body share the basic structure and function of a

FUNCTIONAL MEDICINE MATRIX

Retelling the Physiology and Functoin: Organizing the patient’s Clinical Imbalances
Patient’s Story

Antecedents Assimilation Defense & Repair

(e.g., Digestion, (e.g., Immune,
(Predisposing Factors— Absoirption, Microbiota/GI, Inflammation,
Genetic/Environmental) Respiration) Infection/Microbiota)

Mental Emotional
e.g., cognitive e.g., emotional
Structural Energy
function, regulation, grief,
Integrity perceptual sadness, anger, (e.g., energy,
Triggering Events (e.g., from Subcellular patterns etc, Regulation,
Membranes to Mitochondrial
(Activators)
Musculoskeletal Function)
Structure)
Spiritual
e.g., meaning &
purpose,
relationship with
Communication something greater Biotransformation
Mediators/Perpetuators (e.g., Endocrine, & Elimination
(Contributors) Neurotransmitters, Immune (e.g., Toxicity,
messengers) Detoxification)
Transport
(e.g., Cardiovascular, Lymphatic System)

Modifiable Personal Lifestyle Factors

Sleep & Relaxation Exercise & Movement Nutrition Stress Relationships

© 2015 Institute for Functional Medicine

Name: Date: CC: Version 3

..      Fig. 11.1  IFM Matrix™ Conceptual diagram to guide the practitioner assessment procedure to hear the whole patient’s story preparing for
improved diagnosis of root causes of health issues. (Used with permission from The Institute for Functional Medicine ©2015)
 156 D. Noland

bilayer membrane made of 50–75% phospholipids, fatty

acids, cholesterol with embedded proteins forming channels, The structure and function of cells depend on mem-
and receptors to facilitate ports of entry and exit to and from branes, which not only separate the interior of the cell
the intracellular to extracellular compartments. There are from its environment but also define the internal com-
some carbohydrate molecules functioning as “antennas” partments of eukaryotic cells, including the nucleus
extending from the surface of the cell for messaging and cell and cytoplasmic organelles. The formation of biological
signaling [9, 10]. membranes is based on the properties of lipids, and
The other core physiological system to be investigated all cell membranes share a common structural orga-
when assessing an individual’s fatty acid status is defense and nization: bilayers of phospholipids with associated
repair. Since lipids and fatty acids of the eicosanoid molecules proteins. These membrane proteins are responsible
are the primary influencers and regulators of inflammation, for many specialized functions: some act as recep-
treatment of the defense and repair systems begins to reveal tors that allow the cell to respond to external signals,
the etiology of the inflammatory aspect of an individual’s some are responsible for the selective transport of
condition. Once identified, utilizing the skill set of modulat- molecules across the membrane, and others participate
ing lipid and fatty acid status will help target the intervention in electron transport and oxidative phosphorylation. In
needed to restore structure, function, and wellness. The cell addition, membrane proteins control the interactions
membrane is a primary determinant of the quality of an indi- between cells of multicellular organisms. The common
vidual’s health (see 7 Chaps. 12 and 19) (. Fig. 11.1).
   
structural organization of membranes thus underlies
a variety of biological processes and specialized mem-
brane functions, which will be discussed in detail in
11.4  Nutritional Influences on Body later chapters [9].
Composition and Function

11.4.1  Structure and Functions of the Cell The Cellular, Organelle, and Nuclear Bilayer Membranes of
11 Membrane Each Cell [10]
55 Protect and hold together each compartment.
The prevailing concept of cell membrane structure is the 55 Protect cell compartments from their surrounding envi-
phospholipid bilayer that is impermeable to most water-­ ronment.
soluble molecules, often referred to as the fluid mosaic model 55 Control movement of substances transported in and out
[9]. Most of the phospholipids in the membrane are present of the cell.
as a biomolecular sheet, with the fatty acid chains in the inte- 55 Manage immune responses regarding inflammation
rior and exterior of the bilayer. Membrane proteins are (eicosanoid metabolites).
located either on the internal or external faces of the mem- 55 Maintain cell and mitochondrial membrane integrity—
brane or projecting from one side to the other. An important key to cell survival.
feature of the membrane is “membrane permeability,” allow- 55 Foundational to the core physiological clinical
ing flexibility for molecules to move around [2, 11] imbalances (see . Fig. 11.1).
 

(. Fig. 11.2).
 
55 Provide structural integrity

..      Fig. 11.2  Fluid mosaic model

of membrane structure.
(Reprinted from OpenStax CNX
[88]. With permission from
Creative Commons License 4.0:
7 https://creativecommons.­org/
 

licenses/by/4.­0/)
Lipidomics: Clinical Application
157 11
..      Fig. 11.3 Sodium-Potassium
Pump. A transporter on the
membrane that maintains high
potassium and low sodium
intracellular concentrations Extracellular fluid
relative to the extracellular Potassium ions (K+)
electrolyte concentrations. This
pump functions at the expense
of ATP energy and is influenced
by the dietary intake of the
minerals magnesium, potassium,
and sodium. (Reprinted from
7 Blausen.­com staff [89]. With
 
Sodium-potassium
permission from Creative exchange pump
Commons License 3.0: 7 https://
 

creativecommons.­org/licenses/
by/3.­0/deed.­en.) ADP Pi
Sodium ions
ATP
(Na+)
Cytoplasm

55 Provide defense and repair. A deficit of any of the three minerals will affect the function
55 When compromised or damaged, allow healthy mol- of the Na-K Pump and cellular hydration.
ecules to leave the cell and unwanted materials to enter.
This can be referred to as “leaky cell membranes. 11.4.1.2  The Membrane Barriers: Organelle,
55 Phospholipids, fatty acids, cholesterol, and proteins Cell, Tissue, and Organs
when in balance facilitate repair and maintenance of cell All membrane barriers contain the basic bimolecular bilayer
membranes. membrane structure. That basic structure is found in every
55 Sodium-potassium pump (see . Fig. 11.3).   type of cell, organelle, tissue, or organ function, with only
55 Intracellular cytosol 97% potassium controlled by the slight variation. Examples are that neuron cells have a higher
sodium-potassium pump (. Fig. 11.3).
  percentage of phospholipids than liver cells and heart and
muscle cells have a greater percentage than brown fat cells
11.4.1.1  Cellular Hydration (see 7 Chap. 12).
 

Among the many properties of the cells and organelles is The most important barriers to be considered when
hydration. Measurable aspects of cell hydration include total assessing body systems are:
body water, intracellular water, and extracellular water [2]. 55 Skin (see 7 Chap. 54)
 

These measurements are clinically available using bioelectric 55 Gastrointestinal barrier, with small intestine housing
impedance analysis (BIA) (see 7 Chap. 22). All metabolic
  about 70% of immune cells in the lymphoid tissues (see
characteristics apply to the balance of water between intra- 7 Chap. 24)
 

cellular and extracellular fluids [2, 9]. In healthy cells, there is 55 Blood–brain barrier (see 7 Chap. 12)
 

opposite composition of the intracellular potassium concen- 55 Respiratory-lung barrier, comprised of bronchi, bron-
tration versus the extracellular sodium managed by the chioles, and alveoli cells which together are responsible
sodium-potassium pump (Na-K pump) embedded in the cell for exchanging oxygen intake and carbon dioxide waste
membrane [9]. ATP production is the energy driving the exhalation (see 7 Chap. 52)
 

activity of the pump [2, 10].

Significant differences in the membrane structures of vari-
ous cells, besides phospholipid composition, are in the
55 Intracellular matrix (cytosol) is 97% potassium- presence and amount of cholesterol. Mitochondria have
controlled by the Na-K pump [9] almost no cholesterol embedded in their inner and
55 Extracellular matrix is 97% sodium-controlled by the outer membranes. In all other eukaryotic cells (complex
Na-K pump [9] cells with organelles), cholesterol is present and is impor-
55 Magnesium rate-limiting nutrient for the Na-K tant to the stability of the cell, the sorting of protein struc-
pump [10] tures [2], and guarding from toxic substances entering the
cell.
 158 D. Noland

During the twentieth century, cholesterol developed a 11.5  The Eicosanoid Cascade: Acute
bad reputation driven by the Ancel Keys’ research concern- and Chronic Tissue Inflammation
ing its relationship to cardiovascular disease. More recently, Management
the scientific community has challenged Keys’ research on
cholesterol and saturated fat [4]. The eicosanoid cascade is comprised of a complex group of
It is important to consider the beneficial role of choles- organic molecules with multiple metabolic functions. This
terol in the structure of the membrane. Cholesterol is a “lipid section will focus on eicosanoid functions and their influ-
of its own” [2]. Cholesterol is a sterol and is different from ence on the immune response to initiate and resolve
phospholipids. Cholesterol has a steroid ring structure and inflammation [1, 16]. The 20-carbon eicosanoids are
polar head group (-OH). As an amphipathic molecule pos- derived from the 18-carbon fatty acids omega-6 linolenic
sessing both lipophilic and hydrophilic properties, choles- acid (LA) and omega-3 alpha-linolenic acid (ALA) by
terol easily incorporates into lipid bilayers. Cholesterol has a catalytic action of two enzyme groups, desaturases and
“bulky and stiff tail and small head,” contributing a stabilizing elongases. The dietary amounts of omega-6 and omega-3
order to the cell membrane structure, making the membranes fatty acids affect this process of eicosanoid production.
“stiffer” but allowing the membrane permeability to function. The eicosanoid metabolites are signaling molecules that
Membrane permeability is an important issue of chronic dis- determine the function of many metabolic pathways. The
eases and that the membrane signaling, therefore cell metab- families of eicosanoids include prostaglandins, prostacy-
olism and viability, depends on the phospholipid, cholesterol, clins, thromboxanes, and leukotrienes [10]. Within each
and fatty acid composition [1, 12]. The permeability of the family, there are many metabolites, including recently dis-
organelle and cell membranes requires a balance that is not covered specialized pro-resolving mediators (SPM),
too rigid and not excess (leaky membrane). Membrane per- involved in resolving inflammation [1, 6, 17]. Eicosanoid
meability is affected by several factors like age, dietary his- families may either produce or reduce inflammation
tory, activity level, and hydration. A practical assessment of depending on which molecules are produced by the
cell membrane permeability is the measurement of the phase immune response signaling. Eicosanoids also help regu-
angle (PA), a quantitative measurement available using the
11 bioelectric impedance analysis (BIA) technology (see 7 Chap.
late blood pressure, modulate the immune system, and
 
affect blood clotting [7].
22). The PA is used as a marker of cell membrane integrity The IFMNT practitioner applies their knowledge of the
and permeability. Although the biological significance of the eicosanoid cascade biochemistry and rate-limiting nutri-
PA is not fully understood, many studies have recognized ent cofactors and lifestyle habits that affect elongation and
that low PA values are associated with a poor prognosis and desaturase enzyme functions. With skill in managing
as a prognostic indicator for some cancers [11, 13, 14]. The chronic inflammation, one can target nutritional interven-
BIA instruments have been used in research and clinical tions to restore optimum balance of the eicosanoid metab-
practice for over 30 years and are easy to operate in a clinical olites derived from the essential fatty acids, linoleic acid
setting and relatively inexpensive. This BIA data when added (LA C18:2 ω 6), and alpha-linolenic acid (ALA C18:3 ω3)
to the information from a red blood cell (RBC) fatty acid (see . Fig.  11.4). To assess an individual’s eicosanoid and
 

analysis, blood lipid panel, and disease condition gives some metabolite status, obtain functional lab testing and a diet
indication of cell membrane permeability. history to assess the patient’s fatty acid status and metabo-
Cholesterol is essential to life by providing the base unit lites affecting inflammation. The initial assessment best
for production of hormones, neurological cells (neurons, includes an RBC fatty acid profile, blood lipid panel, and
myelin, brain tissue, etc.), bile, and others. As with all natural dietary history of fat and oil rich foods (see 7 Chap. 58 on
 

components of the chemical body, each cholesterol molecule Fats and Oils Survey). From this data, one can assess fatty
has multiple functions. Each function depends on the bal- acid status and recommend changes to support inflamma-
ance of the amount of cholesterol deposited in the cell mem- tion control.
branes. This balance is foundational to optimized cell function The two arms of the eicosanoid cascade share the desatu-
and may be related to compromised metabolism when cho- rase and elongation enzymes and compete for their use, with
lesterol is too low (studies suggest hypocholesterolemia is preference toward omega-3 metabolites [18]. Each of the
total cholesterol <120–150  mg/dL). On the low-end of the omega-3 and omega-6 metabolite families influence each
spectrum, hypocholesterolemia is associated with increased other and cannot be converted from one family to the other
incidence of mood disorders like depression, as well as can- due to lack of the required enzymes in the human metabo-
cer, and sepsis [15]. During a nutritional assessment, bio- lism. Even though the LA and ALA are the two essential
markers for cholesterol status are important to quantify and fatty acids, their important metabolites like γ-linolenic acid
should consider any medications that influence cholesterol (GLA), di-homo-γ-linolenic acid (DGLA), arachidonic acid
synthesis. The IFMNT practitioner should be skilled at restor- (AA) in the omega-6 family, and EPA and DHA in the
ing cholesterol balance and managing hypercholesterolemia omega-3 family can be obtained from some foods rich in the
along with helping manage clinical symptoms. converted forms. For example, for a person who did not eat
Lipidomics: Clinical Application
159 11

Eicosanoids
Omega-3 family pg = prostaglandin tx = thromboxane Omega-6 family
pgi = prostacyclin It = leukotriene
α-linolenic acid = less inflammatory Linoleic acid Corn, soybean,
Flax, soybeen, = more inflammatory
18:3 ω-3 18:2 ω-6 sunflower, safflower
canola, walnut
∆6 desaturase
Vitamin B3, B6, C, Mg, Zn, Insulin
Hemp, algae, Stearidonic acid γ-linolenic acid Evening primrose Oil,
GMO-soy oil, 18:4 ω-3 GLA 18:3 ω-6 borage oil

elongase
Vitamin C and B3
Eicosatetraenoic acid pge1 pgf1α Dihomo γ-linolenic acid
20:4 ω-3 txa1 DGLA 20:3 ω-6
blocks It4
∆5 desaturase
Vitamin B3, C, Zn
pgd3 pge3 pgf3α pgd2 pge2 pgf2α
Fish, Krill, Eicosapentaenoic acid pgi3 txa3 pgi2 txa2 Ita4 Itb4 Arachidonic acid Meat, eggs,
main
seaweed EPA 20:5 ω-3 Ita5 ltb5 Itc5 ltd5 Itc4 ltd4 Ite4 AA 20:4 ω-6 dairy

Sprecher’s elongase
shunt Vitamin C and B3
Docosapentaenoic acid Docosatetraenoic acid
DPA 22:5 ω-3 22:4 ω-6
∆4 desaturase

Fish, Krill,
algae Docosahexaenoic acid Docosapentaenoic acid
DHA 20:6 ω-3 22:5 ω-6

..      Fig. 11.4  The Eicosanoid Cascade of essential fatty acids, their metabolites, the nutrient cofactors, and foods rich in those cofactors. (Adapted
with permission from: 7 https://commons.­wikimedia.­org/wiki/File:EFA_to_Eicosanoids.­svg)
 

any ALA sources like walnuts, flax oil, or vegetables, ade- 11.5.2  Fatty Acid Desaturation
quate EPA, and DHA could be provided by eating fish (EPA, (See . Fig. 11.4)
 

DHA) or algae (DHA) sources. Another direct source of

EPA, DHA, and LA is grass-fed or pasture-fed beef. If a per- Desaturase enzymes delta-6-desaturase (D6D) and delta-­5-­
son is depleted in the nutrient cofactors for the elongation desaturase (D5D) control the conversion of the essential fatty
and desaturase conversion biochemical steps, it would limit acids LA and ALA and eicosanoid metabolites. The key
the efficiency of those enzymes. Repletion of those nutrient nutrient cofactors for the D6D and D5D are vitamins B3
co-factors can increase the efficiency of the conversion (niacin), B6 (pyridoxyl-5-phosphate), C (ascorbate), and the
enzymes. minerals magnesium and zinc.

11.5.2.1  Delta-6-desaturase (D6D)

11.5.1  Fatty Acid Elongation (See .   Fig. 11.4) Interactions between dietary LA, D6D, and insulin resistance
from the modern Western diet are associated with increased
Elongation chemistry is dependent on the rate-limiting activity of the D6D enzymes, which result in the increased
nutrients vitamin C and vitamin B3 (niacin). Any insuffi- conversion of LA to excess pro-inflammatory AA [20, 21].
ciency or deficiency of those nutrients can significantly ham- Alcohol and smoking can both suppress D6D activity, and
per achieving the balance of the eicosanoid metabolites. This those individuals may have poor conversion of LA to DGLA
balance is foundational to optimized cell function [19]. and AA. The GLA conversion to DGLA is a pivotal occur-
rence because the DGLA has two options for continued pro-
11.5.1.1  Elongase duction of either the prostaglandin 1 series of metabolites or
The elongation of long chain fatty acids is derived from the AA and the proinflammatory prostaglandin 2 series. The
omega-3 and omega-6 essential fats into very long chain fatty D6D and D5D enzymes determine how much the omega-6
acids (VLCFA). The rate-limiting nutrient cofactors are zinc, metabolites proceed in either direction. If D6D is inhibited,
magnesium, and vitamin B6. The elongation of very long not as much DGLA is produced. If DGLA is produced and
(ELOVL) fatty acid by elongase enzymes is influenced by D5D is increased in activity, DGLA will increase production
insulin and high carbohydrate diets [10]. It is important to of AA and lessen the ability to form the anti-inflammatory
assess glucose-insulin management when assessing of lipid PG1 metabolites. For those who smoke and/or drink signifi-
status. cant alcohol, the use of evening primrose or other GLA-rich
 160 D. Noland

oil can support increasing DGLA conversion toward anti-­

inflammatory prostaglandin 1 metabolites and bypass the Linoleic acid COX: cyclooxygenase
Diet LO: leukotrienes
poor activity of D6D [6]. The D6D is encoded by the fatty (LA, 18:2n6)
PG: prostaglandins
acid desaturase (FADS2) gene and its function is rate-­limiting D6D
in polyunsaturated fatty acid biosynthesis [22].
γ-Linoleic acid
(GLA, 18:3n6)
11.5.2.2  Delta 5-desaturase (D5D) Anti-inflammatory
Elongase
D5D activity is responsible for the conversion of omega-6
COX 1 series of PG
DGLA to pro-inflammatory excess AA. Elevated glucose, insu- Dihomo-GLA
(DGLA, 20:3n6) 15-LOX 15-OH-DGLA
lin metabolism, and obesity promote D5D activity, increasing
AA formation and pro-inflammatory conditions. Dyslipidemia D5D
D5D Inhibition
and the use of prescription medications (statins) are usually (compound-326) Arachidonic acid COX 2 series of PG
involved with increased D5D activity [3, 23]. Because of the (AA, 20:4n6) 4-series of LT
5-LOX
epidemic of sarcopenic obesity and obesity overall, awareness
of interventions such as supplemental GLA-rich sources can Pro-inflammatory
direct the omega-6 DGLA to its alternative anti-inflammatory
pathway to prostaglandin 1 series metabolites and contribute ..      Fig. 11.5  Biosynthesis pathway of n-6 polyunsaturated fatty acids.
to decreasing insulin resistance [23]. D5D is also involved in D5D is a key enzyme affected by glucose, insulin, and stress status
gonadal hormone metabolism. An example is when estrogen- of metabolism and can be mediated by diet and lifestyle choices.
dominant conditions develop, the D5D is more activated. This (Reprinted from Yashiro et al. [24]. With permission from Creative Com-
may increase conversion of DGLA to AA instead of a balanced mons License 4.0: 7 https://creativecommons.­org/licenses/by/4.­0/)
 

conversion to the PGE1 anti-inflammatory molecules. Weight

reduction to ideal body weight and weight maintenance can tissues, and can vary based on the nutrigenomic profile of an
improve the healthy function of D5D [24]. individual for the FADS1 and FADS2 genes (See 7 Chap. 17).  

It is important to remember that the omega-6 and omega-3

11 fatty acids cascades compete for the desaturase and elongase
enzyme activities, so inhibiting the omega-6 DGLA to AA con- The functional role of eicosanoids in the inflammatory
version will also affect the D5D activity that converts omega-3 etiology of diseases of metabolic syndrome (MetS) has
ALA to EPA and then DHA. When inhibiting D5D, there may been extensively studied in relation to immune cell
be an increased need for dietary intake of EPA and DHA by recruitment and cytokine, chemokine production and
eating fish and/or fish oil supplementation. D5D enzyme activ- their activation of inflammatory pathways in cancer,
ity is a target of research for diabetes management. D5D inhib- diabetes, and cardiovascular disease (CVD) [11, 26].
itors are currently a target of the pharmaceutical industry [24].
The potential of nutrition therapy to optimize fatty acid status,
reduce simple carbohydrate intake, and achieve weight man- 11.7  Tools of the Trade for Lipid Therapy
agement can be powerful modulators of these enzymes.
More comprehensive lipid blood tests have recently become The toolbox for the IFMNT practitioner considering lipid ther-
clinically available that can improve assessment of a patient’s sta- apy assessments and interventions includes all clinical and
tus. The arachidonic/di-homo-gamma-linolenic acid ratio (AA/ measureable parameters and modalities that influence lipid
DGLA ratio) is a meaningful biomarker for assessing balance metabolism or are influenced by food intake, lifestyle, and/or
between AA and DGLA concentrations that affect the inflam- environment. The following checklists and principles of gather-
mation process and the function of D5D [25] (See . Fig. 11.5).
  ing lipid data suggest laboratory testing and other clinical infor-
mation to contribute to a comprehensive assessment, diagnosis,
and intervention to promote the best outcome for an individual.
11.6  Metabolic Stressors Toolbox to identify fatty acid/nutrition status
55 Nutrition Physical Exam (see 7 Chap. 40)  

Systems biology emphasizes the interactions of all systems to 55 Medical history: diagnoses, medical event history, resi-
influence the phenotype of an organism. New stressors have dential location
arisen in the past century from environmental toxicants, 55 Signs and symptoms: Medical Symptoms Questionnaire
decreased physical activity, highly refined foods, increased (MSQ)
carbohydrate intake, and increased occurrence of metabolic 55 Laboratory testing: basic nutrition, lipids, disease-spe-
syndrome to enable dramatic changes in phenotype due to cific and sometimes patient-specific markers
chronic disease. Some of these stressors are known to influ- 55 Bioelectrical Impedance Analysis (BIA), if available
ence the activity of the elongases and delta-5 and delta-6-­
desaturases, resulting in altered eicosanoid metabolism. The nutrients in . Table 11.2 are the most studied regarding
 

Obesity is one metabolic condition that is associated with lipid metabolism and should be considered as part of a nutri-
disturbed lipid metabolism and low-grade inflammation in tional assessment.
Lipidomics: Clinical Application
161 11

..      Table 11.2  Key lipid nutrient insufficiencies/deficiencies associated with subclinical or acute disease; key immune nutrients founda-
tional for healthy lipid status

Nutrient Clinical or biochemical Reference Symptoms Testing to consider

implication of deficiency

Immune modulators

Omega-6 GLA Eczema, [6] Broken skin lesions RBC fatty acid
Dermatitis Rash, diabetes Gamma linolenic (GLA)
GERD Long-term effects of di-homo-gamma linolenic
Viral infections chronic disease acid

Eicosapentaenoic acid (EPA, Altered mood [27] RBC fatty acid

EPA, DHA, LA, ALA) Skin health
Cardiovascular
Cancer

Malonaldehyde Cancer [6] RBC fatty acid

Altered fatty acid
Metabolism

Choline Poor membrane permeability [28, 29] Neurological Homocysteine

phosphatidylcholine Impaired fat metabolism Fat malabsorption Creatine kinase
phosphatidylethanolamine Fatty liver Muscle damage Liver enzyme ALT
phosphatidylinositol Mitochondrial dysfunction Lipid panel
Released alanine aminotransfer- Folate, RBC folate
ase (ALT) from liver cells

Vitamin D Immune modulator [30–32] Mood disorders Vitamin D25OH

Bone loss Vitamin D 1,25OH
Joint pain Parathyroid hormone (PTH)
Compromised Ionized calcium
immunity

Vitamin A retinol Mucosal immunity [33, 34] Mucosal bacterial/ Vitamin A, retinol
viral infections Β-carotene

Eicosanoids Anti-inflammatory [35–37] Pain RBC fatty acid

Pro-inflammatory Swelling
Immune regulation Cancer
Resolution biology

Rate-limiting co-factors

Folate NK cell activity [38] Fatigue Folate, serum

Cytotoxic cellular immunity Infection RBC folate
Modulate T-cell responses Mood disorder FIGLU

Zinc Regulates intracellular signaling [38–40] Skin conditions Zinc, serum

pathways in innate and adaptive Poor smell RBC zinc
immune cells Poor taste
Frequent illness
Nail spots

Magnesium >300 enzymes cofactor [10] NHANES Magnesium, serum

Urine excretion under stress ~80% US population RBC magnesium
Muscle tension less than RDA
Camps magnesium

Antioxidants

Vitamin C Regulates cellular humoral [41] Connective Vitamin C, blood CPT 82180
immune function  tissue Urine, functional need for
Increases macrophage  impairment vitamin C test: urine
Antihistamine Skin conditions p-hydroxyphenyllactate
Requirements increase during Poor wound healing (HPLA)
infection
Anti-viral
(continued)
 162 D. Noland

..      Table 11.2 (continued)

Nutrient Clinical or biochemical Reference Symptoms Testing to consider

implication of deficiency

Vitamin E 4 tocopherols + 4 tocotrienols [30, 42] Oxidative stress Serum:

protective from oxidative stress/ Premature wrinkles Alpha-tocopherol
lipid peroxides Cysts gamma-tocopherol
Leg cramps

Selenium Thyroid peroxidase metabolism [38] Hypothyroid Selenium, serum

with vitamin E Low glutathione RBC selenium
Selenoproteins special effects on blood levels
cellular immunity Impaired detoxifica-
Resistance to viral infections tion
Central to glutathione peroxidase
structure

GUT secretions

Short-chain fatty acids Intestinal cells [43–48] Inflammation Acetate

(SCFA) Anti-inflammatory Perturbed uric acid Propionate (blood or fecal)
Microbiome-gut- brain axis via cycle Butyrate (blood or fecal)
immune system/vagal nerve Colon disease
Mucosal immunity

Bile acids Fat malabsorption [49, 50] Perturbed fat Bile acids
Metabolic liver diseases digestion US imaging gallbladder
Glyco and Taurochenodeoxycho-
lic Acid
11 Lipotoxic Conditions

Dysfunctional regulation of Neurological [51, 52] Diagnosis specific Diagnosis specific

lipid metabolism and Cancer
homeostasis causes cellular Autoimmune
lipotoxicity, impairs cellular Developmental
processes and contributes Cardiovascular
to the pathogenesis of Psychological
disorders such as obesity,
atherosclerosis, and
neurodegeneration

Anti-Nutrients

Endocrine-disruptors Circadian rhythm disruption that [53, 54] Hormonal imbalance GPL-TOX,
can modulate immune function Insomnia Great Plains Lab toxic organic
Cancer chemical profile

Damaged food components/ Most damaged or toxic substance [55] Chronic disease Diet History
Western Diet & food Lipophilic and embed into the Specific toxic RBC fatty acid analysis
preparation fatty membrane and other tissues symptoms
Trans fat Damaged high-heat foods Weakened immune
Oxidized fat Chemicals integrity
Toxic metals Toxic metals
Toxic chemicals ingested in foods and from food
“new to nature molecules” utensils during food preparation
(cookware, pest control,
pollutants, processed, etc.)

Environmental Toxins

Mold/mycotoxins Neuropsychiatric [56, 57] Toxicities Mold, pathogenic bacteria:

Natural gas carcinogenic Immune disruption [58] Chronic kidney failure Multiple Antibiotic Resistant
Chemical vapors Vulnerable to poor cell signaling [59] Infertility Coagulase Negative
Pesticides Insulin resistance Cancer Staphylococcus
Developmental (MARCoNS) nasal swab
Frequent infections GPL-TOX,
Great Plains Lab toxic organic
chemical profile (pesticides,
toxic chemicals)
Lipidomics: Clinical Application
163 11
11.7.1  Laboratory Principles Vitamin A (Retinol) [61]
Vitamin A is a nutrient cofactor for the eicosanoid desaturase
With laboratory data available, a diagnostic profile can clarify enzymes. It is increasingly recognized in experimental and
the priorities of core physiological imbalances and provide human studies to enable suppression of inflammatory reac-
clues regarding nutrition and lifestyle therapy to restore tions and plays a significant role in normal mucosal immu-
structure and dynamic function of the membrane. From the nity, regulation of T cell-dependent responses, antiviral
IFMNT nutrition assessment, consideration of the two most activity, and cell communication.
likely physiological clinical imbalances is structural integrity Adequate vitamin A status, whether from intake of pre-
and defense & repair (see . Fig. 11.3).
  formed retinol (e.g., animal sources: egg yolk, organ meats,
fish, shellfish, and roe) or from b-carotene (e.g., yellow and
green vegetables) is important for preventing excessive or
11.7.2  Structural Integrity prolonged inflammatory reactions and supporting the eico-
sanoid cascade [61].
The membrane’s structural integrity affects the transport and
communication of the cell membrane and receptors. If there Gut microbiome [55]
is a history of head, neck, dentition, or back injury where Gut commensal bacteria making up the microbiota are criti-
there may be a possible structural misalignment in the cervi- cal for the health of the immune system by defending and
cal vertebrae, the brainstem and vagal nerve may be impaired. repairing the intestinal barrier where >70% of the immune
Someone with this history should be referred to a cranial cells reside. Stool testing provides biomarkers to assess GI
specialist for evaluation and have their lipid status reviewed. ecology. From this data one can develop an intervention plan
to correct and repair imbalances in the gut microbiome (see
11.7.2.1  Assessment Checklist for Structural 7 Chap. 24).
 

Integrity
55 Cell membrane permeability and integrity (BIA phase Inflammatory Load Assessment
angle, fatty acid status) [11] 55 High-sensitivity C-reactive protein (hs-CRP): acute-­
55 Dental periodontitis: infection of the tissues that sur- phase-­reactant and marker of systemic inflammation.
round the teeth-inflammation It is often elevated due to bacterial infection, central
55 Structural-spinal alignment: neuronal membrane [1, 60] adiposity, fatty liver, neoplastic activity, or traumatic
55Cervical C1-C7 – brainstem & vagal assessment – injury. All clinical laboratory references include normal
check vagal tone hs-CRP as ≤1.0. Its elevation implies potential bacte-
55Thoracic T1-T5 – stenosis or injury increased pain rial infection or physical trauma. If no dental/oral
resulting in exaggerated immune inflammatory infection is identified, begin further investigation of
response the root cause. It is important to rule out a recent trau-
55Lumbar L1-L5 – stenosis or injury increased pain matic injury that may be related, and hs-CRP should
resulting in exaggerated immune inflammatory be retested in a month or two to observe if injury has
response affected the hs-CRP.
55 CBC with differential
55 Complete metabolic panel (CMP)
11.7.3  Defense and Repair 55 Lipid panel
55 Erythrocyte sedimentation rate (sed rate)
Defense and repair are managed by a dynamic immune sys- 55 TSH
tem that responds to endogenous and exogenous infection, 55 Bacterial/viral evaluation if indicated; saliva or blood
injury, malnutrition, altered gut microbiome, stress, and 55 Genomic testing (saliva), if available
other potential inflammatory triggers.

11.7.3.1  Assessment Checklist for Defense 11.8  Key Nutrient Cofactors and Foods

and Repair Influencing the Eicosanoid Metabolism
Blood Markers
Vitamin D 25-Hydroxy 11.8.1  Lipids
Vitamin D has many functions. It is a powerful immune
modulator that plays a role in defense and repair. Lipids play critical roles in membrane structure, cell signal-
ing, energy storage, control of inflammation, and as base
units for constructing messenger hormones [2]. Each mem-
Vitamin 25OH serum levels have been associated with ber of the family of lipids has specialized functions. Some
overseeing the dynamics of the cell membrane. Vitamin provide cell signaling, cellular component transporting and
D seems to stimulate anti-inflammatory processes [31]. regulate immune response of inflammation, hormonal mod-
ulation, and other undiscovered functions. When there is
 164 D. Noland

poor structure, dysfunction occurs [62]. The following key mon due to their rapid absorption and not requiring
nutrients below can be obtained from foods and/or dietary bile salts for digestion and can be an easily metabo-
supplements: lized source of energy.
55 Saturated Fatty Acids (SFAs)(C13-16) are made up of
11.8.1.1  Phospholipids (PL) carbon chains with only single bonds. The body can
Phosphatidylcholine (PC), phosphatidylethanolamine (PE), synthesize SFAs and they are also found in SFA-rich
phosphatidylinositol (PI), phosphatidylserine (PS). These foods such as animal meat fats like beef tallow, pork lard,
phospholipids are ubiquitous in all membrane structures and poultry fat, and also cocoa butter.
especially important for the functions of neurological and 55 “New-to-nature” Fats: with high heat and hydrogenation
mitochondrial membranes [6]. The body can synthesize processing of vegetable oils, aberrant fatty acids and lipid
them, and they can also be found in foods. Foods rich in structures can be formed that have been recognized as
phospholipids are animal meats and organs, egg yolk, and unhealthy for human metabolism, with some identified
legumes. as carcinogenic. Examples of these compounds are trans
fats and acrylamides.
11.8.1.2  Fatty Acids:
55 Omega 9 Monounsaturated fatty acids (MUFAs): These
oils are stabilizing components of structures and also 11.8.2  Sterols
have an anti-inflammatory effect in metabolism. Foods
rich in MUFAs are olive oil, avocado/avocado oil, Sterols are naturally occurring unsaturated steroid alcohols,
almonds, sesame, and peanuts. They are mildly heat sen- waxy lipids. The primary sterol for human metabolism is
sitive and best raw or used with low heat. cholesterol, which is the base unit for all hormone produc-
55 Omega 6 Linoleic Acid (LA) (essential) and the eico- tion and vitamin D. Cholesterol is also an important compo-
sanoid metabolites GLA, DGLA and AA. LA is rich in nent of cell membrane structure [2]. Most endogenous
seeds, some nuts, greens, grains and grasses. cholesterol is synthesized by the liver, but dietary cholesterol
55 Omega 3 Alpha Linolenic Acid (ALA) (essential) and can influence total cholesterol levels. Foods rich in choles-
11 the eicosanoid metabolites EPA, DPA, DHA recognized terol are of animal origin: fats from animal milk, meat, egg
for their anti-inflammatory effects on metabolism. The yolk, poultry, seafood, and organ meats.
balance between omega 6 and omega 3 fatty acids is
important with most fatty acid scientists proposing an
optimum ω6:ω3 ratio range of 1:1 to 5:1. 11.8.3  Minerals
55 Saturated fatty acids have been blamed as being detri-
mental for humans. But better understanding that there 11.8.3.1  Zinc
are beneficial saturated fatty acids when maintained at Zinc is a nutrient cofactor for the desaturase and elongase
about 10% of dietary fat [63]. Natural and beneficial enzymes and a nutrient partner with copper. Zinc and cop-
forms of the saturated fats are: per should always be balanced in body fluids (see 7 Chap. 8).
 

55Short chain fatty acids (SCFA) with many critical roles When copper is elevated, it promotes increased fat deposi-
of anti-inflammatory and fuel for colonocytes. Many tion in some organs like the liver. Increased zinc intake can
health benefits are recognized reducing risk of colon modulate the copper to a healthy level and reduce the fat
cancer, autoimmunity, and gastrointestinal disease. deposition [65].
1. Acetate (C2) and Proprionate (C3) SCFAs are
formed in a healthy gut. 11.8.3.2  Magnesium
2. Butyric Acid: butyrate: C4: butyrate-rich sources Magnesium functions as a nutrient cofactor for both the
are butter, mother’s milk, healthy gut microbiome desaturase and elongase enzymes for eicosanoid conversions.
consuming resistant and soluble vegetable and When it is insufficient or deficient, restrictions in function
fruit fibers to produce SCFAs, and sodium or can occur. In the case of magnesium as a cofactor in the
calcium-­magnesium butyrate dietary supple- sodium-potassium pump, the rate of conversion is decreased
ments. If there are infectious or antibiotic insults during a deficiency of magnesium. Magnesium is the cofac-
to the gut microbiome, the production of butyrate tor catalyzing the enzymes driving the sodium-potassium
may be notably reduced [64]. pump, moving substances in and out of the cell through the
55Medium chain triglycerides (MCTs) are composed of lipid membrane [9, 66, 67] (see 7 Chap. 17).
 

a glycerol backbone with three medium-chain fatty

acids (MCFAs) (C6-C12). The MCTs are beneficial as
part of dietary intake. They are heat resistant and rec- 11.8.4  Methyl Nutrients
ommended as cooking oil. Rich sources are coconut
oil, palm kernel oil, and ruminant animal milk (cow, Vitamins B6, B12 (-cobalamins), B9 (Folate), B2 (riboflavin), B3
sheep, goat, horse). Therapeutic use of MCTs for liver (niacin), choline (betaine, phosphatidylcholine/phosphatidyl-
failure and other gastrointestinal conditions is com- ethanolamine), SAMe, and related Vitamin C, B1, B5 [68, 69].
Lipidomics: Clinical Application
165 11
11.8.5  Phytonutrients: Protective Support
for Lipid Structures

55 Inflammation: Phytonutrients are antioxidants that protect

the lipid membrane from oxidative stress through their
powerful polyphenols found in a variety of pigment-­rich
fruits, vegetables, grains, nuts, teas, herbal spices, and
legumes that have anti-inflammatory properties. The mech-
anisms of the plant chemicals include antioxidants, anti-
..      Fig. 11.6  Homocysteine major metabolic pathways in humans.
(Adapted from Dudman et al. [70]. With permission from Oxford Univer- bacterial, and antiviral. Even though phytonutrients are not
sity Press) considered essential nutrients, the evidence is mounting for
their critical role in health maintenance and anti-aging.
55 Biomarkers of poor phytonutrient status: Poor dietary
Methyl nutrients support the process of methylation, intake of high polyphenol foods. Significant biomarkers
having many roles within human metabolism with DNA for inflammation can be related to poor vegetable and
methylation being the underlying mechanism, and they cur- fruit intake and lack of (or imbalance in) dietary intake
rently appear to be primary messengers of epigenetic expres- of healthy fats and oils (see 7 Chap. 58 Fats & Oils Sur-
 

sion (see 7 Chap. 18) identified in the etiology of developing

 
vey)(. Table 11.2)
 

cardiovascular, cancer, and neurological disease conditions. 55 Resource: The Rainbow Diet. Color Can Heal Your Life [73].
Methyl nutrients are involved in the conversion of desaturase
and elongase enzymes. Methylation involves biochemical
pathways where the B vitamins and other cofactors like 11.9  Key Lifestyle Factors Influencing
amino acids are rate-limiting cofactors [70] (. Fig. 11.6).
 
the Risk of Lipid Damage

11.8.4.1  B12 and Folate Metabolism 11.9.1  Sleep [74] (See 7   Chap. 35)
B12 in the natural bioactive forms (methyl-, hydroxy-, or
Sleep and circadian rhythm have a great influence on the
adenosylcobalamin) is a nutrient cofactor that inhibits the
integrity of the immune system. Much evidence has accumu-
excessive formation of arachidonic acid. B vitamins team
lated over the past decades associating poor sleep quantity
together, and folate is an especially important teammate with
and quality with weakening of the immune system, increas-
B12. Folate is critical to many metabolic pathways like nucleic
ing vulnerability to the poor function of cellular structures.
acid precursors, several amino acids, and erythropoiesis,
which is the process in which new erythrocytes are produced.
A biomarker that can suggest folate deficiency is an elevated
11.9.2  Stress (See 7 Chap. 47)
mean corpuscular volume (MCV) on a complete blood count
 

quantitatively measuring size of RBCs. Folate deficiency can

Chronic stress impacts every biological and psychological
be part of the etiology of enlarged RBC or megaloblastic ane-
system. When the chemical microenvironment is under
mia, from ineffective erythropoiesis. Additionally, Vitamins
long-term stress, it pushes the immune system response into
B6 and B12 are cofactors involved in erythropoiesis [71].
chronic inflammation and increased acidity. The vicious
cycle continues until the threshold of resilience and adapta-
11.8.4.2  Niacin, Vitamin A, Vitamin C, and Zinc
tion is exceeded, leading to vulnerability to many chronic
55 Rate-limiting nutrients for DGLA conversion to anti-­ diseases including damage to lipid structures and influencing
inflammatory Prostaglandin 1 (PG1) series the eicosanoid metabolism.
55 PG1 anti-inflammatory action primarily involved in
mediating conditions of allergy, viral, autoimmune
11.9.3  Movement (See 7   Chaps. 36 and 54)
11.8.4.3  Vitamin D, A [72]
These fat-soluble vitamins have many metabolic roles. Their As with all biological systems, there must be movement of
influence on structural integrity and defense and repair (e.g., structures like muscles, heart, lungs (breathing), as well as
inflammation and immune response) modulates the lipid the fluids in the body to maintain health. Without move-
environment and metabolic dynamics. The fat-soluble vita- ment, there is congestion that does not support healthy
mins function synergistically, with the vitamin D and A metabolism. The health of the immune system is dependent
receptors sharing their nuclear receptor, influencing each on the lymphatic system, which is supported by movement.
other. Vitamin D2/3 and A are found in their food-rich The lymphatic circulatory system does not have a pump as
sources together (e.g., liver, caviar, /roe, egg yolk). Vitamin A compared with cardiovascular circulation. The lymphatic
retinol is one of the key nutrient cofactors for the desaturase vessels are “pumped” by physical activity with arm and leg
enzyme activity. movement, abdominal breathing, laughing, etc.
 166 D. Noland

11.10  Chronic Disease and Impaired Lipid

..      Table 11.3  Laboratory: recommended biomarkers for lipid
Metabolism (See Tables . 11.3  
assessment
and 11.4)
Blood tissue testing [75]
11.10.1  Heart Disease/Cardiovascular Lipid panel
Association with the Lipidome
  Total cholesterol, HDL, LDL, triglycerides, lipoprotein particles [1]

Lipids manage and resolve inflammation via the eicosanoid RBC fatty acid analysis
cascade. Chronic inflammation is a hallmark of cardiovascu-   Blood biopsy
lar disease, so if it is well controlled and resolved, the risk of
   ietary fat intake reflected in RBC fatty acid membrane
D
a cardiovascular event is decreased. The current recommen- composition [76, 77]
dation for eating fish or fish oil supplementation to benefit
the cardiovascular system is primarily as a modulator of the Bioelectric impedance analysis (BIA) [11]
eicosanoids to lower the pro-inflammatory excess omega 6   Phase angle: cell membrane permeability of the lipid bilayer
arachidonic acid [78].   Capacitance: ionic potential, membrane surface biomarker

  Intracellular and total body water

11.10.2  Oncology Organic acids [75]
  Urine: first morning collection, fasting
Several of the eicosanoid metabolites are evidenced to be
tumor suppressive [79]. Eicosanoids, including prostaglan-    iew of all major systems (conventional and functional tests as
V
indicated)
dins and leukotrienes, are biologically active lipids that have
been associated with many of the pathologies of chronic dis- Inflammatory load
ease such as inflammatory cancer. Eicosanoid metabolites    linical observation of any inflammation of the face, skin, pain,
C
11 and their function of inflammation control give the IFMNT biomarkers?
practitioner the ability to develop a targeted intervention for
  Laboratory
cancer by assessing the patient fatty acid status and analyzing
the eicosanoid metabolism status [80].     CBC with differential
Prostaglandins and leukotrienes can modulate tumor     Sed rate
epithelial cell proliferation and apoptosis.
    C-reactive protein-high sensitivity
When the prostaglandin 1, 2, and 3 series are in balance,
they can provide a change in the microenvironment toward     Acute phase reactants per diagnosis or signs & symptoms
wellness [81]. Nutrition physical exam: Barriers; rule out potential symptoms or history

  Skin: tone, color, texture, lesions, skin tags, abnormal pigmentation

11.10.3  Neurological   Lung capacity/O2 Sat: optimum 98–100%; history lung disease
or surgery
11.10.3.1  Mitochondrial Dysfunction    astrointestinal health: Comprehensive Digestive Stool Analysis
G
Most neurological conditions involve underlying mitochon- (CDSA) abnormalities
drial dysfunction. The mitochondrial inner and outer mem-    ral cavity: periodontal disease, swollen glands, tonsillectomy
O
branes are sensitive to influences from dietary fat. The inner history
membrane especially requires the phospholipid derived from   E sophagus: symptoms of esophageal pain/irritation, dyspha-
choline, phosphatidylethanolamine (PE), and gamma-­ gia, Heliobacter pylori
linolenic acid (GLA). Lipid nutrition therapy can use seed
  Stomach: pain, digestive upset, surgical history, vagal tone
oils like evening primrose, black currant, sea buckthorn, or
borage to provide adequate GLA in interventions to support    uodenum: structural changes, Small Intestinal Bacterial
D
mitochondrial repair. Evening primrose oil has also been Overgrowth (SIBO)
shown to induce apoptosis and tumor suppression for cancer   Jejunum: structural changes
patients [82].   Ileum: structural changes, abnormal BM/bile circulation reentry

11.10.3.2  Alzheimer’s Disease   Colon: abnormal BM

The brain is approximately 70% fat and phospholipids.   Rectum: abnormal BM, hx colonoscopy
Restoring optimum lipid balance can benefit the structure   Pain: location, barrier involved
and function of the nervous system. Comprehensive medical
nutrition therapy supports high-fat diets in Alzheimer’s and Fatigue
other neurological conditions. The brain can use glucose or   Time of day, meal timing, sleep quality and quantity, sleep apnea
ketones for fuel. Research on the ketogenic diet, where
Lipidomics: Clinical Application
167 11

..      Table 11.4  Lipid-supportive foods, herbs, and dietary ..      Table 11.4 (continued)

supplements
    Co-nutrients
Foods
 Vitamin
     C (contraindicated for hemochromatosis mutation
   hole-foods, pesticide-free, vegetables and fruits in a variety
W genetics)
of colors, adequate protein, healthy fats & oils, herbs, fluids;
 Adequate
     methyl nutrients: B6, folate, B12, choline (betaine)
Minimize or avoid processed and high-sugar foods and
and related B1, B2, B3, B5, Biotin, Vitamin D3, vitamin A (if
beverages; avoidance of antigenic foods.
indicated per personalized assessment)
Oil-/fat-rich foods
 Zinc:
     rate limiting nutrient to D5D, D6D, and elongase
   lant-based: avocado, raw seeds, olives, hearts of palm, nuts:
P enzyme
macadamia, pine nuts, almonds, Brazil nuts, coconut oil
 Magnesium:
     rate limiting nutrient to D5D, D6D, and
   nimal source: organ meats, meat, poultry, fish, shellfish,
A elongase enzymes
roe, krill
Personalize recommendations based on patient assessment
Herbs

  Turmeric/curcumin
ketones are produced from high-fat low-carb diets, inducing
   roteolytic enzymes: Bromelain, papain, trypsin, etc. (contrain-
P
dicated for Alpha-1-Antitrypsin deficiency+ genetics) a “nutritional ketosis”, has shown therapeutic benefit in neu-
rological conditions (see 7 Chap. 23) [83–85].
 

  Resveratrol

  Boswellia 11.10.3.3  Developmental Plasticity

Diet
Fetal and early childhood metabolic plasticity includes rapid
growth of cells requiring lipids. The rapidly maturing brain
  Macronutrient distribution and neurological system are high-fat cells that need lipids for
  Insulin-glucose management membrane structure, cell signaling, and development of the
immune system. Maternal health and nutrition status are
  Meal timing
important to secretion of fat-rich mother’s milk, which lays
  Intermittent fasting the foundation for fetal growth [86].
  Calorie restriction

Dietary supplements 11.10.4  Respiratory

  Lipids
The lung has a major protective barrier function in the body,
 Phospholipids: phosphatidylcholine/phosphatidylethanol-
   
and the lipid composition of the membrane is integral to
amine
modulating inflammation and promoting optimal function.
 GLA:
    evening primrose oil; black currant, sea buckthorn, and Assessing and prioritizing the structural integrity and inflam-
borage mation load using diet history, nutrition physical exam, and
    Arachidonic acid: grass-fed meats, poultry, egg yolk. testing for nutritional status provide the foundation for
developing a targeted intervention.
 EPA/DHA:
    various ratios are available; DHA vegan/algae; fish
(ideally, lower on food chain)

 ALA:
    cold nitrogen processed seed and nut oils flax oil and/or 11.10.5  Autoimmune
ALA-rich raw/soaked nuts, seeds, vegetables; sensitive to
heat, light and oxygen.
Autoimmunity is the loss of immune recognition of self and
    LA: cold nitrogen processed seed and nut oils: refrigerated; non-self with resulting self-damage. Ongoing research has
sensitive to heat, light and oxygen. identified genetic relationships that have susceptibility to the
 Butyrate:
    short chain fatty acid (SCFA); sodium-potassium development of autoimmune conditions (see 7 Chap. 49).  

butyrate, calcium-magnesium butyrate, sodium butyrate, Rx: Chronic inflammation is present in all autoimmune condi-
glycerol phenylbutyrate (Ravicti®), sodium phenylbutyrate tions with resulting oxidative stress and reactive oxygen spe-
(Buphenyl®)
cies that can damage lipid structures. Nutritional therapy
 MCT Oil:
    medium chain triglyceride; sources: coconut, palm considerations to reduce the chronic inflammation can be
and breast milk fats; MCT: Caproic acid (C6:0), caprylic acid reducing or eliminating identified antigenic foods and replete
(C8:0), capric acid (C10:0), lauric acid (C12:0)
nutrients that are insufficient or deficient.
 168 D. Noland

11.11  Case Reviews causes. The patient’s story begins with an investigation to
identify metabolic priorities and the focus of interventions
The following cases give examples of clinical application of using food, dietary supplements, and lifestyle to restore
lipid nutrition therapy. Each patient case presenting to an health. It is important to monitor interventions to assess
IFMNT practitioner needs to be approached as unique. effectiveness and determine if adjustments should be
Every diagnosis or symptom can have a multitude of root made.

Case Review: Simple Childhood Asthma

Diagnosis: Severe asthma 55 EPA 350 mg/DHA 250 mg/GLA 130 mg supplement daily

Male: age 8 55 Vit D3 4000 IU emulsified D3 daily
Medical History: 55 B Complex: bioactive forms – chewable
55 Asthma medications: Singular, albuterol inhaler, glucocorticoid 55 Probiotic 450 billion powder in 6 oz. coconut yogurt daily
inhaler- Budesonide and formoterol (Symbicort), salmeterol 55 Whole grain gluten-free bread for sandwiches, toast with
(Serevent). Fluticasone and salmeterol (Advair Diskus) organic butter
55 Asthma emergency hospital ER event monthly 55 Beverages: water, stevia-sweetened sodas, almond or coconut milk

Laboratory Significant: CBC WBC 3.8, MCV 99 HI, Vitamin D 12 ng/ Monitor: 6-Week Follow-up
mL; +grass and + casein IGE allergens 55 Happy affect, started 2 weeks able to take gym classes outside
Nutrition Physical: depressed affect; depapillation pale tongue 55 Nutrition: decreased probiotic; continued diet and remaining
(low B6, B12, Folate, B2 and iron), corner lips cracked skin (low B2), supplements
pale skin, matty hair
Diet and Supplement history: Eighty percent fast food (hamburg- Follow-up plan: 3 Months
ers, hot dogs, cold cereal, cow milk casein, soda, yogurt, ice cream, 55 Doctor removed four of the medications
toast, candy). No dietary supplementation. 55 No hospitalization for asthma event
Lifestyle: difficulty breathing, grass pollen allergy, no outside play
(reduced sun exposure); poor sleep related to breathing difficulty. Outcome
11 Metabolic Priorities and Intervention Plan
55 Remove antigen: cow’s milk
55 High school soccer team player, no asthma medications,
continued casein-milk free diet and avoid high sugar foods,
55 Remove empty calories: sugar, processed and refined foods, resumed gluten foods
damaged oils 55 Annual physical: recommend Vitamin D25OH and maintain
55 Gut ecology: diet associated with poor gut pre and probiotics 40–60 ng/mL using vitamin D3 supplements and safe sun
55 Get nutrients: exposure.

Case Review – Early-Onset Alzheimer’s

Patient Story: A 64-year-old male who presented with memory Nutrition Assessment
problems and diagnosis of early onset Alzheimer’s disease by 55 Intake: High sugar, processed foods and cured meats
neurologist. Two months previous he showed no interest in 55 Digestion & Assimilation & Elimination: RZ reports a 1/week
activities, could not work. He was a building contractor for 35 years. bowel movement
Medical History: Thyroid cancer, total thyroidectomy, and 55 Utilization: Cellular & Molecular Function:
Hemachromatosis recessive. 55 Minerals: Low magnesium, low-end blood electrolytes, BIA
Medical Data: Anthropometrics: BMI 30; height 76.2”; weight Capacitance 730 (goal ~ 1300)
250 lbs, 55 Antioxidants: Water Soluble: Vitamin C, Phytonutrients: severe
Dietary/Alimentation: High intake of soda (~2 quarts/day) and skin wrinkles-poor Vit C, vegetable/fruit intake
processed foods including gluten containing grains and starches; 55 Protein: Low-end protein status; albumin 3.9
some candy, doughnuts, fried foods, fast food, and canned fruit; 55 Vitamin D & Fat soluble vitamins: Low vitamin D (25 ng/mL)
commercial lunch meats. Low intake of water, essential fatty acids, 55 Oils/Fatty Acids: Low omega-3 and omega-6:GLA intake foods;
vegetables, and whole foods. cholesterol panel is OK
Nutrition Physical Exam: Memory deficits reported by wife and 55 Methylation: elevated Homocysteine implying poor methyla-
observed during exam, wrinkles beyond age appropriate (implies tion; low folate, B12, MCV 101 HI, MCH 33
high oxidative stress), talks very slow and only when asked a
question, poor dentition and dental hygiene, bleeding gums, very Plan: (Continued Early-Onset Alzheimer’s)
coated tongue with central crack. 1. Elimination Diet: Avoid sugars, soda-replace with tea or fresh
Medications: Thyroid, Finasteride, Terazosin for prostate lemonade; avoid cured meats, dairy, processed foods; eat more
enlargement, and a baby aspirin daily. whole foods, sea salt, salads and no nitrate, eat high-quality
Genotypic Risks: Family history of cancer (7 of 8 siblings and meats; increase water intake to 2 qts/day (previous intake
father); brother and uncle with Alzheimer’s; son Hemachromatosis none). GOAL: reduce sugar intake and antigenic foods; increase
(BB polymorphisms). phytonutrients, nutrient-dense-high-fiber food intake. Good
Biochemical Lab: Mildly reduced GFR, high BUN, low TSH (0.03)/ family support.
standard of care post thyroidectomy, PSA 1.19, high Homocysteine 2. Improve Methylation and Oils/Fatty Acids: Focused on
18. Low albumin 3.9, Total Protein 6.3, Globulin 2.3. neurological support;
Lipidomics: Clinical Application
169 11

Supplement with multivitamin, magnesium, EPA/DHA 1:1, Outcome: After implementation of herbal colon cleanse, magne-
GLA 370 mg QD, folate (5-MTHF 800 μg) QD, B12 (Methyl B12 sium and increased water intake, at 2 weeks bowel movements
1000 μg QD), D3 4000 IU QD; herbal laxative support increased to 1/day; Memory improved ~70% within 4 weeks. Great
until BM QD. family support. Client returned to work and driving at 6 months,
3. Adjunctive Physician-Supported Nutrition Support Using IV showing significant improvement. Continue diet, oral supplements.
Lipid Therapy: [phosphatidylcholine (PC) × 2 months, Follow-up monthly for 14 months then every 6 months while
Glutathione, phenylbutyrate, assessed methylation support] continuing oral phospholipid, methyl nutrients and very low sugar
twice a week for 8 weeks then start oral protocol of PC, nutrition program. Continues cognitive function as long as on
Glutathione and Butyrate, methylating nutrients (5-MTHF, B12) supplements after 7 years. Blood homocysteine 9, MCV 92, MCV
as needed) 30.5. Neurologist reversed Alzheimer diagnosis after 14 months.

Case Review: Complex Neurological Condition

Female AR, age 20 55 Specialty Lab: RBC Fatty acid analysis: Very low arachidonic
Weight 70 lb, 46 inches, BMI 15.7 Underweight acid, GLA, DGLA, Hi EPA, Hi DHA
Diagnosis 55 Specialty Lab: lymphocyte micronutrient analysis: LOW:
55 Cardiofaciocutaneous (CFC) syndrome (Q87.1 ICD10); Genes vitamin D, B12, A, carnitine, zinc, magnesium, choline
are: BRAF (~75%), MAP 2K1 and MAP 2K2 (~25%), and KRAS
(<2%). [Congenital malformation syndromes predominantly PLAN: Complex Neurological Condition
associated with short stature]; 23andme.com nutrigenomics: Three-Month Plan
homozygous MTHF +/+, heterozygous VDR −/+ 55 Retest previous abnormal tests
55 Monitor symptoms /behavior – report TF tolerance and any
The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic changes weekly
occurrence, with patients showing multiple congenital anomalies 55 Mother requested investigating possibility that AM and
and mental retardation. It is characterized by failure to thrive, mother were hypothyroid - mother exploring possibility AM
relative macrocephaly, a distinctive face with prominent forehead, was hypothyroid and infant screening was done day of birth
bitemporal constriction, absence of eyebrows, hypertelorism, negative, but protocol is to be tested day 3 after birth. Early
downward-slanting palpebral fissures often with epicanthic folds, screening may have missed hypothyroid condition.
depressed nasal root and a bulbous tip of the nose. The cutaneous
involvement consists of dry, hyperkeratotic, scaly skin, sparse and Three-Month Follow-up
curly hair, and cavernous hemangioma. Most patients have a 55 Review new lab. WNL: B12, serum, methylmalonic acid
congenital heart defect, most commonly pulmonic stenosis and ABNORMAL:, +ANA Titer, +++ EBV, Total + IgG/+IgE, carnitine
hypertrophic cardiomyopathy. 7 https://www.­cfcsyndrome.­org/
  panel: low,
fact-sheet 55 Seizures reduced 50–60% no hospital trips, reduced anti-
55 Epilepsy and recurrent seizures (G40 ICD10): ~200 seizures per seizure Rx
month w/ anti-seizure Rx; three severe seizure hospitalizations 55 Eye contact; no pain appearance touching during bathing.
per month.
55 Severe mental impairment (F79 ICD10) Nutrition Assessment Metabolic Priorities
55 Osteopenia (M85.80 ICD10) 55 B12 deficiency; specific for adenosylcobalamin B12 2000 μg/
day with L-5-MTHF (bioactive folate)
Medical History 55 Request doctor rule out subclinical infection with further viral/
55 Normal 9-month vaginal birth; 5 months developmental delay, bacterial panel
9 months diagnosed “failure to thrive”; started tube feeding; 55 Depleted vitamin/minerals: D, A, B12, -5-MTHF, carnitine,
residential care at home parents phosphatidylcholine/phosphatidylethanolamine, Linoleic Acid,
55 Diet History: Tube feeding Infant Formula until 3 years old; 55 Home tube feeding Lipid Liquid Meal recipe 2 quarts
3–20 years old received Boost™ tube feeding; weight 78–80 lb. 55 2 scoop vegan or beef protein powder
bedridden, Birth lab significant for hypercalcemia 10.9 HI 55 48 oz unsweetened almond or coconut milk; add water to
(<10). No PTH was ordered. Hypothyroid Day 1 screen WNL. achieve TF consistency
55 2 tsp Phosphotidylcholine/Phosphotidylethanolamine
Signs and Symptoms (mitochondrial support)
55 No eye contact 55 2 tsp evening primrose oil (GLA)
55 Appears pain when touching arms and hands during bathing 55 Multivitamin/mineral powder 2 scoop (bioactive B vitamin forms)
55 Tube feeding tolerated 55 Active B12 w (adenosylcobalamin B12) w/ L-5-MTHF 1000 μg 1
tab in TF
Lab History: Significant Findings 55 1–500 mg L-carnitine – open capsule into TF
55 Methylmalonic acid 861 very HI (B12 functional marker) 55 1 blanched egg yolk
55 B12, serum >2000 pg/mL 55 Blend and administer within 24 hours, refrigerate
55 Lipid Panel: Total Cholesterol 128 mg/dL; LDL 55 mg/dL:
Low-end Outcome 14 Months and beyond:
55 Ferritin 24 – Low End 55 Five months free of hospitalization due to severe seizures
55 Vitamin D >120 55 Eye contact daily
55 GGT 88 HI (ideal <10) [can be suggestive of toxcity and/or low 55 Reach for objects
glutathione status] 55 Adult school; at 14 months mouthed quietly to Mom “I love you”.
55 Differential: WBC 6.04; Neutrophils 40.2 low end/Lymphocytes 55 Continues Lipid Shake daily, sometimes adds healthy variety of
44.7 HI foods.
 170 D. Noland

11.12  Conclusion 12. Jaureguiberry MS, Tricerri MA, Sanchez SA, et al. Role of plasma
membrane lipid composition on cellular homeostasis: learning
from cell line models expressing fatty acid desaturases. Acta Bio-
Lipids are the molecular components that comprise the lipi- chim Biophys Sin Shanghai. 2014;46(4):273–82.
dome—the complete lipid profile within the membrane, cell, 13. Barbosa-Silva MC, Barros AJ. Bioelectrical impedance analysis in
tissue, or organism. The lipidome is in the dynamic metabo- clinical practice: a new perspective on its use beyond body compo-
lism of life expressing the genetic information in the DNA sition equations. Curr Opin Clin Nutr Metab Care. 2005;8:311–7.
14. Lukaski H, Kyle U, Kondrup J. Assessment of adult malnutrition and
book of life. The membrane houses the receptors that receive prognosis with bioelectrical impedance analysis: phase angle and
information and direct the biochemistry to survive. The two impedance ratio. Curr Opin Clin Nutr Metab Care. 2017;20(5):330–9.
functions of the lipids that can be modulated by nutrition https://doi.org/10.1097/MCO.0000000000000387.
therapy are membrane structure and inflammation control. 15. Elmehdawi R. Hypolipidemia: a word of caution. Libyan J

This chapter has described the association between a per- Med. 2008;3(2):84–90. Published 1 Jun 2008. https://doi.
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son’s nutritional status and their vulnerability for impaired 16. Levy BD. Resolvins and protectins: natural pharmacophores for
fatty acid status. Nutritional status of an individual is a deter- resolution biology. Prostaglandins Leukot Essent Fatty Acids.
minant of how well their body can respond to and resolve an 2010;82(4–6):327–32. https://doi.org/10.1016/j.plefa.2010.02.003.
infection returning it to a state of wellness. 17. Bannenberg GL. Resolvins: current understanding and future

It is important to consider an individual’s fatty acid status potential in the control of inflammation. Curr Opin Drug Discov
Devel. 2010;13(1):136.
for several chronic disease conditions. Pathophysiology of 18. Ge C, Chen H, Mei T, et al. Application of a ω-3 desaturase with an
chronic disease reveals its contrast to acute disease by its arachidonic acid preference to eicosapentaenoic acid production
long-term development, often asymptomatic and not recog- in mortierella alpina. Front Bioeng Biotechnol. 2018;5:89. Published
nized. Subclinical chronic disease progression can “smolder” 22 Jan 2018. https://doi.org/10.3389/fbioe.2017.00089.
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 173 12

Structure: From Organelle
and Cell Membrane to Tissue
David Musnick, Larissa Severson, and Sarah Brennan

12.1 Introduction – 174

12.2 Part I: Membrane Structure – 174

12.2.1 I ntroduction – 174
12.2.2 Biological Structure – 174

12.3 Part II: Dietary and Lifestyle Influences – 177

12.3.1 I ntroduction – 177
12.3.2 Pathophysiology – 177
12.3.3 Evaluation/Assessment – 179
12.3.4 Prevention/Treatment – 179

12.4 Part III: Organ Structure and Function – 180

12.4.1 I ntroduction – 180
12.4.2 Eye – 180
12.4.3 Skin – 181
12.4.4 Brain – 182
12.4.5 Barriers – 185

12.5 Part V: Musculoskeletal Structure and Influences – 186

12.5.1 I ntroduction – 186
12.5.2 Evaluation/Assessment – 187
12.5.3 Prevention/Treatment – 187
12.5.4 Pathophysiology – 187
12.5.5 Evaluation/Assessment – 188
12.5.6 Treatment/Prevention – 188

12.6 Conclusion – 188

References – 188

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_12
 174 D. Musnick et al.

12.1 Introduction In this chapter, we will discuss structure, starting at the cell
membrane and moving to musculoskeletal and other tissues,
Cellular structure is the foundation on which biochemical while examining key structural questions.
and energetic functions occur. The vast number of processes
that our tissues and organs are capable of accomplishing
derives from the basic molecular structures of which they are 12.2 Part I: Membrane Structure
composed. In other words, unless the individual cells, their
organelles, and their membranes are supported by the proper 12.2.1 Introduction
nutrients and suitable environment, the body systems they
comprise will be unable to function optimally. The membranes of our cells are important in that their integ-
Damage to the cellular structure can result in a multitude rity is critical for cellular function. For this purpose, cell
of dysfunctions. Dietary and lifestyle choices can influence membranes are comprised of a plethora of components nec-
the overall health of our bodies down to the structure of our essary to not only hold all of the vital cellular structures in
cell membranes. Maintaining a diet full of nutrients such as but also have the ability to be selectively permeable in regard
essential omega-3s and omega-6s, and even cholesterol, can to what solutes can pass through the membrane, as well as
help structurally stabilize our cell membranes as well as provide a location for necessary biological reactions to occur.
reduce the susceptibility to leakage of beneficial nutrients out The central component that is arguably the most vital for the
of the cell. cell membrane to fulfill its specific demands are lipids.
In any patient presenting with a constellation of symp-
toms, a clinician should ask if there is a structure, or struc-
tures, that should be evaluated and supported. When 12.2.2 Biological Structure
developing a plan to support a particular structure, both the
clinician and the patient must be aware that this modification Our cell membranes are made up of two stacked sheets of
may take months to years. Short- and long-term goals should lipids, known as the lipid bilayer, with proteins intermittently
be established, and monitoring the structural health and embedded within, at a ratio of about 1:1. Carbohydrates are
integrity should be done periodically. also incorporated throughout, but they only constitute about
There are key questions to ask when evaluating for struc- 10% of the membrane [1]. Phospholipids are amphipathic
12 ture, including: molecules, meaning they have a nonpolar head that is hydro-
55 What structures are compromised in my patient in phobic attached by a phosphate ester bond to two polar tails
relationship to their symptoms or aging process? that are hydrophilic. The lipids arrange themselves in such a
55 Is there a cell type, organelle, membrane, tissue, organ, way that hides their hydrophobic end from the surrounding
or other structure that is related to my patient’s symp- water in our tissues and presents their hydrophilic end, form-
toms? ing a curved bilayer structure appearing as a circle. Their
55 From the cellular to the tissue/organ/skeletal level, what properties make them insoluble in water, proving them to be
is the possible structural compromise/pathology? an effective candidate for protecting the fragile internal com-
55 What is the level of function and dysfunction of these ponents of our cells from our surrounding fluids. Besides
structures? acting as a protective barrier, the membrane also provides an
55 If there is degeneration in the structure, what is the anchor for the internal cytoskeleton to grasp onto, creating a
extent of degeneration? place for cell adhesion, allowing groups of cells to bind
55 Is regeneration of this structure possible? together to form tissues [2]. Another important function of
55 What support could I give these structures? the membrane is to act as a surface for important biological
55 Can function be augmented without improving struc- reactions to occur, including oxidative phosphorylation on
ture? the inner mitochondrial membrane [3]. The membrane also
55 What structural barriers (intestinal wall, blood–brain is home to numerous receptors.
barrier, lung barrier, etc.) are compromised in my Membranes thereby become the most abundant cellular
patient?? structure in all living matter. They can be considered as
55 Is there research to show that the membrane, tissue, or nature’s preferred mode of microencapsulation technology,
organ can be supported and improved in its structure developed as means of compartmentalizing living matter and
and function? protecting the genetic material. The biological membrane is
55 How much of a change in this structure and function the essential capsule of life. Many important biological pro-
can my intervention make? cesses in the cell either take place at membranes or are medi-
55 How long will it take to make changes in this structure? ated by membranes, such as transport, growth, neural
55 What are the most important interventions to improve function, immunological response, signaling, and enzymatic
the health of the cell, tissue, or system, and what is an activity. An important function of the lipid bilayer is to act as
estimated cost of these interventions? a passive permeability barrier to ions and other molecular
55 Can I evaluate the integrity of these structures with a lab substances and leave the transmembrane transport to active
test, imaging study, or assessment of nutrition status? carriers and channels [1] (. Fig. 12.1).
 
Structure: From Organelle and Cell Membrane to Tissue
175 12

..      Fig. 12.1  Schematic model of the plasma membrane of a and thickness variations close to the integral proteins. Whereas the
eukaryotic cell which highlights the membrane as a composite of a lipid molecules in this representation are given with some structural
central lipid bilayer sandwiched between the carbohydrate glycocalyx details, the membrane-associated proteins remain fairly featureless.
(which consist of polysaccharides) on the outside and the rubber-like In order to capture many different features in the same illustration,
cytoskeleton (which is a polymeric protein network) on the inside. the different membrane components are not drawn to scale.
Intercalated in the lipid bilayer are shown various integral proteins (Reprinted from Benton et al. [78]. With permission from Wolters
and polypeptides. The membrane is subject to undulations and the Kluwer Health, Inc.)
lipid bilayer displays lateral heterogeneity, lipid domain formation,

In order for a cell membrane, or a lipid bilayer, to func- practice is the bioelectric impedance analysis equipment
tion optimally, it requires a set of conditions that ultimately measuring the phase angle, often described as a marker of
make the completion of the membrane’s tasks easier and cell membrane fluidity and nutritional status.
more likely to occur properly. Lipid bilayers are soft and pli- The lipid composition of the two monolayers of the
able while retaining a structure in order to bend without lipid bilayer are characteristically different from one
breaking down [1]. In addition, they exist in specific struc- another. The phospholipids phosphatidylcholine (PC) and
tural compositions so that they are stable enough to hold sphingomyelin, as well as cholesterol and glycolipids, are
their shape. The stability of the membranes is largely due to predominantly found on the outer monolayer.
adequate cholesterol molecules embedded throughout the Phosphatidylethanolamine (PE) and phosphatidylserine
membrane as an important structure builder in all cells, (PS) are primarily found on the inner monolayer, facing
making the membrane thicker and less “leaky.” In addition, the inside of the cell. The presence of PS on the inner
cholesterol is a basic unit of some vitamins and hormones. monolayer creates a difference in charges between the two
All animals contain cholesterol in the plasma membranes in monolayers [2]. This is especially important in electrically
amounts from 30% to 50% of total lipids. The organelle mem- excitable cells, like neurons and muscle cells, where changes
branes contain very little: mitochondrial membranes less in membrane potential are used to generate signals within
than 5%, Golgi membranes about 8%, and ER membranes the cell or to the neighboring cells.
around 10% [4]. Finally, membranes are particularly selective
in the way that the individual lipids and transport proteins 12.2.2.1 Phosphatidylcholine
are organized within the bilayer so that they can control their Phosphatidylcholine (PC) is the most common phospholipid
permeability efficiently. contained in the bilayer cell membrane, and  accounts for
The length and degree of saturation of fatty acid chains in over half of the total membrane phospholipids primarily in
the phospholipids affects membrane properties, specifically the outer leaflet [6]. It is an essential nutrient that is con-
fluidity. The breakdown of the different types of fats found in sumed regularly in our diet, from eggs, raw dairy, and some
the membrane is about one-third cholesterol, one-third cruciferous vegetables, as well as available as a dietary supple-
unsaturated fatty acids, and one-third saturated fatty acids, ment or medical intravaneous infusion. PC is used to help
but these ratios fluctuate depending on other variables [5]. maintain cell structure and aid in signaling, particularly in
Unsaturation creates a kink in the fatty acid chain, which neurons [4, 6] (. Fig. 12.2). It organizes itself spontaneously
 

prevents the fatty acids from packing together as tightly, into the bilayer, providing the membrane with the bulk of its
therefore increasing the fluidity of the membrane. The pres- structure. Besides playing an essential role in the cell mem-
ence of cholesterol in the membrane also affects fluidity, brane, phosphatidylcholine is also necessary for the secretion
which will be discussed later in this section. Membrane fluid- of important plasma lipoproteins VLDL and HDL, since both
ity is carefully regulated since enzymatic activity as well as of these molecules are surrounded by a phospholipid mono-
transport processes can stop working if the viscosity of the layer [6]. Phosphatidylcholine is also secreted into bile, where
membrane gets too high. A common tool used in IFMNT it assists with the digestion of dietary fat [6].
 176 D. Musnick et al.

..      Fig. 12.2  Lipid polar head of

phospholipid groups. (Reprinted Substituent Chemical formulaa Polar head group name Abb
from Mouritsen et al. [4]. With Hydrogen –H Phosphatidic acid PA
permission from Springer Nature) Choline –CH2CH2N(CH3)3+ Phosphatidylcholine PC
+
Ethanolamine –CH2CH2NH3 Phosphatidylethanolamine PE
Serine –CH2CH(NH3)COO– Phosphatidylserine PS
Glycerol –CH2CH(OH)CH2OH Phosphatidylglycerol PG
H
myo-inositol HO OH Phosphatidylinositol Pl
H HO
OH H
H H
H OH
aChemical formula for the substituent linked to the phosphate group at position 3 of the glycerol moiety
bAbbreviation for the polar head group nomenclature

12.2.2.2 Phosphatidylethanolamine [1]. Cholesterol is a lipid that is structurally very different

Phosphatidylethanolamine (PE) comprises about 25% of the from the phospholipids that are found in the membrane. It
phospholipids in most membranes, with about 37% PE in the has a steroid ring structure as well as a hydroxyl group as its
inner mitochondrial membrane [7]. This percentage can be polar head. This structural difference makes cholesterol bulk-
up to 45% in nervous tissue, such as neural tissue, nerves, ier than its surrounding lipids, promoting stability in mem-
white matter in the brain, and cells of the spinal cord [7]. It is brane shape. The presence of cholesterol in the membrane
involved in cell fusion and division as well as regulating also makes the membrane less pliable, less susceptible to
membrane curvature [8]. PE contains a polar head group, compression, and leads to a thickening of the membrane.
which in turn lowers the melting point of the phospholipid, This rigidity allows the membrane to maintain its integrity
contributing to the viscosity and fluidity of the lipid mem- and shape, as well as making the membrane tighter and
brane. Beyond the membrane, phosphatidylethanolamine is therefore less permeable.
12 also involved in blood clotting and the secretion of lipopro- In addition to providing stability, cholesterol also plays a
teins in the liver [9]. vital role in protecting the cell membrane from nutrients that
we consume that could be harmful to the cell. Many pharma-
12.2.2.3 Phosphatidylserine ceutical drugs are comprised of amphiphilic molecules,
Constituting 3–10% of the total lipids within the cell, phos- meaning that their target sites within the body are places that
phatidylserine (PS) plays an important role in cell-to-cell are composed of similar molecules, that is, lipid bilayers.
signaling and is involved in the proper localization and acti- Such drugs that are intended to target membranes include,
vation of many intracellular proteins [10]. The location of PS but are not limited to, antipsychotics, antitumoral drugs,
within the membrane directly affects the health of the cell. PS antidepressants, tranquilizers, antihistamines, antifungals,
is located on the inner monolayer, and therefore faces the and analgesics. As these drugs interact with the membrane,
inside of the cell [10]. During the immune system response, they cause it to lose stability, making it susceptible to com-
apoptotic lymphocytes bring PS to the surface of the outer pression and leakage. In addition to amphiphilic drugs,
monolayer, where it becomes a signal for phagocytosis by ethanol-­based alcohols can also have a detrimental effect on
activated macrophages with the process of autophagy and the the lipid bilayers of our membranes. Ethanol congregates on
cell is cleared from circulation [11]. This makes the differ- the glycerol backbone of the lipid bilayer, creating a buildup
ences between the two monolayers critical to the health and of pressure on the membrane. However, cholesterol can help
survival of the cell. Proper biological function depends on protect our membranes from damage due to medication and
the elimination of unwanted, useless cells often referred to as alcohol consumption. The presence of cholesterol can help
“cellular debris”; therefore, the mechanisms of apoptotic cell redistribute the pressure that ethanol places on the glycerol
recognition using PS and the subsequent removal by backbone of the lipids in the bilayer. In addition, due to its
­phagolysosomes are important in order to prevent excess bulkiness in size and structure, it can help squeeze ethanol
inflammation and uncontrolled cell lysis [11]. The decision and other amphiphilic drugs out of the membrane.
to use PS as a dietary supplement should consider the
­individual’s membrane status and adequacy of other impor- 12.2.2.5 Proteins
tant phospholipids like PC and PE. Embedded throughout the lipid bilayer are peripheral (tem-
porary) and integral (permanent) proteins. Peripheral mem-
12.2.2.4 Cholesterol brane proteins are almost exclusively found on the
Cholesterol is a vital component of all biological membranes. cytosolic-facing monolayer. Proteins have many metabolic
In fact, cholesterol is the most abundant type of lipid in our functions in the cell, including providing structure, transfer-
membranes, accounting for 30–50% of the lipid molecules ring molecules across the membrane in and out of the cell,
Structure: From Organelle and Cell Membrane to Tissue
177 12
acting as enzymes in biological processes, and making up higher ratio of omega-3s in the body leads to the production
receptors for molecules outside the cell, such as hormones. of anti-inflammatory molecules, whereas an abundance of
omega-6s leads to the production of inflammatory molecules
12.2.2.6 Carbohydrates [12]. Chronic stressors can also cause inflammation in the
Carbohydrates are also included in the structure and func- body, which can lead to programmed cell death, so it is
tion of the membrane, but to a much smaller degree than fats important to manage stress.
and proteins. They are only present on the outer monolayer, In addition to lifestyle and dietary habits, certain inevitable
facing the extracellular environment. Their function is to act biological processes have the ability to naturally damage cell
as signaling molecules, allowing cells to be recognized by membranes as well. Aging unfortunately has proven to have a
other cells. They do not exist in the membrane as sole mole- negative influence on cell membrane health. As the human
cules, but instead are attached to other proteins or lipids, body ages, the amount of phosphatidylcholine that comprises
creating glycoproteins and glycolipids. our cell membranes decreases as the amount of cholesterol
All of these membrane components ultimately allow the and sphingomyelin increases. Phosphatidylcholine is one of
cell to function optimally, which in turn allows the tissues several phospholipids in the membrane that contribute to its
and organs that these cells comprise to work effectively. With fluidity and ability to react to differing internal conditions.
a properly working cell membrane, essential nutrients are When there is a low amount of phosphatidylcholine, cell
able to be adequately absorbed into tissues, while harmful membranes are more rigid, which ultimately diminishes their
waste is removed and excreted. Cells are able to effectively permeability and movement properties.
communicate with one another, a necessity for cells to work Many clinical conditions can also be attributed to mem-
together to form tissues. Hormone sensitivity and utilization brane phospholipid oxidative damage. Damage to the mem-
increases when the proteins that form hormone receptors on brane is destructive to the health of the overall cell and
the membrane are intact. therefore harmful to the health of tissues and organs that
these cells comprise. The body regulates each system and
reaction under tight control to minimize any unintended
12.3 Part II: Dietary and Lifestyle Influences consequences, but even under normal biological conditions,
there is some level of uncontrolled reactions occurring,
12.3.1 Introduction resulting in inadvertent outcomes. The production of reac-
tive oxygen species is a prime example of unintended conse-
The overall health of our cell membranes, in addition to their quences formed by normal physiological processes.
ability to function at maximum capacity, is largely dependent
on one’s diet and lifestyle habits. However, many are unaware 12.3.2.1 Reactive Oxygen Species
that even our most subtle nutritional choices have the power Reactive oxygen species (ROS) are occasionally formed during
to influence our bodies down to the molecular level, particu- the metabolism of molecular oxygen [13]. This is particularly
larly in regard to the state of our cell membranes. Knowing present in the mitochondria during oxidative phosphoryla-
how vital the role of a cell membrane is in the grand scheme tion. The damage that reactive oxygen species cause can be
of the human body makes knowing what causes harm to detrimental to the cell’s ability to function properly. It is impor-
these membranes equally as important. tant to limit the production of ROS, although some will always
be generated as a natural byproduct of normal cell processes.
The properties of phospholipids as well as the chemical
12.3.2 Pathophysiology reactivity of fatty acids in the bilayer make the cell membrane
an easy target for oxidation [14]. Oxygen and free radicals are
Cell membrane damage occurs in a variety of different mech- more soluble in the fluid lipid bilayer than in the aqueous
anisms, all of which can be detrimental to the body at the environment inside and out of the cell [14]. This attracts oxy-
cellular and macromolecular levels. Considering cell mem- gen molecules to the bilayer, increasing the chances for oxi-
branes consist of a variety of different lipids and proteins, it is dative damage [14]. Polyunsaturated fatty acids are extremely
not difficult for one element to damage a vast majority of the sensitive to oxygen, and the number of double bonds in their
phospholipid bilayer membrane once it has been introduced structure increases their susceptibility to attack by reactive
into just a portion of the membrane. oxygen [14]. Unsaturated fatty acids comprise about a third
Since cell membranes are composed of over 50% lipids, of the total fat content of the cell membrane, and this creates
consuming a diet that is low in fat is damaging to the mem- a large target for oxidation.
brane. A diet rich in monounsaturated fatty acids and essen-
tial fatty acids, especially a balance of the essential omega-3 and 12.3.2.2 Mitochondria
omega-6s producing the eicosanoid metabolites, while limit- In order to properly illustrate the impact that cell membrane
ing long-chain  saturated fat and avoiding ultra-processed health has on greater biological processes, we will explore
vegetable oils with trans-fat and acrylamides supports healthy the mitochondria as an example of an organelle whose
cell membranes [12]. The ratio of omega-3s to omega-6s of energy production relies entirely on the proper function of
5:1 to 1:1 should be properly maintained in balance, since a its membrane.
 178 D. Musnick et al.

Mitochondria are known as the powerhouse of the cell. hydrogen ions are pumped from the matrix of the mito-
Though other cellular processes may produce small amounts chondria across the complexes located on the inner mito-
of adenosine triphosphate (ATP), or the cellular form of chondrial membrane (IMM) into the intermembrane space,
energy, the majority of it comes from the mitochondria via creating a higher concentration of hydrogen ions within the
oxidative phosphorylation. The process of producing ATP intermembrane space than in the matrix. This gives the
occurs specifically within the inner mitochondrial mem- intermembrane space a positive charge and the matrix a
brane, not the cytoplasm [15]. Healthy and high-functioning negative charge, creating an electrochemical gradient. The
mitochondria are imperative for the overall function of the IMM is not permeable to ions, preventing the abundance of
cell and ultimately the greater biological structure because of hydrogen ions within the intermembrane space from cross-
its energy-producing properties. ing the IMM. With the help of ATP synthase, hydrogen ions
Mitochondria contain two membranes, the inner and the are transported into the matrix of the mitochondria. The
outer mitochondrial membranes. This distinct structure pro- energy that is generated from this flow of ions against the
vides plenty of space for mitochondria to function optimally. electrochemical gradient phosphorylates adenosine diphos-
The outer mitochondrial membrane contains an abundance phate (ADP) into adenosine triphosphate, resulting in cel-
of lipids, while the inner mitochondrial membrane contains lular energy.
only about 20% lipids and instead has an abundance of pro- While cardiolipin in the inner mitochondrial membrane
teins  and phospholipids [16]. Oxidative phosphorylation is crucial for the generation of ATP, its proximity to the
occurs within the inner membrane, a process laden with ROS that are generated within the mitochondria also makes
enzymes (proteins) and other complexes. The membranes of it an easy target for oxidative damage. When cardiolipin
mitochondria contain the same phospholipids as the cell and other membrane phospholipids are damaged by oxida-
membrane, with phosphatidylcholine dominating the outer tion, they no longer form a tight ionic barrier from sur-
membrane, and phosphatidylethanolamine dominating the rounding protons and ions, allowing these charged
inner mitochondrial membrane with lessor amounts of phos- molecules to freely move across the membrane. This weak-
phatidylinositol, phosphotidic acid and phosphatidylserine, ens the electrochemical gradient and therefore results in a
while also containing a mitochondria-specific phospholipid, loss of electron transport and therefore diminished cellular
cardiolipin, with a primary role in the mechanism of apopto- energy production.
sis [17]. The mitochondrial membranes contain low levels of It is imperative to protect mitochondria from damage, as
12 cholesterol and sphingomyelin compared to the cell mem- harm to mitochondrial health can lead to impairment in
brane [15]. their function. The more damage to the mitochondria, the
There are many factors that can cause immense damage less efficient they are at generating ATP, and therefore the
to the mitochondria. These include, but are not limited to, more ROS they produce. Consequently, the more ROS that is
statin drugs, antibiotics, chronic stress, age, cigarettes, hyper- produced, the more damage occurs, resulting in a vicious
glycemia, excessive arachidonic acid, excessive exercise, per- cycle of deterioration. Endogenous and supplemental CoQ10
sistent organic pollutants (POPs), and heavy metals [18–22]. are known protectors of the delicate mitochondria from
These all contribute to the formation of reactive oxygen spe- excess ROS exposure.
cies, but the greatest generator of ROS is mitochondrial oxi- There are many diseases and illnesses that can be traced
dative phosphorylation, with about 1–5% of the oxygen back to membrane damage or dysfunction. Fatigue is often
consumed by the mitochondria converted to ROS. Oxidative the first indication of cell damage, due to membrane mal-
phosphorylation includes the conversion of nutrient-derived function. When the membrane is damaged, cells may not be
substrates into ATP. This takes place on the inner mitochon- able to signal efficiently and hormone receptors may not
drial membrane, through the action of five respiratory work as well, resulting in either the overstimulation of hor-
enzyme complexes. The main sites for ROS production are mone targets or the lack of hormone activity.
on complexes I and III of the mitochondrial electron trans- Mitochondrial dysfunction is characterized by the loss of
port chain, where electrons are being transferred from differ- efficiency of the electron transport chain and therefore the
ent oxygen molecules [23]. The desired outcome from this reduction in synthesis of ATP [25]. This decrease in energy
electron transfer is the generation of ATP to provide energy production can lead to symptoms of fatigue. While this seems
for cells. However, in some cases, the transfer can inadver- like an obvious, expected outcome, there are numerous other
tently generate superoxide anion, a dangerous ROS. illnesses that can result from dysfunctional mitochondria.
Superoxide anion is produced from the one-electron reduc- Among these are neurodegenerative disorders, including
tion of oxygen and is a precursor for most reactive oxygen Amyotrophic Lateral Sclerosis (ALS) (7 Chap. 50), Alzheimer’s,
 

species. Parkinson’s, Huntington’s, bipolar, and autism spectrum disor-

The presence of cardiolipin, a phospholipid found in the ders (7 Chap. 31), as well as cardiovascular disorders
 

inner mitochondrial membrane, increases the mitochon- (7 Chap.  47), such as diabetes, metabolic syndrome, athero-
 

dria’s susceptibility to attack by reactive oxygen species. sclerosis, and obesity [25]. Mitochondrial dysfunction can also
Cardiolipin is required for the electron transport chain lead to gastrointestinal and musculoskeletal disorders, includ-
(ETC) by connecting the four ETC complexes as well as ing fibromyalgia and muscular atrophy, as well as chronic
supplying protons for ATP synthase [24]. In the ETC, infections and even ­cancer [25].
Structure: From Organelle and Cell Membrane to Tissue
179 12
12.3.3 Evaluation/Assessment recommendation can be approximately 250 mg of vitamin C
two to three times a day. Along with antioxidants, the choles-
There are many lab tests that can be used to determine cell terol content of the membrane affects how phospholipids are
and mitochondrial function. Some tests are used to deter- packed in the membrane and therefore can affect the effi-
mine how well certain cell components are working, includ- ciency of free radical propagation through the lipid bilayer,
ing blood assessments of lactate and pyruvate levels, which so it is important to not shy away from it. There is no current
can reflect how well mitochondria are oxidizing pyruvate RDA for cholesterol since our bodies synthesize it naturally.
[12]. An increase in lactate compared to pyruvate indicates a Cholesterol in the diet comes from animal sources, particu-
problem with pyruvate metabolism by the mitochondria. larly meat, poultry, eggs, and dairy products.
Other tests look for damaged cell components, which can be
an indicator of oxidative damage. Two useful assessments for 12.3.4.2 CoQ10
detecting oxidative damage include urinary analysis of Coenzyme Q10 (CoQ10) is a vital cofactor in the electron
8-oxo-7, 8-dihydro-2′-deoxyguanosine, an oxidized nucleo- transport chain, facilitating the transfer of electrons between
tide of DNA, which can be used to detect damaged nuclear or complexes I and II by acting as an electron donor or acceptor.
mitochondrial DNA [26]. Another test includes the serum In its oxidized form, ubiquinone, it accepts an electron from
level of the enzyme gamma-glutamyl transferase (GGT) [27]. a molecule in the electron transport chain and is reduced to
Assessing antioxidant levels, including superoxide dismutase ubiquinol. When the reduced ubiquinol donates an electron
and catalase, can also be beneficial in determining the effects to a neighboring molecule, it returns to its oxidized form of
of ROS in the body. The organic acid test is another useful ubiquinone. The reduction and oxidation reactions that
tool that evaluates for cell function by detecting blockages in CoQ10 constantly undergoes make it a valuable antioxidant,
the citric acid cycle. quenching the harmful reactive oxygen species that are spon-
taneously generated during oxidative phosphorylation.
CoQ10 also transfers protons across the inner mitochondrial
12.3.4 Prevention/Treatment membrane, creating a proton gradient, aiding in the genera-
tion of ATP. CoQ10 is the only fat-soluble antioxidant that
There are a multitude of nutritional components that can can be generated by the body, and therefore may not need to
enhance cellular membrane health. Since the cell membrane be obtained from the diet or as a supplement. There is no
is made up primarily of lipids, consuming adequate amounts RDA for CoQ10, however supplementation is recommended
of fat in the diet is essential to maintaining proper structure in order to treat a number of mitochondria-related condi-
and therefore optimal function of the cell. The current tions, including Parkinson’s disease, migraines, and muscular
Acceptable Macronutrient Distribution Range (AMDR) for dystrophy. The recommended supplemented intake of
adults suggests that 25–35% of total calories should come CoQ10 ranges from 100 mg a day to upwards of 300 mg a
from fat. Good sources include fatty fish, nuts, seeds, avoca- day, depending on the condition [28]. There are many foods
dos, and oils. that are high in this nutrient, particularly chlorophyll-rich
vegetables, such as dark, leafy greens, fresh herbs, broccoli,
12.3.4.1 Antioxidants peas, and asparagus, however it may be difficult to get ade-
Considering reactive oxidants are a major detriment to the quate CoQ10 from diet alone when dealing with neurode-
membrane, serious damage can be prevented by consuming generative or other disorders.
adequate amounts of antioxidants, including vitamins E and
C. The lipophilic properties of vitamin E enable it to fit com- 12.3.4.3 Lipoic Acid
fortably in the membrane, protecting the phospholipids’ Lipoic acid is another vital cofactor in mitochondria, aiding
unsaturated hydrophilic ends from free radical attachment in the conversion of food into useful energy, reacting with
and damage. These nutrients are critical in preventing initial reactive oxygen species, and protecting membranes by
oxidation, subsequent peroxidation, and the resulting oxida- reacting with vitamin C and glutathione to recycle vitamin
tive chain reactions. The current Recommended Dietary E [29, 30]. In these ways, it acts as an antioxidant, protect-
Allowance (RDA) for vitamin E, found in nuts, seeds, and ing mitochondria from ROS damage. Lipoic acid is synthe-
safflower oil, is 15 mg/day (or 22.5 IU/day) for adult men and sized in our bodies and studies have found that only 30–40%
women. It is not unreasonable to take 200–400 IU of mixed of supplemented lipoic acid is absorbed, meaning there is
tocopherols with tocotrienols  daily to protect cell mem- no recommended dietary allowance for lipoic acid [31].
branes. The current RDA for vitamin C is 90 mg/day for men Dietary sources include protein-rich foods, such as meat
and 75 mg/day for women and the highest dietary sources and some vegetables, including broccoli and spinach. Alpha
include bell peppers, oranges, kiwifruit, and strawberries. lipoic acid may be more effective in reducing oxidative
Since vitamin C has a reasonably short half-life in the body, it damage if taken it its R form, as R-ALA. Consider supple-
would be reasonable to dose vitamin C two to three times a menting R-ALA in chronic neurological conditions or in
day. The RDA is recommended for the prevention of scurvy, other conditions in which oxidative stress is thought to be a
not for the protection of cell membranes, therefore a good significant issue.
 180 D. Musnick et al.

12.3.4.4 Phosphotidylethanolamine PQQ may be particularly relevant when treating neurological

Primary mitochondrial inner membrane component influ- diseases, such as Parkinson’s and Alzheimer’s. PQQ can also be
encing production of cardiolipin.  PE is the second most used to enhance cardiac function as well as decrease mitochon-
abundant phospholipid in metabolism and a precursor to drial damage after an MI or when a patient is in heart failure.
production of the important primary phospholipid PC.  PE Improving or maintaining mitochondrial health is key to
has many other critical functional roles in membrane metab- overall wellbeing, particularly in treating chronic fatigue and
olism including protein integration into membranes, autoph- many degenerative neurological conditions. The mitochon-
agy, cell division, mitochondrial stability, as well as determing drial membrane can be supported with omega-3 fatty acids,
membrane conformational changes. Nutritional status of PE and it may be worthwhile to use supplemental phosphatidyl-
is dependent on the intake of the essential nutrient, choline.  serine as well as phosphatidylcholine. Reducing exposure to
damage caused by free radicals can be accomplished by con-
12.3.4.5 L-carnitine suming adequate antioxidants, while minimizing exposure
L-carnitine helps transport fatty acids into the mitochondria to mitochondrial toxins, such as statin drugs and persistent
where they are burned as fuel during beta oxidation. The organic pollutants, is an important first step in prevention,
body sufficiently synthesizes and reabsorbs L-carnitine at a and can be helped by purchasing most, if not all, foods as
rate of about 95%, so supplementing this nutrient is not usu- organic. Promoting mitochondrial biogenesis will increase
ally needed, unless severe deficiencies occur. Some dietary the mass of mitochondria in tissues.
sources include meat, poultry, fish, and dairy products in The keys to focus on when it comes to maintaining mito-
high amounts, as well as fruits, vegetables, and grains in rela- chondrial health include reducing exposure to damaging fac-
tively small amounts. Research suggests that a therapeutic tors, consuming nutrients that are beneficial to mitochondrial
dose of L-carnitine to support mitochondria is 1000 mg three function, and preventing oxidative damage in the first place.
times a day, along with the supplementation of 400  mg of Avoiding mitochondrial toxins, such as statin drugs, POPs,
CoQ10 a day to prevent oxidative damage to mitochondria and chronic stress, while also consuming nutrients that are
during oxidative phosphorylation [32]. beneficial to mitochondrial function, such as CoQ10 and
antioxidants, means that oxidative damage to the mitochon-
12.3.4.6 Mitochondrial Biogenesis dria can be reduced and therefore the diseases associated
Besides slowing the loss of mitochondria, it is also important with mitochondrial dysfunction can be prevented.
12 to increase the number of functioning mitochondria and their
size in various tissues. Type 1 and type 2 diabetic patients have
fewer mitochondria as well as less efficient energy production 12.4 Part III: Organ Structure and Function
in their mitochondria. This population should be given sug-
gestions to augment mitochondrial mass and function. As 12.4.1 Introduction
people age, they accumulate higher amounts of mitochondrial
DNA damage and this, along with blunted mitochondrial bio- Disturbances to our major tissues and organs, especially those
genesis, leads to a decline in the numbers of functioning mito- that inhibit their inability to function optimally, are often a
chondria, especially in muscle cells. Type 1 muscle fibers, result of dietary and lifestyle influences that impact cellular
known as endurance or slow twitch, have a higher content of function. The eyes, the brain, and the gastrointestinal tract are
mitochondria than fast twitch fibers. As people age, the den- three crucial components of the body in which any change to
sity of mitochondria decreases in their muscles as well as in structure causes noticeable dysfunction. Since the ability of a
other tissues. Aerobic exercise completed regularly can lead to tissue or organ to function at its full capacity relies on the basic
increased density of mitochondria in muscle. Another method cellular structures of which it is comprised, it is imperative that
of mitochondrial biogenesis includes intermittent fasting; we analyze the components that have the means of diminish-
therefore, patients should be advised to not eat for 12–13 ing or enhancing individual cells within these major systems.
hours from the time of their evening meal to breakfast.
Resveratrol is a sirtuin activator and can be used as a sup-
plement to augment mitochondrial mass. Researchers have 12.4.2 Eye
determined that in order for sirtuin activators, like resveratrol
and exercise, to adequately support healthy mitochondrial 12.4.2.1 Biological Structure
function, adequate NAD+ levels are necessary, and nicotin- The eye is a prime example of how understanding structure
amide riboside has been shown to effectively increase NAD+ allows us to understand the pathophysiology associated with
levels in humans [33]. Nicotinamide riboside can be supple- this organ. The main disease affecting the eye is age-related
mented in doses of 125–250 mg twice a day, along with 125 mg macular degeneration (AMD), which is characterized by the
of resveratrol [34]. Pyrroloquinoline quinone (PQQ) is an anti- gradual loss of central vision, particularly in those over the
oxidant that can decrease mitochondrial oxidative damage, as age of 55. The macula is a small, 3–5.5 mm area within the
well as augment mitochondrial biogenesis. Doses of 20  mg retina, containing the fovea at its center. It is a multilayered
have been used in studies [35]. It has also been shown to have structure that is made up of millions of light-sensing cells
synergistic effects when combined with 300 mg of CoQ10 [35]. that provide central vision. The macula and fovea are rich in
Structure: From Organelle and Cell Membrane to Tissue
181 12
photoreceptive cone cells, which are responsible for light 12.4.2.4 Treatment/Prevention
sensing. The retina also contains the retinal pigment epithe- While there is currently limited success with treating advanced
lium, which, among other functions, helps transport nutri- age-related macular degeneration, there are many things that
ents and water, is involved in the visual cycle, as well as can help to prevent or slow the early progression of the disease.
protects the eye by absorbing light and preventing photo-­ Lutein and zeaxanthin are yellow-pigmented carotenoids
oxidation, via the action of tight junctions [36]. that are found in high concentrations in the macula. In the
fovea, they are present in amounts 1000 times higher than in
12.4.2.2 Pathophysiology other tissues in the body. These xanthophylls help to protect
There are many possible physiologic changes to the different macular photoreceptors and improve vision [43]. Zeaxanthin
structure in the eye that can lead to the development of age-­ absorbs damaging high-energy blue light and protects the
related macular degeneration. macula from free radicals, acting as an antioxidant and sub-
sequently protecting the central vision [43]. Carotenoids are
Dry Form not synthesized by the human body, so they must be
As the eye ages, the retina’s ability to receive proper nourishment obtained from the diet. Good dietary sources of lutein and
is hindered, leading to the accumulation of waste, and resulting zeaxanthin include leafy greens, such as kale, spinach, and
amorphous deposits, or drusen, in the retina [37]. This causes lettuce, as well as broccoli, corn, peas, carrots, oranges, and
the retinal pigment epithelium cells to degenerate and atrophy, eggs. There is currently no recommended dietary allowance
resulting in the loss of central vision. This is classified as the dry, for lutein or zeaxanthin; however, research has shown a
or atrophic, form of AMD. This form slowly progresses and can decreased risk for AMD with intakes of only about 6 mg a
lead to total blindness in a span of 5–10 years [37]. day and a greater decrease in risk by consuming 10 mg a day
of lutein and 2 mg a day of zeaxanthin [44].
Wet Form Omega-3 fatty acids, including DHA and EPA, and carot-
The integrity of the retina can be attributed to the Bruch’s enoids lutein and zeaxanthin have a protective effect on the
membrane, which is the basal lamina of the retinal pigment eye, including anti-inflammatory as well as antioxidant [45].
epithelium, separating the retina and the choroid [38]. When DHA is found in large amounts in the eye, playing a role in
the Bruch’s membrane is broken, this can allow abnormal phototransduction, as well as photoreceptor function [46].
blood vessels to grow underneath the macula and retina [38]. Like cell membranes, photoreceptor membranes function
When these blood vessels bleed, the macula bulges out, caus- optimally when they are fluid and selectively permeable—
ing distorted vision. Resulting vision loss is rapid. This severe properties that are highly determined by their fat content.
form of AMD is called wet, or exudative, and only makes up There is no RDA for omega-3 intake, but research has shown
about 10–15% of AMD cases [39]. stabilization of AMD with supplementation of 120 mg DHA
and 180  mg EPA a day in patients with AMD [47]. Good
Reactive Oxygen Species sources of omega-3s include fatty fish, such as salmon, and
The constant exposure to light that the eyes are faced with leads oils, including vegetable oils.
to a high chance of photo-oxidation. The constant exposure to Zinc, cysteine, and alpha lipoic acid have been shown to
oxygen leads to a high rate of generation of reactive oxygen prevent the progression of AMD and oxidative damage in
species. The role of antioxidants, both enzymatic (i.e., superox- the eye by acting as antioxidants, protecting tissues from
ide dismutase, catalase) and non-enzymatic (i.e., carotenoids free radical damage [42]. Cysteine can be obtained from
lutein and zeaxanthin), are vital to prevent ROS damage. consuming cysteine-rich foods, such as protein-rich foods,
including meat, poultry, and eggs, or supplementing with
12.4.2.3 Evaluation/Assessment N-­acetylcysteine. Alpha lipoic acid also plays a role in regen-
There are many risk factors for age-related macular degen- erating other antioxidants, including glutathione, vitamin
eration, and fortunately many of them are modifiable and C, and vitamin E. Taurine is a cysteine-derived antioxidant
therefore can prevent or help delay the onset of the dis- that is found in high concentrations in the macula [42].
ease. These include smoking, elevated homocysteine lev- Taurine deficiency leads to retinal photoreceptor degenera-
els, altered RBC fatty acid balance, obesity, and other tion and impaired visual acuity and can be supplemented as
­cardiovascular-­related risks, including hypertension, ele- 1000 mg twice a day [42].
vated total cholesterol, diabetes, stroke, and coronary
artery disease [37, 40]. Another risk factor includes light
exposure, particularly to blue light, as this generates free 12.4.3 Skin
radicals and oxidatively damages the eye [41].
All major risk factors for developing AMD are associated 12.4.3.1 Biological Structure
with macular pigment as levels are significantly lower in The largest of the membrane tissues in the body is the skin
patients with the disease [42]. Assessing visual acuity during barrier which, when intact, provides primary protection
a full eye examination is usually the first step toward diagno- from pathogens and undesirables from entering the body.
sis of AMD, along with retinal and choroidal angiography When the skin barrier becomes compromised and loses its
using green dyes [37]. integrity, a variety of insults can appear.
 182 D. Musnick et al.

12.4.3.2  Insults to Skin Barrier Integrity 55 hsCRP

Among the most concerning insults to the skin seen in 55 Sed rate
healthcare settings are infection, skin cancers, allergies/ 55 IGG total
sensitivities, and autoimmune diseases. For infections, 55 IGE total
underlying the vulnerability to protract these infectious 55 Vitamin D25OH
insults can be an injury-wound opening access to the inner 55 Vitamin A retinol
body. With skin cancers, allergies/sensitivities, and autoim- 55 DHEA-s (AM)
mune conditions, the microenvironment terrain becomes 55 Tissue transglutaminase IgG, IgA, IgM
the challenge to assess and know how to treat with consid- 55 Celiac panel
erations of potential antigenic dietary intake, environmen- 55 Dietary and supplement history
tal exposures, inflammation, pathogenic triggers of 55 Medication history
subclinical chronic infections, insufficient or deficient
nutritional status, emotional and biological stresses, and 12.4.3.5 Treatment
genomic propensities. 55 Vitamin C
55 Wounds/wound chronic infection/post-op surgical 55 Biotin
wounds 55 Fats and oils indicated from individual assessment
55 Skin cancers 55 Linoleic acid
55Basal cell carcinoma 55 Gamma linolenic acid
55Squamous cell carcinoma 55 Arachidonic acid
55Melanoma 55 Saturated fats
55 Atopic dermatitis/Eczema 55 Short-chain fatty acids (SCFA)
55 Psoriasis 55 Medium-chain fatty acids (MCT)
55 Cracked lesions on or around lips, mouth 55 CoQ10
55 Dermatitis Herpetiforme (extremities and/or truncal) 55 Vitamin E, full spectrum tocopherols/tocotrienols
55 Acne/Cystic acne 55 Vitamin D3 (dose per blood test vitamin D25OH/VDR
55 Blistering diseases genomic)
55 Pemphigus vulgaris 55 Vitamin A retinyl palmitate (if indicated by testing
12 55 Pemphigus vitamin A retinol)
55 Vitiligo 55 Protein
55 Amino acids
55 Collagen
12.4.3.3 Evaluation/Assessment 55 Carnosine
Inflammation is a common denominator with the above skin 55 Honey, medical
conditions. The primary mechanism of healthy control of 55 Aloe vera
inflammation is from a balance of fatty acids, especially the
omega-6 and omega-3 essential fatty acids and their metabo- Avoid: trans fats, acrylamide, rancid oils, hydrogenated fats,
lites that form the prostaglandins PG1, PG2 and PG3, and heat processed vegetable oils, high oleic-vegetable oils, anti-
phospholipids. Obtaining an RBC fatty acid analysis is biotics, and hormone - containing animal fats.
important to assess the fatty acid composition in order to
develop a targeted intervention of food oils and lifestyle
choices. 12.4.4 Brain
Phytonutrient phenol foods provide anti-inflammatory
support to the role of the prostaglandins in inflammation 12.4.4.1 Biological Structure
control found in the rainbow of color in fruits and vegetables. The brain is composed of mostly fat, about 60%. Brain cells,
The co-nutrients of minerals and vitamins are required for otherwise known as neurons, rely entirely on the function of
the above control systems to heal and keep inflammation at a their membrane to serve their purpose of transmitting elec-
healthy maintenance level. trical signals. In order to communicate with one another,
neurons generate an influx and/or outflux of specific ions
12.4.3.4 I nitial Biomarkers for Assessment across their membrane to produce an electrical signal to send
of Skin Health Status to a neighboring neuron.
55 Nutrition physical exam of skin and signs of nutritional The key to proper function of the brain comes down to
deficits (face, tongue, skin) the integrity of the blood–brain barrier (BBB), as well as the
55 Skin scraping/biopsy pathology integrity of axons, neurons, and mitochondrial membranes.
55 Blood The blood–brain barrier has the important function of letting
55 RBC fatty acid analysis nutrients and certain small molecules into the brain tissue
55 Lipid panel (TC, LDL, HDL, TG) while allowing waste to be eliminated. In addition, the com-
Structure: From Organelle and Cell Membrane to Tissue
183 12
position of the cerebral spinal fluid (CSF) is important to 12.4.4.2 Pathophysiology
consider along with its relationship with the glymphatic cir- The BBB can be damaged during concussions and other con-
culatory system (GCS) function of bathing the brain tissue ditions and is also susceptible to damage from antibodies. If
with CSF four times daily. The glymphatic circulatory system the BBB is disrupted, there can be an increase in autoimmu-
has been more recently understood as separate from the nity to brain tissue, neural inflammation, and oxidative stress
body’s lymphatic system (. Fig. 12.3).   to cell and mitochondrial membranes.

(i) (ii)

epi,
astro,

peri,

bv bv cpec csf

Development
(neuroependyma)

Adult
(ependyma)

csf bv brain brain csf

(iii) (iv)

..      Fig. 12.3  Blood–brain barrier. Protective barriers of the brain. The col- and the level of the pia arachnoid, formed by tight junctions between
lective term “blood–brain barrier” is used to describe four main interfaces endothelial cells of the arachnoid vessels. (iv) The inner CSF–brain barrier,
between the central nervous system and the periphery. (i) The blood–brain present only in early development, formed by strap junctions between
barrier proper formed by tight junctions between the endothelial cells of the neuroependymal cells lining the ventricular surfaces. In the adult, this
the cerebral vasculature. It is thought that pericytes (peri.) are sufficient barrier is no longer present. Both the blood–brain and CSF–brain barriers
to induce some barrier characteristics in endothelial cells, while astro- extend down the spinal cord. The CSF-filled ventricular system is depicted
cytes (astro.) are able to maintain the integrity of the blood–brain barrier in blue, while CNS brain tissue is in brown. The lateral ventricular choroid
postnatally. (ii) The blood–CSF barrier formed by tight junctions between plexuses are shown in red. Abbreviations: astro, astrocyte; bv, blood vessel;
epithelial cells of the choroid plexus epithelial cells (note the plexus vascu- cpec, choroid plexus epithelial cell; csf, cerebrospinal fluid; peri, pericytes.
lature is fenestrated). Resident epiplexus (epi.) immune cells are present on (Reprinted from Stolp et al. [79]. With permission from Creative Commons
the CSF surface of the plexus epithelium. (iii) The outer CSF–brain barrier License 3.0: 7 https://creativecommons.­org/licenses/by/3.­0/)
 
 184 D. Musnick et al.

If damage to the membranes of these neurons occurs to brain autoimmunity, brain damage from free radicals, neuro-­
any extent, the entire cell will be absolutely compromised in inflammatory molecules, neurotoxins, and electromagnetic
its ability to complete its purpose in electrical signaling. fields.
There is a plethora of clinical conditions, many quite severe, Nutritional support for the BBB includes optimizing fatty
which are associated with the degeneration or malfunction in acids and phospholipid dietary and supplemental intake,
the membranes of brain cells. increasing lipid protectors like fat soluble vitamins and
Neurodegenerative diseases are characterized by the pro- CoQ10, and  increasing polyphenols found in blueberries,
gressive loss of neuronal structure or function, leading to especially wild blueberries, in order to decrease oxidative
neuronal dysfunction [16]. Proper neuronal function relies damage. Resveratrol can be used to regulate MMP9 and pro-
on all components to be present and intact. Amyotrophic tect against OxLDL damage of the BBB.  Curcumin, given
lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s 400 mg twice a day, should also be used in the Longvida form
diseases can all be traced back to misfolding and aggregation to inhibit microglial activation and MMP9, as well as to pre-
of certain proteins, resulting in the formation and deposition vent damage to the tight junctions in the blood–brain barrier
of fibrils, tangles, and plaques [16]. The accumulation of [48, 49]. R-lipoic acid taken in 150–200 mg doses twice a day
these harmful proteins is coupled by impairment of mito- can decrease oxidative stress. Sulforaphane inhibits MMP9
chondrial integrity, mutations in mitochondrial DNA, and activates NRF2, which can activate the brain’s own anti-­
reduction of ATP synthesis, oxidative damage, and even cell inflammatory and antioxidant systems [50]. Sulforaphane
death [16]. supplements may not be very effective. Glucoraphanin is the
Structural concerns regarding brain function can be the stored form of sulforaphane in cruciferous vegetables. In
vagus nerve, especially if cervical vertebrae (C1–C2 and C3–C7) order to yield usable sulforaphane, glucoraphanin requires
are misaligned, impacting the brain stem and vagal nerve. the enzyme myrosinase for it to be converted into sulfora-
The vagus nerve is the largest nerve network in the body phane. Cooking cruciferous vegetables destroys the myrosi-
impacting multiple systems including immune, gastrointes- nase enzyme, thus very little sulforaphane can be obtained
tinal function, and others. Assessing and correcting the from steamed or fried cruciferous vegetables. It is important
structural components is important as well as treating the when eating raw cruciferous vegetables to have a healthy gut
function. microbiome in order to enable some myrosinase activity. The
best sources of glucoraphanin include broccoli sprouts and
12 12.4.4.3 Evaluation/Assessment raw broccoli.
BBB antibodies can be measured as antibodies to protein An important goal for supporting the brain should be
S100B.  If this test is positive, the BBB should be treated to to improve the structure and function of mitochondria
restore proper functions. Similar testing should be done for and neuronal membranes. Omega-3 fatty acids with a
antibodies to zonulin and occludin, indicating a possible higher percentage of DHA to EPA, and CoQ10 should be
breach in small intestine barrier function. Increased perme- used, as well as providing a substrate for neuronal mem-
ability of the BBB is synergistically worsened by increased brane phospholipids phosphotidylcholine (PC), phospha-
small intestinal permeability for a number of reasons. tidylethanolamine (PE), phosphotidylinositol (PI) and
Excessive permeability in the small intestine can be a sign of phosphatidylserine (PS). These phospholipid  nutrients
leakage of bacterial endotoxin, as well as food allergens, into may also play a role in preventing synaptic degradation
the brain, leading to more damage to brain tissue. and reducing excitotoxic damage. PE, PI and PS are
Patients with any brain-related matter should be initially anionic phospholipids in the inner leaflet of the plasma
tested for gluten antibodies with a complete gluten antibody membrane of neural tissues. They are made from phospha-
panel. Patients should also be tested for food sensitivities and tidylcholine (PC) and phosphatidylethanolamine in the
immune reactions to the foods that they consume. endoplasmic reticulum in the brain. DHA and PC can pro-
It would be reasonable to test any patient with a signifi- mote phosphatidylserine synthesis. Adequate doses of
cant neurological disease for antibodies to brain proteins. DHA may be in the range of 2–4 g/day, and doses of PC
Assessing the health of the brain can be accomplished in with PE may be in the range of 1–2 g/day [51]. PS can also
various ways and is indirect. It can be useful to test for anti- be taken directly to improve neuronal membranes. After a
bodies to the BBB as well as to various brain tissues. If anti- head injury, PS doses of 300–600 mg twice a day may be
bodies are found, it is important to treat the cause as well as used [51]. When used in the absence of a brain injury,
any symptoms. Quantitative MRI can be performed to assess lower doses, such as 100–200 mg twice a day, may be used
for gross loss of brain tissue, and QEEG and SPECT scans [51]. The patient should also be encouraged to consume
can be done to look at how the different parts of the brain are dietary sources of choline, which include egg yolks, poul-
functioning. try, collard greens, Brussels sprouts, broccoli, Swiss chard,
cauliflower, and asparagus.
12.4.4.4 Treatment When considering maintenance or improvement in neu-
The brain is 60% fat, so it makes sense that consuming ade- roplasticity, one must consider increasing the levels of vari-
quate fat intake in the diet helps nourish the cells of the brain. ous trophic factors, such as nerve growth factor, neurotrophin,
It is also important to restore the BBB in order to prevent and brain-derived neurotrophic factor (BDNF). Increasing
Structure: From Organelle and Cell Membrane to Tissue
185 12
levels of BDNF may lead to axonal and dendritic sprouting, between the body and the lumen of the intestines. The role of
nerve stem cell differentiation, and may enhance synapto- this barrier is to selectively allow the passage of nutrients and
genesis. Aerobic exercise done in the training heart rate zone other small molecules across the epithelium of the intestine,
(220-age) 70–80% for 30–45 minutes can increase BDNF as while blocking larger, harmful molecules. Disruptions to this
well as protect loss of genetic telomere length [52]. Aerobic barrier can lead to possible autoimmune disease, food aller-
exercise can also activate NRF2 gene responses [52]. These gies, mood disorders, and other conditions.
gene responses can decrease brain inflammation and oxida- The alimentary canal consists of the oral cavity, esopha-
tive stress, which can improve neuronal and mitochondrial gus, stomach, and intestines and is lined with sheets of epi-
membranes. thelial cells, forming the intestinal mucosa. The epithelial
Stimulation of neural stem cells and synaptogenesis in the cells are held together by tight junctions, sealing off spaces
brain, especially in the hippocampus, may be encouraged by between adjacent cells, forming an enclosed barrier between
the use of exercise and certain supplements [53]. These the lumen of the intestine and the surrounding tissues [63].
include melatonin 1.5–2 mg taken at night [54, 55], adequate The epithelium is the innermost layer of the gastrointestinal
vitamin D dosing to achieve levels of 50–70 ng/mL [56, 57], tract and is responsible for most of the digestion, absorption,
which would usually be about 5000 IU, and low dose lithium and secretion within the GI tract [64]. Maintaining proper
of 10–20 mg [58]. Low dose lithium aids repair of neurons as integrity of the intestines comes down to the tight junctions
well as induces neurogenesis of hippocampal neurons and holding the epithelial cells together while also regulating the
may lower toxicity of amyloid protein [58]. EGCG green tea permeability of water, ions, and nutrients.
extract is also beneficial, either by drinking green tea or by Tight junctions consist of protein complexes located at
taking 200–400 mg/day [59]. the apical ends of the lateral membranes of the intestinal epi-
Other nutritional interventions to increase BDNF include thelial cells, forming the selectively permeable seal of the GI
consuming blueberries with high polyphenol content. Wild tract [63]. There are four specific complexes, including the
blueberries contain the most of these beneficial nutrients. occludin, claudin, junctional adhesion molecule, and tricel-
Encouraging patients to make smoothies with frozen wild lulin [63]. These proteins interact with the actin in the cyto-
blueberries is the most practical way to ensure patients are skeleton, allowing a barrier to form [63].
consuming polyphenols. High percent cacao and zinc may
also promote BDNF, along with adequate sleep [60]. 12.4.5.2 Pathophysiology
Taurine is an amino acid that can improve brain structure Disruption to the intestinal epithelial barrier, namely
through a number of mechanisms. It can protect the brain increased permeability, leads to overall gut dysfunction and
against osmotic changes, has a neurotrophic effect, can acti- subsequent GI-related diseases, including irritable bowel
vate nerve stem cells, and can enhance neurite (axon or den- syndrome, celiac disease, and leaky gut syndrome [12].
drite) growth. Taurine can be safely dosed at 1000 mg twice a Factors that affect gut permeability include infection, inflam-
day. mation, immune dysfunction, environmental toxins, medi-
Enhancing brain structure can also involve eliminating cations, and the composition of the gut microbiota [12, 63].
certain components from the diet. If there is a head injury, Lipid and zinc deficiencies have also been shown to disrupt
the patient should be taken off of gluten and all dairy prod- tight junctions, alter membrane permeability, and cause
ucts, because of cross-reactivity between these foods and intestinal ulcers [12].
neural tissue with subsequent autoimmune or inflammatory
reactions in the brain. These reactions may be mediated by 12.4.5.3 Evaluation/Assessment
TH1, TH17, or microglial cells in the brain. Gliadin from There are many factors that provide some predictability for
gluten can cross-react with asialoganglioside GM1, myelin intestinal permeability, including the use of NSAIDs, bacte-
basic protein, synapsins, and cerebellar tissue. Milk butyr- rial infections, chronic stress, and hypochlorhydria, with an
ophilin can cross-react with cerebellar tissue and dairy increased likelihood in those with IBS, type 1 diabetes,
casein can cross-react with synuclein and oligodendrocytes migraines, celiac disease, and food allergies [65]. Taking
[61, 62]. cyclooxygenase inhibitors and being deficient in essential
Other dietary changes recommended after a RBC fatty fatty acids can also contribute to intestinal permeability [66].
acid analysis or fats and oils dietary survey are the intake of If a patient displays any of these predictability factors,
beneficial fat-rich foods and supplements when indicated for further lab tests can determine the presence of increased
the individual. intestinal permeability. The lactulose/mannitol test consists
of the patient drinking a specific amount of the disaccharide,
lactulose, and the monosaccharide, mannitol [67]. The
12.4.5 Barriers amount of these sugars that are excreted in the urine indi-
cates how well each of these has been absorbed and therefore
12.4.5.1 Biological Structure the degree of permeability in the intestine [12]. Disaccharides
The lining of the small intestine is a major barrier tissue are absorbed through the paracellular junction complex
whose function is directly supported by the integrity of its within the intestine, indicating the permeability of larger
structure. The gastrointestinal mucosa forms a barrier molecules. Increased excretion of lactulose indicates
 186 D. Musnick et al.

increased absorption of larger sugars and therefore an regular exercise routine can aid in healthy and efficient
increased permeability to molecules that are normally imper- regeneration of musculoskeletal cells as well as maintain cur-
meable in the intestine [67]. rent bone density, joint flexibility, and muscle strength.
However, there is a plethora of ways in which the musculo-
12.4.5.4 Prevention/Treatment skeletal system can begin to develop structural dysfunction.
While damage to the intestinal mucosa can be treated, it is Some of the most common structural changes in the muscu-
beneficial to prevent disruption in the first place. The pro- loskeletal system are loss of muscle (sarcopenia), tendon
biotic species Bifidobacterium longum has been shown to degeneration (tendinosis), degradation of joint structure
prevent damage to intestinal cells as well as increase the (osteoarthritis), and decreased bone density (osteopenia and
production of tight junction cell proteins, improving intes- osteoporosis). Of those large areas, all of them are modifiable
tinal integrity [68]. It has also been shown to successfully with nutritional interventions, except for tendinosis.
treat increased permeability in patients with Crohn’s dis-
ease and ulcerative colitis [68]. Antioxidants have also been 12.5.1.1 Sarcopenia
shown to help prevent oxidative damage to the intestine. Sarcopenia is a loss of muscle tissue and is most associated
These include vitamin C, vitamin E, beta-carotene, grape with aging. Muscle tissue may be replaced with fat and con-
seed extract, milk thistle, and quercetin [69]. Foods that nective tissue. Aging also decreases mitochondrial density
can damage the gut include gluten, dairy, and sugar. Even in muscle tissue. The loss of muscle structure can lead to
in non-celiacs, gluten consumption may damage zonulin injuries, falling, and decreased enjoyment of life and par-
production, which is a protein that is crucial in tight junc- ticipation in sports and activities. Loss of muscle tissue can
tions, increasing permeability to unwanted molecules [70]. be related to a number of contributing factors, including
Dairy can be inflammatory for a lot of people, so it is best hormones, inflammation, nutrition, toxins, and lack of
to avoid it when trying to prevent damage to the gut. Too exercise stimulus. The decline of key hormones, such as tes-
much sugar in the diet feeds the bad bacteria in the gut, tosterone, growth hormone, and DHEA, can increase the
causing an overgrowth of bacteria and degradation of gut rate of sarcopenia as well as ongoing systemic inflamma-
permeability. tion. Resistance training of large muscle groups (biceps,
Nutrients that can provide some treatment to the intes- triceps, chest, upper back, thighs, and abdominal wall) to
tine once it is compromised include L-glutamine, which is the fatigue with sets of 8–12 repetitions should be done two to
12 primary amino acid source for intestinal cells and regulates three times a week. Also, consuming 25–30 g of protein
intercellular junction integrity, and N-­acetylglucosamine containing at least 2.5 g of leucine (a branched chain amino
(NAG), which is a substrate for the glycosaminoglycans acid) can augment muscle building from resistance training
that are normally broken down in a leaky gut. A leaky gut and can slow age-related sarcopenia. Supplementing with
diet should consist of bone broth, steamed vegetables, fer- 20 mg of PQQ one to two times per day can increase mito-
mented foods, and healthy fats. Bone broth contains NAG, chondrial biogenesis so as to improve energy production
as well as collagen and glutamine, which are both elements from muscle [35]. It is also important for an individual to
that make up the gut, while steamed vegetables and healthy consume high quality protein on a daily basis of approxi-
fats help provide essential nutrients, like L-glutamine, that mately 1 g per kilogram of lean body mass. Muscle content
keep the gut working properly. Fermented foods contain can be monitored with body composition equipment. One
necessary probiotics, which keeps the microbiota in the gut of the simplest ways is with a BIA device in which non-fat
healthy. mass is evaluated (7 Chap. 22).
 

Preventing disease in the gastrointestinal tract boils down

to the proper maintenance and regulation of the tight junc- 12.5.1.2 Osteoarthritis
tions that hold everything together. This is a clear example of Osteoarthritis (OA) is the loss of chondrocytes and matrix
how optimal function relies on proper, healthy structure. from a joint leading to joint space narrowing, sclerosis, and
deposits of calcium (osteophytes). Osteoarthritis can be iso-
lated to one joint or be found in multiple weight-bearing
12.5  art V: Musculoskeletal Structure
P joints of the body, including the knee, hips, and spine. Factors
and Influences that contribute include inflammation, obesity, trauma, infec-
tion, lack of adequate precursor nutrients, and possible food
12.5.1 Introduction allergies. Although the most common approach is to simply
work on inflammation with an NSAID, this is an oversimpli-
The musculoskeletal system, which is composed of bones, fied and ineffective approach to OA of a joint. As it turns out,
muscles, tendons, joints, and all other connective tissues, is the pathophysiology of OA is more complex than simply an
responsible for providing structure and support in addition excess of prostaglandins. The following processes appear to
to functional movement of the body. Though aging has an be involved: inflammation (an extensive set of inflammatory
inevitable effect on musculoskeletal health and function, biochemical pathways), lack of adequate precursor nutrients,
there are several strategies that can be used to combat this enzyme breakdown of the joint, and dysfunctional synovial
degeneration. Consuming a balanced diet and maintaining a fluid.
Structure: From Organelle and Cell Membrane to Tissue
187 12
12.5.2 Evaluation/Assessment 12.5.3.3 Strontium
Strontium is a nutrient that may be used to increase OPG and
Evaluation of osteoarthritis is done using a combination of IGF-1 and should be thought of in any individual with both
physical examination, since OA joints show warmth, swell- OA and osteoporosis. The dose would be 680 mg/day.
ing, deformity, or restricted range of motion, as well as imag-
ing studies. X-rays are an excellent, low cost method and may 12.5.3.4 Glucosamine Sulfate
reveal more details than an MRI.  However, MRI would be Stabilized glucosamine sulfate is an essential supplement
important when evaluating details about labral cartilage or that should be used in any case of OA.  It functions as a
meniscus cartilage. building block in the synthesis of structural cartilage
matrix substrates, such as glycoproteins, glycolipids,
GAGs, hyaluronate, and proteoglycans, and is required to
12.5.3 Prevention/Treatment
manufacture joint lubricants and protective agents such as
mucin and mucus secretions [73]. Glucosamine sulfate has
Any osteoarthritis intervention can take 8 weeks or more to
been found to inhibit NF-kB and PGE2 and thus can have
show a decrease in pain and an improvement in function. For
anti-­inflammatory effects [74]. Crystalline stabilized glu-
basic nutritional intervention, consuming sulfur-containing
cosamine sulfate has been shown to inhibit IL-1beta-
vegetables, such as from the cruciferous and onion families,
induced gene expression of matrix degradation factors
on a daily basis is suggested. Providing sulfur to the chondro-
MMP-3 (stromelysin-1) and ADAMTS5 (aggrecanase 2),
cytes in the joint can supply a building block for the joint
thus having an effect on decreasing enzyme-mediated
matrix. It is reasonable to do a trial off of nightshade plants,
chondrocyte degradation [75]. Although glucosamine is
such as tomatoes, potatoes, peppers, and eggplants, for about
not generally found in the human diet, it is made from the
1 month to determine if pain decreases or if function signifi-
exoskeletons of shrimp, crabs, and lobsters for use in med-
cantly improves. If the pain does improve on this diet, the
ical applications. It is also available in a vegan form that is
patient should be kept off of nightshades long term.
made from corn. The clinician should recommend the sul-
There may be an effect from food sensitivities and food
fate form instead of the HCL form, as well as to make sure
allergies. This would be related to an immune complex medi-
that the product is stabilized. It should be dosed one time
ated inflammatory process. In a patient with OA in more
per day at 1500 mg, unless there is more than one large
than one joint or in a person with hand OA or rapidly pro-
joint involved, in which case it can be dosed 1500 mg twice
gressive hip or knee OA, it is important to try an elimination
a day [76, 77].
diet. It is also important to do a food allergy test as well as
gluten antibody test. The individual should be taken off of all
highly reactive foods for about 8 weeks to see if this decreases 12.5.3.5 Osteoporosis and Osteopenia
pain and improves function. Osteopenia is defined as less than 2.5 standard deviations
It is noteworthy that weight loss in overweight or obese below normal of bone density and osteoporosis is defined as
people can improve OA by more than simply mechanical fac- greater than −2.5 standard deviations of decreased bone
tors. As it turns out, obesity can lead to dyslipidemia and density. This condition can lead to compression fractures of
oxidized LDL, which can trigger inflammatory pathways in the spine as well as fracture of the hip and forearm. Of inter-
the joints. There is also an alteration in adipokines, which can est is that the bone structure is an area that may store metal
lead to joint degradation. Any successful approach to weight toxins and certain metals, including lead and cadmium,
loss and achieving closer to ideal body weight can help OA of which may be released during periods of bone loss, such as
various joints. in menopause and andropause. Conventional treatment
programs will use only bisphosphonates; however, these
12.5.3.1 Omega-3 Fatty Acids drugs can lead to dysfunctional bones as well as side effects
Omega-3 fatty acids can often improve OA by decreasing affecting the jawbone.  Consideration of the use of dietary
inflammation. Omega-3 fatty acids can suppress key inflamma- supplementation with a series of menaquinones (MK) (vita-
tory mediators including IL1, TNF-alpha, PGE-2, 5-lox, and min K2) in the form of MK4 and MK7 that promote healthy
cox 2 [71]. They can also inhibit certain metalloproteinases that bone metabolsim. 
break down joints, including MMP-3 and 13, as well as aggreca-
nase. Doses of 3–4 g in two divided doses should be given [71].
Consideration should be given to digestive enzyme (lipase) 12.5.4 Pathophysiology
support in the individual that has difficulty with fat digestion.
There are many contributing factors related to loss of bone
12.5.3.2 Vitamin C density, including declining hormone levels (estradiol and
A key vitamin for joint health is vitamin C. Adequate levels are testosterone), inflammation (including an inflammatory
necessary for collagen and proteoglycan synthesis as well as diet), lack of adequate minerals and vitamins, malabsorption
stabilization of the collagen fibril. Vitamin C should be dosed of nutrients, such as vitamin A and D, and inadequate load-
two to three times per day at doses of 250–500 mg [72]. ing of bones with exercise.
 188 D. Musnick et al.

12.5.5 Evaluation/Assessment 2. Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. 4th
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 191 13

Protective Mechanisms and

Susceptibility to Xenobiotic
Exposure and Load
Robert H. Verkerk

13.1 Introduction – 192

13.2 Biotransformation – 193

13.3 Pathophysiology – 194

13.3.1  echanisms – 194
M
13.3.2 Chronic Diseases Related to Xenobiotic Exposure – 195

13.4 Clinical Considerations – 198

13.4.1  ssessment of Xenobiotic Exposure, Historically and Presently – 198
A
13.4.2 Assessment of Genetic Susceptibility – 200
13.4.3 Assessment of Diet and Lifestyle – 200

13.5 Clinical Strategies – 200

13.5.1  educing or Avoiding Exposure to Xenobiotics – 200
R
13.5.2 Supporting the Body’s Detoxification Capacity – 201

13.6 Conclusions – 202

References – 202

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_13
 192 R. H. Verkerk

13.1  Introduction icity (potential to cause mutations, as measured, for exam-

ple, by the Ames test) [6], genotoxicity (potential to cause
Human exposure to exogenous toxin sources (xenobiotics) damage to a cell’s DNA or RNA), reprotoxicity (potential to
has increased dramatically over the last few decades as a cause adverse effects on sexual function and fertility in
result of industrialization and globalization. This results in males and females, developmental toxicity in the offspring,
exposures that may be greater, more frequent, and qualita- and effects through or via lactation) and teratogenicity
tively different, especially with regard to exposure to new-to-­ (potential to cause birth defects, typically evaluated in labo-
nature substances, compared with exposures that have ratory animals).
typified the greater part of our species’ evolution prior to the The Globally Harmonised System of classification and
Industrial Revolution. labelling of chemicals (GHS) (revision 6, 2015) identifies 10
More than 100 million substances (organic and inorganic categories of health hazard, namely, acute toxicity, skin corro-
chemicals) have been added to the Chemical Abstracts sion/irritation, serious eye damage/eye irritation, respiratory
Service (CAS) registry system since its inception in 1965. or skin sensitization, germ cell mutagenicity, carcinogenic-
About 75% of those were added in the last decade, exemplify- ity, toxic to reproduction (reprotoxicity), specific target
ing the exponential increase in registrations [1]. While the organ toxicity/single exposure, specific target organ toxicity/
number of chemicals manufactured in high volumes and repeated exposure, and aspiration hazard [7].
released into the environment represents a minor fraction of Organs and body systems that have specific sensitivities to
these, it is estimated that there are between 100,000 and xenobiotics include the liver, kidney, nervous system/brain,
200,000 industrial chemicals in common circulation [2]. The mitochondria, endocrine system, immune system, eyes, and
toxicology of the vast majority of these isolated chemicals is skin. Substances that adversely affect one particular system
either unknown or poorly understood. Even less is known are referred to accordingly, for example, hepatotoxins (liver),
about the effects of complex mixtures of compounds to which nephrotoxins (kidney), neurotoxins (nerves/brain), mito-
humans in industrial societies are routinely exposed. chondrial toxins, endocrine disruptors, immunotoxins, etc.
By definition, xenobiotics are substances that are for- Xenobiotic exposure in a given individual may exceed the
eign to an organism, the term stemming from the Greek body’s innate biotransformation capacities and contribute to
word xenos meaning foreigner and bios, life. In relation to a wide range of different pathologies. Some xenobiotics may
human health, the term xenobiotic is typically used to refer affect quality of life, increase the risk of cancer, or impact
to artificial substances, which did not exist in nature before reproductive potential. While the human body has been
their synthesis by humans (e.g. polychlorinated biphenyls, gifted with a multitude of different mechanisms and path-
13 dioxins, pesticides). Alternatively, the term may be used to ways to reduce body burdens of xenobiotics, these have
describe other exogenous toxin sources that are present in evolved to cater for both the types and exposures of xenobi-
much higher concentrations than might be expected natu- otic substances associated with the majority of our evolution-
rally (e.g. following consumption of cadmium or mercury-­ ary history. Mammals such as humans are less likely to be
contaminated fish) or ones that would not be expected to be able to adapt quickly to synthetic xenobiotics as compared
found within a human (e.g. bacterial toxins, mycotoxins). with natural ones to which humans have been exposed dur-
Exposures are typically regarded as being either acute or ing the majority of our species’ evolution. Long generation
chronic. In the case of the former, the toxicity usually mani- times coupled with low selection pressure will limit or slow
fests after a single, major exposure, and symptoms of toxicity the rate of evolutionary adaptation to xenobiotics. Hence,
in one or more organs (e.g. liver, kidney, brain, nervous sys- herbivorous insect ‘pests’ that are pre-adapted to a multitude
tem) are usually evident clinically within a short period of host plant secondary metabolites (phytochemicals) have
(<24 h) following exposure. An example of an acute exposure the capacity to rapidly develop insecticide resistance, a pro-
includes an overdose of non-steroidal anti-inflammatory cess aided by high selection pressure, rapid generational
drugs (NSAIDs) associated with attempted suicide. Chronic turnover rate, and prior adaptation of an array of detoxifica-
toxicity, by contrast, is the result of repeated, lower-dose tion enzymes [8]. Honeybees, by comparison, that have not
exposures over longer periods of time. Again, using NSAIDs needed to adapt to a high phytochemical load, have a much
as an example, long-term usage of this category of drugs can lesser array of protein coding genes, thus creating a marked
result in long-term damage to the liver [3] and gastrointesti- reduction in the diversity of cytochrome P450 enzymes,
nal tract [4], especially the small intestine [5]. glutathione-­S-transferases (GSTs), and carboxyl/cholinester-
Exposure to some xenobiotics may lead concurrently to ases (CCEs) compared with herbivorous insects. This, in
beneficial effects and adverse effects (e.g. pharmaceuticals). turn, likely accounts for the honeybee’s extreme sensitivity to
Exposure to xenobiotics may also yield no evident adverse insecticides [9].
or beneficial effect, owing to a low (i.e. sub-acute) exposure In human evolutionary terms, the time scale during
concentration or insufficient duration or frequency of which most adaptations evolved represents a period of some
exposure. Adverse effects, such as carcinogenicity, may tens of thousands of years, excluding the most recent
arise from either acute or chronic exposure and may be 250  years or so since the Industrial Revolution. The past
delayed, taking years or decades to manifest clinically. 70 years has seen the rapid development of industries reliant
Other categories of delayed adverse effect include mutagen- on organic chemistry (e.g. industrial chemicals, food tech-
Protective Mechanisms and Susceptibility to Xenobiotic Exposure and Load
193 13
nology, plastics, agrochemicals, pharmaceuticals, personal
hygiene, cosmetics) and biotechnology (e.g. nanomaterials, Lipophilic
R xenobiotic
vaccines) that now represent important sources of xenobiotic
exposure of humans. In addition, the growth, intensification
PHASE 1 oxidation reduction
and globalization of large-scale industry, continued reliance
on fossil fuels as the primary energy source, increased human
dependence on technology and the continuing expansion of Electrophilic
R R R–OH
Nucleophilic
polluting transportation systems (road, sea, and air) are asso- metabolites O R–SH metabolities
ciated with significantly increased indoor and outdoor pollu- R=O R–NH2
tion burdens compared with those that occurred over the
majority of human evolutionary history. PHASE 2
glucuronidation
Possible routes of exposure to xenobiotics are shown in glutathione
7 Box 13.1.
  conjugation R–GI
acetylation
Hydrophilic
R–SG R–Ac phase 2
Box 13.1  Routes of Exposure to Xenobiotics
Exposure to xenobiotics occurs via one or more of the following methylation metabolites
routes: sulfation
1. Prenatal [10]: Relevant for xenobiotics capable of placental R–Me
barrier (e.g. tobacco smoke, mercury, lead, SSRI drugs) R–SO3H
2. Oral: Exposure via breast milk, food, water, beverages,
drugs, supplements
3. Inhalation: Relating to both outdoor and indoor pollution
..      Fig. 13.1  Summary of typical biotransformation of a lipophilic
4. Dermal: Especially in relation to cosmetics, toiletries,
xenobiotic
washing water, medications exposed via the skin, eyes, vagi-
nal, and other mucous membranes
5. Intramuscular: Vaccines and their associated adjuvants may for phase 2 conjugase enzymes, and following sulfation,
represent important xenobiotic exposure that bypasses amino acid conjugation, glutathione conjugation, glucuroni-
both the dermal and gastrointestinal barriers.
dation, methylation, or acetylation are rendered both less
toxic and more water soluble, thereby contributing to urinary
or fecal (via the biliary route) excretion (. Fig.  13.1) [15].
 

13.2  Biotransformation Chemically modified (more polar) xenobiotics may also be

excreted via sweat, as volatile substance by lungs or in human
A healthy human body, uncompromised by polymorphisms milk [14].
affecting critical enzymatic biotransformation (detoxifica- There is increasing recognition of the existence of a com-
tion) pathways, is highly adapted to handling a diverse range plex active transporter (pump) system that is capable of act-
of xenobiotic substances below dosage or exposure thresh- ing on specific xenobiotics (most research having been
olds that might yield adverse effects. In fact, the body is gifted carried out in relation to pharmaceutical drugs). These are
with an array of xenobiotic-sensing receptors, such as the sometimes classified into two discrete, additional biotrans-
pregnane X receptor (PXR) that has evolved to regulate genes formation processes, referred to, respectively, as phase 0 and
involved in the metabolism and transport of xenobiotics phase 3 [16, 17].
absorbed from food or the environment and protect the body Both phase 1 and 2 enzymes are highly polymorphic [18].
from their harmful effects [11]. Accordingly, genetic polymorphisms may contribute to sig-
The biotransformation process essentially involves two nificant inter-individual differences in xenobiotic clearance
main phases, referred to as phase 1 and phase 2, respec- and responses [19]. A range of other factors also influence
tively. In the former, non-polar, lipophilic xenobiotics are inter-individual variations in metabolism of, and response to,
most commonly enzymatically converted to polar metabo- xenobiotics, including age, disease status, hormonal changes
lites via a diverse family of cytochrome P450 enzymes in the body, ingestion of medications, net exposure to envi-
(CYP), especially in the liver, and also in the kidney, lung, ronmental chemicals, and changes in lifestyle, including fac-
brain, adrenal gland, and gut. In some cases, the polar tors such as cigarette smoking, alcohol consumption, and
metabolites may be more cytotoxic than the original xeno- diet [20, 21].
biotic, for example, the biotransformation of the insecticide Given the continued unravelling of the science on bio-
DDT to the metabolite DDE [12], or in the activation of transformation mechanisms and the growing body of evi-
polyaromatic hydrocarbons and nitrosamines in the diet to dence demonstrating the influence of diet and lifestyle on
form carcinogens [13]. phase 1 and 2 biotransformation, more attention is being
Other phase 1 enzymes include flavin-containing mono- placed on dietary and lifestyle modifications that not only
oxygenase (FMO), hydrolyses, epoxide hydrolyses, aldehyde reduce the xenobiotic load (i.e. behavioural adaptation to
dehydrogenase, monoamine oxidases, and xanthine oxidase xenobiotics) but also ones that enhance xenobiotic clearance
[14]. In general, these phase 1 metabolites become substrates via different and multiple biotransformation pathways.
 194 R. H. Verkerk

Dietary composition and individual bioactive constitu- to complex mixtures as compared with isolated xenobiotics;
ents can have particularly profound effects on the metabo- [26] the complexity of multigene-environment and epigene-
lism of xenobiotics. Animal studies have demonstrated that tic interactions; the confounding effect of dietary and life-
diets rich in specific saturated and polyunsaturated fats may style choices; and profound inter-individual variations in
alter CYP expression, notably of CYP2E1 [22, 23]. susceptibility and tolerance [27].
Inter-individual responses vary not only according to the Dysfunction in homeostatic processes often involve dis-
potency of the xenobiotic agent(s) and the frequency of turbances to the function of interrelated ‘super-systems’ (e.g.
cumulative exposure, but also as to the individual’s capacity inflammatory, immune, endocrine, neurological) or they
to biotransform and eliminate the agent(s) at a given time. may be linked to specific organs or tissues (e.g. liver, kidney,
This capacity is dependent on numerous factors, including mitochondria, motor neurons).
age, health (including inflammatory) status [24], body size/ While there are very large gaps in our knowledge of the
weight, nutrition, lifestyle, epigenetic background, and poly- mechanisms by which xenobiotics induce adverse effects,
morphisms affecting biotransformation enzymes. three of the most well-researched mechanisms are as follows:
The clinical phenomenon of multiple chemical sensitivity 1. Interference with critical biotransformation steps. A
is increasingly well recognized and was usefully defined at a number of xenobiotics are known to block critical steps
workshop of experts, conducted at the request of the in the production of biotransformation enzymes. For
U.S. Environmental Protection Agency (EPA) in 1988, ‘as an example, mercury (e.g. as a contaminant in food) or
adverse reaction to ambient doses of toxic chemicals in our nitrous oxide (as a gaseous anaesthetic or airborne
air, food, and water at levels which are generally accepted as pollutant) act as potent inhibitors of cobalamin-depen-
subtoxic’ [25]. The expert workshop concluded that adverse dent methionine synthase [28, 29], a critical intermedi-
reactions manifest in susceptible individuals depending on a ary in the methionine cycle that is required to synthesize
variety of factors, including: endogenous glutathione, which has the capacity to
1. The tissue or organ involved detoxify both xenobiotics.
2. The chemical and pharmacologic nature of the toxin 2. Induction of supra-physiological oxidative stress. Normal
3. The individual susceptibility of the exposed person metabolic processes, exposure to xenobiotics in our
(genetic makeup, nutritional state, and total load at the food and environment generate both reactive oxygen
time of exposure) species (ROS) and reactive nitrogen species (RNS) [30].
4. The length of time of the exposure Radical ROS species, characterised by the presence of
5. The amount and variety of other body stressors (total one or more unpaired electrons, are highly reactive,
13 load) and synergism at the time of reaction short-lived molecules, reacting especially with DNA,
6. The derangement of metabolism that may occur from proteins, and lipids, causing an alteration in their
the initial insults [25] function. While ROS are vital to numerous processes,
including signalling cell growth and differentiation,
Intra-individual variation in susceptibility to xenobiotics regulating enzyme activity, vasodilation and protecting
may also occur temporally, with some patients developing the host from pathogens and foreign particles, excessive
increasing tolerance, or, conversely, increased susceptibility, oxidative stress may give rise to DNA, cellular or tissue
following continued or repeat exposure to particular xenobi- damage, or to alterations to enzyme function or intra-
otics. cellular signalling pathways. This may, in turn, trigger a
wide range of chronic diseases, including heart disease
[31] or cancer [32].
13.3  Pathophysiology 3. Dysregulation of xenobiotic nuclear receptors. A v­ ariety
of nuclear receptors, ligand-specific transcription
13.3.1  Mechanisms factors, have evolved to sense the presence of toxic
metabolites of endogenous metabolism as well as exog-
Given the huge array of xenobiotics to which humans are enous xenobiotics to which humans are exposed, most
now exposed [26] and the general acceptance of their key notably in the diet. They play a crucial role in biological
importance in the pathogenesis of chronic diseases, such as development, differentiation, metabolic homeostasis,
certain types of cancer, it is perhaps surprising that so little, and protection against xenobiotic-induced stresses [33].
rather than so much, is known about the specific mecha- Depending on the ligand and the presence of specific
nisms by which their effects are mediated. Among the chal- cofactors, these nuclear receptors regulate transcrip-
lenges to our improved understanding of the real-world tion factors that, when functioning properly, control
interactions between xenobiotics and humans are the sheer biological functions. However, when expression of these
number of xenobiotics to which humans are exposed (and nuclear receptors is dysregulated, they are associated
the lack of toxicological knowledge about most of these); the with a wide range of chronic diseases, including asthma,
quantitative and qualitative differences in chemical load over type 2 diabetes, obesity, atherosclerosis, osteoporosis,
time; the challenges facing the study of the effects of exposure and cancer [34, 35].
Protective Mechanisms and Susceptibility to Xenobiotic Exposure and Load
195 13
In humans, nuclear receptors can be divided into two main eases, given that real-world interactions over multiple
groups according to their ligand-binding specificity [36]: decades are likely to give rise to what has been referred to as
1. Orphan receptors, e.g. constitutive androstane receptor symphonic causation [40].
(CAR, NR1I3), pregnane X receptor (PXR, NR1I2), aryl Given also the vast array of environmental chemicals to
hydrocarbon receptor (AhR), and peroxisome prolifera- which humans are now exposed, it is usually not possible to
tor-activated receptors (PPAR), expressed particularly in determine accurately the contribution of environmental
the liver and intestines and also in a wide range of other chemicals to chronic disease. Notwithstanding this dilemma,
tissues. exposure to some xenobiotics has been strongly related to
These receptors express a broad range of biotrans- specific chronic diseases.
formation enzymes including CYP1A, CYP1B, CYP2B, One of the most comprehensive efforts to associate
CYP3A, CYP2Cs, CYP2A, GSTA1, ALDH1A, MRP3, ­xenobiotic agents with genetic mediators of disease has been
and MDR1 [32], as well as phase-2 enzymes such as through the open-source Comparative Toxicogenomics
Uridine diphospho-­glucuronosyltransferases (UDPGT), Database (CTD) [7 www.­ctdbase.­org], an NC State University
 

glutathione S-­transferases (GSTs), and sulfotransferases initiative. The database divides chemicals for which an
(SULTs) [37]. inferred relationship has been made with human diseases
While it has been established that phenobarbital and specific genes into 13 groups and provides an inference
is a major ligand, these receptors have been found to score (high score = high inference), with links to the relevant
be promiscuous, engaged in ‘cross-talk’ by stimulating peer-reviewed references. . Table 13.1 provides examples of
 

expression of multiple genes, and their function may be proven or inferred associations.
promoted (agonist) or repressed (antagonist) by a very The great investment in cancer research over recent
broad range of environmental, occupational, and natural decades, the increasing recognition of the importance of envi-
products, including many pesticides, pharmaceuticals, ronment factors as key triggers in carcinogenesis (as well as in
dietary chemicals, herbal remedies, and industrial chem- the pathology of other inflammatory and metabolic diseases),
icals, typically at micromolar concentrations [36]. along with the emergence of cancer as the leading cause of
Presently, more than 11,000 ligands have been added death in most industrialized, and increasingly in less-indus-
to the Orphan Nuclear Receptor Ligand Binding Data- trialized, countries, has stimulated increased interest in estab-
base (ONRLDB) [7 www.­onrldb.­org], with more than
  lishing scientific consensus over the carcinogenic status of
6500 of these being unique. Orphan receptors for which xenobiotics. This role is largely fulfilled by the International
endogenous ligands are later discovered are referred to Agency for Research on Cancer (IARC), an intergovernmen-
as ‘adopted orphan’ receptors. tal agency of the World Health Organization (WHO), which
2. Steroid receptors, e.g. androgen receptor, estrogen recep- publishes comprehensive monographs of the present state of
tor (ER), glucocorticoid receptor (GR), and vitamin knowledge on carcinogens or potential carcinogens.
D receptor (VDR). These receptors are responsive to . Table  13.2 provides a summary of current classifications
 

steroid hormones and exposure to nanomolar concen- (including monograph 118) into the five IARC groups.
trations of endocrine-disrupting chemicals (EDCs) such While the IARC has had a long history of criticism from
as xenoestrogens which may disrupt normal estrogen independent quarters for making ‘soft-touch’ decisions that
signalingsignalling and lead to disease (e.g. estrogen- avoid negative impacts on the chemical or tobacco industry,
related cancers) [38]. it has committed to be more objective [41]. The 2015 deci-
Disruption of the function of these receptors and sion to include processed meats in Group 1 and the world’s
their cross-talk with a broad range of signalling path- top-selling herbicide, glyphosate, in Group 2A, are likely
ways means that xenobiotics affecting steroid receptors examples of this shift.
may contribute to a daunting range of endocrine-related While the body of evidence linking a wide range of envi-
diseases including metabolic diseases such as cardiovas- ronmental chemicals to a variety of cancers is indisputable
cular, type 2 diabetes and obesity [36], and thyroid [42], the evidence for an association between environmental
diseases [39]. chemicals and metabolic diseases like obesity and cancer, as
well as processes such as inflammation (refer to . Table 13.1),
 

a key mediator of most, if not all, chronic diseases [43], con-

13.3.2  Chronic Diseases Related tinues to grow.
to Xenobiotic Exposure Increasing evidence suggests that xenobiotics may inter-
act adversely with the gastro-intestinal (GI) mucosa and
Chronic diseases are multifactorial and manifest following microbiome, adversely affecting signalling in the immune,
highly complex multi-gene/multi-environment interactions, endocrine, and neurological super-system, as well as affect-
usually over many decades. With limited exceptions (e.g. ing nutrient assimilation and increasing the risk of a broad
asbestos- or smoking-related cancers), given the plethora of range of chronic diseases, including obesity, type 2 diabetes,
possible causations, it is often difficult to identify with a high non-alcoholic fatty liver disease (NAFLD), cardiovascular
degree of certainty specific causes for particular chronic dis- disease, cancer, and mental diseases [44].
 196 R. H. Verkerk

..      Table 13.1  Chemicals for which associations with human diseases and specific genes have been inferred

CTD chemical category Top interacting genes Examples of strongly inferred chemical/human chronic disease
relationships [no. genes associated]

Amino acids, peptides, CASP3, TNF, GSTP1, IL6, CXCL8, Glutathione/prostatic neoplasms [74 genes]
and proteins IL1B, MAPK3, ABCB1, MAPK1, Bleomycin/pulmonary fibrosis [35 genes]
HMOX1 Cyclosporine/obesity [96]

Biological factors TNF, IL6, IL1B, NOS2, PTGS2, Lipopolysaccharides/inflammation [79 genes]
IFNG, HMOX1, RELA, CXCL8, Mycotoxins/inflammation [15 genes]
MAPK3 Aflatoxins/liver neoplasms [2 genes]

Carbohydrates TNF, NOS2, IL1B, IL6, PTGS2, INS, Lipopolysaccharides/liver cirrhosis [117 genes]
RELA, IFNG, CASP3, NFKBIA Fructose/diabetes mellitus [46 genes]
Glucose/carcinoma [59 genes]

Chemical actions and MGEA5, CYP19A1, TNF, IL1B, AR, Estrogens/carcinoma (hepatocellular) [36 genes]
uses CASP3, IL6, MAPK1, ACHE, ESR1 Air pollutants/breast neoplasms [58 genes]
Water-pollutant chemicals/breast neoplasms [51 genes]
Pesticides/prostatic neoplasms [51 genes]
Adjuvants (immunologic)/inflammation [12 genes]

Complex mixtures TNF, IL6, CXCL8, IL1B, NFE2L2, Tobacco smoke pollution/stomach neoplasms [102 genes]
PTGS2, CYP1A1, HMOX1, NOS2, Smoke/breast neoplasms [101 genes]
CAT Particulate matter [lung neoplasms] [79 genes]
Chinese herbal drugs/carcinoma (hepatocellular) [55 genes]
Vehicle emissions/breast neoplasms [250 genes]
Petroleum/prostatic neoplasms [26 genes]
Particulate matter/autoimmune diseases [18 genes]

Enzymes and coen- POR, SLC5A6, AKR1B8, CAT, NAD/obesity [8 genes]

zymes PPARA, CASP3, GAPDH, CYP3A4, Thioctic acid/hypertension [41 genes]
NQO1, NQO2 Leucovorin/heart diseases [2 genes]

Heterocyclic com- NOG, AHR, PPARA, CYP1A1, TNF, Tetrachlorodibenzodioxin (TCDD)/liver cirrhosis [763 genes]
13 pounds CASP3, MAPK1, MAPK3, HMOX1,
CYP3A4
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (heterocyclic amine)/
carcinoma (multiple) [109+ genes]
Nicotine/stomach neoplasms [65 genes]

Hormones, hormone ESR1, AR, ESR2, PGR, FSHB, EGF, Dihydrotestosterone/prostatic neoplasms [77 genes]
substitutes, and MAPK1, MAPK3, LHB, TNF Testosterone/breast neoplasms [173 genes]
hormone antagonists Estradiol/mammary neoplasms [112 genes]
Estrogens /carcinoma (hepatocellular) [36 genes]

Inorganic chemicals APP, CASP3, TNF, HMOX1, CAT, Cadmium/prostatic neoplasms [166 genes]
MAPK1, MAPK3, HIF1A, NOG, Asbestos/malignant mesothelioma [36 genes]
IL1B Sodium chloride (dietary)/hypertension [52 genes]
Sodium arsenite/ carcinoma (hepatocellular) [147 genes]
Arsenic/prostatic neoplasms [168 genes]
Hexavalent chromium/lung neoplasms [42 genes]

Lipids TNF, NOG, IL6, NOS2, IL1B, Dietary fats/prostatic neoplasms [222 genes]
PTGS2, IFNG, RELA, PPARA, Arachidonic acid/inflammation [30 genes]
MAPK3 Palmitic acid/insulin resistance [18 genes]

Nucleic acids, nucleo- CASP3, TP53, TNF, STAR, IL4, Decitabine (demethylation chemotherapy drug)/carcinoma (hepatocel-
tides, and nucleosides IFNA1, CDKN1A, IL6, IL1B, MAPK1 lular) [94 genes]
Azathioprine (immunosuppressive drug)/colonic neoplasms [14 genes]

Organic chemicals NOG, TNF, CASP3, MAPK1, Benzo(a)pyrene/prostatic neoplasms [382 genes]
PPARA, MAPK3, CYP1A1, AHR, Bisphenol A/prostatic neoplasms [462 genes]
PTGS2, ACHE Diethylhexyl phthalate/breast neoplasms [112 genes]
DDT/carcinoma (hepatocellular) [38 genes]
Polychlorinated biphenyls/breast neoplasms [75 genes]
Benzene/lung neoplasms [54 genes]
Dieldrin
Acrylamide/breast neoplasms [35 genes]
1,2,5,6-dibenzanthracene (polyaromatic hydrocarbon)/carcinoma [24
genes]
Glyphosate/colonic neoplasms [13 genes]
Protective Mechanisms and Susceptibility to Xenobiotic Exposure and Load
197 13

..      Table 13.1 (continued)

CTD chemical category Top interacting genes Examples of strongly inferred chemical/human chronic disease
relationships [no. genes associated]

Polycyclic compounds AHR, ESR1, CYP1A1, TNF, CASP3, Benzo(a)pyrene/prostatic neoplasms [382 genes]
AR, HMOX1, MAPK1, MAPK3, Polycyclic hydrocarbons (aromatic)/breast neoplasms [28 genes]
ESR2 Simvastatin/liver cirrhosis [31 genes]
Naphthalene/lung neoplasms [34 genes]

Based on data from: Comparative Toxicogenomics Database [CTD] [7 www.­ctdbase.­org]

 

..      Table 13.2  International Agency for Research on Cancer (IARC) categorisation of carcinogens and examples

IARC Scientific basis of Number of Examples

category IARC classification entries
(2017)

Group 1 Carcinogenic to 120 Alcoholic beverages, aflatoxins, aristolochic acid, arsenic, asbestos, benzene,
humans benz(a)anthracene, cadmium, benzo(a)pyrene, coal, coal tar, chromium (VI)
compounds, diesel exhaust, dioxin, ethanol in alcoholic beverages, lindane,
Epstein-Barr virus, Estrogen-progestogen menopausal therapy (combined),
Estrogen-­progestogen oral contraceptives (combined), ethylene oxide, formalde-
hyde, Helicobacter pylori infection, Hepatitis B and C virus (chronic infection),
human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
ionizing radiation, leather dust, untreated mineral oils, naphthylamine, nickel
compounds, paints (occupational exposure of painters), polychlorinated biphenyls,
outdoor air pollution, processed meat (consumption of ), radionuclides, various
forms of radium and their decay products, rubber manufacturing industry, salted
fish (Chinese style), shale oils, crystalline silica dust, solar radiation, soot, Tamoxi-
fen, tobacco (smoking, second-hand smoke, smokeless, chewing), trichloroethyl-
ene, ultraviolet-­emitting tanning devices, vinyl chloride, wood dust, X- and
Gamma-radiation

Group 2A Probably carcino- 81 Acrylamide, anabolic steroids, adriamycin, wood (and other biomass) fuels,
genic to humans bitumens, Captafol, chlorinated toluenes, chlorozotocin, Cisplatin, creosotes, cyclo-
pentalpyrene, dibenzacridine, dibenzopyrene, dimethylhydrazene, dimethyl
sulphate, ethyl carbamate (urethane), ethylene dibromide, emissions from high
temperature frying, occupational exposure as hairdresser or barber, glyphosate,
inorganic lead compounds, infection by Plasmodium falciparum (that causes
malaria), mate (hot), Merkel cell polyomavirus, 5-methoxypsoralen, methyl
methanesulfonate, N-methyl-­N’-nitro-N-nitrosoguanidine (MNNG), ingested
nitrates or nitrites (under conditions that result in endogenous nitrosation),
nitrogen mustard, 1-nitropyrene, N-nitrosodimethylamine, N-nitrodimethylamine,
2-nitrotoluene, application of non-arsenical insecticides (occupational exposure),
petroleum refining, polychlorinated biphenyls (PCBs), red meat (consumption of ),
shift work involving disruption of circadian rhythms, styrene-­7-­8-oxide, tetrachlo-
roethylene (perchloroethylene), 1,2,3-trichloropropane, vinyl bromide, vinyl
fluoride

Group 2B Possibly carcino- 294 Aflatoxin M1, acetaldehyde, acetamide, para-­aminoazobenzene, anthraquinone,
genic to humans benzofuran, benzophenone, benzyl violet 4B, bitumens, occupational exposure to
straight-run bitumens and their emissions during road paving, caffeic acid, carbon
black, carbon tetrachloride, chloroform, cobalt and cobalt compounds, cobalt
metal without tungsten carbide, coconut oil diethanolamine condensate,
para-dichlorobenzene, diethanolamine, ethylbenzene, gasoline, human immuno-
deficiency virus type 2 (infection with), human papillomavirus types 26, 53, 66, 67,
70, 73, 82, lead, magnetic fields (extremely low-frequency), methylmercury
compounds, metronidazole, mitoxantrone, naphthalene, nickel (metallic and
alloys), nitrobenzene, ochratoxin A, pickled vegetables (traditional in Asia),
phenobarbital, styrene, talc-based body powder (perineal use)

(continued)
 198 R. H. Verkerk

..      Table 13.2 (continued)

IARC Scientific basis of Number of Examples

category IARC classification entries
(2017)

Group 3 Not classifiable as 505 Aciclovir, actinomycin D, amaranth, para-aminobenzoic acid, ampicillin, anaesthet-
to carcinogenicity ics (volatile), arsenobetaine and other organic arsenic compounds that are not
in humans metabolized in humans, atrazine, benzoyl peroxide, bisphenol A, diglycidyl ether
(Araldite), bisulfites, caffeine, carrageenan (native), chlorinated drinking water,
chloroquine, cholesterol, chromium (metallic), coal dust, coumarin, crude oil,
cyclamates (sodium cyclamate), diazepam, electric fields (extremely low-­
frequency), electric fields (static), ethylene, fluorides (inorganic, used in drinking-­
water), haematite, human papillomavirus genus beta (except types 5 and 8) and
genus gamma, lead compounds, organic (NB: Organic lead compounds are
metabolized at least in part, to ionic lead both in humans and animals. To the
extent that ionic lead, generated from organic lead, is present in the body, it will
be expected to exert the toxicities associated with inorganic lead), magnetic fields
(static), mineral oils (highly refined), acetaminophen (paracetamol), polyethylene,
polypropylene, polystyrene, saccharin and its salts, tea, temazepam, vitamin K
substances

Group 4 Probably not 1 Caprolactam

carcinogenic to
humans

Emerging evidence suggests that xenobiotics may cause 13.4  Clinical Considerations
significant alteration to the microbiota in the human gut.
Antibiotics and other oral pharmaceuticals may create sig- Where xenobiotics are thought to have been a trigger or medi-
nificant short- or long-term changes in GI microbiome sta- ator of a particular disease or condition, an integrative and
bility as well as changes to the relative abundance of particular functional medicine approach necessitates three main areas of
bacterial taxa. Older patients on long-term prescriptions and investigation prior to the development of a treatment plan:
13 polypharmacy may suffer reduced microbiota stability and
diversity [45]. A study on the effect of the antibiotic cephalo-
sporin on wild gorillas showed that the drug had a statisti-
cally significant tendency to increase Firmicutes (Gram 13.4.1  Assessment of Xenobiotic Exposure,
positive) and decrease Bacteroidetes (Gram negative) colony Historically and Presently
numbers and species diversity, [46] a pattern that is associ-
ated with obesity in humans [47]. This assessment, likely based on patient interview, should
Further evidence implicates certain groups of pesticides, take into account known prenatal, childhood, occupational,
persistent organic pollutants (e.g. polychlorinated biphe- and other lifetime exposures.
nyls), heavy metals (e.g. cadmium, mercury), food additives, Xenobiotics may be categorized according to the CTD
and nanomaterials in further disturbances to the GI micro- (. Table 13.1); given the extreme sensitivity to xenoestrogens,
 

biota [48]. consideration should be given to even very low levels of expo-
Xenobiotics, most notably excitotoxins and neurotoxins sure to xenobiotic hormones or hormone analogues that act
capable of passing the blood–brain barrier such as those as endocrine disrupting chemicals (EDCs) even at nanomolar
transported by P-glycoprotein, are increasingly implicated concentrations, close to the limit of analytical detection.
in neurological diseases such as Parkinson’s disease [49, All five routes of potential exposure (7 Box 13.1) should be
 

50], especially among those who are genetically more sus- considered, taking into account indoor pollutants (e.g. flame
ceptible (e.g. organophosphate insecticide-exposed indi- retardants, mycotoxins from moulds), xenobiotics in foods
viduals homozygous for the paraoxonase 1 (PON1–55) (e.g. preserved meats, polyaromatic hydrocarbons/heterocyclic
gene) [51]. amines on charred/high temperature cooked foods, food addi-
Other organs, tissues, and organelles that may be particu- tives, sugar, pesticide contamination), outdoor pollutants, chlo-
larly vulnerable to xenobiotics are those directly involved in rinated/fluoridated drinking water, cosmetics, toiletries, etc.
biotransformation (liver, kidney) [52], excretion (colon, Risk is determined by both the exposure (including dose
bladder, urethra) [53], and energy production (mitochon- and frequency) and an individual’s susceptibility, the latter
dria) [54]. being heavily predicated genetically (. Table 13.3).
 
Protective Mechanisms and Susceptibility to Xenobiotic Exposure and Load
199 13

..      Table 13.3  Important single nucleotide polymorphisms (SNPs) affecting biotransformation of xenobiotics

Phase Gene Gene variant Risk allele Example of impact Reference

Phase 1 CYP1A1∗1 (M1) Msp1T>C C Metabolic of estrogens and Moorthy et al. (2015) [55],
polyaromatic hydrocarbons into Sharma et al. (2014) [56]
CYP1A1∗2 (M2) Ile462ValA>G G carcinogenic reactive metabolites

CYP1A2∗1C 3858G>A A Metabolic activation of heterocy- Wang et al. (2012) [57]

clic amines (HCAs) and aromatic
amines (AAs) (e.g. in high
temperature cooked meats)

CYP1A2∗1F 164A>C C CC (homozygote) individuals are Cornelis et al. (2006) [58]

‘slow’ metabolizers of caffeine

CYP2E1 96-bp insertion N/a Bioactivation of N-nitroso Jiang et al. (2013) [59],
compounds derived from Cross and Sinha (2014)
processed meats containing nitrite [60]
preservatives

Phase 2 COMT Val158M A Slow COMT expression may lead to Tahara et al. (2009) [61]
reduced methylation and increased
DNA damage

MTFHR C677T T Homozygote (and to a lesser extent Stover (2011) [62],

heterozygote) individuals of each Alizadeh et al. (2016) [63]
polymorphism have impaired
MTHFR A1298C T methylation, increased risk of
neurotransmitter disturbances and
cardiovascular disease, and are
slow (~70% reduced) metabolizers
of folic acid to bioactive 5’-methyl-
tetrahydrofolate

N-­acetyltransferase Multiple, incl. Various Holders of non-wild type alleles Sabbagh et al. (2011) [64]
(NAT)2 590A, 341C, may have various combinations of
481T, 803G alleles making them slow
and 282T acetylators, affecting the metabo-
lism of many drugs

Glutathione S-trans- Deletion Null Deletions of these members of the Bolt and Their (2006) [65]
ferase (GST)M1 GST gene (mu and theta 1
positions) superfamily are
GSTT1 Deletion Null associated with reduced glutathi-
one conjugation and elevated risk
of some cancers

Aldehyde dehydro- rs671 G>A A Significantly reduced capacity to Way et al. (2017) [66]
genase (ALDH2) convert aldehydes (including from
alcohol consumption) to acetate

PON1–55 55 L>M M MM homozygotes are more O’Leary et al. (2005) [67],

susceptible to adverse effects Manthripragada et al.
following exposure to organophos- (2010) [68]
phate insecticides; associations
with increased risk of Parkinson’s
disease

Phase 1/ SULT2B1 Multiple, Various Key member of the steroid metabo- Ji et al. (2007) [69]
Phase 2 including lizing sulfotransferase (SULT) gene
SULT2B1b and superfamily; imbalanced metabo-
SULT2B1a lism of hydroxysterois hormones
and cholesterol
 200 R. H. Verkerk

In some cases, it may be necessary to determine the pres- toxin, for example, garden chemicals, dry cleaning, car
ence of specific chemicals using relevant tests, e.g. lipid-­ exhaust, second-hand smoke
soluble chemicals following fat biopsy, water-soluble 55 Reduce or eliminate the use of toxic household cleaners
chemicals via urine or sweat, or neurologically active pesti- (use low toxicity, environmentally friendly versions,
cides using acetylcholinesterase assay. wear gloves to avoid skin contact)
55 Avoid unfiltered, municipal tap water. A reverse osmosis
or distillation system are the only two systems that
13.4.2  Assessment of Genetic Susceptibility remove xenoestrogens, although it is advised to re-­
mineralize water (to at least pH 7.5) with a suitable
An increasing array of genetic tests is commercially available mineral source prior to drinking
to evaluate specific single nucleotide polymorphisms (SNPs) 55 HEPA/ULPA filters and ionizers can be helpful in
that increase (or decrease) susceptibility to xenobiotic agents reducing dust, moulds, volatile organic compounds, and
(. Table 13.3).
 
other sources of indoor air pollution
Special consideration should be given to individuals 55 Avoid high-temperature cooking, such as frying and
expressing multiple high-impact polymorphisms relating to deep frying
compromised biotransformation. 55 Avoid using PTFE-coated non-stick-treated pans (that
may release fluorine gas during high-temperature
cooking)
13.4.3  Assessment of Diet and Lifestyle 55 Do not drink water or drinks from plastic bottles, unless
they are guaranteed BPA-free (use glass bottles)
Of key importance are elements of diet and lifestyle that affect 55 Avoid storing food in plastic containers, or covering
exposure to, or enhance, biotransformation of xenobiotics. food in plastic wrapping, especially where food contact
Diets including regular consumption of highly processed occurs, unless it is guaranteed to be phthalate-free (use
or ready-made foods, high-temperature cooked foods, and glass or earthenware for food storage)
ones low in a diversity of vegetables and fruit generally contain 55 Clean and monitor heating systems for release of carbon
larger amounts of synthetic additives, contaminants or other monoxide
xenobiotic compounds as well as fewer disease protective com- 55 Include houseplants throughout house (including
pounds. Food and lifestyle diaries are a useful means of gaining bedrooms) to help filter the air and increase oxygen
information about a patient’s habits and potential exposures. concentration
13 55 Air dry-cleaned clothes in well-ventilated space before
wearing or storing
13.5  Clinical Strategies 55 Use solvent-free (water-based) paints if decorating
interior spaces
Key strategies may be divided into those that reduce total 55 Avoid inhaling heavy traffic fumes, especially when
xenobiotic load. exercising heavily (e.g. running, cycling). A respirator
containing both particulate and carbon filters will reduce
the level of harmful exposure, but filters should be
13.5.1  Reducing or Avoiding Exposure changed regularly
to Xenobiotics 55 Understand all sources of possible workplace exposure
and take action to avoid or minimise. In some cases, it
The most important way of modifying risk to environmental may be helpful to engage the relevant trade union for
toxins is to avoid, or at least reduce, exposure to them. The assistance
following section draws on strategies proposed by renowned 55 Use a carbon filter on baths or showers (and replace
functional medicine doctor, Mark Hyman, MD [70]. regularly according to manufacturer specifications) or
Reduction or avoidance strategies include: reduce their duration
55 Avoid processed foods; consume whole foods, home-­ 55 Avoid chlorinated swimming pools; preferably, swim in
prepared for freshness and to avoid nutrient loss where sea water or other natural, open water or use seawater or
possible ozone-treated pools
55 Consume organically certified or guaranteed pesticide-­free 55 Prospective mothers should ensure they have minimized
produce. This is especially important when consuming fatty exposure to environmental toxins 6–12 months before
foods (e.g. dairy produce, vegetable oils, fatty meats) that planning to get pregnant and should minimise exposure
tend to accumulate pesticides, veterinary drugs, and POPs to xenobiotics throughout breastfeeding
55 Reduce or eliminate personal care products that contain 55 Avoid taking antacids, paracetamol, or other common
harmful ingredients (e.g. phthalates, parabens, PEGs, over-the-counter medications and seek support for
propylene glycol) natural/non-drug alternatives
55 Eliminate or avoid excess exposure to petrochemicals, 55 Remove allergens and dust in living areas as much as
agrochemicals, and other sources of environmental possible
Protective Mechanisms and Susceptibility to Xenobiotic Exposure and Load
201 13
55 Minimize exposure to electromagnetic radiation (EMR) 55 Freshly made vegetable juices, e.g. kale, celery, cilantro,
from cellular or cordless phones by ensuring time spent beets, parsley, ginger, and carrot (the latter should be
with handset close to head or body is kept to a mini- limited because of its high sugar content)
mum. Do not carry phones in pockets or close to the 55 Herbal detoxification teas, e.g. burdock root, dandelion
body unless turned off. Do not sleep with phone near root, ginger root, liquorice root, sarsaparilla root,
bedside if left on. Use ‘air tubes’ or speakers to reduce cardamom seed, cinnamon (not cassia) bark, etc.
proximity of phone to head/body when talking. Use 55 High-quality, sulfur-containing proteins; eggs, plant
radiation protection cases or sleeves on mobile devices protein (not soya) isolates, as well as garlic and onions
55 If working on computer, ensure screens and main 55 Citrus peels, caraway and dill oil (limonene sources)
computer are at least 30 cm from body. Use separate 55 Bioflavonoid/polyphenol-rich berries, grapes, citrus, and
wired keyboard and low-radiation screen if laptop is other fruits
main computer 55 Dandelion greens may help in liver detoxification,
55 Do not use cordless telephones as most base stations improve the flow of bile and increase urine flow
emit EMR equivalent to transmission mast 250 m from 55 Celery may increase urine flow
house. Use corded phones for landlines 55 Fresh cilantro may help eliminate ‘heavy metals’
55 Avoid excessive time (more than 1–2 h/day) watching 55 Rosemary, as fresh herb or extract, promotes expression
television or using screens and sit more than 3 m away of biotransformation enzyme genes, chelates heavy
from television when watching metals, antioxidant, anti-inflammatory
55 Avoid use of microwave ovens 55 Turmeric/curcuminoids (in fresh and dried turmeric and
55 Avoid excessive exposure to sun (avoid burning) curry powders): exhibit multi-target functions including
55 Avoid any exposure to X-rays other than those regarded detoxification, antioxidant, and anti-inflammatory effects
medically essential 55 Chlorophyll in dark green leafy vegetables, wheat grass, etc.
55 Reduce heavy metal exposure (predatory and river fish,
some municipal drinking waters, lead paint, thimerosal-­ 13.5.2.3  Dietary/Food Supplements that May
containing products, etc.) Support Enhanced Biotransformation
55 Full-spectrum, high-quality multivitamin and mineral
formula including bioavailable nutrient forms
13.5.2  Supporting the Body’s Detoxification 55 Buffered vitamin C (with mineral ascorbates): 1000–
Capacity 4000 mg a day in divided doses (to avoid loose stools) in
powder, capsule, or tablet forms during periods of
There is a large body of research, as well as decades of clinical increased detoxification. If dosage causes loose stools,
experience, supporting nutritional approaches to enhanc- lower dose
ing biotransformation (detoxification) processes in the 55 Milk thistle (Silybum marianum): 200–600 mg silyma-
body [71, 72]. rin/day
55 Rosemary (Rosmarinus officinalis) extract: 200–500 mg
13.5.2.1  Improve Elimination of Toxins dry extract/day (standardized to 6–10% rosmarinic acid)
55 Try to ensure 1–2 bowel movements a day 55 Turmeric curcuminoids with bioavailability enhancer
55 Drink 6–8 glasses of clean drinking water a day (e.g. turmeric essential oils, cyclodextrin, piperine):
55 Sweat regularly (use exercise, steam baths, and/or saunas 200–600 mg curcuminoids/day, in divided doses
to encourage sweating) 55 Astaxanthin (from Haematococcus pluvialis): 5–20 mg/day
55 Regular physical activity and exercise, yoga, or lymphatic 55 Vitamin B6 (as pyridoxal 5′-phosphate): 10–25 mg/day
massage can improve lymph flow and assist elimination 55 Vitamin B12 (as methylcobalamin): 500–10,000 μg/day
of toxic metabolites 55 Folate as (6S)-5-methyltetrahydrofolate (glucosamine
55 Consume adequate soluble and insoluble fibre: approx. salt), calcium methylfolate, or food-form folates [73]:
30g/day 1500 μg/day
55 Consume legumes (generally cooked to reduce/eliminate 55 Omega-3 fatty acids (as EPA and DHA): 2000–5000 mg/
lectins), whole grains (preferably gluten-free), veg- day
etables, fruits, nuts, and seeds 55 Liposomal glutathione: 400–800 mg/day
55 Consume fermented foods as natural probiotic sources
Additional supplements (for use under medical supervision):
13.5.2.2  Foods that Support Biotransformation 55 N-acetylcysteine: 500–1000 mg a day
55 Cruciferous vegetables (cabbage, broccoli, collards, kale, 55 Amino acids: taurine 500 mg twice/day, glycine 500 mg
Brussels sprouts) containing indole-3-carbinol, sulfora- twice/day
phane, etc., at least 1–2 cups daily 55 Alpha-lipoic acid: 100–600 mg a day
55 Garlic cloves (several daily) or garlic (preferably kyolic 55 L-carnitine: 1000–2000 mg a day in divided doses
aged) supplement 55 Bioflavonoids (citrus, pine bark, grape seed, green tea):
55 Decaffeinated green tea; preferably morning 50 mg/day
 202 R. H. Verkerk

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Sych Z. Polymorphism in the P-glycoprotein drug transporter MDR1 sulfotransferase SULT2B1 pharmacogenomics: gene sequence
gene: a possible link between environmental and genetic factors in variation and functional genomics. J Pharmacol Exp Ther.
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 205 14

Detoxification
and Biotransformation
Janet L. Black

14.1 Introduction – 206

14.2 Primary Approach – Avoidance – 206

14.3  econdary Approach – Caring for Organs

S
of Detoxification – 207
14.3.1 L iver Considerations – 207
14.3.2 Kidney Considerations – 208

14.4 Tertiary Approach – Detoxification Support – 208

14.4.1 S tart with Food – 208
14.4.2 Supplementation Use – 209

References – 210

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_14
 206 J. L. Black

14.1  Introduction Encountering a patient immediately following an alco-

holic binge, one notes a distinctive odor emanating from
Detoxification is the process by which the body breaks down the skin; this is the body’s way to eliminate alcohol metabo-
and removes substances that are undesirable and have poten- lites. We often don’t think of the skin as an organ of elimina-
tial for harm. These can be endogenous waste products or tion, but waste products and toxins, such as heavy metals,
such exogenous substances as medications, environmental phthalates, and other environmental toxins do diffuse into
toxins or any substances that we ingest, inhale or absorb. the sweat glands for elimination in the sweat [5, 6]. Saunas
Detoxification is a natural process of the body carried out con- are often promoted for their detoxification effects due to the
tinuously by the liver, the kidneys, the skin, and the lungs [1]. benefits of sweating. Vigorous exercise with sweating has
“Detox” is a popular topic and there is a lot of disagree- similar outcomes.
ment about what it is and how to do it. While many compa- The lungs are primarily designed to remove carbon
nies sell detoxification products, the claims that these products dioxide in exhaled breath, but the lungs are also able to filter
are essential to cleanse the body are often exaggerated. The and remove other waste products [7]. A well-known exam-
body is designed to effectively eliminate toxins in the majority ple is a diabetic patient in ketosis exhaling ketones in the
of cases. Using a radical detoxification product and then breath, with its characteristic odor. While this is often
returning to the same poor dietary and lifestyle habits is like described as a fruity odor, the actual chemical odor being
going on an extreme diet for weight loss and then returning to eliminated is acetone. Other metabolites are also eliminated
the prior way of eating. The approach of using an aggressive by the lungs when in abundance, which brings up images of
detoxification product is not necessarily effective to help the a breathalyzer in the hands of a police officer. However,
body function properly and may even result in harm. Better exhaled breath has the potential to surpass blood and urine
approaches to detoxification are discussed below. for toxicity testing because breath gives unlimited supply,
The critical role of detoxification is handled primarily by does not require trained medical personnel, is noninvasive,
the liver [2]. Rich blood flow is seen throughout the liver, and does not produce potentially infectious waste such as
bathing its columns of orderly arranged cells separated by needles.
spaces. As the blood is transported through the spaces
between the liver cell units, it is filtered and chemicals, dead
cells, drugs, microorganisms, and other debris are removed 14.2  Primary Approach – Avoidance
from the bloodstream. Important in this process, Kupffer
cells are specialized macrophages found in the liver sinusoids The primary approach to detoxification is avoidance of the
and make up more than 80% of macrophages found in the exposure when possible. Unfortunately, the majority of pop-
entire body. Kupffer cells are especially important for elimi- ulations around the world are exposed to chemicals and for-
nation of infectious agents circulating in the blood filtered eign substances that were not present until the early twentieth
14 through the liver, but also important for other debris and century. Estimates suggest there are almost 100,000 chemi-
toxin degradation [3]. A significant elaborate system of cals in current use with only a fraction of them rigorously
breakdown of the removed debris is handled by several step tested for safety in humans [8]. A further concern is that
processes, beginning with the inherited cytochrome P450 tested chemicals are evaluated based on a single exposure
enzymes that require important cofactors for function in without interaction with other chemicals, unlike the daily
the  form of nutrients such as B vitamins [2]. (Please see experience where humans are exposed to a chemical soup
7 Chap.  13). This critical first phase of the detoxification
  from personal care products, food contaminants, drugs, pes-
addresses fat-soluble toxins that are chemically converted ticides, etc. Since exposure to multiple chemicals occurs
into intermediate metabolites that become more water-solu- daily, the risk of toxicity is actually much higher and taxes the
ble. The second phase completes the chemical transforma- detoxification system. This makes the concept of avoidance
tion into water-soluble compounds on their way to excretion even more critical, and patients need to be educated about
into bile and subsequently into the gastrointestinal tract for the potential sources of exposures. The more patients are
removal from the body. Amino acids, vitamins, and other aware of exposures, the better equipped they will be to reduce
cofactors are important for this second phase. More in-depth them. Ultimately this leads to reduced burden on the normal
understanding can be gained from 7 Chap. 13.
  biological processes [9].
The kidney’s filtering system is comprised of glomeruli What we now call “organic food” was simply called
that remove waste products and toxins from the blood with “food” 100  years ago. People had relatively small plots of
subsequent excretion into the urine [4]. Urinary excretion is land where they usually had a combination of animals and
one of the primary ways that toxins are eliminated. Kidneys crops. The manure from the animals and other organic
not only eliminate wastes but also maintain levels of water waste were composted to provide fertilizer for the garden
and minerals, produce renin to manage blood pressure, syn- and field plantings. Currently, the majority of crops are
thesize erythropoietin to make red blood cells, and synthe- farmed large in monoculture plots using chemical fertiliz-
size the active form of Vitamin D for strong bones and a ers, pesticides, herbicides, and fungicides. Monoculture
variety of other functions. We want to do everything we can farming and use of chemicals on the land have led to nutri-
to keep these important organs healthy. ent depletion of the soil [10, 11]. Some crops are “Roundup
Detoxification and Biotransformation
207 14
Ready,” meaning that they are genetically modified to with- disturbs the balance of these microorganisms can create
stand large amounts of herbicide (glyphosate). Besides being problems. Therefore, any chemical-containing products, par-
a risk for cancer, kidney disease and other health problems, ticularly antibacterial-containing products for everyday use,
glyphosate can bind with minerals in the soil including cop- should be discouraged [9].
per, iron, magnesium, manganese, nickel cobalt and zinc, The Food and Drug Administration does not approve
making them less available in our food [12]. Roundup is also cosmetics or personal care product ingredients but is, by
sprayed on other crops, such as wheat, as a desiccant prior to law, charged with regulating these ingredients [20]. For
harvest [13, 14]. example, the FDA has banned the use of triclosan in soaps,
It is not only plant food that is modified with chemicals. but triclosan may still be found in other products such as
Animals are factory farmed in crowded warehouses or toothpaste [21]. Otherwise, unless there is evidence of obvi-
pens, making them more susceptible to distress and disease ous harm, ingredients are not premarket-approved. Because
[15]. They are fed food containing genetically modified we apply these products directly to the skin, any toxins con-
(GMO) corn and soy and are given antibiotics and hor- tained in them can be absorbed. The European Union has
mones to hasten weight gain. When cattle are crowded into banned more than 1100 chemicals that are allowed in the
pens full of urine and feces, is it any surprise that E.coli, a United States [22]. One way to avoid the most toxic prod-
fecal-borne bacteria, can end up in the meat [16]? It is not ucts is to use the Environmental Working Group website
a healthy situation for the animals or those who consume (7 ewg.­org), which lists products and rates them according
 

them. to ingredients.
Cattle are intended to eat grass and similar plant materi- Cleaning products are even more likely to contain toxic
als as they have four stomachs designed to break down the ingredients when compared to cosmetics and personal care
cellulose. Feeding cattle grain is not a healthful alternative. products. Most cleaning products do not list their ingredi-
Nor is crowding the animals in pens without exercise options ents on the label, and many consumers are unaware of what
or giving them chemicals and antibiotics to produce rapid their exposure may be. There are green products that do list
weight gain. These procedures produce a marbling appear- ingredients and are less toxic, and can be found easily locally.
ance in meat that many people desire and create a milder Once again, the Environmental Working Group is a source of
flavor; but these practices do not contribute to animal health information that can guide buying decisions. Another option
and well-being or health benefits for those who consume the is to make products from safe ingredients and recipes are
meat produced in this manner. found on the internet for this purpose.
When large amounts of urine and feces are produced in Are you aware that the “new car smell,” the smell of fresh
small contained areas by animal factory farming, there is paint, the smell of new carpet and similar smells include
often contamination of nearby groundwater [17]. When cat- chemical fragrances? These are volatile organic compounds
tle, poultry or hogs are rotated on pastures in traditional (VOCs) and should be avoided as they can be toxic [23]. Air
farming techniques, their wastes fertilize the ground without fresheners, fabric softeners, oven cleaners, flame retardants,
overwhelming the area. Just as with human detoxification, and plastic food containers should also be avoided for similar
nature has the means to handle the waste products in small reasons [9]. Unscented products and low VOC products are
quantities. preferred. If fragrance is desired, essential oils provide a
Our water supply can be contaminated by other sources better alternative than artificial fragrances which contain
of toxins. Herbicides such as Roundup, pesticides, lawn multiple chemicals and phthalates (hormone-disrupting
chemicals, factory farm waste, heavy metals, and prescrip- chemicals).
tion drugs can all be found in tap water [9]. If the water is Now that we have discussed the first step, avoidance of
from a metropolitan water supply (as opposed to a private toxins, let us look at ways that we can support the detoxifica-
well), it may also contain fluoride (a neurotoxin) and will tion process by care of organs of detoxification and aiding
have chlorine or chlorinated by-products that have been used excretion through liver and kidneys.
to kill microorganisms. The list of possible contaminants is
too long to include here, but the recommendation is to use
filtered tap water [9]. Reverse osmosis systems are the most 14.3   econdary Approach – Caring
S
effective at removing these, but other filters are also helpful. for Organs of Detoxification
Bottled water may be no different than tap water, plus there is
the risk of leaching endocrine-disrupting contaminants like 14.3.1  Liver Considerations
bisphenol-A (BPA) from the plastic bottle, especially if
exposed to sunlight [18]. Because of poor dietary intake high in sugars and damaged
Common everyday sources of toxic chemicals are in per- fats, people may have impaired liver function. One very
sonal care and cleaning products. We have become obsessed common problem is what is commonly called “fatty liver”
with cleanliness and with killing germs to a degree that is or hepatic steatosis. Fatty liver may occur in those with
unhealthy. Our bodies are hosts to around 100 trillion micro- excessive alcohol intake, but a more common problem is
organisms that live in the gastrointestinal tract and on the non-­alcoholic fatty liver (NAFLD). This can be either iso-
skin, and these are necessary for health [19]. Anything that lated fatty liver, nonalcoholic steatohepatitis (NASH), or
 208 J. L. Black

NAFLD, which is more severe and associated with inflam- 14.4   ertiary Approach – Detoxification
T
mation, ­obesity, and metabolic syndrome [24]. Patients Support
often have no symptoms but will probably have abdominal
obesity. It can be found via imaging (ultrasound, CT or 14.4.1  Start with Food
MRI), or if more severe, via elevated liver enzymes. NASH
and NAFLD can progress to cirrhosis as scarring accumu- After protecting the organs of detoxification, the next step is
lates in the liver tissue. The treatment for fatty liver is pri- aiding in support of the body’s inherent detoxification path-
marily lifestyle changes, including abstinence from alcohol, ways [36–38]. The baseline issues for patients to enhance
weight loss, and controlling blood sugar. High fructose detoxification are a clean, good diet and adequate hydration,
corn syrup is especially detrimental to the liver and should with clean water providing the best source for fluid intake
be eliminated from the diet [25]. Coffee appears to reduce [36, 37]. Liquids containing caffeine with a diuretic action,
the build-up of scarring in NASH, so it is beneficial [26]. such as coffee, soda and, to a lesser extent, tea, result in the
The first-line treatment for non-diabetic NASH is Vitamin body losing more water than is ingested. Caffeinated drinks
E [27]. Other things that may be beneficial include omega-3 should not be the primary source of dietary liquid intake.
fatty acids, N-acetylcysteine (NAC), glycyrrhizin (from lic- Alcohol also has a diuretic function and inhibits organs of
orice root) and whey protein [28–33]. Both NAC and whey detoxification. Fruit juices are generally high in sugars and
protein have high levels of cysteine which can increase glu- not likely healthy choices for detoxification purposes. If
tathione, an antioxidant that is liver-protective. Whey pro- patients prefer juice and do not want to eat adequate amounts
tein may also aid in weight loss. of vegetables and whole fruit, a blender can be used to make
Other liver diseases include viral hepatitis, chemical hep- a smoothie with predominantly vegetables and minimal
atitis (such as results from acetaminophen overdose), cirrho- fruit. A juicer that extracts the juice and leaves the fiber
sis, and cancer. The presence of any of these can affect the behind is not recommended. Fiber is a very important part of
liver’s ability to break down toxins by deficiencies in Phase I the diet in maintaining gastrointestinal health and slowing
and Phase II nutrients and by generally overwhelming the the absorption of sugars. Vegetables and fruit provide anti-
detoxification pathways [2]. oxidants and phytonutrients essential for good health [39,
40]. Vegetables should be the mainstay of the diet, especially
colorful vegetables such as dark leafy greens, dark yellow,
14.3.2  Kidney Considerations orange, and purple varieties. Fruit also provides important
nutrients and fiber, but if used predominantly may provide
Chronic kidney impairment can result from diabetes and/ too much sugar.
or hypertension [34]. The kidneys may also be damaged by Sugar has an inflammatory effect and should be avoided
as much as possible [41]. Artificial sweeteners, such as aspar-
14 direct injury, such as a severe blow or something that
decreases blood flow such as an acute hemorrhagic injury tame, have controversial yet concerning effects on human
that results in significant blood loss. A backup of urine may health and should be avoided during detoxification [42]. If
also damage the kidneys, such as with prostate enlarge- added sugar is used, it should be organic cane sugar. Concerns
ment, with certain medications or with kidney stones that are also raised regarding genetically modified foods (GMO),
block the urine outflow. Infections may start in the bladder although this area also remains controversial [43, 44]. We
and ascend into the kidneys which, if not treated promptly, just don’t know enough about the safety of GMO foods, but
can result in problems such as scarring. Infections from there is emerging research to show there are differences that
hepatitis, HIV, and strep also may affect the kidneys. may be detrimental to health [44]. Sugar beets are a common
Autoimmune diseases, like lupus, that attack body tissues GMO crop and most of the commercially available sugar uses
can also damage kidneys. Long-term use of NSAIDS and GMO sugar beets. Corn sweeteners, such as high-fructose
lead poisoning are other risks. corn syrup, are also produced using GMO corn. Because
Kidney impairment can be diagnosed by increased many healthcare practitioners now advise against high-fruc-
microalbumin in the urine and elevated creatinine in the tose corn syrup and many patients seek to avoid it, manufac-
blood [35]. The estimated glomerular filtration rate (eGFR) turers may refer to it by a different name on food labels [45].
is calculated from the creatinine level and considers age, Stevia and monk fruit are safe sweeteners derived from
gender, and race. These should be monitored regularly in plants [29]. Stevia comes in liquid and powder forms and is a
patients with diabetes and/or hypertension and other safe sweetener but may have an aftertaste if too much is used.
chronic medical conditions; keeping blood pressure and Other sweeteners considered low-glycemic are the GMO or
blood glucose under good control is paramount. Non-GMO birch or corn derived polyols (examples are xyli-
Angiotensin-converting enzyme (ACE) inhibitors and tol, erythritol, malitol). They contain about 40% fewer calo-
angiotensin II receptor blockers (ARBs) are commonly ries than sugar and do not cause a rapid increase of blood
used to control blood pressure and reduce proteinuria and sugar. They are partially absorbed in the gastrointestinal tract
are often prescribed for normotensive diabetics for their which can produce a laxative or loosening of the stool for
kidney protective effects. some people.
Detoxification and Biotransformation
209 14
In the 1950s, the role of sugar as an etiology of heart A recent study on long-term gluten-free diets and heart
disease began to come to light. However, in 1965, the Sugar disease indicated that a gluten-free diet increases the risk of
Research Foundation paid scientists to do a literature coronary heart disease [48]. They concluded that gluten-free
review that downplayed the role of sugar and laid the blame diets should not be recommended for people without celiac
on fat and cholesterol [41]. This led to decades of poor disease. The answer to this dilemma may reside in the types
nutritional advice and patients still follow low-fat, low- of food used in substitution of wheat/gluten. Many gluten-­
cholesterol diets to this day. Recommendations to follow a free products available to consumers are processed and high
low-fat diet resulted in higher carbohydrate consumption, in carbohydrates and simple sugars, but not high in fiber and
obesity, metabolic dysfunction, and NAFLD [24]. Rather nutrients. This dietary substitution is not particularly condu-
than low-fat diets, food sources should be rich in beneficial cive to good health. The fiber content of whole grain is a big
fats. Healthy fats are an important part of the diet (See reason why it is routinely recommended, but it is possible to
7 Chaps. 10 and 11). Healthy fat ratios should be higher in
  get high-quality fiber by eating plenty of high-fiber vegeta-
omega-3 fatty acids rather than omega-6 fatty acids and bles and fruit. Otherwise, the addition of such high-fiber
other fats, like medium-chain fats and omega-9 fats, are to substances as psyllium husk is an alternative dietary fiber
be recommended. Unfortunately, healthy omega-6 fats are source.
not consumed as often as the highly processed damaged Dairy consumption is another concern during detoxifica-
vegetable oils which are high in inflammatory omega-6 tion. In the case of lactose intolerance, dairy sensitivity may
fatty acids. Processed foods tend to contain fats that are the be easy to recognize. Casein, the protein in dairy, may also
damaged omega-6 fatty acids and may even contain trans- cause intolerance but is more difficult to assess. Regardless,
fats and should be avoided, especially during detoxification. most detoxification programs recommend eliminating dairy.
It is important to strike a balance between omega-3 fatty Again, an elimination diet with subsequent challenge is a
acids and unprocessed omega-6 fatty acids obtained from good way for the patient to see if dairy is contributing to their
natural sources. We also now know that saturated fat and health problems. If dairy is used, it should be organic.
cholesterol are not the demons they have been made out to The diet should contain adequate protein with sources
be, but have roles in healthy diets and normal metabolism. from meat, poultry, fish, eggs, dairy, nuts and seeds, and
Recommended dietary sources of fats include, but are not legumes [49]. The recommended daily allowance (RDA) for
limited to, coconut oil, olive oil, avocados, grass-­fed butter, protein is 0.80 g/kg per day. This is a minimum amount and
and fatty fish (wild-caught). a higher intake of protein may be indicated in active indi-
Wheat and gluten have been a subject of much interest in viduals to maintain and promote muscle growth. However,
recent years with books like Wheat Belly and Grain Brain most Americans eating a standard diet are easily exceeding
becoming best sellers [46, 47]. Gluten-free products are now the RDA for their protein requirement. Most can obtain
found ubiquitously because of the popularity of gluten-free adequate good quality protein while reducing the quantity of
diets. Certainly, the wheat we are using today has been bred meat by choosing a predominantly plant-based diet [49].
to contain more gluten, which is advantageous for bakers Protein is essential to support enzymatic detoxification pro-
wanting to create light, fluffy bakery products. Unfortunately, cesses because of the amino acids supplied. Patients who
the gluten, gliadin, and agglutinin found in wheat, especially might be at risk for not getting enough good quality protein
the modern hybrids, are irritating to the digestive tract and include vegans or those who are severely restricting calories.
can lead to intestinal permeability, AKA “leaky gut” [46]. The
use of glyphosate as a desiccating agent prior to harvest has
also been implicated in the rise of gluten intolerance [13, 14]. 14.4.2  Supplementation Use
Intestinal permeability associated with gluten intolerance has
been linked to the rise in autoimmune conditions, obesity, It is imperative that nutritional counseling be sought to
and other chronic health problems. Therefore, many detoxi- ensure those preparing for detoxification are getting all the
fication programs recommend eliminating the use of grains, necessary nutrients in their diets to support the detoxifica-
especially wheat. tion process. Because our food may not provide an optimal
While some people find that they must completely elimi- level of nutrients, a good multivitamin/mineral supplement
nate grains from their diet, others can tolerate limited provides a back-up for what is not received in the diet. Of
amounts without any problems. One of the best ways to importance for detoxification are the B vitamins, which are
determine sensitivity is to try an elimination diet for a period co-factors in many enzymatic reactions. One concern for
of several weeks. When wheat or gluten is added back to the restricted diets is vitamin B12. Since Vitamin B12 is only
diet as a challenge, the subsequent reaction – or lack of one – found in animal products, those who do not eat animal prod-
can be evaluated and assessed (See 7 Chap. 24 for guide to
  ucts will need to use a supplement. As people age, their
elimination diet). This author has found that, in many absorption of Vitamin B12 is lower so older people may also
patients, eliminating sugars and grains result in a remission need to take this as a supplement. Magnesium, selenium and
of some symptoms, such as gastrointestinal problems, aller- zinc are minerals that are frequently deficient and critical for
gic symptoms, and a reduction in chronic pain. enzymatic conversion of endogenous and exogenous toxins.
 210 J. L. Black

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14
 213 15

Drug–Nutrient Interactions
Mary Demarest Litchford

15.1  ffect of Food and Nutrients on Drug Kinetics and

E
Efficacy – 214

15.2  ffect of Drugs on Food and Nutrient Kinetics and Nutrition

E
Status – 215

15.3 Role of the Nutrition Professional – 215

References – 218

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_15
 214 M. D. Litchford

Prescription and non-prescription drugs have improved the body composition has the potential to reduce transport pro-
health and well-being of humans. Yet, the potential for altera- teins and regulatory hormones involved in drug distribution.
tions in drug performance and/or changes in nutritional status The loss of visceral muscle mass contributes to the changes in
exist. A drug interaction is a situation in which a substance cardiac output, reduced blood flow to the liver and reduced
affects the kinetics of a drug or produces a new side effect. glomerular filtration rate that may alter drug elimination
Bioactive components in some food have the potential to [8–10].
interact with drugs and either reduce or enhance pharmaceu- Individuals taking drugs for a long duration who experi-
tical effects. Dietary supplements, herbals, and botanicals may ence insidious weight loss may be taking drug dosages based
contribute additional interactions with drugs. Typically, drug– on a higher body weight. These individuals are at higher risk
nutrient interactions are considered adverse side effects [1–4]. for drug–nutrient interactions. In obese patients, there is a
risk for accumulation of fat-soluble drugs or a prolonged
clearance of drugs resulting in increased risk for drug
The International Dietetics & Nutrition Terminology Ref- toxicity.
erence Manual [5] defines a food-medication interaction
as an ‘undesirable or harmful interaction(s) between food
and over-the-counter medications, prescribed medica- 15.1  Effect of Food and Nutrients on Drug
tions, herbals, botanicals and/or dietary supplements Kinetics and Efficacy
that diminishes, enhances, or alters the effect of nutri-
ents and/or medications.’ Food and dietary supplements may alter drug kinetics and
bioavailability. The bioavailability of a drug is the amount of
the drug that reaches systemic circulation. Drugs taken orally
Identification of potential risk for drug–nutrient interactions have a lower bioavailability than drugs administered intrave-
is an essential component of the comprehensive nutrition nously.
assessment performed during the nutrition care process. The The presence of food and nutrients in the stomach and
likelihood of interactions may be increased when the patient small intestine may increase, decrease or have no effect on
is malnourished, has an underlying illness, takes botanical the bioavailability of the drug. For example, immediate-
and herbal supplements, consumes alcohol daily, has food release bisphosphonates, such as alendronate sodium, taken
allergies or food intolerances, follows a restrictive therapeu- with food, significantly reduce drug absorption [11].
tic diet, has health beliefs that limit food choices, takes more However, delayed-release bisphosphonates, such as risedro-
than two medications, does not follow medication instruc- nate delayed-release, may be taken before or after a meal
tions, and/or is a growing child or older adult. Individuals without significantly reducing drug absorption [12].
with acute and chronic inflammatory conditions are at risk Furanocoumarins found in grapefruit segments, grape-
for sub-optimal serum albumin levels. Albumin is the most fruit juice, Seville oranges, tangelos, minneolas, and other
important drug-binding protein in the body. Hypoalbumin- exotic oranges inhibit the actions of cytochrome P450
15 emia diminishes the number of drug-binding receptor sites enzymes required for oxidative metabolism of numerous
and may result in reduced drug bioavailability [3]. drugs. This interaction is of greatest concern for oral drugs
It is in the patient’s best interest to minimize drug–nutri- with low bioavailability. Moreover, the effects of grapefruit
ent interactions. Patients who avoid these interactions are segments and grapefruit juice on the actions of cytochrome
more likely to experience the drug’s intended effect and less P450 enzymes can last up to 72 hours [3, 4].
prone to discontinue taking the drug earlier than recom- The presence of food and nutrients in the gut may
mended. Avoiding drug-induced nutrient deficiencies helps enhance the drug bioavailability. For example, the absorption
to maintain nutritional status, avoid falls, and injuries that of cefuroxime axetil (antibiotic) is increased when taken with
may be caused in part by nutrient imbalances [6, 7]. a meal versus a fasting state [13]. The bioavailability of iron
Not all patients have optimal nutritional status when a sulfate supplements is enhanced if taken with food or with
new drug is recommended. The undernourished individual ascorbic acid. However, certain food components and nutri-
may have nutrient insufficiencies that evolve into frank defi- ents may inhibit iron absorption, including high phytate
ciencies due to a drug-induced adverse effect. Malnutrition foods, bran, fiber supplements, coffee, tea, dairy products,
with loss of lean muscle mass is of concern because of altera- and calcium supplements [14, 15].
tions in protein-binding, drug distribution and drug elimina- Drug bioavailability may be altered when achlorhydria
tion. Drug distribution is the movement of an active drug or hypochlorhydria persists either due to the action of
from the bloodstream to the site of effect. It is affected by a another drug or because of a medical condition. Drugs used
number of factors, including lipophilicity and plasma protein to treat chronic acid suppression raise the pH of the stom-
binding. Drug elimination includes metabolism and excre- ach. The higher pH prevents drugs such as ketoconazole
tion of the drug. (antifungal) from reaching its optimal effect [3, 4].
Malnourished individuals experience loss of fat mass, . Table 15.1 summarizes common effects of food and nutri-
 

skeletal muscle mass and visceral muscle mass. The altered ents on drug kinetics.
Drug–Nutrient Interactions
215 15

..      Table 15.1  Common effect of food and nutrients on drug kinetics

Drug Food, macronutrient or Potential food–drug interaction

micronutrient

Antibiotics Milk Calcium and magnesium in milk may complex with drug and
reduce bioavailability [16–18]

Anticonvulsants Grapefruit juice, grapefruit Reduce bioavailability by inhibiting the actions of the cytochrome
segments, Seville oranges, P450 3A enzymes [19]
tangelos, minneolas, and other
exotic oranges

Antihypertensives Licorice Licorice may cause hypermineralocorticoidism with sodium

retention, increased potassium loss, edema, increased blood pressure
and depression of the renin-angiotensin-aldosterone system [20]

Calcium channel drugs with Grapefruit juice, grapefruit Reduce bioavailability by inhibiting the actions of the cytochrome
Calcium Channe l drugs segments, Seville oranges, P450 3A enzymes required for oxidative metabolism of numerous
HMG-CoA Reductase Inhibitors tangelos, minneolas, and other drugs [3, 4, 19]
exotic oranges

Celiprolol (beta-blocker) Orange juice Hesperidin, present in orange juice, is responsible for the decreased
absorption [21]

Monoamine oxidase inhibitors Tyramine-containing foods Consuming foods containing tyramine with MAOI may trigger a
hypertensive crisis [22]

Psychotropics Grapefruit juice Components in grapefruit juice interfere with the intestinal efflux
transporter P-glycoprotein (P-gp) [23, 24]

Warfarin Foods rich in vitamin K Inconsistent intakes of vitamin K rich foods may alter the effective-
ness and safety of warfarin [25, 26]

Cranberry juice Consumption of cranberry juice is reported to alter the effective-

ness and safety of warfarin in some individuals [27, 28]

15.2  Effect of Drugs on Food and Nutrient reabsorption of the nutrient. Drugs that decrease normal
Kinetics and Nutrition Status nutrient excretion of sodium may result in water retention.
Drugs that cause damage to the absorptive surfaces have
Drugs have the potential to alter food and nutrient intake the greatest potential to affect nutrient absorption. Common
and kinetics. Nutrients are essential for metabolic processes, offenders include chemotherapeutic agents, nonsteroidal
and micronutrients reserves, or pools, are quickly depleted anti-inflammatory drugs, and prolonged antibiotic therapy.
when the metabolic rate is increased, absorption and utiliza- . Table  15.2 summarizes potential drug-induced nutrient
 

tion of key nutrients are reduced, or excretion of nutrients is deficiencies.

increased.
Drugs have the potential to impact nutrition status in
many ways. Many prescription and non-prescription drugs 15.3  Role of the Nutrition Professional
reduce appetite, which reduces total nutrient intake. Other
drugs increase the appetite for all food or specific categories Malnutrition and nutrient deficiencies are often viewed as
of foods, e.g., refined carbohydrates, resulting in excessive problems unique to developing countries and regions of the
energy and refined sugar intake. Moreover, drugs can reduce world affected by environmental disasters, famine, or politi-
the absorption of key nutrients in the gastrointestinal tract in cal unrest. However, malnutrition and nutrient deficiencies
a variety of ways, including altering the stomach pH, binding are seen globally. Malnutrition diagnoses may be overlooked
the nutrient into an unusable form, and damaging the because the medical team is not mindful of the potential for
absorptive surfaces. nutrient losses to occur. It is essential to recognize that some
Drugs may increase the metabolism of nutrients, thereby drug-induced nutrient insufficiencies and deficiencies are
increasing requirements and depleting nutrient reserves. insidious and others develop quickly. Drug-induced nutrient
Moreover, drugs may block the conversion of a pre-vitamin deficiencies are compounded by malnutrition. The early
to its active form. Key nutrients may be lost in urine and signs and symptoms of nutrient insufficiencies and deficien-
feces. Drugs may increase or decrease urinary excretion. An cies are often nonspecific and may be overlooked or misdiag-
increase in urinary excretion is typically due to a reduction in nosed. Laboratory assessments used concurrently with
 216 M. D. Litchford

..      Table 15.2  Common effects of drugs on food and nutrient kinetics

Drug category Macronutrient or Potential consequences of food–drug interaction

micronutrient loss

Antacids, magne- Calcium, magne- Increased stomach pH and reduced absorption of key nutrients that are best absorbed in
sium and aluminum, sium, phosphorus, the duodenum with a low pH including folic acid [29], calcium, phosphorus, copper, and
calcium carbonate, folic acid, copper, iron [30, 31]
proton pump iron, vitamin B12
inhibitors (PPI) It is unclear how PPI’s promote hypomagnesemia [30–32]

Aluminum can bind the phosphate in small intestine, thus lowering serum levels. The body
responds by releasing calcium and phosphorus stores from the bones. Calcium levels are
tightly controlled in the blood. Excess calcium is excreted in the urine [30]

Increased pH impairs the body’s ability to cleave vitamin B12 from its protein carrier in order
to be transported via intrinsic factor (IF). IF is synthesized by the parietal cells in the stomach
in the presence of a low pH. An increased pH reduces the synthesis of IF, which will result in
reduced absorption of vitamin B12 [33]

Antiarrhythmic: Magnesium Digoxin promotes increased renal excretion of magnesium [34]

digoxin

Antibiotics, Folic acid May interfere with folic acid metabolism if taken for a prolonged period of time [35]
sulfonamide
combination drugs

Antibiotics, Magnesium, iron, Drug binds to iron, magnesium, zinc, and calcium creating insoluble complexes [36, 37]
fluoroquinolones zinc, calcium

Antibiotics, Magnesium, iron, Drugs binds to iron, magnesium, zinc, and calcium creating insoluble complexes. May
tetracyclines zinc, calcium, reduce bacterial synthesis of vitamin K2, menaquinone, in the colon. Long-term use may
vitamin K, B result in depletion of B vitamin stores [38]
complex vitamins

Anticonvulsants Vitamin B6, vitamin May interfere with vitamin B6, vitamin B12, and folate absorption, resulting in lower serum
B12, folate levels [39, 40]

Anticonvulsants Biotin May accelerate catabolism of biotin resulting in lower serum levels [41]

Anticonvulsants Vitamin D Lower serum levels reported possibly related to low bone density and osteomalacia [42]

Anticonvulsants Calcium Reduced absorption possibly related to vitamin D deficiency [43]

15 Anticonvulsants Vitamin K Drugs may decrease half- life of vitamin K and impair its key functions [44, 45].

Antihyperglycemic Vitamin B12 Metformin appears to inhibit the absorption of vitamin B12 [46]
metformin

Antihypertensive: Zinc ACEI and ARB therapy has been shown to increase urinary excretion of zinc [47]
ACEI angiotensin-­
converting enzyme
inhibitor; ARB,
angiotensin
receptor blocker

Antihypertensive: Potassium ACEI and ARBs are associated with increased serum potassium, which may or may not be
ACEI angiotensin-­ offset by the reduction of potassium due to loop diuretics [48, 49]
converting enzyme
inhibitor; ARB,
angiotensin
receptor blocker

Antihypertensive: Vitamin B6, copper Hydralazine may interfere with vitamin B6 metabolism. It may promote increased excretion
hydralazine of copper [50, 51]

Antihypertensive: Potassium RAAS have the potential to cause hyperkalemia by interfering with the production and
RAAS renin-­ secretion of aldosterone [52–56]
angiotensin-­
aldosterone system

Antimanic: lithium Sodium Lithium may increase sodium excretion [57]

Drug–Nutrient Interactions
217 15

..      Table 15.2 (continued)

Drug category Macronutrient or Potential consequences of food–drug interaction

micronutrient loss

Antineoplastic: Folic acid Methotrexate is a folic acid antagonist that interferes with nutrient utilization [58, 59]
methotrexate

Antiplatelet agents Iron, folic acid, Long-term use associated with reduced levels of iron, folic acid, sodium, potassium, vitamin
sodium, potas- B12 [60, 61]
sium, vitamin B12

Antipsychotics, Riboflavin Drug increases the excretion of riboflavin that may lead to deficiency in individuals with
phenothiazine class, insufficient riboflavin intakes [62]
tricyclic antidepres-
sants

Antitubular: Vitamin B6, niacin Drug may deplete vitamin B6 and niacin stores resulting in peripheral neuropathy and
isoniazid (B3), vitamin D, pellagra [63, 64]
calcium, phos-
phate May impair vitamin D metabolism and consequently reducing calcium and phosphate
absorption [65]

Beta-adrenergic Potassium Beta-blockers have the potential to cause hyperkalemia by causing redistribution of
blockers (beta- potassium from the intracellular space into the serum [66, 67]
blockers)

Beta-2 agonists Magnesium, Reduced serum levels of magnesium and potassium reported. The degree of deficiency is
potassium exacerbated when beta-2 agonist is taken with theophylline [68, 69]

Bile acid seques- Vitamins A, D, E, K, Bile acid sequestrants bind fat soluble vitamins, beta-­carotene, and iron [70]
trants beta-carotene, iron

Bile acid seques- Magnesium, iron, Alterations in calcium, magnesium, and zinc metabolism may be explained by inadequate
trants calcium, zinc and vitamin D absorption in the duodenum followed by an increased secretion of parathyroid
folic acid hormone [71]

Bronchodilator: Vitamin B6, Reduced levels of pyridoxal phosphate may be related to altered tryptophan metabolism or
theophylline potassium, impaired vitamin B6 utilization. Reduced levels of potassium and magnesium have been
magnesium reported, possibly related to increase urinary excretion [72–75]

Colchicine Vitamin B12 In animals, colchicine may reduce vitamin B12 absorption and efficiency of ileal receptor
(antigout) sites leading to a vitamin B12 insufficiency or deficiency [76, 77]

Diuretics: loop Sodium Loop diuretics reduce sodium reabsorption in the proximal tubule. Patients who are
prescribed a sodium-­restricted diet as part of medical management of hypertension are at
greater risk of hyponatremia [57]

Diuretics: loop Potassium Loop diuretics reduce potassium reabsorption at the site of action and enhance potassium
secretion in the distal tubules of the nephron. In addition, aldosterone can also contribute
to hypokalemia after administration of loop diuretics [78]

Diuretics: loop Magnesium Loop diuretics reduce magnesium reabsorption in the loop of Henle and proximal tubule. It
is also dependent on sodium and chloride concentrations. Magnesium depletion promotes
the efflux of potassium from cells and subsequent urinary excretion [79–81]

Diuretics: loop Thiamine Long-term use is associated with reduced levels of thiamine. Loop diuretics promote
thiamine losses up to twice baseline loss. Increased loss is associated with an increase in
urine flow rate, but it is not related to sodium excretion. Up to 1/3 of CHF patients were
found to be thiamine deficient [82–88]

Diuretics: loop Zinc Long-term use of loop diuretics reduce zinc reabsorption in the proximal tubule [89]

Diuretics: loop Calcium Loop diuretics reduce calcium reabsorption in the proximal tubule. It is also dependent on
sodium and chloride concentrations [90]

Diuretics: thiazide Calcium Thiazide diuretics reduce calcium reabsorption in the proximal tubule. It is also dependent
on sodium and chloride concentrations [90]

(continued)
 218 M. D. Litchford

..      Table 15.2 (continued)

Drug category Macronutrient or Potential consequences of food–drug interaction

micronutrient loss

Diuretics: thiazide Sodium Thiazide diuretics reduce sodium reabsorption in the proximal tubule. Patients who are
prescribed a sodium-­restricted diet as part of medical management of hypertension are at
greater risk of hyponatremia [57]

Diuretics: thiazide Potassium Thiazide diuretics reduce potassium reabsorption at the site of action and enhance
potassium secretion in the distal tubules of the nephron.
In addition, aldosterone can also contribute to hypokalemia after administration of loop
diuretics [91]

Diuretics: thiazide Magnesium Thiazide diuretics reduce magnesium reabsorption in the loop of Henle and proximal
tubule. It is also dependent on sodium and chloride concentrations. Magnesium depletion
promotes the efflux of potassium from cells and subsequent urinary excretion [79–81]

Diuretics: thiazide Zinc Long-term use of thiazide diuretics reduce zinc reabsorption in the proximal tubule [92]

Glucocorticoids Zinc Glucocorticoids may promote development of zinc deficiency in some patients [89, 90]

Glucocorticoids Calcium, Chromium Glucocorticoids increase urinary losses of chromium and calcium [93, 94]

Immunosuppres- Magnesium Cyclosporine promotes renal magnesium wasting [95]

sant: cyclosporine

Immunosuppres- Vitamin D Hydroxychloroquine may inhibit the conversion of 25-hydroxyvitamin D to the active form,
sant: Hydroxychlo- i.e., 1,25 dihydroxyvitamin D [96]
roquine

Laxatives, cathartics Calcium, potas- Laxatives reduce transit time in the gut leading to diarrhea and increased fecal loss of
sium calcium and potassium [97]

Mineral oil laxatives Vitamins A, D, E, K Mineral oil-based laxatives may reduce the absorption of fat soluble vitamins [98]

Peripheral Vitamin B6 Peripheral vasodilators interfere with vitamin B6 metabolism and may result in lower
vasodilator levels [50, 99]

nutrition-focused physical exams are essential tools to detect in nutrition status are essential to determine the efficacy of
drug-induced nutrient insufficiencies and deficiencies. interventions.
15 The nutrition professional’s approach to detect drug- The nutrition professional does not work in a vacuum. As
induced nutrient insufficiencies and deficiencies is deter- a member of an integrative healthcare team, the nutrition
mined by the patient’s health history. For example, patients professional provides valuable insight and findings to
who are starting on a new drug are looked at prospectively. improve the health and well-being of patients.
The nutrition professional uses clinical judgment to predict
the potential for drug-induced nutrient insufficiencies and
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 221 16

The Enterohepatic Circulation

Robert C. Barton Jr.

16.1 Enterohepatic Circulation (EHC) - Definition – 222

16.2 Introduction – 222

16.3 Overview – 222

16.4 Details of Microanatomy, Physiology, and Biochemistry – 222

16.4.1  ortal Vein – 222
P
16.4.2 Portal Tracts – 222
16.4.3 Liver/Hepatic Lobule – 223
16.4.4 Hepatic Sinusoids and Hepatocytes – 223
16.4.5 Interaction of Sinusoidal Blood with the Hepatocyte
Basolateral Cell Membranes – 223
16.4.6 Metabolic Zonation/Organization of Hepatocytes by their
Function – 224
16.4.7 Functions of the Liver – 225
16.4.8 Xenobiotics – 225
16.4.9 Where Are Xenobiotics Found? – 226
16.4.10 A Few Examples of Problems Caused by Xenobiotics – 227
16.4.11 Biotransformation – 227
16.4.12 Cytochrome P450 Genes and Enzymes – 228
16.4.13 Single-Nucleotide Polymorphisms – 228
16.4.14 Bile and the Biliary System – 228
16.4.15 Small Intestine – 229
16.4.16 Microbiome/Metabolome – 230
16.4.17 Enteric Nervous System – 230
16.4.18 Gut-Associated Lymphoid Tissue – 231
16.4.19 Enteric Endocrine Cells – 231
16.4.20 Terminal Ileum – 231
16.4.21 Large Intestine – 231

16.5 Conclusion – 231

References – 232

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_16
 222 R. C. Barton Jr.

Derivation of the name their systemic effects [11, 12]. The metabolic effects of bile acids
Enteron - Intestine (Greek) are also garnering increased attention [13, 14]. Thus, under-
Hepar - Liver (Greek) standing of the functions of the EHC has increased dramatically
over nearly 100 years, and we can only expect this to continue.

16.1  Enterohepatic Circulation

(EHC) - Definition 16.3  Overview

The circulation of bile acids, bilirubin, drugs, or other sub- To refresh our understanding of the structure of the EHC, the
stances from the liver to the bile, followed by entry into the following drawing and comments will provide an overview.
small intestine, absorption by the enterocyte and transport The purpose of this section is to provide a basic, common
back to the liver. Recycling through liver by excretion in bile, understanding of the EHC as a system (. Fig. 16.1).
 

reabsorption from intestines into portal circulation, passage

back into liver, and re-excretion in bile [1].
16.4  Details of Microanatomy, Physiology,
and Biochemistry
16.2  Introduction
The following sections will present a much more detailed
The purpose of this chapter is to provide insight into the func- understanding of some of the individual components of the
tioning of the enterohepatic circulation (EHC) as it relates to EHC,  how they relate together, and how the EHC interacts
the practice of clinical nutrition. The focus will not be on dis- with the rest of the body. This will help provide a framework
ease management; rather, it will be on ways in which improv- for further study, and to provide a foundation for under-
ing the health and function of the tissues and organs of the standing why nutrition needs to be incorporated into the root
EHC might be approached. of medical education. In one sense, nothing said here is new,
Health professionals, of any level of training or experi- but will aid in expanding understanding of nutritional thera-
ence, are the intended audience. To be inclusive, the content pies [15].
may be helpful for those who aspire to become health profes-
sionals, those who want to understand human physiology in
greater depth and anyone who is interested in learning how to 16.4.1  Portal Vein
create a better state of health. This chapter should help those
with training in conventional Western medicine who employ The portal vein and its tributaries drain the entire intestinal
a “mainstream” approach to healthcare, but who feel that tract from the gastroesophageal (GE) junction at the top of
there is more to patient care than they are equipped to deliver. the stomach, all the way to the anus. This is a distance of
It should help open channels of communication and new 33 feet (11 yards) in the average adult. Through these veins,
thought processes to investigate ways to deliver patient- all the blood flowing from the stomach, small, and large
focused healthcare and guide the practitioner to find a new intestines is carried directly to the liver. Veins, in general,
16 group of like-minded professionals. carry blood toward the heart. In the case of the portal vein
The foundation of what we do is basic science. Yet science and its tributaries, the blood ultimately reaches the heart, but
is always growing. What we know now about the EHC is after being processed in the liver. This portal venous system
vastly different from what was known in 1923, the date of one is separate from and parallel to the systemic veins, which
of the earliest publications on the subject [2]. The role of the carry blood from all the other organs and tissues in the body
EHC in the recirculation and conservation of bile salts is directly to the heart.
foundational and was known from the beginning. But the
awareness that the EHC also handles hormones, drugs, and
other substances, both endogenous and exogenous, emerged 16.4.2  Portal Tracts
over the next 40 years [3–8]. In the subsequent 50 years, these
topics have been extensively studied and documented. The In the liver, the portal vein branches like a large tree. The tiniest
role of the EHC in the metabolism of xenobiotics (see below) branches are called portal venules, which travel through the
began to emerge later. The first use of the term “xenobiotic” liver in a network of fibrous channels called portal tracts. In
in the Medline database was in 1965 [9]. addition to the portal venules, the portal tracts carry tiny arteri-
The term gut “microbiome” first appeared in 2002, and it oles from the hepatic artery, which carry highly oxygenated
became clear that colonization with healthy bacteria is critical blood directly from the heart. About 70% of the blood supply to
for the normal structural and functional development, and the the liver comes from the portal venules and so from the
optimal function of the mucosal immune system [10]. Other intestines, the remaining 30% from the hepatic arterioles
­
areas of important research include the relationships between (. Fig. 16.2).
 

the microbiome, the gut-associated lymphoid tissue, the enteric Also coursing through the portal tracts are bile ductules,
nervous system, and the enteric endocrine cells in regard to which carry bile out of the liver; lymphatic channels, which
The Enterohepatic Circulation
223 16
..      Fig. 16.1 (1) Portal vein &
portal tributaries. Carries blood
from the intestinal tract into liver;
(2) Liver. Functions: nutrients
synthesized into metabolic
compounds transported and
utilized by organs; detoxification Liver
processes; stabilization of blood Gall bladder
Draining into
glucose; synthesization of ATP; Common bile duct
bile production; (3) Bile ducts and
gallbladder. Bile, the main secre-
tory product of the liver, is stored
and processed in the gallbladder;
(4) Small intestine. Duodenum: Portal vein Common bile duct
(entering liver) Drains into duodenum
first part of the small intestine (small intestine)
& portal tributaries
receiving bile and pancreatic (draining entire
enzymes; jejunum and ileum: small Intestine &
second and third portions of the colon)
Colon
small intestine where digestion
occurs; (5) Terminal ileum. Final 6
inches of the small intestine where
95% of the bile is absorbed and
recirculated to the liver, histori-
cally the origin of the term entero-
hepatic circulation; (6) Large Terminal
intestine or colon. The final five Small intestine
Ileum
feet of the intestine where stool
is concentrated, other metabolic
processes occur, and the resulting
feces are discharged through the
anus; further absorption of bile
also occurs, entering the portal
circulation. (Adapted from [49].
With permission from Wolters
Kluwer Health)

carry lymphatic drainage away from the liver; and branches The central hepatic venule is the smallest branch of the hepatic
of the autonomic nervous system, evidence of the input of vein, which carries blood back to the heart.
the autonomic nervous system into functioning of the liver
on a cellular level.
16.4.4  Hepatic Sinusoids and Hepatocytes

16.4.3  Liver/Hepatic Lobule Exiting the portal tracts, blood from the portal venules
merges with blood from the hepatic arterioles and flows into
Viewed under light microscopy, the liver parenchyma con- a vast vascular web called the hepatic sinusoids, which extend
sists primarily of a single cell type, the hepatocyte or liver throughout the liver (. Fig. 16.3). Blood flow into the sinu-
 

cell. Hepatocytes occur in extensive sheets of cells with an soids is regulated by specialized tissues in the portal venules
essentially uniform appearance, which are interwoven with and hepatic arterioles as they emerge from the portal tracts.
the hepatic sinusoids. (See section below) The classic unit of Hormones, autonomic nervous input, and other factors influ-
hepatocyte organization is called the hepatic lobule. This ence this sinusoidal blood flow. Part of the cell membrane of
structure is composed of six portal triads and a central vein, each hepatocyte (the basolateral membrane) is adjacent to a
and can be seen under the microscope. However, because the sinusoid. It is through this basolateral membrane that trans-
lobule is a three dimensional structure in vivo , the classic port of molecules into the hepatocytes occurs for processing.
hexagonal lobular structure is seldom seen in photomicro-
graphs of a 2-dimensional cut section.
Each lobule consists of an average of six portal tracts form- 16.4.5  Interaction of Sinusoidal Blood
ing the corners of a hexagon made up of hepatocytes, with a with the Hepatocyte Basolateral Cell
central hepatic venule (CV) or terminal hepatic venule (THV) Membranes
located approximately in the center. Blood enters through the
portal tracts at the periphery of the lobule, flows into the sinu- In the sinusoids, the liquid part of the blood, the serum,
soids adjacent to the hepatocytes, is processed while traversing bathes the basolateral membranes of the hepatocytes. These
the sinusoid, and then empties into the central hepatic venule. cell membranes are highly specialized to carry out specific
 224 R. C. Barton Jr.

Bile ductule Hepatic arteriole Portal venules

Sinusoids

..      Fig. 16.2  (Portal tract photo) Portal tracts course in a vast network nels and branches of the autonomic nervous system are not visible in
through the liver with the terminal branches of the portal venules this photomicrograph. The cells around the portal tract and adjacent
carrying blood from the intestinal tract and hepatic arterioles carry- to the sinusoids are periportal hepatocytes in which many synthetic
ing highly oxygenated blood from the heart. Portal blood mixes with and energy-producing steps occur. (Courtesy of Beverly B. Rogers MD,
16 hepatic arteriolar blood and flows into the sinusoids. Lymphatic chan- Emory University School of Medicine)

functions, and these functions vary as the blood flows Northridge, personal communication). In other words, inter-
through the sinusoids. As with cell membranes throughout actions between serum molecules with the basolateral mem-
the body, the basic hepatocyte cell membrane structure con- brane of hepatocytes are not simply random collisions. There
sists of molecules called phospholipids. Cholesterol is also a are dynamic and specific interactions which direct individual
vital membrane component. Membranes are highly struc- molecules to their corresponding transport channels so the
tured, yet fluid and flexible. Studding the membranes are processes of hepatic metabolism can proceed in orderly fash-
hundreds of different types of transport channels, usually ion. Other aspects of the sinusoidal anatomy (fenestrated
constructed from proteins, which allow molecules to move in endothelial cells, space of Disse, Kupffer cells, stellate cells, and
and out of the hepatocytes in coordinated fashion. others), although fundamental and vital, will not be discussed
Interactions of serum molecules with the basolateral cell here, and the reader is referred to texts to expand knowledge.
membrane transport channels are not haphazard or random.
As with cell membranes anywhere in the body, enzymes which
comprise the transport channels seem to have a specific affin- 16.4.6  Metabolic Zonation/Organization
ity for molecules they transport based on many factors, includ- of Hepatocytes by their Function
ing pH, electrostatic forces, molecular size and folding (S
Finnegan, Research on lactase and carbohydrase enzymes The first article on metabolic zonation was published by Katz
(Lactaid and Beano), Quality Control Director, Body Bio and Jungermann in 1976 [16]. Techniques have since been
Corporation, personal communication, 2016; R Silva, developed whereby the hepatocytes adjacent to the portal
Emeritus Professor of Chemistry, California State University tract (periportal hepatocytes) and those adjacent to the cen-
The Enterohepatic Circulation
225 16

..      Fig. 16.3  (Sinusoid photo) Scanning electron micrograph show- some of the hepatocytes. (The cells designated K are kupffer cells, and
ing rows of hepatocytes (H) adjacent to hepatic sinusoids (S) with bile are not discussed here.) (Reprinted from Schiff et al. [50]. With permis-
canaliculi visible as small, winding grooves visible on the surface of sion from Wiley)

tral vein (perivenular hepatocytes) can be isolated from one Zone 1 (Z1) is more highly oxygenated than Zone 3 (Z3)
another, and their properties studied [17]. The hepatocytes in [17]. Many details of metabolism in Z1 and Z3 have been
a liver lobule vary in their function, depending on their posi- identified (. Fig.  16.5), but there is much yet to be discov-
 

tion along the path from the portal tract to the central ven- ered. The details of this metabolic zonation can vary from
ule. The generally uniform appearance of the liver under light time to time. Some of the driving forces have been identified,
microscopy does not accurately depict the highly specialized including oxygenation, pH, hormones, nutrients, metabo-
and tightly regulated functions of different hepatocyte popu- lites, cytokines, and molecules called morphogens, the most
lations (. Fig. 16.4).
  well-known of which is named Wnt (beta) catenin, [17].
While the hepatic lobule describes structure, the concept of In summary, at the microscopic level of function, the
the liver acinus, first put forth by Rappaport [18], is related to complex processes of hepatic metabolism are proceeding and
hepatocyte function. Periportal hepatocytes have a higher oxy- constantly adjusting to both what is delivered from the portal
gen content and perform different metabolic functions com- circulation and to inputs from the rest of the body, including
pared to perivenular hepatocytes. Rappaport called the periportal hormonal signals and those from the autonomic nervous
area, Zone 1, the perivenular area, Zone 3, with Zone 2 repre- ­system.
senting the intermediate area between Zones 1 and 3 [17, 18].
In their study on the microvasculature of the liver,
Matsumoto and Kawakami found the organization of the 16.4.7  Functions of the Liver
vascular flow through the sinusoids is reflected in the pre-
cise detail seen on the microscopic level [19]. What might The liver is the most potent synthetic factory in the body and a
otherwise seem like a random flow of blood from the portal significant organ for waste processing and disposal. See
venules and hepatic arterioles into the liver parenchyma via . Table 16.1 for a summary of some of the important functions.
 

the sinusoids is, in fact, a highly structured hemodynamic

process which feeds the blood flow through the sinusoids in
an organized fashion, with the resulting effluent flowing into 16.4.8  Xenobiotics
the central hepatic venules [19, 20]. The results of their find-
ings are congruent with the acinus concept, with periportal The term “xenobiotic” is derived from two Greek words,
and perivenular hepatocytes performing different functions. xenos meaning foreign or strange, and bios meaning life.
 226 R. C. Barton Jr.

..      Fig. 16.4  [Hepatic lobule

photomicrograph (a) and draw- a
ing (b)]. (a) Photomicrograph:
Portal tract (lower left) and
central venule (upper right) with
sheets of hepatocytes inter-
spersed with the intervening vas-
cular sinusoids. Blood entering
the liver through the portal tract
flows into the sinusoids where it
is processed and flows out of the
liver through the central venule.
Hepatic lobules typically consist
of six portal tracts. (b) Diagram:
Depiction of five classic hepatic
lobules. Triangles correspond to
portal tracts, from which blood
flows to centrally located central
venules; detailed microvas-
cular work of Matsumoto and
Kawakami contribute to concept
of the hepatic acinus proposed
by Rappaport; metabolic func-
tions occur in these hepatic 20X original magnification
lobular structures. (a) (Courtesy PAS with diastase stain of liver showing central vein (upper right)
of Beverly B. Rogers MD, Emory blending into sinusoid.
University School of Medicine). Portal tract is lower left
(b) (Reprinted from Schiff et al.
[50]. With permission from Wiley) b Matsumoto and Kawakami Rappaport

Nodal region
Zone 1 (periportal)
Periportal (sickle) zone
Zone 2
Intermediate zone
Zone 3 (perivenular)
Pericentral zone
16
Preterminal portal tract

Septal portal venule Terminal portal venule

Central vein Terminal hepatic venule

Xenobiotic can be defined as a chemical compound foreign cyte, nutrients can be used in synthesis of macromolecules
to a given biological system. With respect to animals and (building blocks for the body), metabolized through the elec-
humans, xenobiotics include drugs, drug metabolites, and tron transport chain to produce ATP, and for other purposes.
environmental compounds such as pollutants that are not A xenobiotic, on the other hand, must undergo a process
produced by the body. In the environment, xenobiotics called biotransformation. The products of biotransformation
include synthetic pesticides, herbicides, and industrial pol- are excreted from the liver in the bile, or in a minority of
lutants that would not be found in nature [21]. For further cases, sent into the systemic circulation, where some accu-
information see 7 Chap. 13.
  mulate in other organs including the brain, liver, lung, fat,
An important functional distinction is that molecules kidney, and/or bone (See . Table 16.2).
 

absorbed from the small intestine and transported to the liver

can be viewed as either “nutrients” or “xenotiobitcs”. A nutrient
molecule, once it reaches the liver, does not require further 16.4.9  Where Are Xenobiotics Found?
breakdown or processing to be used metabolically. Examples of
nutrients include amino acids from proteins, monosaccharides We are exposed daily to many harmful environmental chem-
from complex carbohydrates, and cholesterol. In the hepato- ical toxicants. The Centers for Disease Control and Prevention
The Enterohepatic Circulation
227 16

ThV
Z3 Damage due to anoxia, alcohal,
biotransformation of grugs and nutritional deficiency
Glucokinase 3 α-Hydroxysteroid dehydrogenase
Pyruvate kinase Glycolysis β-Hydroxybutyrate dehydrogenase
6-Phosphogluconate dehydrogenase Glucose 6-p-dehydrogenase
Glucose-6-phosphate isomerase Esterases
Fatty acid oxidation Ketoreductase
Malic enzyme
Isocitrate dehydrogenase Gluconeogenesis Thiolacetic sacid esterase
Acetyl CoA carboxylase
NAD-NADP-tetrazolium Hexokinase Lipase
Phosphorylase Glutaminase Malate dehydrogenase
reductase (diaphorases) γ-Glutamyl transpeptidase Glucose 6-phosphatase Lipogenesis
Tyrosine aminotransferase Fructose-1, 6-bisphosphatase
Alanine aminotransferase UDP glucose; glycogen
and pigment
Glutamic pyruvate transminase α-4-Glucosyltransferase formation
Z3 Ornithine carbamoyl transferase Phosphoenol pyruvate
Glutathione caraboxykinase
Lysosomes Lactate dehydrogenase Bile-salt–
Carbamoyl
Phosphate synthetase independent
secretion of
canalicular bile
1 Z
Z1
Rich Golgi volume
Mitochondria; numerous, larger
more inner membranes Z3
Cytochrome oxidase
Glutathione peroxidase Mitochondria; smaller, less
Succinate dehydrogenase inner membranes
Alkaline phosphatase
ATP-ase Increased microbodies
ß-GIucuronidase acid peptidases
BD
PV No arterioles
Ornithine aminotransferase
Glutamic dehydrogenase
Glutamine synthetase
HA Glutathione S-transferase
Biotransformation
ThV
Rich in smooth ER; increased microsomal activity Z3
Alcohol dehydrogenase
Cytochrome P-450
NADH and NADPH tetrazolium reductase
NADPH cytochrome C reductase

..      Fig. 16.5  (Schiff Z1 and Z3 characteristics) Diagram depicting which metabolize xenobiotics. Blood flowing from the portal tracts is
some of the known metabolic processes occurring in Zone 1 (peripor- first exposed to the hepatocytes in Zone 1, periportal areas, ultimately
tal) and Zone 3 (perivenular) of hepatic lobules. Zone 1, biosynthetic reaching Zone 3, the perivenular hepatocytes. (Reprinted from Schiff
and energy producing processes; Zone 3, biotransformation enzymes et al. [50]. With permission from Wiley)

(CDC) lists 265 environmental chemicals, many of which diethylstilbestrol which showed the exposed individual’s sub-
were shown to be present not just in the environment, but in sequent risk in the development of vaginal cancer [23].
the tissues of individuals studied [22]. It would be profitable Subsequently, a consensus statement from the Wingspread
for the reader to access the CDC report and scan through it Conference in 1991 began with this statement, “We are cer-
to get a sense of the vast number of xenobiotics modern tain of the following: A large number of manmade chemicals
humankind is exposed to and understand this report gives that have been released into the environment, as well as a few
only a partial listing. The report details xenobiotic exposures natural ones, have the potential to disrupt the endocrine sys-
that may be present from multiple sources, including air, tem of animals, including humans” [24]. One important
water, food, skincare products, and cleaning chemicals, and approach to mitigating the problem of harmful xenobiotic
from a vast number of industrial sources that find their way exposures is addressing the liver’s biotransformation enzyme
into homes and the environment. systems, through which they are processed.

16.4.10  A Few Examples of Problems Caused 16.4.11  Biotransformation

by Xenobiotics
In the liver, xenobiotics, that is any molecules not treated as a
One of the first papers linking the harmful effects of environ- nutrient, are processed through the biotransformation
mental chemical exposures with fetal development was enzymes [25]. These biotransformation enzymes are located
 228 R. C. Barton Jr.

16.4.12  Cytochrome P450 Genes

..      Table 16.1  Important functions of the enterohepatic
circulation and the liver and Enzymes
Proteins (including albumin), lipids (fats, including cholesterol) The cytochrome P450 enzymes (CYP 450) are numbered to
and complex carbohydrates are synthesized and transported out indicate a specific group within the gene family, a letter indi-
of the liver
cating the gene’s subfamily, and a number assigned to the
Production of ATP, the principle energy storage molecule in the specific gene within the subfamily. A specific CYP gene codes
body, via the electron transport chain for the corresponding CYP enzyme. As of 2012, there were
Bile acids formed and secreted into the biliary system; also 57 human CYP enzymes, each with its specific propensity to
perform metabolic functions within the hepatocytes metabolize certain categories of xenobiotics [25–27]. One
example would be CYP 450 2D6, which is one of the cyto-
Glucose homeostasis occurs in the balance between gluconeo-
genesis (formation of the storage molecule glycogen) and chromes responsible for metabolizing hypertensive drugs.
glycolysis (release of glucose from glycogen) Another is CYP 450 2E1, which plays a role in the hepatotox-
icity of acetaminophen. There has been extensive research
Foreign substances (xenobiotics) are metabolized, mostly into
nontoxic substances, which can be secreted into the bile or sent into the CYP 450 genes and enzymes, and there are extensive
to long-term storage depots elsewhere in the body references regarding the CYP 450 enzymes and xenobiotic
metabolism [24, 26, 28, 29].
Important communication functions carried out by hormones
and the autonomic nervous system

16.4.13  Single-Nucleotide Polymorphisms

..      Table 16.2  Classes of xenobiotics Where there are genes, there are gene mutations. These muta-
tions code for altered proteins with varying structures and
Food additives activities. A common form of gene mutation is the single
Pharmaceuticals
nucleotide polymorphism (SNP), in which a single n ­ ucleotide
in a gene is changed, which may result in altered enzyme
Environmental pollutants, including many categories of function. There are extensive publications on the effects of
synthetic molecules
these polymorphisms on disease patterns and susceptibility
Heavy metals and drug metabolism [30, 31]. There are more than 6000
Genetically modified foods; unless the GMO modifications
review articles in the PubMed database detailing polymor-
produce nutrients, which are native to the human body, these phisms and their clinical effects.
foods fall into the category of xenobiotics In summary, if a healthy biologic system depends on
the normal function of its enzyme systems, mutated genes
and altered enzymes may have adverse effects on health.
almost exclusively in the perivenular hepatocytes, Z3, in the These consequences may vary from inconsequential to
liver acinus. Most xenobiotics are fat-soluble, serve no useful devastating. Perhaps nowhere else in the human body is
physiological purpose, and must be eliminated from the
16 body. In most situations, this occurs in a two-step process.
the problem with mutated genes and altered enzymes more
prevalent than in the liver’s biotransformation enzyme sys-
Phase I biotransformation (detoxification) occurs in the tems, which critically impact xenobiotic transformation.
smooth endoplasmic reticulum of the perivenular hepatocytes. Also important to understand is that while the biotransfor-
Most commonly, once a xenobiotic molecule enters the hepa- mation systems in the liver are vast, they are not infinite. If
tocyte, it encounters the cytochrome P450 enzymes, which our purpose is to create health, the focus should be on
convert the molecule into a highly energetic intermediate. feeding the system substances that are nutrients, not xeno-
These intermediates are then metabolized by Phase II biotrans- biotics, and allowing the pathways in the liver to function
formation enzyme pathways. The names of these pathways are as efficiently as possible. This requires optimizing nutrient
sulfation, glucuronidation, acetylation, methylation, amino intake and minimizing exposure to unnecessary xenobiot-
acid conjugation, and glutathione conjugation [25]. ics. Improving the function of Phase II biotransformation
The majority of the products of Phase II enzymatic reac- in an individual patient should serve to eliminate, or to
tions are secreted into the bile. A small percentage of the ameliorate the adverse health effects of many harmful
excretory products from the hepatocyte do not go into the xenobiotics.
bile; they are secreted back through the basolateral membrane
into the sinusoid, from which they enter the systemic circula-
tion and are carried to other organs and tissues. This most 16.4.14  Bile and the Biliary System
likely represents the pathway by which heavy metals (lead,
mercury, cadmium, etc.) reach and are ultimately stored in Bile is secreted from each hepatocyte into the bile cana-
other organs, such as the brain, kidney, lung, bone, and the liculus through a secretory process requiring energy [13].
liver itself. Please see 7 Chap. 13 for more in-depth discussion.
  . Figure  16.5 shows a bile canaliculus as it travels along
 
The Enterohepatic Circulation
229 16
adjacent hepatocytes on its way to the bile ductule in the 16.4.15  Small Intestine
portal tract. The bile ductules merge into the bile duct sys-
tem, which transports bile out of the liver. Bile then flows The small and large intestines can be seen as the main diges-
down the common bile duct and through the sphincter of tive organs of the body (. Fig.  16.6). The small intestine
 

Oddi into the second part of the duodenum, where it includes the duodenum, jejunum and ileum for a combined
mixes with intestinal content and begins its multifaceted length of about 25 feet. The large intestine or colon is about
function. 5  feet long. In the small intestine, proteins, carbohydrates,
When there has not been a recent meal, the sphincter of fats, vitamins, minerals and trace elements are processed,
Oddi is tightly closed, and the bile is diverted into the gall- and the products of digestion are absorbed through the intes-
bladder. However, the gallbladder is more than a simple stor- tinal wall.
age compartment. It concentrates bile and performs other The inner lining of the small intestine contains circular
important functions. When food is eaten, hormones, includ- folds called plicae, the surface of which is studded with leaf-­
ing cholecystokinin (CCK), are released, which cause gall- or-­finger like projections called villi. Enterocytes, the absorp-
bladder contraction, relaxation of the sphincter of Oddi, and tive cells in the small intestine, make up 90% of the cells
a bolus of bile is released into the duodenum. lining the villi [33]. The apical surface of each enterocyte
Bile is a micellar liquid. This means that the lipids/fats faces the intestinal lumen and is itself further folded into
(cholesterol, phospholipids) and proteins secreted by the microscopic tubular structures called microvilli. Because of
hepatocytes, when they reach a certain concentration in the the plicae, villi and microvilli, the absorptive surface of the
bile, spontaneously form into round or cylindrical transport small intestine which is exposed to food and other ingested
structures, which are carried in the ionic transport solution material is vastly increased - about the size of a tennis court
of the bile into the duodenum. Some molecules are carried in in an average adult.
the micellar component of bile, some in the aqueous or liquid Considering the large number and varied types of
component. Bile contains bile acids which are essential to ingested substances presented to the lining of the small intes-
normal fat digestion, and have other metabolic properties. tine, and the large surface area involved, the small intestine
Bile is a potent antioxidant, and carries products from hepatic performs a monumental task of identifying toxins and patho-
biotransformation out of the liver [32]. gens, digesting nutrients, maintaining the barrier function of

a b

20X original magnification

H&E

20X original magnification

Lymphatic space H&E
Ganglion cells
Peyer Patch

..      Fig. 16.6  Aspects of small intestine lining. (a) Photomicrograph of or not. (b) Photomicrograph of submucosal lymphoid tissue known
villi lining the mucosal surface of the small intestine. The predominant as a Peyer’s patch, part of the GALT (gut-associated lymphoid tissue).
cell type is the enterocyte, through which nutrients and xenobiotics Note lymphatic channels, and the capillaries which lead into the portal
pass. Approximate surface area of the small intestinal lining in an adult venous drainage. Fibers of the extensive enteric nervous system (the
is that of a tennis court, indicating the immense task of the enterocytes largest concentration of nervous tissue outside the central nervous
in distinguishing what should and should not be allowed to enter the system, and so called the “second brain” by some) are not visible in this
submucosal space, and hence the portal circulation. Everything swal- exposure. Enteric endocrine cells (EEC), part of the intestinal lining, are
lowed passes through the stomach into the small intestinal lumen, likewise not specifically distinguished. (Courtesy of Beverly B. Rogers
goes through processes of digestion, interacts with microbiome, and MD, Emory University School of Medicine)
is sorted and evaluated, to determine if it will be allowed into the body
 230 R. C. Barton Jr.

the intestinal wall, and choosing which substances to allow to of a healthy barrier function of the intestinal wall [35].
pass into the portal circulation. However, if the constituents of the microbiome are patho-
genic, the normal function of the microbiome is altered. The
composition of the microbiome is affected by diet, antibiot-
16.4.16  Microbiome/Metabolome ics, stress, and other factors.
The term “Metabolome” refers to the multiple metabolic
After partially digested food from the stomach combines processes associated with the microbiome. There are more
with bile and pancreatic secretions in the second part of the than 3000 articles referencing the metabolome, the first of
duodenum, it then passes into the jejunum and encounters which appeared in 2000 [39].
the microbiome. In an average adult, the microbiome is four
to five pounds of microorganisms which live in the lumen of
the small and large intestines [34–37]. The microbiome 16.4.17  Enteric Nervous System
begins to form immediately after birth. An infant’s first stools
are meconium, which is essentially digested amniotic fluid; An important part of overall intestinal function is nerve cells
cultures taken of meconium in healthy infants are sterile. in the wall of the small intestine forming a separate and intri-
Within a few days after delivery, microorganisms can be cate enteric nervous system (. Fig. 16.7). There are multiple
 

grown in culture. These microorganisms originate from the neuron types in multiple locations. These neurons communi-
breast, skin, and secretions from the birth canal. Breast feed- cate from one part of the intestine to another and back and
ing promotes growth of Bifidobacteria, which have been asso- forth with the central and autonomic nervous systems. There
ciated with the healthy nature of stool flora in infants [38]. is bidirectional information flow between the ENS and the
Bifidobacteria are well-known to be one of the more com- CNS and between the ENS and the sympathetic prevertebral
mon probiotic species in the microbiome [38]. In adults, if ganglia [11, 12].
the microbiome consists of healthy probiotic bacteria, such Sensory distress from the enteric nervous system can lead
as Lactobacillus, Bifidobacteria, and others, this contributes to symptoms such as nausea, bloating and pain. But most of
significantly to healthy intestinal function and thus to the the sensory signals from the intestine are not consciously per-
overall health of the individual. The microbiome assists in ceived. The enteric nervous system has been called the second
nutrient metabolism, protection against pathogens, process- brain [40] because of its many functions and its vast numbers
ing of antigens and presenting them to the ­ individual’s of neurons. There are more neurons in the enteric nervous
immune system, processing of xenobiotics, and maintenance system than anywhere else in the body except the central ner-

Oral Anal

3 Longitudinal muscle
4 5 8
9
1 Myenteric plexus
7
16 2 10
6
Circular muscle

15 12 14 17
11 13
Submucosal plexus
16
Arteriole Muscularis mucosa

Gland Mucosa

..      Fig. 16.7  Neurons found in small intestine defined by function, and motility reflex); (10) descending interneurons (migrating myoelec-
cell body morphology, chemistry, neurotransmitters, and projections tric complex); (11) submucosal IPANs; (12) non-cholinergic secretomo-
to targets. Neuron types: (1) ascending interneurons; (2) myenteric tor/vasodilator neurons; (13) cholinergic secretomotor/vasodilator
intrinsic primary afferent neurons (IPANs); (3) intestinofugal neurons; neuron; (14) cholinergic secretomotor (non-vasodilator) neurons; (15)
(4) excitatory longitudinal muscle motor neurons; (5) inhibitory lon- uni-axonal neurons projecting to the myenteric plexus; (16) motor
gitudinal muscle motor neurons; (6) excitatory circular muscle motor neuron to the muscularis mucosa; (17) innervation of Peyer’s patches
neurons; (7) inhibitory circular muscle motor neurons; (8) descending not illustrated, motor neurons to enteroendocrine cells. (Adapted from
interneurons (local reflex); (9) descending interneurons (secretomotor Furness [51]. With permission from Wiley)
The Enterohepatic Circulation
231 16
vous system. A number of commonly used phrases reflect this 16.4.21  Large Intestine
plentiful innervation of the GI tract, and its function in inter-
acting with the central and autonomic nervous systems: “I The large intestine, or colon, begins in the right lower abdo-
knew it in my gut,” “I had a gut instinct,” or “the bowels of men in a bulging pouch called the cecum. The terminal ileum
compassion.” empties into the cecum through the ileocecal valve (IC). The
structure of the IC is such that it prevents reflux of contents
from the cecum back into the ileum. The colon is approxi-
16.4.18  Gut-Associated Lymphoid Tissue mately 5 feet long, and digestion and nutrient absorption are
essentially complete by the time the intestinal contents enter
The small intestine has the job of sorting out whether mole- the cecum. There is a vibrant microbiome in the colon [47,
cules presented to its lining cells are friend or foe, as every- 48], and no doubt there are many metabolic functions yet to
thing ingested is not an ideal nutrient. Some substances can be clarified. One main role of the colon is reabsorption of
trigger allergic reactions while some are frankly toxic. Some water and electrolytes, preparing the stool to be passed from
molecules may be a known nutrient, but trigger the immune the body through the anus.
system to develop an autoimmune disease, the most well-­
known being celiac disease and the reaction to gluten/gliadin
proteins [41].
The lining of the small intestine serves as a barrier 16.5  Conclusion
between the outside world (ingested substances) and the
body. This is called the intestinal barrier function, or the Based on the structure and function of the EHC, the inges-
intestinal firewall [42]. Sometimes the function of the lin- tion of proper nutrients, possessing a healthy microbiome,
ing of the small intestine in forming a barrier to the outside maintaining an intact intestinal barrier function, and keep-
world is compromised in various ways. Molecules may ing exposure to xenobiotics to a minimum, the whole EHC
translocate or leak through the mucosal membrane by system will function as it was designed. However, if the
alternate pathways and can end up in the intercellular space microbiome is unhealthy, if the intestinal barrier function
below the mucosal lining enterocytes. This leads to allows toxic molecules to be taken up, or if there are insuffi-
increased intestinal permeability (referred to by some as cient nutrients or an overload of xenobiotics, the system will
“leaky gut”) [43]. not function well. This is a reasonable place to begin in
When non-nutrient molecules pass through the intesti- patient care. Using this paradigm and approach, patient care
nal lining, the gut-associated lymphoid (GALT) system is becomes conceptually simple: restore a healthy microbiome,
stimulated. In the small intestine, GALT resides throughout restore a healthy intestinal barrier function, ensure delivery
the intestinal wall in vast numbers of microscopic collec- of proper and optimal amounts of nutrients, take into
tions of lymphoid tissue. In the distal small intestine and account biochemical individuality, and minimize harmful
colon, these cell clusters occur in larger structures called xenobiotics. The goal becomes identifying ways in which
Peyer’s patches. function deviates from this norm and taking steps to restore
normal function. This is a vastly different approach from
waiting until an identifiable disease develops and is diag-
16.4.19  Enteric Endocrine Cells nosed, then treating that disease with medication and/or
surgery. In many cases the approach discussed above, based
There are more hormones produced in specialized cells of on correcting altered function, deals with the problem long
the small intestine than in any other organ in the body [44, before it forms.
45]. Hormones are messenger molecules that convey vari- Integrative nutritional care use is the closest approach to
ous messages between cells, between different parts of the returning to the roots of human physiology and biochemis-
small intestine, and between the small intestine and other try and allowing these principles, along with patients’ needs,
organs. to guide practice. In this approach, nutritional principles are
applied first, along with other principles of a healthy body.
Other healthcare disciplines are included in the treatment
16.4.20  Terminal Ileum process as they are found to be useful; none are excluded.
The conversations may include naturopaths, chiropractors,
The last 6 inches of the small intestine are structurally differ- herbalists, nutritionists, homeopaths, acupuncturists – any-
ent from the rest. This segment is called the terminal ileum. one who seems to have something to offer. At times, phar-
Vitamin B12 is absorbed at this location [46]. In this seg- maceuticals are needed. From the author’s observation,
ment, about 95% of the bile, which has remained inside the integrative nutritional therapy is not just a new buzz-word
intestinal lumen to perform its functions, is reabsorbed and or catch-­phrase. It is not a new discipline, to be replaced at
returned to the liver through the portal circulation. This some point by another. It represents the closest paradigm
absorption and recirculation of bile was the origin of the found leading to understanding the principles of human
name “entero-hepatic circulation”. physiology and allowing the use of nutrition to emerge from
 232 R. C. Barton Jr.

that awareness. Integrative and functional nutrition ­properly 20. Matsumoto T, Komori R, Magara T, Ui T, Kawakami M, Tokuda T, Taka-
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normal structure of the human liver, with special reference to its
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 235 17

A Nutritional Genomics Approach

to Epigenetic Influences
on Chronic Disease
Christy B. Williamson and Jessica M. Pizano

17.1 What Is Epigenetics? – 236

17.1.1 T he Epigenetics of Cardiometabolic Disease – 238
17.1.2 The Epigenetics of Psychiatric and Neurodegenerative Diseases – 240

17.2  he Epigenetics of Irritable Bowel Disease

T
and Dysbiosis – 244
17.2.1 The Epigenetics of Nutrient-Associated Diseases – 259

17.3 Epigenetics of Cancer – 261

17.3.1 Epigenetics of Mitochondrial Insufficiency – 262

17.4 Introduction to Pharmacogenetics – 263

17.4.1 Final Thoughts – 264

References – 264

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_17
 236 C. B. Williamson and J. M. Pizano

»» “Nutritional genomics refers to the application of “omics” hypomethylation activates it, thus in essence, hypomethylat-
technologies, together with systems biology and ing means to turn on the gene, while hypermethylation will
bioinformatics tools, to understand how nutrients typically turn it off. The goal is to have proper methylation,
interact with the flow of genetic information to impact not over or undermethylation. This chapter is an overview of
various health outcomes” [1]. Nutritional genomics is an the topics and is not an exhaustive review.
umbrella term that encompasses two distinct but related
fields: nutrigenomics and nutrigenetics. Nutrigenomics
may be defined as the measurable effect of nutrients on
the genome, proteome, microbiome and metabolome.
17.1 What Is Epigenetics?
Thus, the use of laboratory measures such as organic
The term epigenetics was originally coined by Waddington in
acids, amino acids, homocysteine, etc. may serve as an
1942. It was derived from the Greek word “epigenesis,” which
indicator of whether a gene is functioning or impaired
described the influence of genetic processes on development
due to a SNP, and to what degree. This clinical data may
[2, 3]. Modern day epigenetics is the study of gene expression
then be used to develop a personalized nutrition plan to
through histone or methyl modulation along with RNA
influence the biochemical pathways in which the SNP
silencing rather than the alteration of the genetic code
interacts. Nutrigenetics is similar as it also explores the
itself.  Epigenes are  additional instruction layered on top of
measurable interactions of nutrients on the genome,
our inherited genetic code (A, T, C, G, U); this additional
however, nutrigenetics is focused on the measurable
instruction is known as the epigenome. If we think of the
interactions between diet and disease risk and which
genetic code as the manuscript, the epigenetic information
dietary interventions influence intervention outcomes.
could be viewed as the highlighted or tagged sections. These
This may help predict how a patient may respond to a
“tags” or markers indicate to the instructional processors that
dietary intervention in terms of controlling or
something is either important or that it can be ignored.This is
exacerbating disease risk. It is therefore instrumental in
the science that turns “on” or “off ” the genes, which can result
the design of personalized nutrition plans to ameliorate
in both positive and negative outcomes.
symptoms or in the prevention of the development of
There are a multitude of “tags” that guide the genomic
various disease types. 
processors. Some are methyl groups, others are histone mod-
Nutrigenetics is focused on genetic variation and disease pre- ifiers, and some even modify RNA, one of the processors!
diction or the way that diet influences the risk of developing These tags work together to either increase or restrict access
a disease. Nutrigenetics is most often practiced by geneticists to the genome, therefore controlling the expression of the
and genetic counselors who are skilled in computational sta- proteins found within the genome. The really interesting part
tistics. Remember, this is disease prediction. Nutrigenomics is about these tags is that they are not corrected like our genetic
focused on how nutrients affect the genome and the bio- code. These tags or markers can change based on our life-
chemistry we can measure related to those lifestyle choices. style, experiences, diet, exercise habits, and exposure to
Measurement in this case is typically through metabolomics chemicals. This fluidity allows the epigenome to “learn” and
and microbiome analyses. Due to the reliance on metabolo- adapt to the current environmental circumstances. These
mics for validation, advanced nutrition professionals are the epigenetic markers can even survive what is called global
primary nutrigenomics practitioners. These are two distinct DNA demethylation, or the wiping clean of epigenetic mark-
fields under one large umbrella. Epigenetics intermingles ers from the gametes when a zygote is formed. Interestingly,
17 easily through both fields, making the scope a bit more chal- there is a process called imprinting whereby one of the par-
lenging to decipher. ent’s genes is “dominant” and silences the other allele. These
In these next sections, we will discover the salient genet- imprinted genes keep their epigenetic tags, even through
ics associated with several conditions. Some conditions and global demethylation. These are the tags that survive from
interventions will be strictly nutrigenetic in nature while oth- generation to generation and influence genetic expression.
ers are more nutrigenomic. There will be some overlap as that As the new embryo forms, other epigenetic tags physically
is the nature of the field. We will dive deeply into the nutri- record each cell’s experiences on the genome. In this record-
tional genomics and epigenetics of cardiometabolic disease; ing or writing stage, the epigenome ultimately stabilizes gene
neurodegenerative diseases like Alzheimer’s disease and expression allowing for proper embryonic development [4].
Parkinson’s disease; common psychiatric conditions such as Maternal diet, smoking status, mental state, and social
depression, anxiety, schizophrenia and bipolar disorder; environment can do one of two things. This environmental
understand the genomics of irritable bowel disease, mito- information can hypomethylate CpG islands, which in
chondrial insufficiency, cancer and nutrient-related autoim- essence turns on the gene, or it can result in RNA silencing,
mune diseases followed by an introduction to thus turning off the gene [4]. This means that the trauma that
pharmacogenomics. We will elucidate the effect that stress your great grandmother experienced at the turn of the twen-
has on methylation and the epigenome and discuss how tieth century could potentially increase your risk of develop-
common toxic exposures can influence methylation. ing a mental illness, such as depression. Fathers also have
Remember, hypermethylation silences gene expression while epigenetic transfer as well, thus, it also means that your
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
237 17
“health-nut” father could also confer more favorable cancer
and cardiovascular epigenetics [5].
There are three major systems that control epigenetics
including DNA methylation, histone modification, and
­non-­coding RNA (ncRNA)-associated gene silencing [4].
There are also less well-studied processes such as acetylation
and ubiquitination. In addition to these processes, the “sys-
tems” are also modifiable. For example, histone proteins are
responsible for packaging DNA via chromatin complexes
into dense chromosomes. Histone structures may be modi-
fied by acetylation of lysine residues, methylation of lysine
and arginine residues, phosphorylation of serine and threo-
nine residues, ubiquitination of lysine residues on histone
tails, sumoylation, and ADP ribosylation. Histone acetyl-
While pregnant, both of their mothers were fed
transferases (HATs) add acetyl groups to lysine residues on Bisphenol A (BPA) but DIFFERENT DIETS:
histone tails, whereas histone deacetylases (HDACs) can The mother of this mouse The mother of this mouse
remove the acetyl groups [4, 6, 7]. received a normal mouse received a diet supplemented
DNA methylation typically occurs at CpG islands, which diet with choline, folic acid,
betaine and vitamin B12
are most commonly found in gene promoter regions [6]. It is
at this CpG island that DNA methyltransferases (DNMTs)
coordinate the addition of a methyl group to the 5-carbon ..      Fig 17.1  These two mice are genetically identical and of the same
position of the cytosine residues where it regulates transcrip- age. The larger yellow obese Agouti mouse on the left received a diet
tion. DNMT1 exclusively maintains normal methylation by without methyl nutrients. The smaller brown healthy Agouti mouse on
exact duplication of DNA between cell generations. DNMT2, the right received a diet with methyl nutrients (choline, folic acid,
betaine and B12). Both mice were fed BPA in each diet. In the
on the other hand, is responsible for methylation within laboratory, BPA appears to reduce methylation of the agouti gene. With
embryonic stem cells. Methylation has also recently been dis- the mother fed the regular (BPA-modified) diet, the pups were more
covered to occur in non-CpG cytosines within undifferenti- likely to be yellow and obese and more prone to develop cancer and
ated stem cells [4, 7–9]. Methylation is important as not all diabetes. When the mothers were fed the BPA-modified diet plus
genes are expressed at all times. In fact, most are repressed. methyl nutrients, the pups were more likely to be born healthy and
brown, and they were of ideal weight. The methyl nutrient supplemen-
Methylation is an epigenetic means of keeping genes sup- tation counteracted the negative effects of the exposure. (Adapted
pressed until they are needed. Remember, methylation, espe- from Jirtle R, Dolinoy D. Agouti Mice. Retrieved from: 7 https://
 

cially hypermethylation, silences gene expression. Pause and commons.­wikimedia.­org/wiki/File:Agouti_Mice.­jpg. With permission
consider for a moment the use of methylated vitamins and from Creative Commons License 3.0: 7 https://creativecommons.­org/
 

what implications this may have on DNA expression. Further, licenses/by/3.­0/deed.­en.)

methylation is important for determining chromosomal rep-
lication timing. During hypomethylation there is late-­ come. Maternal dietary differences in methyl (CH3) intake
replication, which may be demethylated slowly during cell dictates the presence of a yellow hair color either as a band
division. Hypermethylation, on the other hand, leads to within primarily brown hair in wild-type mice, or as fully
much earlier replication during S phase. Those hypermethyl- yellow hair in those with mothers who had decreased meth-
ated genes are typically repackaged with acetylated histones. ylation. This is related to the agouti viable yellow (Avy) gene.
Hypomethylation will cause the building of nucleosomes This phenotype is accompanied by obesity and is a result of
that contain deacetylated histones [9]. In this way, methyla- paracrine signaling issues resulting in hyperphagia in mice
tion may control the “turning off ” of genes. pups. The consequence of this epigene is that the mice
Lastly, small non-coding RNA molecules (MicroRNAs) expressing the aberrant agouti gene are more likely to develop
are a range of molecules that also help to control the expres- diabetes and cancer later in life. The difference between pups
sion and function of genes. They are non-coding RNAs that expressing the wild-type genetics versus the polymorphism
regulate gene expression post-transcriptionally or after the is the overmethylation status allowing for suppression of the
protein has been processed by the ribosome. Typically, they agouti gene. To further influence the expression of this gene,
repress protein production by altering the capabilities of supplementation with choline, vitamin B12, and folate both
messenger RNA and by a process called translational prior to and during pregnancy repress agouti expression [6,
silencing [10]. In this way, they are able to repress gene 11, 12] (. Fig. 17.1).
 

function and expression. MicroRNAs are accountable for Another classic example of the influence of nutrition on
targeting approximately 30% of genes and can influence epigenetic expression is the Dutch Hunger Winter Study. This
tumor suppression, apoptosis, cellular proliferation, and study looked at a cohort of people conceived during a famine
cell movement [6]. that occurred over 6 months during the last winter of World
Agouti mice illustrate how nutrition may modify pheno- War II (1944–1945). During this time, the caloric intake
typic expression, epigenetic expression and disease risk out- decreased from approximately 1400 kilocalories in October
 238 C. B. Williamson and J. M. Pizano

1944 to less than 1000 kilocalories towards the end of (+ 14%) [21]. This dietary intervention potentially activated
November 1944. Caloric intake further declined at the peak these genes and increased the risk of CVD.
of the famine to 400–800 kilocalories from December 1944 It has been suggested that those with the ε2/ε2 variation
to April 1945. Despite the plummeting amounts of kilocalo- restrict their saturated fat intake to less than 12 g/day to pre-
ries during this time, the proportion of fats, carbohydrates, vent dysbetalipoproteinemia and myocardial infarctions
and proteins remained the same [13–15]. The study found a [21]. However, there are further complications with sug-
positive correlation between famine, calorie restriction and gested saturated fat intake recommendations. The apolipo-
obesity in the offspring of women pregnant during this time. protein A2 (APOA2) gene determines the amount of
This association was further correlated to obesity-related dis- saturated fat required to prevent dyslipidemia in those with
eases in adulthood such as atherosclerosis, hyperlipidemia, DM2. Those with the CC genotype at rs5082 have an
coronary artery diseases, and increased risk of cardiovascular increased risk for dyslipidemia and should decrease satu-
mortality [13–15]. As a segue into obesity and obesity-related rated fat consumption to less than 10% [22]. The current
disorders, we will explore specific epigenetic influences and nutritional United States Department of Agriculture (USDA)
single nucleotide polymorphisms (SNPs) associated with guideline already recommends the consumption of less than
cardiometabolic disease. 10% of calories per day from saturated fats (20 grams) [23].
While this may seem auto-confirmatory, recently there is an
extreme trend towards ketogenic, or very high fat diets. For
17.1.1  he Epigenetics of Cardiometabolic
T those with either the ε2/ε2, ε4/ε4 or APOa2 genotypes, a
Disease high fat diet would clearly be contraindicated as it would sig-
nificantly increase their risk of heart attack and cardiometa-
Cardiometabolic disease encompasses a cluster of disease bolic disease. The frequency of APO ε4/ε4 is much higher
characteristics including atherosclerosis, dyslipidemia, dia- than APOε2. For European ethnicity, the frequency is 2.9%,
betes mellitus type 2 (DM2), hypertension (HTN), increased African American ethnicity 3.6%, and Asian ethnicity is 1.0%
waist circumference and obesity [16]. All of the aforemen- while carriers of APOε4 are 24%, 34.1% and 15.4%, respec-
tioned conditions have genetic etiologies that can increase tively [19, 20]. The Yang study reviewed carriers, thus the
the risk or prevalence of the disease in affected individuals. results are associated with having only one deleterious allele.
To begin, let us look closely at genetics that increase the Hypertension is a hallmark diagnostic of cardiometabolic
risk for cardiovascular disease (CVD). Apolipoprotein E disease. For patients with hypertension and diabetes, treat-
(APOε) is a cholesterol carrier that assists in lipid transport ment should be initiated when blood pressure is 140/90 mm
[17]. It does so by merging with endogenous lipids to form Hg or higher, regardless of age [24]. Genomically, hyperten-
lipoproteins that are responsible for restructuring other lip- sion is related to the angiotensin-converting enzyme (ACE)
ids and cholesterol. These lipoproteins also circulate these and the angiotensinogen gene (AGT). Angiotensinogen,
lipids in the bloodstream. The three isoforms of APOε are which is formed in the liver and controlled by AGT, is broken
APOε2, APOε3, and APOε4. The APOε3 isoform is consid- down by renin to form angiotensin I.  Angiotensin II is
ered to be the neutral genotype and confers no additional formed from angiotensin I by ACE, which is then acted upon
CVD risk. However, the ε2/ε2 variation is associated with by the angiotensin receptor (AT1R) and ultimately converts
familial hypercholesterolemia, or genetically related high to aldosterone. Angiotensin II regulates vasodilation and
cholesterol [18]. Dysbetalipoproteinemia is a rare familial constriction, the sympathetic nervous system, antidiuretic
dyslipidemia characterized by approximately equally ele- hormone, and hormones in the adrenal glands. Aldosterone
17 vated serum cholesterol and triglyceride levels due to accu- is the primary adrenal hormone for this system, as it regu-
mulated remnant lipoproteins in apolipoprotein ε2/ε2 lates sodium retention, potassium excretion and ultimately
homozygotes [18]. This genotype is very rare with the fre- fluid balance [25]. This is the underlying mechanism for
quency in European ethnicity at 0.3%, African American hypertension drugs called ACE inhibitors, blocking angio-
ethnicity at 0.4%, and Asian ethnicity at 0.2% as compared tensin II production and thereby lowering aldosterone pro-
to the ε3/ε3 genotype with 57.4%, 41.7% and 74.6%, respec- duction and the above-described regulatory mechanisms.
tively [19, 20]. This type of predictability is nutrigenetics However, when there is a deletion in the ACE gene, there will
and is not likely to be a candidate for epigenetic alteration. be an increase in aldosterone and angiotensin II because the
However, Yang, et  al. (2007) found that for those with a regulator has been removed [26]. This can result in anxiety,
single variant of APOε2, there was a 2.2-fold increased risk increased cortisol, memory problems, hypertension, and
of myocardial infarction if there was a concurrent high satu- autoimmunity [27]. This imbalance in aldosterone will also
rated fat intake. They also found that for those that carry a alter the electrolyte balance, specifically, a decrease in sodium
single variation of the APOε4 gene, there was a 1.6-fold excretion, thus sodium retention and/or swelling and an
increased risk of myocardial infarction when paired with a increased excretion of potassium potentially resulting in
high saturated fat diet. Compared to non-carriers, the hypokalemia [25]. Alterations in the AGT gene exacerbate
APOε2 carriers who consumed a high saturated fat diet the ACE deletion genotype while also carrying an inherent
resulted in consistently elevated LDL cholesterol levels by (+ risk for pre-eclampsia, hypertension and insulin resistance.
17%) and carriers of the APOε4 variant had an increase of AGT directly increases angiotensinogen levels, thereby alter-
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
239 17
ing the renin-angiotensin-aldosterone system (RAAS) axis. thiolactones. When there is an increase in homocysteine, the
Caproli, et al. found that almost 50% of all hypertensive cases result is an elevation of oxidizing thiolactones. When there
were what they termed “salt-sensitive.” They found that are alterations in this gene, there is the potential for elevated
hypertensives carrying both the ACE and AGT polymor- levels of homocysteine and HDL-­specific protein damage
phisms responded favorably to a reduced sodium diet (less [30]. A specific SNP in PON1, rs662 (A) confers a higher risk
than 1500 mg per day). Those individuals who did not carry of coronary heart disease and diabetes because it encodes for
one or both of these polymorphisms are considered non-salt-­ lower amounts of PON1 activity, thereby increasing oxidative
sensitive and did not have any measurable effect when stress and CVD-related disorders [31]. Specifically, when
restricting sodium. This study elucidates that salt restriction there are errors in PON1, HDL is oxidized, conferring a
is not always beneficial for all hypertensive patients [25]. higher risk of cardiovascular disease. It has been shown that
both Vitamin E supplementation and a diet higher in mono-
unsaturated fats can help decrease both oxidized HDL and
Diagnostic and Testing Guidelines for Diabetes the activity of altered PON1. It should be noted that a diet
Mellitus Type 2 high in saturated fat alone can inhibit the activity of PON1
The diagnostic criteria for pre-DM2 consist of fasting plasma even in the absence of genetic alteration, thus creating a func-
glucose (F/PG) 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 tional enzyme deficiency. In this way, a diet high in saturated
mmol/L) (impaired fasting glycaemia) OR 2-hour PG in the 75-g
fats can increase the risk of both cardiometabolic disease and
oral glucose tolerance test (OGTT) 140 mg/dL (7.8 mmol/L) to
199 mg/dL (11.0 mmol/L) (impaired glucose tolerance) OR markers such as homocysteine [32, 33].
hemoglobin A1C (A1C) 5.7–6.4%, while the diagnostics for DM2 When presented with cardiometabolic disease, one of the
are A1C ≥6.5% OR FPG ≥126 mg/dL (7.0 mmol/L). most researched and used supplements is omega-3-fatty acid,
Fasting is defined as no caloric intake for at least 8 hour.∗OR often as fish oil. Typically, when we think of endothelial nitric
2-hour PG ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test
oxide synthase (eNOS/NOS3), we are associating it with vaso-
should be performed as described by the World Health Organization
(WHO), using a glucose load containing the equivalent of 75 g anhy- dilation, vascular smooth muscle relaxation via cGMP-­
drous glucose dissolved in water OR in a patient with classic symp- mediated signal transduction pathway, vascular endothelial
toms of hyperglycemia or hyperglycemic crisis, a random plasma growth factor (VEGF)-induced angiogenesis in coronary ves-
glucose ≥200 mg/dL (11.1 mmol/L) [28]. sels, and its ability to promote blood clotting via platelet acti-
vation. One intriguing hypothesis is that perhaps the
mediating effects in CVD from NOS modulation depend on
Diabetes or dysregulated blood glucose is the other pillar of omega 3-fatty acid status. There is a SNP in NOS3 that deter-
cardiometabolic disease. Type 2 diabetes (DM2) is a disease mines whether increasing omega 3-fatty acids will decrease
of insulin resistance, most often caused by central obesity triglyceride levels in those with dyslipidemia. In rs1799983, it
and lack of exercise. This is considered a disease of lifestyle, was found that subjects with the risk allele T (TT or GT) who
thus epigenetically influenced. The idea that there may be an had low levels of omega 3-fatty acids had 25% increases in
underlying genetic component to DM2 is appealing in many serum triglyceride levels when compared to those with the
ways. Currently, the research is only suggestive of correla- GG genotype. This study suggested that those carrying the T
tions rather than causations. One such example is the allele increase their omega-3-fatty acid intake by 1.24 grams/
Transcription Factor 7 Like 2 (TCF7L2) locus. Those with the day. Once subjects repleted with omega 3-fatty acids, their tri-
TT genotype at rs12255372 have a 67% increased risk of glyceride levels normalized [34]. This may be the mechanism
developing DM2. There is also preliminary evidence that this behind the plethora of research that indicates that a
SNP could possibly increase the risk of breast cancer and Mediterranean diet [35] or a diet high in fish like the Okinawan
aggressive prostate cancer [29]. Those with the genotype diet [36] confer such benefits in regards to CVD and cardio-
should include low glycemic index/glycemic load foods, metabolic disease. It also may suggest a potential genetic com-
reduce sugar consumption and limit processed grains to ponent to omega-3 therapy in CVD and hypertriglyceridemia
mediate this risk [29]. Interestingly, the global risk was not and should be a consideration in prescription/supplemental
mediated in all study subjects, suggesting that the epigenome omega-3 therapy. It is also important to consider the corollary
and environmental conditions were influencing the disease for this SNP, meaning those who do not have the risk allele
risk outcomes. This suggests an association between family and who may not be fish oil responders.
history, genetics and disease outcomes. This brings us to the final pillar of cardiometabolic dis-
Further, when considering diabetes risk associated with ease – obesity. It would be helpful for individuals and practi-
dyslipidemia, it is important to consider the gene Paraoxonase tioners if there simply were a “fat” gene to determine whether
1 (PON1). PON1 has both esterase and lactonase activity. The dieting would be effective. Unfortunately, we have yet to find
esterase enzymes assist in the catabolism of pesticides and the genetic holy grail of obesity, but we have made some
certain pharmaceutical drugs while also protecting high and progress. Enter the fat mass and obesity gene (FTO). There
low-density lipoproteins from oxidation. Alterations in this has been quite an evolution of this gene and our understand-
gene could result in abnormally high levels of lipid peroxides, ing of its implications. To start, it was once a five-membered
inflammation and compromised detoxification. The lac- haplotype, meaning that there were five causally associated
tonase activity is specific to the catabolism of homocysteine SNPs within the FTO locus that “predicted” the impact of
 240 C. B. Williamson and J. M. Pizano

FTO [37]. Later, this group was revised to a three-membered 17.1.2  he Epigenetics of Psychiatric
T
haplotype, and then finally in 2015, a so-called causal variant and Neurodegenerative Diseases
was discovered [38]. SNP rs1421085 (C, C) confers a 1.7×
increased obesity risk while the heterozygous form confers The gold standard of diagnostics for psychiatric diseases is
1.3× increased obesity risk [39]. These are pretty low odds the Diagnostic and Statistical Manual of Mental Disorders,
risks, and the magnitude does not exceed 4, meaning that 5th Edition, DSM-V. Dementia is characterized in the DSM-­
this gene may play a minor role in obesity-related risks. This V; however, Alzheimer’s disease (ALZ) is not specifically cat-
SNP disrupts the pathway for adipocyte thermogenesis egorized [46]. This is a conundrum as more than half of
involving ARID5B, IRX3, and IRX5, all regulatory genes for dementia cases have ALZ as an etiology [47]. DSM-V charac-
adipogenesis. Evidence suggests that because IRX3 binds so terizes dementia as having “multiple cognitive deficits, which
strongly to FTO, that other obesity-linked SNPs may be asso- include memory impairment and at least one of the follow-
ciated with IRX3 but not necessarily with FTO expression ing: aphasia, apraxia, agnosia or disturbance in executive
[40]. As you can see, we are merely scratching the surface. functioning. Social or occupational function is also impaired.
Unfortunately, we are unlikely to find a single answer to our A diagnosis of dementia should not be made during the
complex obesity epidemic; instead, understanding and course of a delirium (a dementia and a delirium may both be
adjusting the epigenetics of obesity and cardiometabolic dis- diagnosed if the dementia is present at times when the delir-
ease are far more promising. This epigenetic adjustment may ium is not present) [46].” Interestingly, the same apolipopro-
include changes to diet and lifestyle, as well as optimizing tein (APOƐ) that increases the risk for cardiovascular disease
methylation status. (CVD) is also associated with ALZ. This raises the epigenetic
Two conditions associated with cardiometabolic disease question of true disease etiology: Is ALZ a disease of environ-
include polycystic ovarian syndrome (PCOS) and hemo- mental exposures and lifestyle choices rather than Mendelian
chromatosis (HFE). PCOS presents with infertility, hirsut- genetics? Many would argue yes, and some have even gone so
ism, polycystic ovaries, and insulin resistance, three out of far as to rename ALZ type 3 diabetes [48]. When we consider
five of these having considerable overlap with cardiometa- inheritable diseases, we should also remember that families
bolic syndrome [41]. The genomics of PCOS are heteroge- often experience identical environmental influences.
nous and have minimal GWAS (genome-wide associations). Therefore, it is challenging to decipher true genetic etiology
The SNPs that are associated with PCOS have been found and risk when the epigenome greatly confounds such
only in non-obese PCOS patients, which is not the typical ­concepts.
presentation of the disease [42]. There is, however, a sulfa- Let us consider the nutrigenetics, or Mendelian genetics,
tion gene, sulfotransferase 2A1 (SULT2A1), which may have that are associated with ALZ. As with cardiovascular disease
a role in adrenal androgen excess in women with (CVD), the e3 variant in APOε is considered to be neutral
PCOS.  Sulfotransferases are important for the metabolism with an odds ratio of 1 [49]. The ε2/ε2 genotype is actually
of drugs and endogenous compounds. They convert them protective of ALZ with approximately a 0.5 (0.22–1.1) odds
into more hydrophilic, water-soluble sulfate conjugates that ratio [49]. While the frequency of this ε2/ε2 genotype is quite
then may be safely excreted. SULT2A1 specifically catalyzes rare and protective for ALZ, it also increases the risk for beta
the sulfation of steroids like DHEA and bile acids from the dyslipidemia. This is a case where the phenotype would pres-
liver and adrenal glands. Alterations in these genes may ent with CVD and not ALZ.  However, the more common
increase the risk of PCOS by increasing endogenous levels genotype, ε4, connects the two conditions clearly. Carrying
of DHEA and/or be associated with hirsutism and insulin one variant of ε4 is associated with approximately 3.4 (3–3.8)
17 resistance [43]. times increased odds of developing ALZ. Carrying two cop-
Next is a clearly nutrigenetic condition, hemochromato- ies of the ε4 variant exponentially increases the risk resulting
sis (HFE). HFE C282Y accounts for 85% of all hemochro- in an approximately 12.9 (10.2–16.2) times increased odds
matosis cases. Another minor variant, HFE H63D, is risk of developing ALZ in populations of European ancestry
responsible for the remaining 15% of cases, often with a [49]. Thus, for those that carry even one of the ε4 variants,
milder presentation [44]. Hemochromatosis is an iron- there is an increased risk for both CVD and ALZ. Further
overload syndrome that results in cirrhosis of the liver, dia- associating CVD with ALZ, Corneveaux et al. also found a
betes, hypermelanotic pigmentation of the skin, heart consistent relationship with ALZ disease risk predictability
disease, liver cancer, depression, and fatigue [45]. This con- to polymorphisms in angiotensin-converting enzyme (ACE),
dition can be exacerbated by hepatitis infections and it is one of the hypertension-related SNPs [49]. There are many
associated with hypogonadism in males. When these genes other genetic factors that play into the overall risk of develop-
are present, it is best to avoid excessive dosages of vitamin C ing ALZ that should also be considered outside of APOe,
as to not increase the absorption of non-heme iron. When ACE, and CVD genetics. Studies have identified certain
presented with cases of liver disease, diabetes and cardio- GWAS SNPs that are associated with both early and late onset
vascular disease, when the genomics does not necessarily ALZ, as well as many other regulating factors such as amyloid
make sense, it is important to rule out genetically inherited precursor protein (APP), Presenilin 1(PSEN1) and Presenilin
conditions such as HFE. 2 (PSEN2) [50]. The jury is still out on the etiology of ALZ
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
241 17
and CVD; however, dietary and lifestyle choices clearly play exercise,  sound therapy and prayer are helpful strategies to
an epigenetic role in the development of both diseases [49] reduce daily stress [55].
The DSM-V diagnostic criteria for generalized anxiety Delving a bit deeper into the genetics and epigenetics of
disorder (GAD) include the following: “The presence of anxiety, there are two major enzymes (genes) that can control
excessive anxiety and worry about a variety of topics, events, either catecholamine regulation (dopamine, epinephrine and
or activities; the worry is experienced as very challenging to norepinephrine) or other excitatory neurotransmitters like
control; the anxiety and worry are associated with at least glutamate. For more detailed information on catecholamine
three of the following physical or cognitive symptoms (in synthesis, please refer to 7 Chap. 18. The regulatory enzyme
 

children, only one symptom is necessary for a diagnosis of for the catecholamines is called catechol-o-methyltransferase
GAD): edginess or restlessness, tiring easily; more fatigued (COMT) (another methyl-transferase). COMT transfers
than usual; impaired concentration or feeling as though the methyl groups from SAM to the catecholamines dopamine,
mind goes blank; irritability (which may or may not be epinephrine and norepinephrine while assisting in their deg-
observable to others); increased muscle aches or soreness; radation (. Fig.  17.1) [56]. COMT also transfers other
 

difficulty sleeping (due to trouble falling asleep or staying methyl groups, like those found in foods like green tea, citrus
asleep, restlessness at night, or unsatisfying sleep) [46].” (quercetin), and potatoes, along with the hormone catechol
Generalized anxiety disorder (GAD) affects approxi- estrogen [57]. The issue with this being a methyltransferase is
mately 22% of the population, and more often in females that it is dependent on the flow of methyl groups generated in
than males [51]. With GAD affecting approximately one one-carbon metabolism, and recycled or processed in meth-
quarter of the population, there are epigenetic lifestyle fac- ylation pathways. Having both too little SAM and too much
tors and genomic alterations that need to be addressed. s-adenosyl homocysteine (SAH) can create inhibition or
First, our modern lifestyle prizes working excessive downregulation of enzymatic activity resulting in an increase
hours, typically away from home, while also trying to man- of catechols. This can be independent of genetic alteration
age the basics of life, family, and household. Many work so creating a functional inhibition of this enzyme [58]. This
many hours that they compromise their sleeping habits enzyme has broader applications and connects neurotrans-
(impaired cortisol regulation), not to mention their diet mitter regulation, estrogen metabolism and diet. Like most
(obesity, nutrient deficiency) and activities outdoors (vita- nutrigenomic enzymes, this one is dependent on a nutrient
min D deficiency). Each of these factors are individually cofactor, or “catalyst” that is required for the enzyme to func-
enough to alter the epigenetic activation of disease. In tion properly (note: this is not a true catalyst in chemical
7 Chap. 18, the complex system of methylation is detailed.
  terms as the catalyst is not always consumed, rather in these
In brief, methylation is the process of moving methyl cases, we are describing a circumstance where the substrate is
groups from one bio-molecule to the next, ultimately func- being converted to a product and this reaction requires a
tioning in the regulatory capacity for everything from DNA cofactor). The cofactor for COMT is the incredibly important
synthesis, expression and modulation to other complex mineral, magnesium [59]. In addition to serving as a cofactor
systems such as detoxification. Many of our modern dis- for COMT, magnesium is also a cofactor for 300 other enzy-
eases can be connected to alterations in this complex sys- matic processes in the body [60, 61]. The phenotype for this
tem due to the implications of regulating gene expression type of anxiety typically excludes panic attacks, but there is a
[52]. GAD, panic disorder and milder presentations of ruminating presentation of anxiety and an increased risk for
anxiety are not exceptions. insomnia [62] and palpitations [63]. Anecdotally, those with
There is an enzyme called phenylethanolamine COMT inhibition (functional or SNPs) typically have “type
N-­methyltransferase (PNMT) (notice the word, methyl- A” personalities due to increased dopamine and epinephrine
transferase; it transfers a methyl group from one molecule to levels, are often successful and may or may not have disor-
another). In this case, PNMT specifically converts norepi- dered sleep patterns.
nephrine to epinephrine [53]. In more common terms, these Magnesium deficiency can be the result of many things,
bio-molecules are called noradrenaline and adrenaline. including downregulation of the COMT enzymes. If you
Chronic activation of this enzyme increases adrenaline and consider basic sciences and relate that all enzymes have a
results in anxiety, insomnia, and ultimately adrenal fatigue substrate, a catalyst and a product, when there is an upregula-
[53]. The cofactor for this particular enzyme is the universal tion of this pathway, there will be a depletion of the substrate
methyl donor, s-adenosyl-methyltransferase (SAM) [54]. and catalyst with an increase in the product. If there is a
When SAM releases its methyl group, it is first converted to downregulation, there is either a catalyst deficiency (nutrient
s-adenosyl-homocysteine and ultimately into homocysteine, deficiency) or a SNP.  In the case of upregulation, COMT
an inflammatory amino acid metabolite associated with neu- depletes methyl donors by moving them too swiftly away
roinflammation and CVD.  Therefore, chronic stress can from the catecholamines, thus ultimately decreasing these
result in anxiety, elevated levels of homocysteine, CVD and a levels while simultaneously decreasing its catalyst cofactor,
depletion of beneficial methyl donors, thereby increasing magnesium. This may present with fatigue and potentially
overall disease risk. This enzyme provides the biological basis dopamine depression. To validate this on an organic acids
for the connection between chronic stress and disease. Mind-­ test, the markers vanilmandelate (VMA) and homovanillate
body techniques such as yoga, tai-chi, meditation, gentle (HVA) would be decreased showing excessive breakdown. In
 242 C. B. Williamson and J. M. Pizano

DHFR
Phe Trp Arg
7,8 Dihydrobiopterin (BH2) Tetrahydrobiopterin (BH4)
NADPH
NADPH
PAH BH4, Fe+++ TPH BH4, Fe+++ NOS FAD
FMN
Heme
O2

DHFR Dihydrofolate Reductase

PAH Phenylalanine Hydroxylase Tyr 5-HO-TRP Citrulline
TH Tyrosine Hydroxylase +
TH BH4, Fe+++ AADC B6 Nitric Oxide
AADC Aromatic L-amino Acid Decarboxylase
DßH Dopamine Beta Hydroxylase
MAO Monoamine Oxidase Serotonin
COMT Catechol-O-Methyltransferase
MAO FAD
TPH Tryptophan Hydrocylase L-DOPA
NOS Nitric Oxide Synthase AADC B6
5-HIAA
HVA Homovanillate
VMA Vandilmanillate

M D
FA
Dopamine

AO
5-HIAA 5-Hydroxyindoleacetic Acid
CO SAM

DßH Cu++, Ascorbate

T
g,

M
M

HVA Norepinephrine
M
CO , SA

COMT Mg, SAM

g

T
M

M
D
AO
FA
M

M AM

Epinephrine
S

VMA
g,
T
M
CO
D
AO
FA
M

Copyright © 2019 NGI, LLC VMA

..      Fig. 17.2  BH4 and neurotransmitter synthesis. (Courtesy of Nutritional Genomics Institute, LLC)

downregulation, there is a “block” in the pathway, resulting cation or withdrawal), medical conditions, or another psy-
in the inhibition of catecholamine breakdown, thereby chiatric disorder. Other symptoms or signs may include
resulting in increased levels of these neurotransmitters and headache, cold hands, diarrhea, insomnia, fatigue, intrusive
the presentation of anxiety. The HVA/VMA pattern will be thoughts, and ruminations.” [46] (. Fig. 17.2).
17
 

reversed in this case. If the presentation is consistent and There is another presentation of anxiety as alluded to
there is a known alteration in COMT, magnesium threonate above. While this phenotype of anxiety can also include
may ameliorate symptoms and anxiety. This particular form symptoms such as insomnia, it includes panic attacks
of magnesium has the potential to cross the blood-brain bar- ­associated with panic disorder. Panic attacks are associated
rier and is considered to be a superior form for neurological with an enzyme that converts the excitatory neurotransmit-
conditions [64]. Interestingly, clinically, this pathway strives ter glutamate into the inhibitory neurotransmitter,
for homeostasis. Many patients will experience a refractory γ-Aminobutyric acid (GABA). Not to be confused with gen-
response or increased anxiety or insomnia when given mag- eralized anxiety disorder, however, the name of this enzyme
nesium. In these cases, it is important to investigate the other is glutamic acid decarboxylase 1 or GAD1. When there are
enzyme that also degrades these neurotransmitters, mono- alterations in these enzymes, there is a “block” in the conver-
amine oxidase. sion, resulting in an increase in glutamate and a decrease in
According to the DSM-V, panic disorder includes the fol- GABA. This block is typically related to the limitation of the
lowing: “panic attacks must be associated with longer than 1 cofactor, vitamin B6 in the active form of pyridoxal-5-phos-
month of subsequent persistent worry about: (1) having phate (P5P). To “validate” the decreased activity of this SNP,
another attack or consequences of the attack, or (2) signifi- there is an organic acids marker called xanthurenate. When
cant maladaptive behavioral changes related to the attack. To elevated, this is confirmation of a P5P deficiency [65].
make the diagnosis of panic disorder, panic attacks cannot Glutamate is found in a variety of foods, especially pro-
directly or physiologically result from substance use (intoxi- cessed foods. Its most notorious conformation is monoso-
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
243 17
dium glutamate or MSG. MSG can increase glutamate levels 6. Fatigue or loss of energy
in the brain and increase both neuronal and gastrointestinal 7. Guilt/worthlessness: Feelings of worthlessness or
inflammation via nuclear factor kappa-beta (NF-κB) [66]. excessive or inappropriate guilt
Glutamate is also a modulator of the kynurenine pathway, 8. Concentration: Diminished ability to think or concen-
which is limited by tryptophan and modulated by the nutri- trate, or more indecisiveness
ents pyridoxal-5-phosphate (vitamin B6), niacin (vitamin 9. Suicidality: Thoughts of death or suicide, or has suicide
B3), iron, and magnesium. This association is consistent with plan
the presentation of anxiety with concurrent depression as DSM-V proposed (not yet adopted) anxiety symp-
tryptophan is the precursor to serotonin. Alterations in this toms that may indicate depression: irrational worry,
pathway may result in an increase in quinolinate, a neuro-­ preoccupation with unpleasant worries, trouble relaxing,
inflammatory metabolite responsible for modulating feeling tense, fear that something awful might happen”
N-methyl-D-aspartate (NMDA) receptors in the brain. [46].
Excessive stimulation of the NMDA receptors results in neu-
ronal inflammation and is associated with conditions like Lastly, we will discuss depression. Please refer to . Fig. 17.2
 

autism spectrum disorder and ALZ [67]. These GAD1 iso- for additional information regarding the synthesis and catab-
forms provide potential etiologies for panic disorders being olism of dopamine and serotonin along with specific variant
genetically inherited [68]. For those having alterations in information. Clinically, there are two types of depression
GAD1, supplementation with P5P, magnesium, niacin, and [71]. The first and most commonly known is related to sero-
potentially iron (if deficient) can help to modulate the panic tonin deficiency. This mechanism has spawned an entire
attack phenotype. If there is concurrent depression, consider class of pharmaceutical drugs called selective serotonin reup-
also supplementing with tryptophan or 5-­hydroxytryptophan. take inhibitors (SSRIs). While success is found in a portion of
The GAD enzyme has another interesting association. In MDD patients with SSRIs, there is a considerable portion of
cases where there is a homozygous alteration in the GAD non-responders [72]. Clinically, serotonin deficiency-­related
enzyme, there is an increased risk for glucose dysregulation. depression encompasses feelings of worthlessness, a ten-
This particular alteration results in a peculiar presentation, dency to withdraw from social activities, lack of motivation
whereas there are moderately elevated levels of plasma blood and excessive sleeping. To validate serotonin depression,
glucose with low levels of fasting insulin. This presentation there is an organic acids marker called 5-­hydroxyindoleacetic
typically has the phenotype of reactive hypoglycemia, thin acid (5-HIAA), a serotonin catabolism metabolite. This
habitus and an erroneous diagnosis of DM2 [69]. The con- marker will be low if there is a restriction in serotonin metab-
nection between these two clinical presentations lies in the olism with concurrent suppression of the amino acid trypto-
physiology of GAD being expressed in both the brain and phan [67]. There may also be variations in the enzymes that
the beta islet cells of the pancreas [70]. To correct the dis- create serotonin, such as tryptophan hydroxylase. The cofac-
crepancy, moderate to high dosages of P5P provide an inter- tors for this enzyme are (tetrahydrobiopterin) BH4, P5P,
vention to stabilize the glucose dysregulation. Interestingly, riboflavin, and copper. Addressing any abnormalities found
ACE inhibitors also modulate this particular mechanism, in these nutrients could potentially relieve the strain on the
contributing to the complexity of a clinical diagnosis [71]. enzyme responsible for forming serotonin [67]. In cases such
An ACE deletion and homozygous GAD isoform would cre- as these, consider supplementing with tryptophan,
ate the phenotype of cardiometabolic disease. Clinically, this 5-hydroxytryptophan or St. John’s wort. It should also be
would be difficult to distinguish, perhaps other than the thin noted that in addition to the expected downregulation phe-
habitus. The lesson is to not make assumptions about the eti- notype, there are also upregulations in the genes that regulate
ology of disease based solely on clinical presentation. The this pathway. Monoamine oxidase A (MAO-A) specifically
reality is often complex.Depression (major depressive disor- regulates serotonin catabolism and is the enzyme that stimu-
der, MMD) is defined by the DSM-V as: “depressed mood or lated the class of medications known as MAOIs or mono-
a loss of interest or pleasure in daily activities for more than amine oxidase inhibitors. In these cases, you may find that
2 weeks; mood represents a change from the person’s base- 5-HIAA is actually elevated along with the validation marker
line; impaired function: social, occupational, educational; for riboflavin, glutaric acid [73].
specific symptoms, at least five of these nine, present nearly The second, less frequently recognized form of depres-
every day: sion involves dopamine deficiency. Clinically, these patients
1. Depressed mood or irritable most of the day, nearly present with a decreased interest or pleasure in most activi-
every day, as indicated by either subjective report (e.g., ties. Often in these cases, there is an upregulation in dopa-
feels sad or empty) or observation made by others (e.g., mine beta hydroxylase (DβH), which converts dopamine to
appears tearful) norepinephrine. DβH requires the cofactors of vitamin C and
2. Decreased interest or pleasure in most activities, most of copper, elucidating the characteristic low copper phenotype
each day in dopamine depression [74]. A blockage in this enzyme is
3. Significant weight change (5%) or change in appetite associated with schizophrenia treatment outcomes as it can
4. Change in sleep: Insomnia or hypersomnia theoretically increase dopamine levels [75]. Dopamine can
5. Change in activity: Psychomotor agitation or retardation also be restricted by one of four dopamine receptors. There
 244 C. B. Williamson and J. M. Pizano

may be functional blocks in these receptors due to autoanti- normal and a positive confirmation test of anti-­endomysium-­
bodies or polymorphism. Acute neuropsychiatric conditions IgA antibodies (EMA) [79]. As we begin to explore the
like pediatric autoimmune neuropsychiatric disorders asso- genetic susceptibility of CD, we will encounter a condition
ciated with streptococcal infections (PANDAS) and pediatric that has recently been coined to explain the sudden rise in
acute-onset neuropsychiatric syndrome (PANS) are also gluten sensitivity in the absence of CD. This new condition
associated with autoantibodies to dopamine receptors. In the has been named non-celiac gluten sensitivity (NCGS), and it
majority of these cases, supplementing with mucuna pru- is associated with heterozygous alterations in the human leu-
riens, also known as the velvet bean, supplies a direct precur- kocyte antigen (HLA) genes that determine CD. HLAs are a
sor to dopamine, L-DOPA and resolves the symptoms of highly polymorphic gene complex that encodes for the major
dopamine depression [76]. histocompatibility complex (MHC) proteins. These MHC
Sometimes, there will be abnormalities in both dopamine proteins are primarily responsible for immune regulation
and serotonin. If there is evidence to support this conclusion, and are the genes that require matching for organ transplants
then there may be an enzyme deficiency in aromatic L-amino [80]. Alterations in these genes increase the risk of several
acid decarboxylase (AADC). This enzyme is P5P-dependent autoimmune diseases.
and is responsible for both the conversion of L-DOPA to About 90–95% of CD patients carry a certain genotype
dopamine and 5-hydroxytryptophan to tryptophan. called HLA-DQ 2.5. When there is a homozygous mutation
Supplemental P5P is again the correct intervention for for this genotype, there is a 50-fold increased risk of develop-
depression. It is also possible that there are genetic abnor- ing CD [81]. The other remaining 5–10% of CD patients have
malities or functional blocks in both the serotonin and dopa- a milder alteration in HLA-DQ 8. The presence of a homozy-
mine pathways, thus this consideration should not be gous alteration in this genoset results in a 17-fold increased
disregarded. For overall support, supplementation with P5P, risk of CD development [81]. In some cases, especially in
magnesium and riboflavin are complementary for the resolu- NCGS, there are heterozygous alterations in these SNPs or
tion of anxiety and depression. other related SNPs that result in a genotype called HLA-DQ
2.2. Please refer to the Epigenetic SNPs chart associated with
this chapter for specific details, genes and SNPs regarding
17.2  he Epigenetics of Irritable Bowel
T HLA-DQ 2.5, HLA-DQ 8, and HLA-DQ 2.2 (see
Disease and Dysbiosis . Table 17.1).
 

Interestingly, 40% of the general population also has

For every client that has a neurological condition, there are alterations in these DQ genes, yet they do not develop CD.
five more that have a variation of dysbiosis, leaky gut or irri- NCGS can also be present in the absence of any known
table bowel disease (IBD). In this section, we will briefly genomic alteration, which complicates the suspected etiolo-
discuss dysbiosis, environmental factors such as dietary gies [81]. Dr. Stephanie Seneff proposes that this dramatic
influences and probiotic use associated with dysbiosis, and rise in NCGS and CD is associated with the relatively recent
the genetics of celiac disease (CD). This is not an exhaustive advances in biotechnology. Glyphosate is commonly known
review and is designed as an introduction. It is important to as Roundup ® and is trademarked by Bayer AG [45]. This
remember that humans have a symbiotic relationship with chemical is not only a ubiquitous herbicide, but the majority
our microflora. While it is popularly believed that our of our mega crops have been genetically altered to be
microbes outnumber us in a ratio of 10:1, these numbers “Roundup-ready” or have the ability for the plant organism
have recently been recalculated to show that while there are to survive glyphosate application, while killing the other
17 still more microbial species than there are human, the ratio “weeds.” These genetically modified organisms (GMOs) can
is closer to 1:1 [77]. Regardless of these ratios, the concept potentially compromise the cytochrome p450 system, result
that we equally share the control panel with the microbiome in NCGS, irritable bowel syndrome and unfavorable altera-
has considerable implications on our health, disease, and tions in the microbiome as well as negatively stimulate the
longevity. immune system [82]. Unfortunately, GMO wheat, corn, and
Celiac disease affects only a small percentage of the popu- soy comprise a large portion of the American diet as recom-
lation. It is estimated that between Europeans and Americans, mended by the USDA [83]. Here we see can clearly see the
there is an approximate 0.5–1.26% frequency of CD [78]. CD advancements in crop productivity directly impacting the
presents with damaged epithelial cells of the intestine, mal- epigenome and risk for CD and NCGS. These environmental
nutrition, diarrhea, anemia, osteoporosis, dermatitis herpeti- conditions (i.e., how much of these foods we consume) ulti-
formis, dental enamel hypoplasia, an increased risk of cancer mately determine if these genes are to become epigenetically
and neurological symptoms such as headache, brain fog, and activated. Remember, the presence of the genetic alteration
paresthesia [78, 79]. The etiology of this disease is an autoim- increases the risk of the disease, but it not solely diagnostic.
mune reaction to the gluten protein found in cereal grains This balance of the microbiota is far more important than
such as wheat, barley and rye [79]. The current guidelines for we imagined in the age of antibiotics. Further, there is a great
the diagnosis of CD includes: Signs and symptoms suggestive deal of variability in the microbiomes of individuals. We have
of CD, anti-transglutaminase type 2 antibody (anti-TG2) learned that these nuances relate to health status, age, diet,
with levels typically more than 10 times the upper limit of microbial interactions, and even host genotype.
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
245 17

..      Table 17.1  Epigenetic SNPs hart

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

Epigenetics of cardiometabolic/
neurodegenerative diseases

7 www.­snppros.­com
 

APOε 2 N/A Dysbeta-­lipoproteinemia Lipid panel, CMP; rs7412 (T)

Apolipoprotein E 2 ↑Cholesterol, ↑triglycer- those with this rs429358 (T)
ε2/ε2 is protective of Alzheimer’s ides genotype should
disease but associated with familial limit saturated
hypercholesterolemia fat intake to 12
Dysbetalipoproteinemia is a rare g/day; advanced
familial dyslipidemia characterized lipid panel/MPO
by approximately equally elevated
serum cholesterol and triglyceride
levels due to accumulated remnant
lipoproteins in apolipoprotein ε2/ε2
homozygotes

APOε 3 N/A Considered to be the Lipid panel, CMP rs7412 (C)

Apolipoprotein ε 3 neutral genotype for rs429358 (T)
both CVD and ALZ.

APOε 4 N/A ↑Cholesterol; a high Lipid panel, CMP, rs7412 (C)

Apolipoprotein ε 4 saturated fat intake was investigate other rs429358 (C)
Carrying a single copy of the ε4 associated with a ALZ-related
variant is associated with about 2.2-fold increased risk of genetics
1.5–2 times increased odds of MI among carriers of
developing Alzheimer’s disease APO ε∗2 (OR = 3.17; 95%
(ALZ) CI, 1.58–6.36) and with a
Two copies of the ε4 variant is 1.6-fold increase among
associated with approximately nine carriers of the –491T and
times increased odds risk of APOε ∗4 variants
Alzheimer’s disease populations of together (OR = 2.59; 95%
European ancestry CI, 1.38–4.87). Consis-
tently, a high fat diet
elicited a greater
response in LDL
cholesterol among
carriers of APOε ∗2
(+17%) and APOε ∗4
(+14%) compared to
noncarriers (+6%)

APOA2 N/A ↑Cholesterol, ↑triglycer- Lipid panel, CMP, rs5082 (C)

Apolipoprotein A2 ides advanced lipid
In diabetics, this gene determines Those with the CC panel/MPO
the amount of saturated fat required genotype have an
to prevent dyslipidemia increased risk for
dyslipidemia and should
decrease saturated fat
consumption to less
than 10%
(continued)
 246 C. B. Williamson and J. M. Pizano

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

ACE del N/A ↑Aldosterone can result Lipid panel, CMP, rs4343(A) is a proxy for ACE
Angiotensin converting enzyme in anxiety increased monitor blood Del16; GA, AA genotypes
Deletion results in upregulation of cortisol, learning, pressure; modify should restrict sodium intake to
activity memory problems, stress less than 1500 mg/day
Results in higher rate of conversion hypertension and
of angiotensin 1 to angiotensin 2 autoimmunity
↑aldosterone Electrolyte balance
issues, specifically,
↓sodium excretion (so
sodium retention/
swelling) and ↑excretion
of potassium excretion
(low potassium);
cardiovascular complica-
tions

AGT N/A ↑Insulin resistance, Lipid panel, CMP, rs699, M235T

Angiotensinogen gene ↑hypertension, monitor blood (C)
Specifically increases angiotensino- ↑angiotensinogen pressure; modify When combined with
gen levels, exacerbating the ACE Electrolyte balance stress ACEdel16=salt sensitive
deletion; requires renin to degrade; issues, specifically, hypertension— restrict sodium
works in the adrenals ↓sodium excretion (so intake to less than 1500 mg/
Associated with insulin resistance, sodium retention/ day
especially when combined with ACE swelling) and ↑excretion
Associated with increased hyperten- of potassium excretion
sion and its associated diseases like (low potassium);
pre-eclampsia and heart disease cardiovascular complica-
tions

FTO Molecular ↑Weight gain, ↑insulin Lipid panel, CMP, rs1421085(C)

Fat mass and obesity oxygen, resistance, ↑risk for DM2 fasting Insulin
Causal variant that disrupts a alpha-keto-­
pathway for adipocyte thermogen- glutarate
esis involving ARID5B, IRX3, and and iron
IRX5; mechanistic basis for the
genetic association between FTO
and obesity

TCF7L2 N/A TTs have a 67% Lipid panel, CMP, rs12255372(T); slightly
Transcription factor 7 Like 2 increased risk of HBA1C, fasting increases (~1.5×) risk for type-2
Increased risk of diabetes mellites 2 developing DM2. They insulin diabetes and possibly breast
17 should include low GI/ cancer and aggressive prostate
GL foods, reduce sugar cancer
consumption and limit
grains to reduce this risk

NOS1 NADPH and ↑Orotate, ↑citrate, Potential rs7298903(C)

Nitric oxide synthase 1 NADP+ ↑isocitrate, ↑cis-­ abnormalities in rs3782206(T) rs2293054
Catalyzes the conversion of arginine aconitate arginine, [Val1353Val]
to nitric oxide citrulline, nitric
Also creates the byproduct citrulline oxide
Lipid panel to
screen for
hypertension
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
247 17

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

NOS2 Manganese ↑Orotate, ↑citrate, Potential rs2297518(A/T)

Nitric oxide synthase 2 ↑isocitrate, ↑cis-­ abnormalities in rs2248814(G/C)
Inducible nitric oxide synthase aconitate arginine, rs2274894(T)
(iNOS) is considered a reactive free citrulline, nitric
radical involved in neurotransmis- oxide
sion along with antimicrobial and
antitumoral activities
Found in the immune and cardiovas-
cular systems and is involved in
immune defense against pathogens
May be induced by lipopolysaccha-
rides and cytokines
Commonly found in inflammatory
disorders

SOD2 Manganese Increased risk of RBC minerals, rs1799895(G)

Superoxide dismutase 2 ischemic heart disease in lipid panel; Do R213G
Superoxide dismutase is an 9188 participants from not practice high
antioxidant enzyme required to cata- the Copenhagen City intensity exercise
lyze the dismutation of two Heart Study without
superoxide radicals into hydrogen Later found to reduce guidance
peroxide and oxygen the risk of chronic
Protects tissues from oxidative stress obstructive pulmonary
disease and acute
exacerbations of chronic
obstructive pulmonary
disease in three
independent, large
population studies.

PON1 Displaces Those with alterations Lipid panel, CMP, rs662 (A) confers a higher risk
Paraoxonase calcium have an increased risk of fasting insulin, of coronary heart disease
Esterase enzymes that break down pesticide poisoning, Homocysteine;
pesticides and pharmaceutical drugs diabetes, atherosclerosis Increase MUFA
Involved in protecting both HDL and and heart disease and Vitamin E
LDL from oxidation. Its lactonase High fat diet alone
activity is involved in the breakdown inhibits enzyme
of homocysteine thiolactones

HFE-C282Y Avoid ↑Ferritin levels, Hepatic iron rs1800562

Accounts for 85% of all hemochro- excessive sometimes accompanied concentration in C282Y (AA)
matosis cases Vitamin C with ↑transferrin hemochromato-
Hemochromatosis results in cirrhosis saturation and ↑hepatic sis- affected
of the liver, diabetes, hypermelanotic iron concentration (HIC) patients ranges
pigmentation of the skin, heart from 5000 to
disease, liver cancer, depression and 30,000 μg/g
fatigue (normal values,
Made worse with hepatitis infections 100–2200 μg/g)
Associated with hypogonadism in TIBC ranges from
males 200 to 300 μg/dL
in hemo-­
chromatosis-­
affected patients
(normal range,
250–400 μg/dL)
(continued)
 248 C. B. Williamson and J. M. Pizano

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

HFE-H63D Avoid ↑Ferritin levels, Hepatic iron rs1799945 – H63D (GG/CC) Risk
Accounts for 15% of all hemochro- excessive sometimes accompanied concentration in allele C
matosis cases. Hemochromatosis Vitamin C with ↑transferrin hemo-­
results in cirrhosis of the liver, saturation and ↑hepatic chromatosis-­
diabetes, hypermelanotic pigmenta- iron concentration (HIC) affected patients
tion of the skin, heart disease, liver ranges from 5000
cancer, depression and fatigue to 30,000 μg/g
Made worse with hepatitis infections (normal values,
Associated with hypogonadism in 100–2200 μg/g)
males TIBC ranges from
Risk allele C can result in mild 200 to 300 μg/dL
presentation, but was also found to in hemo-­
be associated with iron deficiency in chromatosis-­
women affected patients
(normal range,
250–400 μg/dL)

SULT2A1 N/A May have a role in CMP, 24-hour rs11083907(A)

Sulfotransferase 2A1 adrenal androgen excess urinary rs11569679(T)
Sulfotransferases are important for in women with hormones test, rs2547231(C)
the metabolism of drugs and polycystic ovary FHS, LH, SHBG rs296366 (T)
endogenous compounds and syndrome (PCOS) rs4149449(T)
convert them into more hydrophilic rs4149452(T)
water-soluble sulfate conjugates
that then may be excreted. SULT2A1
catalyzes the sulfation of steroids
and bile acids in the liver and
adrenal glands

Epigenetics of psychiatric diseases

GAD1 P5P ↑Xanthurenate, Fasting insulin, GAD1: rs2241165(C)

Glutamic acid decarboxylase 1 mutations may result in CMP, HBA1C rs2058725(C) rs3791850(A)
Converts the excitatory neurotrans- anxiety/panic disorders,
mitter glutamate into the inhibitory increased blood glucose
neurotransmitter levels and hemoglobin
GABA A1C, with decreased
GAD67 isoform encoded by the insulin levels
GAD1 gene is the rate-limiting
enzyme in GABA synthesis from
glutamate in the brain
17 COMT Magnesium ↓VMA, ↓HVA (downregu- Consider RBC rs4680(A)
Catechol-O-Methyltransferase SAM lation; most common; Magnesium rs4633(T)
Transfers methyl group from SAM to suggests methyl
the catecholamines. trapping) ↑VMA, ↑HVA
Breaks down dopamine, epinephrine (Upregulation –suggests
and norepinephrine. methyl dumping)
Transfers methyl group from SAM to
catechols from foods, (green tea,
potatoes), antioxidants (quercetin),
and hormone catechols (estrogen)

PNMT Phenylethanolamine SAM/methyl ↑VMA, ↓SAM; Stress, Check COMT rs149585781(A)

N-­methyltransferase donor insomnia, anxiety, Status rs3764351 rs773317399(A)
Converts norepinephrine to methyl donor depletion
epinephrine The connection between
stress and disease
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
249 17

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

DR1 Copper is ↓HVA; Associated with RBC copper, rs4867798(C)

Dopamine Receptor 1 the cofactor bipolar disorders ceruloplasmin, rs251937 (C/G)
Most abundant dopamine receptor for DBH attention deficit Iron panel with haplotype is: rs265981(C)
in the central nervous system hyperactivity disorder ferritin (iron and rs4532(A) rs686(T)
Regulates neuronal growth and and alcoholism copper have the
development same trans-
Mediates some behavioral responses porter)
Modulates dopamine receptor
D2-mediated events
Reward and pleasure centers

DR2 Copper is ↓HVA; Dopamine is RBC copper, rs6277(C)

Dopamine receptor 2 the cofactor required for fine motor ceruloplasmin, rs1799732(−/−)
DR2 is associated with adult walking for DBH control, cognition, mood Iron panel with
behavior, associative learning, and neurotransmitter ferritin (iron and
auditory behavior, behavioral balance. (High levels = copper have the
responses to cocaine and ethanol, schizophre nia or same trans-
feeding and grooming behavior and paranoia; low levels = porter)
myoclonic dystonia Parkinson’s)

DR3 Copper is ↓HVA RBC copper, rs167771(G)

Dopamine receptor 3 the cofactor ceruloplasmin,
Localized to the limbic areas of the for DBH Iron panel with
brain that are associated with ferritin (iron and
cognitive, emotional and endocrine copper have the
functions same trans-
May be associated with susceptibil- porter)
ity to hereditary essential tremor 1

DR4 Copper is ↓HVA; Linked to many RBC copper, rs916457(T)

Dopamine receptor 4 the cofactor neurological and ceruloplasmin, rs752306(T) rs3758653(C)
Responsible for neuronal signaling for DBH psychiatric conditions Iron panel with rs1800443(G) rs4331145(A)
in the mesolimbic system of the such as schizophrenia, ferritin (iron and
brain bipolar disorder, copper have the
Regulates emotion and complex addictive behaviors and same trans-
behavior eating disorders (i.e., porter)
anorexia nervosa)
Target for drugs that
treat schizophrenia and
Parkinson’s disease
Involved in behavioral
fear response; response
to cocaine and ethanol;
olfactory learning;
response to amphet-
amines, histamine and
steroid hormones;
involved in short term
memory and social
behavior

Nutrient–specific disease associa-

tions

VDR - TAQ Vitamin D VDR-TAQ SNPs are often Calcidiol rs731236(A)

Vitamin D receptor linked to better
Its affinity for calcitriol is roughly tolerance of methyl
1000× greater than its affinity for donors (conflicting
calcidiol. evidence)
(continued)
 250 C. B. Williamson and J. M. Pizano

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

VDR-Bsm Vitamin D Rapidly converts Calcidiol, rs1544410(A)

Vitamin D receptor calcidiol to calcitriol calcitriol Risk allele A: women have an
Its affinity for calcitriol is roughly Clinical picture includes increased risk of low bone
1000× greater than its affinity for consistently low calcidiol mineral density. Conversely, A
calcidiol levels with elevated 26 study meta-analysis
calcitriol levels estimated a decreased risk of
Adverse effects are osteoporosis associated with
common when calcidiol the G;G genotype
is supplemented in
higher levels (50,000 IU)

VDR – GWAS Vitamin D Homozygotes were asso- Calcidiol, rs2107301(T)

Vitamin D receptor – Genome-wide ciated with an ~2.5× calcitriol
association higher risk of prostate
cancer compared to
homozygote carriers of
the more common (C)
allele in the 630
Caucasian patients
studied

TCN1 Vitamin B12; ↑MMA; Transports up to Serum B12; rs526934(G)

Transcobalamin I hydroxoco 80% of vitamin B12. check FIGLU and
Secreted by the salivary glands and balamin Thought to function as a serum folate to
is a B12 binding protein. TCN1 helps bypasses this circulating storage form rule out folate
B12 survive the HCL in the stomach transporter and may prevent trapping
and the complex travels to the bacterial use of the
intestine vitamin

TCN2 Vitamin B12; ↑MMA; major part of the Serum B12; rs1801198(G)
Transcobalamin 2 hydroxoco secondary granules check FIGLU and
Once inside the enterocytes of the balamin found in neutrophils and serum folate to
ileum, B12 breaks apart from TCN1 bypasses this facilitates the transport rule out folate
to bind to TCN2, which then carries transporter of cobalamin to the liver; trapping
B12 to the liver 20–30% of cobalamin is
transported on the TCN2

GIF Vitamin B12 ↑MMA, pernicious Intrinsic factor, rs558660(G)

Gastric intrinsic factor anemia, familial MMA, serum B12;
Is produced by the parietal cells and pernicious anemia, acute check FIGLU and
is also a B12 binding protein lymphoblastic leukemia, serum folate to
17 high-altitude polycythe-
mia
rule out folate
trapping
In gastritis (non-H. pylori Consider GI/stool
related), those with the testing
FUT2 secretor variant
had decreased amounts
of GIF secretion. This was
true even in heterozy-
gous FUT2 mutations

GSTT1Del 1200 mg Potential ↑ in pyrogluta- Potential rs79605217

Glutathione S-transferase theta 1 Vitamin C/ mate, alpha-hydroxybu- abnormalities in (G/C)
Conjugates reduced glutathione day tyrate and glutamate, rs796052136(−/−)
Many exogenous and endogenous alpha-­ketobutyrate cysteine, glycine
hydrophobic electrophiles
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
251 17

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

BCMO1 Iron May increase plasma Signs and rs12934922(T)

Beta-carotene 15, 15΄-monooxygen- beta-carotene and symptoms of rs7501331(T)
ase 1 decrease plasma retinol retinol defi- rs11645428 (A)
Converts beta-carotene into the May cause between a ciency; check rs6420424(A)
active form of vitamin A, retinol 32% and 59% decrease VDR and vitamin rs6564851(G) confers higher
(beta-­carotene ->trans-retinol) in conversion of D status beta carotene levels
Nomenclature: renamed BCO1 in beta-carotene to Plasma vitamin A
early 2018 trans-retinol

Dysbiosis/GI disease
SNPs

FUT2 N/A ↓Bifidobacteria, Non-secretors rs601338 (G>A) causes

Fucosyltransferase 2 ↑D-Lactate; ↑MMA, are resistant to non-secretor status. Further
Determines secretor status ↓serum B12, ↓microbi- norovirus linkage has been found with
Secretor status allows for expression ome diversity Serum B12 rs516246(T)
of the ABH and Lewis histo-blood FUT2 non-secretors are Consider stool
group antigens in various secretions at an increased risk of testing
including the intestinal mucus celiac disease FUT2 and
MUC2 (mucin 2)
polymorphism increases
risk for colitis in those
with Crohn’s disease

Celiac HLAs N/A ↑D-Lactate, ↑arabinitol, Signs and DQ 2.5 = rs2187668 (T) DQ7 =
Those with these DQ genotypes ↑benzoate, ↑phenylac- symptoms rs4639334 (A) DQ8 = rs7454108
have an increased risk for develop- etate, ↑p-hydroxy-­ suggestive of CD (G) DQ 2.2 requires a test of
ing celiac disease benzoate, Anti-­ three genes, two for inclusion,
↑p-hydroxy-phenyl-­ transglutaminase rs2395182 (T) and rs7775228
acetate, ↑indican type 2 antibody (C). DQ4 excludes a DQ2.2 as
(anti-TG2) levels evidenced by rs4713586(C)
more than 10 The rs2040410(A) allele is
times the upper associated with DRB1∗0301,
limit of normal and the rs7454108(C) allele is
Positive associated with DQB1∗0302
confirmation (and thus DQ8)
tests of
anti-­
endomysium-­IgA
antibodies (EMA)

HLA-DQ2.5 N/A ↑D-Lactate, ↑arabinitol, Signs and rs2187668 (T)

90–95% of all celiac patients have ↑benzoate, ↑phenylac- symptoms (DQB1∗0201) is linked to
this genotype etate, ↑p-hydroxy- suggestive of CD DQA1∗0501; creating the

benzoate, ↑p-hydroxy-­ Anti-­ DQ2.5 haplotype

phenyl-acetate, ↑indican transglutaminase
type 2 antibody
(anti-TG2) levels
more than 10
times the upper
limit of normal
Positive
confirmation
tests of
anti-­
endomysium-­IgA
antibodies (EMA)

(continued)
 252 C. B. Williamson and J. M. Pizano

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

HLA-DQ8 N/A ↑D-Lactate, ↑arabinitol, Signs and rs7454108 (G) (DQB1∗0302)

Half of the remaining 5–10% of ↑benzoate, ↑phenylac- symptoms
celiac patients have DQ8 etate, ↑p-hydroxy-­ suggestive of CD
benzoate, Anti-­
↑p-hydroxy-phenyl-­ transglutaminase
acetate, ↑indican type 2 antibody
(anti-TG2) levels
more than 10
times the upper
limit of normal
Positive
confirmation
tests of
anti-­
endomysium-­IgA
antibodies (EMA)

HLA-DQ 2.2; GS221 ↑D-Lactate, ↑arabinitol, Signs and rs2395182(T), rs7775228(C),

Increased risk gluten intolerance and ↑benzoate, ↑phenylac- symptoms not rs4713586(C)
for autoimmune disorders such as etate, ↑p-hydroxy-­ suggestive of CD
celiac disease benzoate, Anti-­
↑p-hydroxy-phenyl-­ transglutaminase
acetate, ↑indican type 2 antibody
(anti-TG2) levels
more than 10
times the upper
limit of normal
Positive
confirmation
tests of
anti-­
endomysium-­IgA
antibodies (EMA)

APB1 Copper ↓ DAO, ↑Ulcerative colitis RBS copper, rs1049793(G/T)

AP2-like ethylene-responsive symptoms cerruloplasmin
transcription factor
Responsible for extracellular
histamine degradation (encodes the
enzyme Diamine Oxidase)

17 Mitochondrial Disease

NDUFs3 N/A May be Fatigue and exercise Check CoQ10 rs4147730(A)

NADH: ubiquinone oxidoreductase, limited by intolerance status
iron-sulfur protein fraction 3; Complex NAD, Homozygous mutations Deficiency is
1 electrons should respond well to marked by
Cleavage of NDUFS3 is the first step and treatment with elevated
in GZMA-induced (AKA blood ubiquinone riboflavin, thiamin, hydroxy-­
coagulation factor IX/Christmas Thiamine is carnitine and higher methyglutarate.
factor) cell death the cofactor doses of coQ10 Check fatty acid
Leigh syndrome for several oxidation—may
mitochon- result in
drial increases in
enzymes and adipate, suberate
stimulates and ethylmalo-
energy nate
conversion Elevated anion
gap can indicate
a need for
thiamine
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
253 17

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

NDUFs7 N/A May be Fatigue and exercise Check CoQ10 rs1142530 (T)
NADH: ubiquinone oxidoreductase, limited by intolerance status rs2332496(A)
iron-sulfur protein fraction 7; Complex NAD, Homozygous mutations Deficiency is
1 electrons should respond well to marked by
Highest in heart and skeletal muscle and treatment with elevated
Leigh Syndrome causes poor ubiquinone riboflavin, thiamin, hydroxy-­
feeding, episodes of apnea and Thiamine is carnitine and higher methyglutarate
cyanosis, acute gastroenteritis, the cofactor doses of coQ10 Check fatty acid
moderate hypertrophic obstructive for several oxidation, may
cardiomyopathy, extensive white mitochon- result in
matter hypodensity, mild ventricular drial increases in
enlargement, and hypodense enzymes and adipate, suberate
symmetric lesions in putamen and stimulates and ethylmalo-
mesencephalon energy nate
conversion Elevated anion
gap can indicate
a need for
thiamine

NDUFs8 N/A May be Fatigue and exercise Check CoQ10 rs1051806(T)

NADH: ubiquinone oxidoreductase, limited by intolerance status rs2075626 (C)
iron-sulfur protein fraction 8; Complex NAD, Homozygous mutations Deficiency is
1 electrons should respond well to marked by
Required in the electron transfer and treatment with elevated
process ubiquinone riboflavin, thiamin, hydroxy-­
Thiamine is carnitine and higher methyglutarate
the cofactor doses of coQ10 Check fatty acid
for several oxidation, may
mitochon- result in
drial increases in
enzymes and adipate, suberate
stimulates and ethylmalo-
energy nate
conversion Elevated anion
gap can indicate
a need for
thiamine

COX5c May be COX5A is associated CBC, Echocardio- rs8042694(G)

Cytochrome oxidase C subunit limited by with sideroblastic gram, EKG,
5c ubiquinone anemia and cardio-­ 8-HO-2DG, Lipid
Cytochrome C (Complex 4) genes are Responds to encephalo-­myopathy peroxides
the last step in the mitochondrial riboflavin Glutaric Acid
respiratory chain. This last step
transfers all of that energy to
oxygen, and having multiple SNPs in
these genes creates free radicals

COX6c May be COX6C is associated with CMP, 8-HO-2DG, rs4626565(C)

Cytochrome oxidase C subunit limited by an increased risk for Lipid peroxides
6c ubiquinone prostate cancer and
C Cytochrome C (Complex 4) genes Responds to kidney disease Glutaric
are the last step in the mitochondrial riboflavin Acid
respiratory chain. This last step
transfers all of that energy to
oxygen, and having multiple SNPs in
these genes creates free radicals

(continued)
 254 C. B. Williamson and J. M. Pizano

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

ATP5c1 Hydrogen, Extreme fatigue, Check all other rs1244414(T)

ATP Synthase, H+ Transporting, phosphate Fibromyalgia syndrome, mitochondrial
Mitochondrial F1 Complex, Gamma group decreased viability, subunits to
Polypeptide decreased caspase ensure proper
Encodes a subunit of mitochondrial 3/7 activity nutrient
ATP synthase repletion
Mainly expressed in heart
Located in the mitochondrial matrix,
complex V of oxidative phosphoryla-
tion

ATP5g3 Hydrogen, Extreme fatigue, Check all other rs36089250(C)

ATP synthase, H+ transporting, phosphate fibromyalgia syndrome, mitochondrial
mitochondrial Fo complex subunit C3 group decreased viability subunits to
(Subunit 9) ensure proper
Encodes a subunit of mitochondrial nutrient
ATP synthase repletion
Mainly expressed in heart, located in
the mitochondrial matrix, complex V
of oxidative phosphorylation

Cancer–related SNPS

TNFa N/A AGONIST: Cannabidiol, Consider regular/ rs1800629(A)

Tumor necrosis factor alpha echinacea, larch increased cancer rs361525(A)
Pro-inflammatory cytokine that is arabinogalactan screenings
associated with both anti and ANTAGONIST: Astraga- Consider stool
pro-cancer effects lus, andrographis, testing
resveratrol, alpha lipoic
acid, Vitamin C,
co-enzyme Q10,
Lactobacillus rhamnosus,
curcumin

PTEN N/A AGONIST: Astragalus, Consider regular/ rs701848(C)

Phosphatase and tensin homolog butyrate, honokiol, increased cancer rs121909229 (A/C)
Tumor suppressor gene that retinoic acid, Vitamin D; screenings rs121909233(A)
regulates apoptosis PTEN is increased by
Diseases associated with PTEN: TNF-α (pro-­inflammatory
Bannayan-Riley-Ruvalcaba syn- cytokine).
drome, Cowden disease, Cowden
ANTAGONIST:
17 syndrome-­like phenotype, Cowden
syndrome, Endometrial carcinoma, PTEN inhibition
Lhermitte-­Duclos disease, Macro- decreases nitric oxide
cephaly/autism syndrome, (NO) production; high
Malignant melanoma, Oligodendro- fat diet; resveratrol
glioma, PTEN hamartoma tumor
syndrome with granular cell tumor,
Prostate cancer, Proteus syndrome,
Squamous cell carcinoma, head and
neck, Vater association with
hydrocephalus;
In cancer, PTEN is frequently
mutated or lost in human tumors
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
255 17

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

NAT1/2 Acetylators rs4986782 Check glutathi- NAT2∗4 is wild type and consid-
N-acetyltransferase 1 protein like darkly increases the risk for one status and ered to be a “rapid” metabolizer
Involved in phase II xenobiotic colored smoking-induced lung conjugation (rs1801279, rs1041983 and
metabolism and helps with the berries and cancer, head and neck Check CYP rs1801280)
biotransformation of aromatic and grapes cancers enzymes to Slow phenotype:
heterocyclic amines (purple and Slow phenotype ensure proper 1. rs1801289(C) + rs1799929(T)
Detoxifies hydrazine and acrylamine red colored associated with detoxification 2. rs1801280(C) + rs1799929(T)
drugs fruits and increased risk of several + rs1208(G)
vegetables) cancers 3. rs1801280(C) + rs1208(G)
Fast phenotype 4. rs1801280(C)
associated with bladder 5. rs1801280(C) + rs1799930(A)
cancer 6. rs1041983(T) + rs1801280(C)
Remove charred meats + rs1799929(T) + rs1208(G)
and other xenobiotics 7. rs1041983(T) + rs1801280(C)
+ 1700020(T) + rs1208(G)
8. rs1041983(T) + rs1801280(C)
+ rs1799930(A)
9. rs1041983(T) + rs1799930(A)
+ rs1208(G)
10. rs1799929(T) +
rs1799930(A)

Pharmacogenetics

CYP1A1 Heme Fast metabolizer 24-hour urinary CYP1A1∗2C rs1048943(C)

Substrates: estrone, brassica phenotype; associated hormones CYP1A1∗4 rs1799814(T)
vegetables containing diindolyl- with increased risk for testing
methane (DIM) or Indole-3-carbinole breast cancer
(I3C), polycyclic aromatic hydrocar-
bons, caffeine, aflatoxin B1, and
acetaminophen

CYP1A2 Heme GA: 26% increased risk Caffeine rs2472300(A)

95% caffeine metabolism for MI with two or more suppression test; rs762551
Other substrates: theophylline, cups of coffee 24-hour urinary Risk Allele A increases activity
phenacetin, acetaminophen, AA: 53% increased risk of hormones (fast metabolizer)
estrogen MI with two or more testing Risk Allele C decreases activity
cups of coffee (slow metabolizer)
Limit caffeine consump-
tion to less than 200 mg/
day
High caffeine intake may
result in increased
estrogen levels and
therefore hormone-­
related cancers (breast,
ovarian, uterine,
prostate, and testicular).
See pharmacogenetics
resources

(continued)
 256 C. B. Williamson and J. M. Pizano

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

CYP1B1 Heme COMT SNPs (downregu- RBC magnesium CYP1B1 L432V (rs1056836 (G) Is
Substrates: hydroxylation of lation) may compound for COMT status protective against prostate
estrogens, oxidizes 17-beta-estradio SNPs in CYP1B1 and 24-hour cancer)
to the carcinogenic 4-hydroxy Increases risk for breast, urinary CYP1B1 N453S rs1800440(C) is
derivative, tamoxifen, polycyclincar- ovarian and prostate hormones associated with decreased
omatic hydrocarbon, aflatoxins, cancers testing levels of urinary 2-OHE and
theophylline, phenacetin, and 16-alpha in premenopausal
warfarin women and is associated with
breast and endometrial cancers
CYP1B1 R48G
rs10012(C/G)

CYP2E1 Heme Chronic detoxication Check glutathi- CYP2W1∗1B

Substrates: Acetaminophen, caffeine, challenges one synthesis C9896G (rs2070676): GG is
alcohol, chlorzoxazone, enflurane, See pharmacogenetics induced by alcohol, coffee and
aniline, benzene, chlorzoxazon, resources smoking; CC is wild type with
dacarbazine, eszopiclone, halothane, no up or downregulation
isoflurane, isoniazid, methoxyflu- CYP2E1∗4
rane, paracetamol, sevoflurane, A4768G (rs6413419 (A)) Works
theophylline, trimethadione, with other CYP genes to
zopiclone detoxify carcinogens.

CYP2D6 Heme Very common in most N/A CYP2D6 T100C

Substrates: antidepressants, populations; mixed (rs1065852): T risk allele is a
antipsychotics, analgesics, antitus- regulation often results non-functioning or partially
sives, beta-blockers, antiarrythmics, in adverse drug functioning variant causing
and antiemetics reactions decreased activity
See pharmacogenetics CYP2D6
resources C2850T (rs16947) AA increased
risk for upregulation
CYP2D6 S486
S485T (rs1135840): G risk allele
causes upregulation

CYP2C9 Heme SNPs indicate down- N/A CYP2C9∗2

Substrates: warfarin, NSAIDs, regulation C430T (rs1799853(T))
amitriptyline, apixaban, azilsartan, See pharmacogenetics (~20% decrease) CYP2C9∗3
clopidogrel, Benadryl, gliben- resources A1075C
calamide sulfonylurea glimepiride (rs1057910(C)) (~40% decrease)

CYP2A6 Heme Inhibited by grapefruit Check VKORC1 CYP2A6∗2

17 Substrates: nicotine, aflatoxin B1,
cotinine, coumarin, dexmedtomi-
juice
SNPs indicate down-
status for
warfarin
A1799T
rs1801272(T)
dine, docetaxel, efavirenz, irinotecan, regulation sensitivity status CYP2A6∗3 rs1057910(C)
letrozole, methoxsalen, oxaliplatin, Chronic detoxification
pilocarpine, tegafur, valproic acid, challenge phenotype
warfarin, methyl tert-buty (gasoline See pharmacogenetics
additive), halothane, methoxyflurane resources
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
257 17

..      Table 17.1 (continued)

SNPS Co factors Organic acids/clinical Amino acids/ rs Numbers

associations other tests/
interventions

CYP2B6 Heme SNPs indicate down- N/A A136G

Substrates: nicotine, alfentanil, regulation rs3530384
bupropion, cyclophosphamide, Chronic detoxification C1132T
ifosfamide, methadone, nevirapine, challenge phenotype rs34097093
propfol, sertraline, sorafenib, See pharmacogenetics C26470T
tamoxifen, vaprioc acid, methoxet- resources rs8192719)
amine G23280A
rs2279344
G29435A
rs7260329
I328T
rs28399499
L262A
rs2279343
Q172H
rs3745274
R22C
rs8192709
T1421C
rs1042389
T20715C
rs36079186
T23499C
rs2279345

CYP2C19 Heme Mixed regulation may Urinary CYP2C19∗17

Substrates: antidepressants, result in adverse drug Hormones 806C>T rs12248560 (T) Ultra
antiepileptics, proton pump reactions testing rapid metabolizer
inhibitors, clopidogrel, proguanil, See pharmacogenetics Check depres- CYP2C19∗2 rs4244285 (A)
propranolol, gliclazide, carisoprodol, resources sion etiology represents decreased activity or
chloramphenicol, c yclophospha- (dopamine vs downregulation
mide, indomethacin, nelfinavir, serotonin)
nilutamide, progesterone, tenipo-
side, warfarin

CYP3A4 Heme Check CoQ10 markers Urinary CYP3A4∗1B

Substrates: Lidocaine, erythromycin, such as hydroxy-­ hormones Test; 392G>A (rs2740574): GG
cyclosporine, ketoconazole, methylglutarate adrenal stress involved in oxidative deactiva-
testosterone, estradiol, cortisone, Grapefruit causes index test tion of testosterone
alfentanil, alfuzosin, almotriptan, decreased clearance of a GG/AG alleles confer 10X
alprazolam, amiodarone, amitripty- substrate and higher increased risk of aggressive
line, amlodipine, anastrozole, plasma levels prostate cancer in African
aprepitant, aripiprazole, astemizole, See pharmacogenetics American men (>54%)
astazanavir, atorvastatin, bepridil, resources CYP3A4∗3
bexarotene, etc. M455T rs4986910(C) involved
in estrogen metabolism
Significantly decreased risk of
breast cancer with the minor
allele T

CYP3A5 Heme N/A Urinary CYP3A5∗2

Substrates: Olanzapine, tacrolimus, See pharmacogenetics hormones test rs28365083(T) is a non-­
nifedipine, cyclosporine, testoster- resources functioning allele
one, progesterone, androstenedione CYP3A5∗3 rs776746(G) is
associated with down
regulation

Courtesy of Nutritional Genomics Institute, LLC

 258 C. B. Williamson and J. M. Pizano

Fucosyltransferase 2 (FUT2) mutations, in particular, appear compensating for the decreased availability of carbon
to be the cause of many abnormalities in the microbiome. sources. Further, a condition that results in decreased amino
FUT2 encodes the fucosyltransferase 2 enzyme, which deter- acids may cause a stress response in the individual and there-
mines secretor status. Secretor status allows for expression of fore the onset of autophagy of intestinal epithelial cells that
the ABH and Lewis histo-blood group antigens in various may ultimately cause IBD [86]. It is important to note that
secretions including the intestinal mucus. The presence of a these perturbations can result in sub-clinical intestinal
particular SNP in FUT2, rs601338 (G>A) results in the non- inflammation even in apparently healthy individuals with
secretor status. There is also another potential candidate SNP, FUT2 polymorphisms. Supplementation with zonulin tight-
rs516246 for which there has been considerable linkage to ening nutrients like zinc carnosine can be helpful in those
phenotypic expression. It appears that 20% of individuals with FUT2 associated intestinal permeability [87].
who are of European descent have this non-secretor FUT2 Lastly, to round out the genomic potential for IBD, spe-
polymorphism [84]. cifically Crohn’s disease, there is a gene called amiloride
A 2011 study concluded that those with FUT2 polymor- binding protein 1 (ABP1/AOC1). This gene is involved in
phisms (non-secretors) had only half of the bifidobacterial histamine metabolism and poses an interesting intersection
diversity and richness found in secretors. In particular, between diet and disease. A specific copper dependent SNP
absence of bacterial denaturing gradient gel electrophoresis in this gene, rs1049793, is associated with an exacerbation in
(DGGE) genotypes of species such as Bifidobacterium adoles- Crohn’s disease symptoms. ABP1 is specifically responsible
centis, Bifidobacterium catenulatum/pseudocatenulatum, and for the regulation of polarized epithelial cells, a mechanism
Bifidobacterium bifidum were noted. In addition to the noted that is dysregulated in IBD [88]. This effect can be com-
absence of beneficial bacteria, they also found that there are pounded if there are also alterations in FUT2 and/or MUC2.
increased levels of potentially harmful bacteria such as It is important to assess copper and cobalamin status in these
Blautia et rel., Dorea formicigenerans et rel., Ruminococcus cases.
gnavus et rel., and Clostridium sphenoides et rel [84, 85]. There are two mechanisms for histamine degradation, one
Further, FUT2 non-secretor status also places individuals at working intracellularly and the other working via extracellu-
higher risk for various diseases including Crohn’s disease, lar histamine degradation. Intracellular histamine metabo-
ulcerative colitis, type 1 diabetes, vaginal candidiasis and uri- lism is carried out by histamine methyltransferase (HNMT)
nary tract infections [84, 85]. Additionally, non-secretors while extracellular degradation occurs via another enzyme
have decreased carbohydrate availability in the intestine, called diamine oxidase (DAO). ABP1 is one gene that encodes
which can cause increased risk of Salmonella and C. difficile DAO, thus regulating extracellular histamine degradation
following antibiotic treatment [84]. While more recent stud- [89]. Histamine is released in the body upon mast cell degran-
ies have called this relationship into question, supplementa- ulation and there are four regulatory histamine receptors
tion with beneficial bifidobacteria can still be helpful in those (H1R-H4R). H1 receptors are found throughout the body in
with FUT2 polymorphisms. smooth muscle, vascular endothelial cells, the heart and cen-
A study that investigated Crohn’s disease risk in those tral nervous system. H2 receptors trigger the gastric secretion
with FUT2 polymorphism found that mucin 2 (MUC2) of histamine to regulate hydrochloric acid production. Less is
might also play a role in this risk [86]. MUC2 is secreted in known about H3 and H4 receptors; however, H1–H3 recep-
mucin in the colon and helps provide a barrier that excludes tors are primarily found in the brain and H4 receptors are
bacteria from the mucosal cell surface. This mechanism ulti- found in the periphery [90]. Histamine is responsible for a
mately decreases the risk for colitis [86]. Aberrant glycosyl- staggering number of biological effects, which vary based on
17 ation of MUC2 core proteins have been shown to cause receptor, cell location and target cell. Examples include gastric
spontaneous colitis in mice; thus, it appears that FUT2 nega- acid secretion, neurotransmitter release, smooth muscle con-
tively impacts microbial adhesion and/or the use of glycans striction, vasodilation, tachycardia, arrhythmia, stimulation
that may lead to dysbiosis. of nociceptive nerve fibers, and an increase in estrogen and
This association with dysbiosis was further related to the endothelial permeability, which results in dysbiosis and an
revelation that non-secretors were deficient in several path- increase in mucus production [89].
ways responsible for amino acid metabolism, but interest- The signs and symptoms associated with Crohn’s disease
ingly had higher metabolism rates for carbohydrates and include increases in Bacteroides, decreases in Firmicutes and
lipids, cofactors, and vitamins and glycan biosynthesis [86]. anti-inflammatory F. prausnitzii, chronic diarrhea, increased
These metabolic abnormalities can alter the integrity of the smooth muscle contractions, excessive bowel mucus produc-
mucosal epithelium, which then alters the microbial compo- tion, bleeding from the rectum, weight loss, and fever [91].
sition. Interestingly, the decrease in the production of amino As evidenced, there is the potential for considerable overlap
acids is often reported in those with inflammatory bowel dis- between histamine intolerance and Crohn’s disease. Crohn’s
ease (IBD). Alternatively, the metagenome shows an alter- disease presentation and the histamine intolerance associ-
nate pattern. It showed that while those with IBD had ated with the consumption of certain trigger foods appear to
decreased amino acid biosynthesis and carbohydrate metab- have a linear relationship, whereas alterations in ABP1
olism, these conditions resulted in an increased nutrient decrease DAO, which ultimately results in histamine intoler-
uptake. This could potentially suggest that the microbiota are ance and intestinal permeability [92]. There are several foods
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
259 17
(i.e., epigenetic activators) that are thought to be high in his- min B12 deficiency. This is not something that occurs over-
tamine that may need to be avoided. Examples include fer- night as vitamin B12 is stored long term in the liver, typically,
mented foods, alcohol, pickled foods, mature cheeses, anywhere from 3 to 5 years. Specifically, approximately
smoked meats, shellfish, beans, nuts, and wheat. Some foods 2–4 mg of vitamin B12 is stored in the body, of which 50% is
are also considered to be histamine liberators. These include found in the liver [95]. Of those 2–4 mg, adenosylcobalamin
most citrus fruits, strawberries, cocoa and chocolate, nuts, represents 70% of the vitamin B12 stored in the body, which
papaya, beans, tomatoes, wheat germ, and additives (benzo- is also mostly found in the liver. Humans cannot utilize a
ate, sulfites, nitrites, and glutamate). There are also foods that nutrient if it is only in the storage form, held captive by the
block diamine oxidase (DAO) which can be problematic, as a liver. Thus, the non-storage form, methylcobalamin, is the
block in extracellular histamine degradation would ulti- main form of vitamin B12 found in the blood. Please take
mately result in excessive circulating histamine. Examples notice of the specific words here, this one is methylcobala-
include alcohol, black tea, energy drinks, green tea, and mate min; therefore, it has a methyl group that can be donated,
tea. Most fresh meats, fruits, vegetables, eggs, grains, cooking located in the center of the cobalamin ring. This is important
oils, herbs, and non-citrus juices are low in histamine and are when we consider the vital role that vitamin B12 plays as the
non-degranulating. Other known dietary triggers for hista- connection between one carbon metabolism and methyla-
mine intolerance may include sulfur, gluten, oxalates, salicy- tion. Methionine synthase and methionine synthase reduc-
lates, and lectin, all of which may play a role in IBD [93]. tase (MTR and MTRR) recycle homocysteine back to
The relationships between diet, genomics, microbiota, methionine to produce SAM. This enzyme is the connection
and disease are being discovered exponentially. Once we between the one-carbon cycle and methylation. MTR and
have mastered the other “omics,” there is the potential for MTRR must be able to convert adenosylcobalamin into
truly precise medicine, disease modulation and nutritional methylcobalamin, gaining the methyl group from methy-
intervention. lenetetrahydrofolate reductase (MTHFR). Lastly, there is the
hydroxyl form of cobalamin, and as the name implies, it car-
ries a hydroxyl group in the center of the cobalamin ring. A
17.2.1  he Epigenetics of Nutrient-
T hydroxyl group is one molecule of hydrogen and one mole-
Associated Diseases cule of oxygen. If you remember from basic chemistry, water
is made of two molecules of hydrogen bonded to one mole-
To continue with the relationship between nutrients and dis- cule of oxygen. Water is in the most stable electrochemical
eases, we will discuss the relationship between vitamin B12, form; thus, a hydroxyl group will be searching for another
vitamin D, and autoimmune disease. These two vitamins are hydrogen to stabilize its structure. This particular biochemis-
two of the most vital nutrients for not only proper ­one-­carbon try allows this form of B12 to bypass several of the transport
metabolism and methylation, but also for nutrient absorp- mechanisms for vitamin B12 [97]. Hydroxocobalamin and
tion and hormone regulation. The first of these is a vitamin methylcobalamin are also stored, but to a lesser extent, in the
that, if measured accurately, would be found to be deficient in muscles, bone, kidney, heart, brain, and spleen. When ana-
such a large subset of the population that the governments lyzing whole blood, methylcobalamin comprises 60–80% of
would consider fortification. Enter the cobalamins, com- vitamin B12 found in the blood and adenosylcobalamin
monly known as vitamin B12. comprises up to 20% of total plasma cobalamin [95]. It is
There are technically four forms of cobalamin [94]. The important to remember this when measuring serum cobala-
most commonly supplemented is called cyanocobalamin. If min as it is primarily a proxy for methylation status and not a
we break apart the word into fundamental blocks, we have a true assay for cobalamin status or cellular levels.
cobalamin structure, which resembles hemoglobin, and this Now that we understand the basics of cobalamin, we need
four-membered ring has a special center group, which in this to discuss how these molecules are transported and utilized
case would be cyanide. This is the synthetic version of vita- in vivo. There are two major transporters for cobalamin. The
min B12. That means that it is man-made, and is the cheapest first is transcobalamin I (TCN1 or haptocorrin), and it is a
supplement option. Biochemically, cyanocobalamin is the binding protein secreted by the salivary glands and assists in
most stable form of B12. This molecular stability is the result the complexes’ survival from the acidity in the stomach.
of having the non-reactive cyanide molecule housed in the Once bonded with vitamin B12, and it has successfully sur-
center [95]. While the amount of cyanide found in typical vived digestion from hydrochloric acid (HCL), the complex
B12 supplementation is not inherently dangerous, it does travels to the intestine. Meanwhile, gastric intrinsic factor
require additional energy, such as ATP, for the body to safely (GIF), a vitamin B12 binding protein which requires HCL for
excrete the cyanide from the body. This means that there is a production, is produced by the parietal cells. After the TCN1/
potential net loss of ATP, or cellular energy, when this form B12 complex has arrived in the less acidic environment of the
of the vitamin is taken internally [96]. There are three better intestine, the TCN1/B12 complex can then bind to the intrin-
options: adenosylcobalamin, hydroxocobalamin and methyl- sic factor formed from GIF and be absorbed in the ileum.
cobalamin. Once inside the enterocytes of the ileum, vitamin B12 breaks
To start, we need to understand vitamin B12 metabolism apart from TCN1 to bind to TCN2, which then carries vita-
and deficiency. It can take a very long time to develop a vita- min B12 to the liver [95].
 260 C. B. Williamson and J. M. Pizano

TCN1 transports up to 80% of vitamin B12 and is thought all contribute to the function of VDR and disease [100].
to function as a circulating storage form. The remaining VDRs also control calcium homeostasis. Certain VDRs can
20–30% of cobalamin is transported on TCN2. When cobal- theoretically elevate calcitriol while lowering calcidiol.
amin is bound to TCN1, it may prevent bacterial use of the Calcitriol increases the level of calcium in serum by increas-
vitamin, which has implications on and from the microbi- ing the uptake of calcium from the intestines, increasing the
ome. In addition to being a B12 transporter, TCN2 is a major release of calcium from bones [100]. VDRs are also involved
part of the secondary granules found in neutrophils connect- in tissue modulation. They can regulate apoptosis, cellular
ing B12 status to the immune system [95]. If there are poly- proliferation and differentiation via matrix metalloprotein-
morphisms in either of these transporters, it may cause an ases and plasminogen activators. They also modulate the
increase in serum vitamin B12 (often even without supple- immune system and have the potential to modulate B cells, T
mentation) with an increase in the organic acid methylmalo- cells, dendritic cells, monocytes, and natural killer cells. Low
nic acid (MMA). This means that there will be high serum levels of vitamin D, calcitriol specifically, are associated with
levels and low tissue concentration. Sometimes, if only TCN1 autoimmune disease [100].
is present, serum levels may also be low. The use of hydroxo- Here are four VDR SNPs that may be encountered. The
cobalamin can bypass this transport issue and assist with first represents a causal link to cancer development. It was
repletion [95]. found that rs2107301 (T;T) homozygotes were associated
So, we have learned that TCN2 is involved in the function with an ~2.5× higher risk of prostate cancer compared to
of neutrophils, but are there other, more overt autoimmune homozygote carriers of the more common (C) allele in the
diseases associated with defects in any of these genes? The 630 Caucasian patients studied [101]. Vitamin D status as an
most notorious disease is pernicious anemia, which is the epigenetic influencer can ultimately increase one’s risk for
result of intrinsic factor deficiency or malfunction. prostate cancer, elucidating the importance of vitamin D
Alterations in GIF are also associated with an increased prev- repletion. Interestingly, vitamin D status is also a regulator
alence of familial pernicious anemia, acute lymphoblastic for melanoma, suggesting that those that spend more time
leukemia, and high-altitude polycythemia. GIF deficiency is indoors are ultimately at an increased risk for both forms of
also responsible for many cases of non-H. pylori related gas- cancer [102].
tritis [98]. This non-H. pylori-related gastritis is compounded There are two other commonly reviewed VDR SNPs; how-
by the presence of even a heterozygous FUT2 non-secretor ever, the evidence for and against them is inconclusive. These
variant, as FUT2 decreases GIF secretion. This circumstance two SNPs are called VDR fok and VDR taq. The first has cir-
would result in cobalamin deficiency [99]. On the contrary, cumstantial evidence to suggest that polymorphisms can
the FUT2 secretor status is associated with elevated levels of result in blood sugar regulatory issues. VDR-taq SNPs are
plasma vitamin B12. This is because the non-secretor v­ ariants also circumstantially linked to better tolerance of methyl
do not produce H-type antigens, the antigen which is present donors and may cause a decrease in calcidiol levels [103,
in blood group O. There is some association with decreased 104]. Unfortunately, there is insufficient evidence to support
plasma vitamin B12 levels on non-type O blood [99]. nutrigenomic interventions based on these SNPs.
Next, we will briefly discuss vitamin D, its receptors Lastly is VDR-bsm. This VDR provides instructions for
(VDR) and consequences associated with defects in these making nuclear vitamin D receptors and is involved in the
receptors. There are many additional resources on the asso- binding of calcitriol and calcitriol receptor activity. When the
ciations between vitamin D and autoimmune disease beyond risk allele A is found in rs1544410, women have an increased
those discussed in this chapter. First, we will review vitamin risk of low bone mineral density. Conversely, a 26 study
17 D nomenclature. Calcidiol (25(OH)D) is the form typically meta-analysis estimated a decreased risk of osteoporosis
measured in serum. This is a combination of both vitamin associated with the G;G genotype [103, 104]. Clinically, this
D2 and D3 levels from endogenous and exogenous sources. VDR often causes rapid conversion of vitamin D2/3 to the
Next is calcitriol, or 1–25-OH(D), the active form of vitamin active form calcitriol. This over-conversion results in elevated
D. Calcidiol is converted into calcitriol and this mechanism calcitriol/1,25-dihydroxy vitamin D with normal to low
is tightly controlled in the absence of VDR polymorphisms. 25(OH)D levels. This phenotype erroneously presents with
VDRs have many regulatory roles. To start, VDRs control an apparent vitamin D deficiency, because calcidiol is low.
genes and have hormone-binding and DNA-binding However, the gene activating, hormone modulating, immune
domains. Specifically looking at DNA, VDRs form a complex system influencer calcitriol is too high. In these cases, the
with the retinoid-X receptor (vitamin A receptor), and that patient is often prescribed more supplemental vitamin D,
heterodimer is what binds to DNA, either turning it on or which can result in adverse reactions like nausea, dizziness,
turning it off (vitamin A and vitamin D are required cofac- syncope, tachycardia, and autoimmunity [105]. Calcitriol
tors) [100]. In most cases, VDRs activate transcription and initiates the transcription of genes of your immune system
gene expression, but VDRs have also been known to suppress (modulates B cells, T cells, dendritic cells, monocytes, and
transcription. The affinity VDRs have for calcitriol, the active natural killer cells). If there is not enough calcitriol, these
form of Vitamin D, is roughly 1000×x greater than its affinity genes are not activated. However, if there is too much cal-
for calcidiol [100]. Thus, VDRs are specifically implicated in citriol from VDR bsm, these immune cells receptors are
epigenetic control. Pollutants like smoke and lack of sunshine blocked. As you can see, at either end of the spectrum there
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
261 17
is a connection between inflammation, autoimmunity and
VDR bsm SNPs [106]. An interesting intersection to meth- Methionine
ylation is that excess calcitriol causes more copies of the cys-
tathionine beta synthase (CBS) gene to be transcribed,
thereby increasing hydrogen sulfide and may exacerbate
transsulfuration/detoxification issues. Please see 7 Chap. 18
 
DMG

for more information on CBS [107]. MTR/MTRR BHMT

Vitamin B12 Zn

Betaine
17.3 Epigenetics of Cancer

Cancer is a multifactorial disease state that, again, could

Homocysteine
have an entire textbook devoted to epigenetic regulation. In
this section, we will bridge mitochondrial insufficiency and
disease to key cancer pathway genomics. We will begin with CBS
B6
an overview of glutathione synthesis. This begins in trans-
sulfuration with an enzyme called CBS. This enzyme is
responsible for the catabolism of a regulatory molecule Cystathionine
homocysteine into our endogenous antioxidant, glutathi- SUOX
one. When there is proper function of CBS, the results are Mb
taurine, sulfate and glutathione; all anti-inflammatory bio-
molecules, if within normal limits. In a normally function- Sulfate Glutathione
ing CBS, hydrogen sulfide enhances the production of
reactive oxygen species (ROS) while simultaneously increas- Copyright © 2019 NGI, LLC Taurine
ing glutathione, the cells’ self-protection mechanism against
ROS. This results in a net zero of ROS. Hydrogen sulfide in
..      Fig. 17.3  Transsulfuration and CBS upregulation. There are three
physiological dosages is beneficial to mitochondrial func-
regulatory pathways of homocysteine recycling to consider: MTR/
tion as it protects it from cytotoxicity. In the case of isch- MTRR, BHMT, and CBS; CBS is the only disposal route. CBS upregulation
emia, hydrogen sulfide actually blocks cytochrome oxidase, will result in decreased levels of homocysteine, whereas CBS down-
resulting in a decrease in mitochondrial damage. It also regulation will result in elevated levels of homocysteine. (Courtesy of
upregulates an important mitochondrial detoxification Nutritional Genomics Institute, LLC)
enzyme called superoxide ­dismutase (SOD) while concur-
rently decreasing ROS. Hydrogen sulfide is also a regulator Now that we know how glutathione is produced and
of apoptosis, a precursor to sulfation and acts as a neuro- have an introduction to a few of the regulatory mecha-
protectant by increasing glutathione and moving another nisms, what does glutathione have to do with cancer? There
important enzyme, cystathionine gamma lyase (CGL – also are two glutathione-­S-transferase genes that are directly
vitamin B6 dependent) to the mitochondria which results in implicated in cancer prevalence. These enzymes are respon-
an increase of cellular ATP [108]. sible for binding the powerhouse antioxidant, glutathione,
However, there are variants for this CBS enzyme in its special reduced form, to toxicants, which assists in the
(. Fig. 17.3) that result in up or down regulation of this pro-
 
cytochrome P450 system’s removal of them. These genes,
cess. While somewhat controversial, clinically, CBS upregu- rather the absence of them, have a defined role in human
lation can result in sulfur sensitivity, meaning there is an carcinogenesis.
increased sensitivity to sulfur-containing foods and drugs. In Glutathione S-transferase theta 1 deletion (GSTT1) con-
upregulation (CBS C699T), we end up with excess sulfate, jugates reduced glutathione along with many exogenous and
glutamate, ammonia, and cortisol with decreased levels of reactive oxygen species (hydrophobic electrophiles). It is
glutathione, all of which are inflammatory. This results in a absent in 38% of the general population [111]. This enzyme is
net increase of ROS and the excess hydrogen sulfide inter- concentrated in the liver, heart, brain, skin, and blood and
feres with proper mitochondrial function [108]. In down- the deletion results in a higher prevalence of cancer develop-
regulation (CBS A360A), there is a functional block that ment in these tissues [111]. Glutathione S-Transferase Mu 1
results in elevated levels of homocysteine, a higher incidence (GSTM1) also conjugates reduced glutathione and functions
of CVD, and decreased glutathione due to limitation [109]. in the detoxification of electrophilic compounds, including
Glutathione is also processed through the gamma-glutamyl carcinogens, therapeutic drugs, environmental toxins and
cycle, which is a transport system for the amino acids that products of oxidative stress [112]. Null mutations or dele-
form glutathione, cysteine, glutamate, and glycine. If there is tions in this gene are associated with an increase in various
a decrease in glutathione in the absence of a CBS upregula- cancers and compromised detoxification [112]. Both
tion, investigating SNPs within this cycle could provide an enzymes are associated with vitamin C deficiency [113]. Not
etiology to the deficiency [110]. having the coding genes for either of the enzymes places one
 262 C. B. Williamson and J. M. Pizano

at considerable risk for the development of several types of Tumor necrosis factor alpha (TNF-α) is a pro-­
cancer, depending on the environmental toxin exposure. In inflammatory cytokine that is associated with both anti- and
addition to vitamin C deficiency status, both enzymes can be pro-cancer effects. This means that in some cases, such as
modulated by selenium and vitamin E [114]. melanoma, we would not want to upregulate this enzyme
In addition to these glutathione- and transsulfuration-­ [121]. However, the majority of the current research does
related genes, there are also acetylation-related genomics. suggest that for most cancers, it would be wise to upregulate
The N-acetyltransferase 1 and 2 (NAT1 and NAT2) proteins this protein, as it is pro-inflammatory to the cancer itself.
are involved in phase II xenobiotic metabolism and help with Like PTEN, there are several factors that can increase or
the biotransformation of aromatic and heterocyclic amines. decrease transcription. Agonists include cannabidiol, echi-
It also detoxifies hydrazine and acrylamine drugs [115]. This nacea and larch arabinogalactan while antagonists include
is done via N-acetylation, which results in the detoxification astragalus, andrographis, resveratrol, alpha lipoic acid, vita-
of monocyclic aromatic amines. This detoxification process is min C, ubiquinol, curcumin, and Lactobacillus rhamnosus
ultimately responsible for the formation of DNA adducts, or [122–127]. As evidenced, there are many common interven-
a segment of DNA bound to a cancer-causing chemical that tions that are actually epigenetic modulators that can ulti-
precipitates the onset of cancer development. mately increase or decrease one’s overall risk of cancer
NAT2 is specifically responsible for the detoxification of development.
smoke, caffeine, drugs, exhaust fumes and many other envi-
ronmental toxins (heterocyclic aromatic amines). Drugs
reported to be metabolized by NAT2 include isoniazid, sul- 17.3.1 Epigenetics of Mitochondrial
fadimidine, hydralazine, dapsone, procaine amide, sulfapyri- Insufficiency
dine, nitrazepam and some sulfa drugs [116]. These
polymorphic conditions can result in fast and slow acetyl- Mitochondrial function was alluded to in regard to cystathi-
ators (N-acetyl transferase) phenotypes. The slow acetylators onine gamma-lyase. Without a full review of mitochondrial
have a higher incidence of breast, lung, colon, head and neck, function, we will focus on several key regulatory enzymes. As
and bladder cancer, with the latter seeming to be the pre- a refresher, mitochondria are the cells’ powerhouse for ATP
dominant cancer for this group [117]. The fast acetylator production. There are five major complexes, and the majority
variants predominantly result in colon cancer [117]. The key of these mitochondrial genes (mtDNA) are maternally inher-
to assisting these enzymes is to reduce the toxin exposure to ited. Mitochondria convert energy into ATP through the
reduce the stress on these enzymes. Avoidance of smoke, pes- process of oxidative phosphorylation via the electron trans-
ticides, insect sprays, charred meats, red meat, metal toxicity, port chain, with the final conversion being carried out by an
chemicals, and solvents and the addition of acetylators like enzyme called ATP synthase. This process is dependent on
darkly colored fruits and vegetables high in anthocyanins hydrogen, ubiquinol, riboflavin, niacin, carnitine, thiamine,
balanced with adequate fiber will help mediate the cancer manganese, antioxidation, and succinate [128]. Any defi-
predisposition. ciency in these biomolecules can result in a functional mito-
Next, let us look into regulatory pathways for cancer. The chondrial deficiency.
first is a tumor suppressor gene that regulates apoptosis, The first enzyme we will discuss is part of complex 1.
phosphatase and tensin homolog (PTEN). There are several There are eight sulfur subunits in NADH ubiquinone oxido-
diseases and cancers associated with a loss of PTEN function: reductase, iron-sulfur protein fraction; however, only three
Bannayan-Riley-Ruvalcaba syndrome, Cowden disease, have actionable interventions (NADH-ubiquinone oxidore-
17 Cowden syndrome-like phenotype, Cowden syndrome, ductase 76 kDa subunits 3/7/8—NDUFS3/7/8). Children
endometrial carcinoma, Lhermitte-Duclos disease, macro- that have severe mutations in these genes have Leigh’s syn-
cephaly/autism syndrome, malignant melanoma, oligoden- drome, which is fatal in infancy. Non-ClinVar homozygous
droglioma, PTEN hamartoma tumor syndrome with granular alterations in these subunits typically respond well to treat-
cell tumor, prostate cancer, proteus syndrome, squamous cell ment with riboflavin, thiamin, niacin, carnitine, and higher
carcinoma, head and neck and vertebral (V) abnormalities, doses of coenzyme Q10 (coQ10) [67]. Ultimately polymor-
anal (A) atresia, tracheoesophageal (T) fistula, esophageal phisms increase the  production of free radicals (ROS) and
(E) atresia, renal (R) abnormalities (VATER) associated with addressing the subunit ahead in the chain (NDUF) will lessen
hydrocephalus [118]. There are several herbs and vitamins stress on these enzymes. Broad-spectrum antioxidants are
that can either upregulate or downregulate this enzyme. helpful in these cases, antioxidant vitamins such as C and E,
Substances that would upregulate this enzyme, or agonists, and the mineral selenium help  to quench the excess
include astragalus, butyrate, honokiol, retinoic acid, and vita- ROS. Minor alterations in these enzymes can result in fatigue
min D [119, 120]. PTEN is also increased by TNF-α (pro-­ and exercise intolerance and typically respond well to treat-
inflammatory cytokine), which we will discuss next. ment with riboflavin, carnitine and higher doses of coQ10
Substances that block PTEN, or antagonists, include a high [128–130].
fat diet and resveratrol [119, 120]. PTEN inhibition also SOD 2A16V is the antioxidant enzyme responsible for
decreases nitric oxide (NO) production, which could poten- mitochondrial detoxification. It codes for the superoxide dis-
tially result in hypertension and neurotransmitter ­imbalances. mutase 2 enzyme and its role is to bind to the oxidant super-
A Nutritional Genomics Approach to Epigenetic Influences on Chronic Disease
263 17
oxide and convert it to less toxic by-products to be processed Phase 1 detoxification is comprised of cytochrome P450,
and removed. It has the cofactor of manganese and not hav- a superfamily of enzymes with many sub-divided families
ing this functioning enzyme increases the risk of certain can- that are used in detoxification. All of the cytochrome enzymes
cers and idiopathic cardiomyopathy. Unfortunately, intense are named using “CYP” for cytochrome P450 and are fol-
exercise compromises this enzyme and, in terms of intense lowed by an Arabic numeral (i.e., CYP1, CYP2, CYP3, etc.).
exercise, is related to a “dose-dependent” activity rate based These families are then further subdivided into subfamilies
on the number of substitutions [131]. Thus, those with altera- with the addition of a capital letter (i.e., CYP1A, CY1B,
tions in this mitochondrial enzyme should take caution with CYP1C, etc.). Individual members of each subfamily are then
high-intensity exercise and supplement with manganese to numbered in the order they were identified (i.e., CYP1A1,
help assist with mitochondrial function. CYP1A2, CYP1A3, etc.). Phase 1 detoxification converts
The COX or cytochrome C oxidase genes code for the lipid-soluble molecules entering the liver into more water-­
carrier protein between complex 3 and 4. This last transfer soluble intermediary metabolites. These metabolites are
allows for all of the built-up energy in the form of hydrogen often more toxic, not less. A range of substances including
to bind with oxygen to make water. This mechanism is the drugs, dietary components such as charcoal-broiled meats,
cellular requirement for breathing. Like complex I insuffi- steroid hormones, the vitamins niacin and riboflavin, as well
ciency, having multiple SNPs in these genes creates free radi- as xenobiotics such as dioxin, exhaust and paint fumes,
cals. Specifically, alterations in COX6C are associated with organophosphorus pesticides, and fragrances may induce
prostate cancer and kidney disease and COX5A has associa- P450 enzymes [136].
tions with sideroblastic anemia and cardioencephalomyopa- Phase 2 detoxification includes acetylation, glucuronida-
thy. Both of these enzymes are concentrated in heart and tion, glutathione conjugation, peptide conjugation, methyla-
skeletal muscle, elucidating the associated disease patholo- tion, and sulfation. Glutathione is our primary endogenous
gies [132]. antioxidant that is essential for proper phase 2 detoxification.
The last step is the conversion of this collected energy Glutathione is a tripeptide formed from the amino acids glu-
into ATP. ATP synthase is required for the final conversion of tamate, cysteine, and glycine. It accounts for approximately
adenosine diphosphate (ADP) into the usable form of energy, half of our cysteine requirements. In phase 2 detoxification,
ATP. There are SNPs in the ATP5C1 gene that code ATP syn- glutathione is used to conjugate and excrete toxins and drugs,
thase. Alterations in this gene result in a decreased output of making them more water-soluble. Genetic SNPs in glutathi-
ATP and increased ROS. Remember, ATP is our cellular cur- one synthase (GSS) may impair glutathione production
rency, and a decrease in production will ultimately result in within the gamma-glutamyl cycle [137]. This enzyme aids in
increased ROS. Alterations in ATP synthase have also been the production of glutathione and requires magnesium as its
associated with accelerated aging, ALZ and an increased cofactor. When GSS levels diminish, it is associated with
prevalence for cancer [133]. Overall, we want to upregulate hemolytic anemia [138]. Further, mutations may lead to ele-
mitochondrial function, starting with complex one and mov- vation of the urinary organic acid pyroglutamate [67].
ing along through the complexes while assuring that there is Methylation connects to phase 2 detoxification via the
adequate antioxidation.  It is important to recognize that adjoining pathway transsulfuration. Here we see the enzyme
mitochondria are sequential chains. Therefore, nutrient cystathionine beta-synthase (CBS) converts homocysteine to
cofactors should be added in order and not all at one time for cystathionine, which ultimately leads to the production of
optimal expression.  taurine, sulfate, and glutathione (. Fig. 17.2) [139].
 

Acetylation is associated with the biotransformation of

aromatic and heterocyclic amines. The enzymes
17.4 Introduction to Pharmacogenetics N-­acetyltransferase 1 and 2 (NAT1 and NAT2) determine
whether an individual is considered to be a slow, intermedi-
Pharmacogenomics is one of the more defined areas of ate, or rapid metabolizer. It requires two slow metabolizer
personalized medicine. It describes how genes may affect alleles to result in the slow metabolizer phenotype [116,
a person’s response to a medication, combining pharma- 117]. This means that the rapid metabolizer allele is domi-
cology and genomics to tailor medical treatment on an nant, and the slow metabolizer allele is recessive. Sulfation
individual basis. This field assists physicians on the selec- includes 12 phase 2 enzymes used in the biotransformation
tion of pharmaceuticals, length of treatment, and dosage. of drugs, hormones, and xenobiotics, as well as bioactiva-
Studies in pharmacogenomics work to associate SNP bio- tion of carcinogens. Sulfotransferases are important for the
markers with pharmaceutical treatment outcomes. metabolism of drugs and endogenous compounds and con-
Challenges occur in that related pharmaceuticals such as vert them into more hydrophilic water-soluble sulfate con-
statins have different degrees of heritability, meaning that jugates that then may be excreted. Sulfotransferase 2A1
each must be investigated separately [134]. The modern (SULT2A1) catalyzes sulfation of steroids and bile acids in
pharmaceutical industry will often develop drugs in a the liver and adrenals [43].
genetically guided manner. This has allowed for adoption Glucuronidation converts fat-soluble compounds to
of genetic testing to be used clinically prior to prescribing water-soluble compounds for excretion and conjugates drugs
a medication [135]. such as salicylates, morphine, acetaminophen, and benzodi-
 264 C. B. Williamson and J. M. Pizano

azepines; xenobiotics such as phenols, polycyclic aromatic may have differing effects, either inducing or inhibiting,
hydrocarbons, nitrosamines, aflatoxin, and heterocyclic while other genes such as PON1 and ATP binding cassette
amines; and dietary and endogenous substances such as bili- subfamily B member 1 (ABCB1) also influence the metabo-
rubin, melatonin, bile acid, steroid hormones, and fat-soluble lism of this drug [143].
vitamins [67].
Currently, pharmacogenomics is only used for a handful
of current diseases and conditions such as depression, mood 17.4.1 Final Thoughts
disorders, heart disease, cancer, asthma, and HIV/AIDS. For
example, the breast cancer medication herceptin or trastu- Epigenetics and the technology associated with the “omics”
zumab, only works for women who have an overproduction revolution have and will continue to shape the way medicine
of the herceptin 2 (HER2) protein [135]. Mercaptopurine is a and precision nutrition is practiced. As with the FTO SNP
medication used for acute lymphoblastic leukemia. It can revolution, this field requires constant review of (and contri-
only be used for those who do not have a genetic variant in bution to) the literature and an ever-expansive open mind. It
NUDT15 c.515C>T, as it may interfere with the clearance of is imperative that practitioners view the complex interactions
the drug. Improper dosing can result in severe side effects between diet, lifestyle, genomics, and medications to accu-
and increased risk for infection. Dosage may be adjusted to rately practice precision medicine and nutritional genomics.
an individual’s genetics. In the case of children with acute In essence, one may not “treat” a SNP or combination of
lymphoblastic leukemia, it may increase the risk of SNPs. Rather, practitioners of the future will be required to
6-­mercaptopurine induced myelosuppression and may also not only understand genetics, but also epigenetics, genomics
cause liver function abnormalities [15, 135]. Lastly, the anti- and the complexity of influencers that determine gene
viral drug abacavir may only be used in HIV-infected patients expression.
without polymorphism to HLA-B∗57:01, as this SNP can be
associated with severe cutaneous adverse drug reactions
(SCARs) which may be potentially life threatening [140]. References
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17
 269 18

Nutritional Influences
on Methylation
Jessica M. Pizano and Christy B. Williamson

18.1 What Is Nutritional Genomics? – 270

18.2 How Are Diseases Inherited? – 270

18.3 Epigenetics and SNPs – 270

18.4 One-Carbon Metabolism Basics – 271

18.5 Introduction to Methylation – 273

18.6 Homocysteine Metabolism – 273

18.7 Connecting Neurotransmitters to Methylation – 275

18.7.1 T etrahydrobiopterin (BH4) – 275
18.7.2 Catecholamines – 275
18.7.3 Serotonin – 276
18.7.4 Iron and Neurotransmitters – 276

18.8 Final Thoughts – 278

References – 283

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_18
 270 J. M. Pizano and C. B. Williamson

18.1 What Is Nutritional Genomics? ..      Table 18.1  Example of a Punnett square with one parent’s
gene running horizontally and the other vertically
Nutritional genomics is comprised of both nutrigenomics
and nutrigenetics. Ordovas and Mooser define nutrigenom- Father’s genes Mother’s genes
ics as the exploration of the effect of nutrients on the genome,
a a
proteome, and metabolome, whereas nutrigenetics looks at
the effect of genetics on the interaction between diet and dis- A Aa Aa
ease [1]. Nutrigenomics falls clearly in the scope of practice a aa aa
of nutritionists, dietitians, and other health professionals that
practice nutrition, whereas genetic counselors and geneti- The genetic possibilities of the offspring are created by taking a
cists more appropriately practice nutrigenetics as it involves gene from each parent. In this example, there is a 50% chance
that the offspring will be heterozygotes and a 50% chance they
diagnostics and disease prediction. Nutrigenomics is more will be homozygotes
about understanding the unique, measurable nutritional
needs an individual might have based on single-nucleotide
polymorphisms (SNPs). Simplistically, one can think of an
SNP as a genetic spelling mistake where one letter is substi- the offspring will be homozygous recessive, and, therefore, be
tuted for another. They may occur in coding regions, non-­ severely affected by the disease. Similarly, there is also a 25%
coding regions, or intergenic regions. In order to be classified chance that the offspring will not have any mutations at all.
as an SNP, two or more versions of a sequence must each be The probability of inheriting such a mutation is often plotted
present in at least 1% of the general population [2]. An SNP using a Punnett square (See . Table 18.1). In 1912, Cambridge
 

is not altogether different from a point mutation in that both University professor of genetics Reginald Crundall Punnett
include a change in a base pair (adenine, guanine, cytosine, created a square that illustrated Mendelian inheritance [6].
and thymine); however, an SNP is not always deleterious in This is classical inheritance. The majority of SNPs analyzed in
nature [3]. As alluded to, SNPs can be variable in their effects. the field of nutrigenomics consist of epigenetically activated
Some can cause positive changes while others may be more SNPs that may or may not follow Mendelian inheritance pat-
detrimental. Some SNPs increase enzyme activity while oth- terns; thus caution is advised in the interpretation of nutrig-
ers decrease enzyme function, referred to respectively as up- enomic SNPs in this classical fashion (. Table 18.1).
 

or downregulation [3]. This change in enzyme activity can

impact nutrition as each enzyme has one or more cofactors.
Thomas Devlin in the Textbook of Biochemistry with Clinical 18.3 Epigenetics and SNPs
Correlations defines a cofactor as an “ion or molecule that on
binding to the catalytic site of an apoenzyme renders it One may ask, is it altogether possible to be able to predict
active” [4]. Typically cofactors are vitamins and minerals; disease activity from the mere presence of an abnormality?
therefore, SNPs that have been epigenetically activated have The term “epigenetics,” which was coined by Waddington in
the potential to cause micronutrient deficiencies. This is par- 1942, was derived from the Greek word “epigenesis” which
ticularly true for upregulated variants as they will quickly use originally described the influence of genetic processes on
up body stores of the requisite nutrient. By increasing the development [7]. Epigenetics is the study of the modification
intake of a required nutrient it is, therefore, possible to of gene expression rather than the alteration of the genetic
improve enzyme function and potentially compensate for a code itself, and in this way can be considered “lifestyle”
deleterious SNP. genetics. It is influenced by age, environment, diet, exercise
habits, and disease state. This is the biochemistry that turns
18 “on” or “off ” the “good” or “bad” genes we all have.
18.2 How Are Diseases Inherited? If you will recall the basic variations of genomic altera-
tions, an SNP and a point mutation both confer a change to a
An autosomal gene is located on a numbered chromosome base pair; however, the point mutation is always deleterious
and typically affects both males and females in the same [3]. The SNP may be beneficial, neutral, or deleterious [8].
manner. For every gene there are two alleles. One allele is Thus, herein lies the question of predictability. If we can make
inherited from the mother and the other from the father. the assumption that most SNPs confer disease risk, then we
When there is an absence of genetic change in either allele, would be likely to find a linear association to demonstrate
we refer to this as the wild type. When one contains a muta- this phenomenon. However, epigenetics, or the ability to turn
tion and the other does not, this is called a heterozygous on and off genetic expression via lifestyle alterations, explains
mutation. When both alleles contain an alteration, this is why an individual might have an SNP and have no effect
called a homozygous mutation. In autosomal inheritance, if while another individual with the same SNP may experience
both parents are heterozygotes, there is a 50% chance that the a change. In essence, there may be evidence that there is a del-
offspring will be heterozygous and, therefore, affected by the eterious SNP, but that does not make the SNP active. For
condition. In many diseases, this is considered to be the “car- example, 80–85% of women who carry the BRCA1 or BRCA2
rier” status [5]. Conversely, there is also a 25% chance that genes go on to develop breast cancer [8]. How then do the
Nutritional Influences on Methylation
271 18
other 15–20% escape this fate? It is most often associated vated D-Lactate and decreased levels of Bifidobacteria, it
with their diet, lifestyle, and their parents’ and grandparents’ would be contraindicated to recommend any probiotic strain
diets and lifestyles. The idea that your grandfather survived or food item that contained Lactobacilli [11]. Signs and
the potato famine and, therefore, he confers activated genet- symptoms of D-lactic acidosis include altered mental status
ics to increase your risk of diabetes does seem a bit unfair [9], (drowsiness to coma), slurred speech, disorientation or
but not from the perspective of the genome. The alteration impaired motor coordination, hostile, aggressive, abusive
actually increased your grandfathers’ survival during a time behavior, inability to concentrate, nystagmus, delirium, hal-
of stress, despite increasing your risk for diabetes in times of lucinations, irritability, excessive hunger, headache, weak,
plenty [9]. droopy eyelids, hand tremor when the wrist is extended, and
Epigenetic influence can be measured by analyzing the blurred vision [11]. As indicated, there are a wide variety of
metabolome, proteome, virome, microbiome, epigenome, clinical signs and symptoms as well as confirmatory metabo-
and transcriptome [10]. Currently, in the realm of nutrition, lomic and microbiome data that can indicate whether an
there is a heavy focus on the microbiome and metabolome. SNP is “active” or deleterious. Do not treat an SNP; first con-
In these analytes, we are able to pinpoint genomic expression, firm that it is active.
activation, and deactivation. The entirety of this practice is
outside of the scope of this textbook; however, herein are a
few examples to demonstrate the effectiveness of functional 18.4 One-Carbon Metabolism Basics
testing.
In the case of cystathionine beta synthase (CBS) upregu- One-carbon metabolism can be thought of as a folate conver-
lation, a practitioner would want to “validate” that a hetero- sion system. This system moves only one carbon at a time,
zygous or homozygous mutation was in fact epigenetically creating oxidized or reduced forms of folate. This is beneficial
active. To do so, they would look at an organic acid marker because uncoupled carbons are highly volatile and result in
called xanthurenate. This marker identifies functional pyrox- oxidative stress. There are three molecules that participate in
idine (B6) deficiencies [11]. Pyroxidine (vitamin B6) in the this process. The first is tetrahydrofolate (THF), the usable
active form is called pyridoxal-5-phosphate, and it is the form of folate in the body. However, to generate THF, first
cofactor for CBS. When the CBS enzyme is actively upregu- dihydrofolate (DHF) or dietary folate must be converted into
lated, there will be an elevation of xanthurenate which “con- tetrahydrofolate (THF) by dihydrofolate reductase (DHFR)
firms” that this cofactor is in fact being depleted. Further, in [13]. DHFR not only preferentially metabolizes dihydrofo-
the case of CBS upregulation, one would also expect to find a late, but it is also subject to negative feedback inhibition via
decreased level of certain amino acids such as homocysteine, synthetic folic acid, and thus can be functionally blocked by
methionine, and potentially an increase in cystathionine excessive folic acid consumption [14]. If there is a polymor-
[11]. CBS upregulation may also result in elevated levels of phism in DHFR, it is prudent to supplement with forms of
ammonia and/or glutamate, a potential outcome of excess folate that bypass this system, such as folinic acid. Folinic
cystathionine. Therefore, one would expect to find a support- acid is available in a supplemental form as calcium folinate
ive pattern in both organic acids and amino acids testing that and as the prescription drug Leuvocorin [15]. The goal is to
points to ammonia excess. There would be potential amino get to the least oxidized state; for one-carbon metabolism
acid abnormalities in glutamate, arginine, citrulline, aspar- that is 5-methyltetrahydrofolate, the product of MTHFR. As
tate, fumarate, and nitric oxide as well as elevations in the a reminder, methylenetetrahydrofolate reductase (MTHFR)
organic acid markers orotate, citrate, isocitrate, and cis-­ catalyzes the conversion of 5,10-methylenetetrahydrofolate
aconitate [11]. Why is this clinically important? It allows a (an intermediate level of oxidation) to 5-­methyltetrahydrofolate
practitioner to understand the importance of not formulat- (the lowest level of oxidation), a co-substrate for homocyste-
ing a nutrition plan simply by the genetics alone. Rather, it is ine remethylation to methionine [16]. The highest oxidative
essential to explore the confluence of the genome and the state for folates is the formino or formyl form. These metabo-
metabolome so that the nutrition plan reflects the current lites are formed when there is an increase in cellular oxida-
epigenetic expression and not simply the potential of what tion as a result of cellular folate deficiency, potentially caused
the genome could represent. One may have an upregulated from alterations in MTHFR and/or DHFR.
CBS variant; however, unless the metabolomic scenario The next player on this carbon team is called S-adenosyl-­
described above is present to confirm or validate the epigen- methionine or SAM. SAM is considered to be the universal
etic activity of this SNP, there is no need to “treat” the SNP. methyl donor [17] as it is formed from methionine and then
In the case of gastrointestinal dysbiosis, there is an organic “donates” or releases the carried methyl donor for processes
acid marker called D-lactate. SNPs in fucosyltransferase 2 such as purine and neurotransmitter synthesis. Once SAM
(FUT2) may result in an elevation of this marker [12]. A has released its methyl donor, it is converted into S-adenosyl-­
practitioner would want to “confirm” this type of genomic homocysteine (SAH), the intermediary between SAM and
alteration by analyzing a stool sample, specifically looking for homocysteine. At this point, homocysteine is either con-
significantly decreased amount of Bifidobacteria. Decreased verted back to methionine via methionine synthase (MTR)
levels of Bifidobacteria inhibit bacterial competition, which or betaine homocysteine methyltransferase (BHMT) or it
results in Lactobacillus overgrowth [10]. In the case of ele- can enter the transsulfuration pathway to form other sulfur-­
 272 J. M. Pizano and C. B. Williamson

Dietary folate/Folic acid Methionine

DHFR
NADPH DHF

DHFR Methionine DMG

NADPH THF
MTR/MTRR BHMT
Vitamin B12 Zn
DMG Betaine
BHMT
MTR/ MTRR Zn
5,10-Methylene THF
Vitamin B12
Betaine
Homocysteine

5-MTHF CBS
Homocysteine
5-methyltetrahydrofolate B6
“Methyl Trap” CBS
MTHFR B6
FAD, NADP Cystathionine
SUOX
Taurine, Glutathione, Sulfate Cystathionine Mb
Copyright © 2019 NGI, LLC

Sulfate Glutathione
..      Fig. 18.1  Methylation cycle: homocysteine sits at the bottom of
the methylation pathway. It may be remethylated to methionine via Copyright © 2019 NGI, LLC Taurine
MTR/MTRR or via BHMT. Alternatively, it may be converted to cystathio-
nine via CBS and is the only true disposal route (transsulfuration)
..      Fig. 18.2  The pathway on the left is one-carbon metabolism. This
pathway’s ultimate goal is to use folate for formation of a methyl group
containing amino acids such as cysteine and taurine [18]. via the creation of 5-methyltetrahydrofolate. This methyl group is then
This process of SAM moving methyl donors around to passed off to the pathway on the right, methylation. Here, the methyl
homocysteine is again called methylation (. Fig. 18.1). This
  group is accepted by vitamin B12, transforming it from the adenosylco-
is an oversimplification of this process as there are many balamin form to the methylcobalamin form. Methylation then recycles
this methyl donor to aid in DNA regulation (epigenetics). When there is
additional fates of SAM; however, this is the basic process of insufficient vitamin B12 available to accept the methyl donor from
recycling the methyl donor that has been created in one-car- folate, it becomes trapped in the 5-methyltetrahydrofolate form and is
bon metabolism by MTHFR. unable to be converted back to THF, the usable form of folate in the
The last player is cobalamin or vitamin B12. MTR takes the body. This is what is referred to as the folate trap. In summation,
methyl donor created by MTHFR (5-­methyltetrahydrofolate) one-carbon metabolism is a methyl donor creation center, and
methylation is a methyl donor recycling center with MTR/MTRR being
and converts the storage form of vitamin B12 known as ade- the connection between the two pathways
nosylcobalamin into a usable methyl recycler known as meth-
ylcobalamin. It is actually methylcobalamin that transfers the
methyl donor from MTHFR to form methionine which in methylated form. Please note the nomenclature; the only dif-
18 turn forms SAM. Methionine synthase and the methylcobala- ference between methyl-tetrahydrofolate and tetrahydrofo-
min it forms are also partially responsible for homocysteine late is the addition or subtraction of a methyl group [19].
catabolism (. Fig. 18.2).
  Clinically this will result in an elevation of formiminogluta-
Within this system of one-carbon metabolism, there is a mate (FIGLU) (remember, the formino form is at the highest
phenomenon referred to as “folate trapping.” Referring back oxidative state), indicating a cellular folate deficiency along
to the reaction of MTHFR, the conversion from with oxidative stress [11]. Paradoxically, it will also increase
5,10-­methylenetetrahydrofolate to 5-methyltetrahydrofolate serum folate levels. This occurs because serum folate mea-
is irreversible. This means that when 5-­methyltetrahydrofolate sures all forms of folate, mostly methylfolate, and FIGLU is
tries to convert back into tetrahydrofolate it must be able to specifically measuring usable THF [11]. If you were to erro-
hand off the methyl group to successfully convert adenosyl- neously add in more folate, especially methylated folate, this
cobalamin into methylcobalamin. It must also convert back will increase the amount of 5-methyltetrahydrofolate, thus
into the folate cycle substrate THF. If, for some reason, this exacerbating the discrepancy between cellular and serum
conversion cannot occur, there could potentially be either a folate levels. Other clinical associations include reduced
polymorphism in MTR or a vitamin B12 deficiency. In this methylation capacity as evidenced by a decrease in methio-
circumstance, MTR cannot recycle vitamin B12 into the nine, SAM, SAH, homocysteine, and ultimately, glutathione
methylation cycle and the folate will get “trapped” in the [11]. The correct intervention is not to add in more folate as
Nutritional Influences on Methylation
273 18
indicated by the elevation in the urinary organic acid impede methylation as it absorbs S-adenosylmethionine
formiminoglutamate (FIGLU), rather it is to assist with the (SAM), our universal methyl donor [23]. Exposure to envi-
methyl transfer by correcting the cobalamin deficiency [11]. ronmental toxins such as heavy metals and chemicals may
A cellular deficiency in cobalamin can be determined by an also inhibit methylation as these xenobiotics can block regu-
elevation in methylmalonic acid (MMA) [11]. In cases where latory enzymes in the pathway as well as require additional
there is a known polymorphism in DHFR, the importance of glutathione production from an adjacent pathway (transsul-
removing excess synthetic folate in the form of synthetic folic furation).
acid is incredibly important as a block in this enzyme will Stress can also have a negative impact on methylation.
further restrict one-carbon metabolism, methylation, trans- This relationship exists because stress influences the release
sulfuration, and neurotransmitter synthesis [20]. of the neurotransmitters norepinephrine and epinephrine
via cortisol [24]. Epinephrine, commonly known as adrena-
line, is created from norepinephrine via an enzyme called
18.5 Introduction to Methylation phenylethanolamine N-methyltransferase (PNMT) [25].
This enzyme requires a methyl group and, when upregulated,
Methylation is a biochemical pathway in the body that can deplete overall methyl stores. Thus, an excessive need for
describes the adding or subtracting of a methyl group from conversion (stress) will place continuous demands on SAM
different compounds. A methyl group is simply one carbon and can negatively impact the other processes of methyla-
and three hydrogens (CH3). At the center of methylation is tion. Finally, having too much of a substrate (as in over-­
homocysteine, an amino acid. The pathway works by either supplementation with methylated supplements) can cause
recycling homocysteine back to its precursor methionine negative feedback inhibition, which may also impede the
or by disposing with homocysteine all together. When methylation pathway by targeting certain SNPs and blocking
looking at the difference between homocysteine and its their actions.
precursor methionine, it is important to understand that Remember, the presence of a genetic SNP alone is not suf-
the only difference is the presence of an additional methyl ficient to cause a decrease in enzyme function. An epigenetic
group on methionine. In fact, methionine is methylated influence must occur for this to happen.
homocysteine. Methylation interacts with several addi-
tional pathways including transsulfuration, one-carbon
metabolism, the tetrahydrobiopterin (BH4) cycle, and the 18.6 Homocysteine Metabolism
urea cycle.
Homocysteine is localized at the bottom of the methylation
pathway as the segue to the transsulfuration pathway. It is
Methionine = homocysteine + methyl group (CH3) produced from the amino acid methionine as it is methylated
Methionine is synthesized from homocysteine and a methionine. Homocysteine in excess or deficiency can have
methyl group (CH3). This may occur by recycling deleterious consequences. To address the most common
homocysteine back to methionine via MTR/MTRR or issue with homocysteine (elevation), there are three routes of
via BHMT. homocysteine metabolism. The two recycling routes are
comprised of methionine synthase (MTR)/methionine syn-
thase reductase (MTRR) and betaine homocysteine methyl-
The National Institute of Health (NIH) defines methylation transferase (BHMT). The only true disposal route is via
as “The attachment of methyl groups to DNA at cytosine cystathionine beta synthase (CBS) and provides a connection
bases; correlated with reduced transcription of the gene and between the methylation and transsulfuration pathways.
thought to be the principal mechanism in X-chromosome MTR and MTRR recycle homocysteine back to methio-
inactivation and imprinting” [21]. Methylation is involved in nine with the assistance of a methyl group produced by
gene regulation, biotransformation, neurotransmitter syn- methylenetetrahydrofolate reductase (MTHFR). This
thesis, estrogen catabolism, immune cell production (such as accounts for approximately half of homocysteine catabolism.
T cells and natural killer cells), DNA and histone synthesis, MTR is vitamin B12 dependent and assists in maintaining
energy production, creation of the myelin sheath on nerve adequate intracellular methionine required for production of
cells, and building and maintaining cell membranes via S-adenosyl methionine (SAM), the universal methyl donor
phosphatidylcholine. Nutritionally, methylation may be [11]. It is also responsible for maintaining sufficient intracel-
influenced by the presence or absence of sufficient nutrients lular folate pools as it supplies a methyl donor to one-carbon
that are required as either cofactors or substrates in the path- metabolism [11]. In the folate cycle, MTHFR converts 5,10
way. The genetics of the individual and presence of activated methylenetetrahydrofolate into 5-methyl folate, a co-­
SNPs dictate the likelihood of requiring more or less of a par- substrate of homocysteine metabolism. Then, 5-methyl folate
ticular nutrient. Pharmaceuticals such as antacids, metho- “hands off ” its methyl donor to adenosylcobalamin, in effect
trexate, and metformin may also influence methylation by pushing out the adenosyl group and replacing it with a
decreasing the absorption of nutrients required as cofactors methyl group to form methylcobalamin, the usable form of
for the enzymes [22]. Use of high-dose niacin can also cobalamin required for methylation.
 274 J. M. Pizano and C. B. Williamson

MTRR assists MTR in the maintenance of sufficient vita- BHMT function. Betaine may be found in foods such as
min B12 to support appropriate homocysteine remethyl- wheat, spinach, shellfish, and beets and may also be created
ation. If it cannot perform in this role, either via an SNP or from choline endogenously [28, 30]. This pathway also inter-
functional B12 deficiency, the 5-methyl folate becomes sects with choline metabolism and more advanced methyl-
“trapped” and is no longer able to participate in one carbon transferases, which ultimately regulate epigenetic expression
metabolism or methylation. There is a specific methionine (. Fig. 18.1).
 

synthase SNP that increases homocysteine levels and may CBS provides the only true disposal route for homocyste-
also contribute to dyslipidemia in men, known as MTRR ine and accounts for approximately half of all homocysteine
A66G [26]. This presentation is particularly true if there is a catabolism. It catalyzes the conversion of homocysteine to
concurrent MTHFR C677T polymorphism as the result of cystathionine utilizing vitamin B6 and magnesium as its
this SNP also increases homocysteine. cofactors. This enzyme is important as it sits between the
BHMT provides a short cut through methylation. It sup- junction of methylation and transsulfuration, the pathway
plies a methyl group that allows for the conversion of homo- that ultimately leads to the generation of the endogenous
cysteine back to methionine as well as converting betaine to antioxidant glutathione. In this way, it has the ability to influ-
dimethylglycine (DMG). While hypothetically BHMT poly- ence detoxification via channeling sulfur down into the trans-
morphisms could have an effect on homocysteine levels, sulfuration pathway and, ultimately, into the gamma glutamyl
there is conflicting evidence to support the idea that SNPs pathway, a mechanism for glutathione production. CBS gen-
have any measurable effects. BHMT is thought to account for erates both cystathionine and hydrogen sulfide (H2S) as its
up to half of the homocysteine remethylation capacity, products. For CBS, there are both upregulated and downreg-
according to some studies [27], while it is thought to account ulated variants. CBS C699T is considered to be upregulated
for less than 1% of homocysteine recycling in others [28]. and CBS A360A is downregulated [31] (. Fig. 18.3).  

BHMT aids MTR in increasing the availability of methionine Upregulation of CBS will cause decreased levels of vita-
so that it may be used to produce SAM [29]. Zinc serves as a min B6, magnesium, glutathione, and homocysteine [11].
cofactor for BHMT and a polymorphism may increase an Vitamin B6 deficiency should be confirmed via xanthurenate
individual’s zinc requirements. Betaine is also required for before supplementing in this sensitive population [11].
the production of DMG, thus it is a necessity for proper Upregulated CBS can compromise the ability to recycle

Dietary folate/Folic acid

7,8 dihydrobiopterin DHFR

NADPH
Epinephrine BH2 DHF
Norepinephrine
Dopamine Serotonin NO DHFR Methionine
NADPH THF

DMG
BHMT
DHFR MTR/ MTRR Zn
Phe Trp Arg NADPH 5,10-Methylene THF Vitamin B12

18 Betaine

5-MTHF
Homocysteine
MTHFR
FAD, NADP
Monoamine Synthesis Tetrahydrobiopterin CBS
B6
BH4

Copyright © 2019 NGI, LLC Taurine, Glutathione, Sulfate Cystathionine

..      Fig. 18.3  The intersection of major biochemical pathways detoxification), and the tetrahydrobiopterin pathway via DHFR, which
including one-carbon metabolism, methylation, and transsulfuration is essential as a cofactor in the production of the monoamine
are essential for the regulation of DNA expression. They also interact neurotransmitters including dopamine, norepinephrine, epinephrine,
with additional pathways including the gamma glutamyl cycle, which serotonin, and nitric oxide
produces glutathione to be used in glutathione conjugation (phase 2
Nutritional Influences on Methylation
275 18
homocysteine back to methionine and to generate neurotransmitters. BH4 is a cofactor required for the
SAM. Further, there will be increased generation of hydrogen hydroxylation of the aromatic amino acids (i.e., phenylala-
sulfide, which can increase the production of ammonia, cor- nine to tyrosine, tyrosine to DOPA, and tryptophan to sero-
tisol, and glutamate resulting in excitotoxicity [32]. Further, tonin). BH4 is also a necessary cofactor for the conversion of
ammonia depletes tetrahydrobiopterin (BH4) through arginine into nitric oxide via nitric oxide synthase (NOS)
increased production of nitric oxide [30]. In this way, poly- [35]. In this way, BH4 serves an integral role in the produc-
morphisms can lead to insufficient production of serotonin, tion of all of the monoamines including dopamine, norepi-
dopamine, norepinephrine, and epinephrine. The CBS nephrine, epinephrine, and serotonin as well as nitric oxide.
C699T variant is often found in those with autism, Down Lord and Bralley state, “Restricted BH4 cofactor availability
syndrome, connective tissue disease, cancer, and homocys- has been suggested as an etiologic factor in neurological dis-
tinuria [33]. A high organosulfur diet in this population will eases, including DOPA-responsive dystonia, Alzheimer’s
cause increased urinary sulfate levels but will typically not disease, Parkinson’s disease, autism and depression; as well
allow for the generation of glutathione. For this reason, it as in other conditions such as insulin sensitivity and vascu-
may be helpful to limit high organosulfur foods such as eggs, lar disease” [11].
onion, garlic, and cruciferous vegetables to tolerable quanti-
ties for a short time to relieve stress on this enzyme.
The increased flux of sulfur through CBS forces sulfur too 18.7.2 Catecholamines
quickly downstream which taxes sulfate oxidase (SUOX), a
lower capacity enzyme. This may cause increased require- The synthesis of all catecholamines starts with the essential
ments for the mineral molybdenum, SUOX’s cofactor [34]. amino acid phenylalanine, which is then converted to the
SUOX catalyzes the oxidation of sulfite to sulfate in the final amino acid tyrosine via phenylalanine hydroxylase (PAH).
reaction in the oxidative degradation of the sulfur amino This reaction requires both BH4 and iron as cofactors.
acids cysteine and methionine [34]. SNPs in SUOX are rare Tyrosine is then consequently converted to L-DOPA via
and, when present, can result in neurological abnormalities tyrosine hydroxylase and is the rate-limited step also using
that are often fatal at an early age. the cofactors BH4 and iron [36]. Dopamine is then generated
CBS downregulation, on the other hand, limits the sulfur from L-DOPA via aromatic L-amino acid decarboxylase
amino acids by slowing the conversion of homocysteine to (AADC), a vitamin B6-dependent enzyme [37]. At this junc-
cystathionine. The resultant elevation of homocysteine is, ture, there are two paths for dopamine. It may be catabolized
therefore, associated with hypertension and other cardiovas- via monoamine oxidase B (MAO-B) using flavin adenine
cular disorders. Similar to upregulation, this will create an dinucleotide (FAD) as its cofactor along with catechol-O-­
increased requirement for vitamin B6 (CBS’s cofactor). Like methyltransferase (COMT) using magnesium and SAM as
those with upregulated variants, individuals who have CBS its cofactors to form the urinary organic acid homovanillate
downregulation have limited availability to generate glutathi- (HVA) [11, 36]. Alternatively, dopamine may also be used to
one from sulfur amino acids such as cysteine [11]. To stimu- generate norepinephrine via dopamine beta hydroxylase
late this enzyme to form glutathione, sulfate, and taurine, (DβH) [22]. This reaction requires copper and ascorbate as
supplement with P5P and, potentially, cysteine in the form of its cofactors. Norepinephrine may then be catabolized by
N-acetyl cysteine. COMT and MAO-B to the urinary organic acid vanilman-
Once cystathionine is generated through CBS, it then is delate (VMA), or it may be converted via COMT to epineph-
converted to cysteine via cystathionine gamma-lyase (CGL) rine, which ultimately is also catabolized by COMT and
[11]. This enzyme also requires vitamin B6 as its cofactor and MAO-B to VMA [11, 22].
is known to cause significantly higher plasma homocysteine COMT is highly polymorphic and is a very common
levels and cystathioninuria [13]. Further, polymorphisms are clinical finding. More often, heterozygosity is found rather
associated with hypertension as this enzyme regulates blood than homozygosity. This enzyme is important not only for
pressure via endogenous signaling of H2S [32]. Replenishing the transfer of methyl groups from SAM to the catechol-
vitamin B6 as the active pyridoxal-5-phosphate (P5P) may amines but also from SAM to catechols from foods (e.g.,
help restore proper enzyme function and allow for proper green tea and potatoes), catechol antioxidants such as quer-
sulfur influx into the gamma glutamyl cycle. cetin, and the hormone catechol estrogen [38]. Additionally,
this enzyme is essential for the catabolism of dopamine, nor-
epinephrine, and epinephrine [38]. Research has shown that
18.7 Connecting Neurotransmitters the COMT Val allele is related to the presence of higher
to Methylation anxiety. This is likely due to the effect of COMT on the dopa-
minergic tone in the prefrontal cortex and the resultant effect
18.7.1 Tetrahydrobiopterin (BH4) on cognition [39]. There is some thought that gender may
also be a factor in anxiety secondary to the COMT val158met
While DHFR is a key enzyme in one-carbon metabolism, it polymorphism due to this enzyme’s necessity in the catabo-
also is an important precursor to the tetrahydrobiopterin lism of estrogen. Therefore, women are more likely to experi-
(BH4) cycle, one that determines cellular levels of several ence higher levels of anxiety than men [39].
 276 J. M. Pizano and C. B. Williamson

Since methyl donors help to upregulate the production 18.7.3 Serotonin

of monoamines, including the catecholamines, they may
be problematic for those with epigenetically activated In serotonin synthesis, the pathway begins with the amino
(downregulated) COMT SNPs. While methyl donors acid tryptophan being converted to 5-hydroxy-tryptophan
should not necessarily be avoided in the long run, it is (5-OH-TRP) by tryptophan hydroxylase (TPH) using both
important to insure proper COMT function prior to sup- BH4 and iron as its cofactors [11]. 5-OH-TRP is conse-
plementation. When supplementing vitamin forms that quently converted to serotonin by AADC [11]. Monoamine
contain methyl donors such as methylcobalamin, oxidase A (MAO-A) is then used to break serotonin down
L-methylfolate, and trimethylglycine, many practitioners into the urinary organic acid 5-hydroxyindoleacetic acid
consider it important to dose only small amounts in the (5-HIAA) [11].
presence of COMT since hypothetically methyl donors MAO-A SNP rs6323 is an upregulated variant causing
may increase production of catecholamines, which could increased enzyme activity leading to decreased amounts of
tax COMT. These supplements may be dosed several times amines. The G variant encodes for higher activity. A study by
per week rather than daily as another way of preventing Slopien et al. in 2012 found that there was a particularly high
increased anxiety. rate of depression in postmenopausal women that had this
Given that magnesium is the cofactor for COMT, the variant and that there was MAO-A activity ranging more
presence of a polymorphism supports investigating erythro- than 50-fold over controls [43]. This enzyme also has down-
cyte (RBC) magnesium levels and supplementing with a regulated variants including rs5906883, rs5906957, rs909525,
well-absorbed form of magnesium if needed. Some forms of rs9593210, and rs2072743. These downregulated variants
magnesium, such as magnesium sulfate, oxide, and citrate decrease enzyme activity leading to increased amounts of
work as osmotic laxatives and are not very well absorbed amines such as serotonin (. Fig. 18.4).
 

[40]. Magnesium glycinate is well absorbed and may provide Serotonin is considered to be the neurotransmitter most
an additional calming effect since it is chelated to the amino closely associated to depression. A common nutritional inter-
acid glycine, which also serves as an inhibitory neurotrans- vention for depression is to supplement folate. This interven-
mitter [41]. Another good option is magnesium threonate as tion is effective because folate (5-MTHF) is responsible for
it is the only form of magnesium that may cross the blood– regenerating oxidized BH4. When there is insufficient BH4,
brain barrier [42]. 5-MTHF may be substituted for BH4 at the enzymatic level.
MAO-B catalyzes the oxidative deamination of bio- This is due to the similarity in chemical structures of BH4 and
genic and xenobiotic amines (i.e., histamine and tyra- 5-MTHF, enough so that endothelial nitric oxide synthase
mine), is a part of the metabolism of neuroactive and (eNOS) can use 5-MTHF as a substitute cofactor [12]. This
vasoactive amines in the central nervous system and may account for folate’s antidepressant effect.
peripheral tissues, and preferentially oxidizes dopamine
(as opposed to MAO-A, which preferentially oxidizes sero-
tonin and noradrenaline). Variants include rs1799836, 18.7.4 Iron and Neurotransmitters
rs10521432 (C112982T), and rs6651806 (T57758G).
MAO-B inhibitors are a type of pharmaceutical that is Iron is a cofactor, along with BH4, for PAH, TH, and TPH. This
often used for those with Parkinson’s disease to slow the may account for why patients with iron-based anemia often
breakdown of dopamine. struggle with mood. Without sufficient iron, the enzyme tryp-

..      Fig. 18.4  Tryptophan is the

precursor of serotonin and is
18 metabolized by tryptophan
Serotonin metabolism
monooxygenase with the Aro
cofactors of BH4 and iron to aci matic
dd
5-Hydroxytryptophan eca L-am
5-HTP followed by AADC with the han ase rbo ino
cofactor of P5P. Monoamine y p top ygen xyl
Tr noox B6 ase
oxidase A preferentially
Mo 4, Fe2
catabolizes serotonin and uses BH Serotonin
the cofactor FAD to create the
organic acid metabolite 5-HIAA L-Tryptophan
Oxidase
Monoamine
FAD

Copyright © 2019 NGI, LLC 5-Hydroxyindoleacetate (5-HIAA)

Nutritional Influences on Methylation
277 18
tophan dehydrogenase is unable to convert the amino acid Nitric oxide (NO) is synthesized from the amino acid
tryptophan into the intermediate 5-hydroxy-­ tryptophan, arginine and is produced in the endothelial cells of blood ves-
which is ultimately converted to serotonin by aromatic sels. It is a gaseous substance that diffuses readily through
L-amino acid decarboxylase (AADC) using its cofactor vita- membranes and helps to regulate blood flow by dilation of
min B6 [37]. This will cause a decreased capacity to synthesize muscles encircling blood vessels. Therefore, nutritionally, a
serotonin which, when deficient, is the major neurotransmit- relative arginine deficiency can occur in diseased coronary
ter associated with depression. Some depression, however, arteries. As such, replenishing arginine may allow for arterial
may also be dopamine mediated. Iron deficiency anemia can dilation. NO can also help control glucose uptake by muscles
also impact this type of depression as dopamine synthesis [44]. This neurotransmitter is unstable and acts quickly,
relies on the conversion of phenylalanine to tyrosine via the undergoing oxidation to nitrite or nitrate within seconds
enzyme phenylalanine hydroxylase (PAH). This enzyme relies [44]. It plays an important role in neurotransmissions, blood
on both BH4 and iron as its cofactors [37]. Additionally, the clotting, and control of blood pressure (via endothelium-­
conversion of tyrosine to L-DOPA is also iron and BH4 reliant derived relaxing factor activity) [44]. Nitric oxide synthase
as tyrosine hydroxylase requires these nutrients as cofactors. It (NOS’s) ability to influence smooth muscle reaches beyond
is then L-DOPA that may be converted into dopamine via the the cardiovascular system and allows for regulation of other
enzyme AADC in both the central and peripheral nervous smooth muscle actions such as peristalsis [44]. Further, NOS
systems [22] (. Figs. 18.5 and 18.6).
  is associated with the neurotoxicity found in stroke and other

DHFR Phe Trp Arg

7,8 Dihydrobiopterin (BH2) Tetrahydrobioptrerin (BH4)
NADPH
NADPH
PAH BH4, Fe+++ TPH BH4, Fe+++ NOS FAD
FMN
HEME
O2

Tyr 5-HO-TRP Citrulline

+
TH BH4, Fe+++ AADC B6 Nitric oxide

Serotonin

MAO FAD
L-DOPA
AADC B6
5-HIAA
M D

Dopamine
FA
AO
CO SAM

DßH Cu++, Ascorbate

T
g,
M
M

HVA Norepinephrine
M M
CO , SA

COMT Mg, SAM

g

T
M
D
AO
FA

M AM
M

Epinephrine
CO g, S

VMA
T
M
D
AO
FA
M

Copyright © 2019 NGI,LLC VMA

..      Fig. 18.5  BH4 and neurotransmitter synthesis. DHFR dihydrofolate hydroxylase, MAO monoamine oxidase; COMT catechol-O-methyltrans-
reductase, PAH phenylalanine hydroxylase, TH tyrosine hydroxylase, ferase, TPH Tryptophan hydroxylase, NOS Nitric oxide synthase, HVA
AADC aromatic L-amino acid decarboxylase, DβH dopamine beta homovanillate, VMA vanilmandelate, 5-HIAA 5-hydroxyindoleacetic acid
 278 J. M. Pizano and C. B. Williamson

..      Fig. 18.6  Nitric oxide

synthase pathway
Nitric oxide synthase (NOS)
NADPH, O2 1/2 NADPH, O2
NADP+, H2O 1/2 NADP+, H2O
Arginine Hydroxyarginine Nitric
Nitric oxide Nitric oxide oxide
synthase synthase

Copyright © 2019 NGI, LLC Citrulline

neurodegenerative diseases [45]. In the immune system, it encoded by NOS3 [51]. Found in the endothelium, it is involved
helps to stimulate immune cell activation and helps neurons in vasodilation, vascular smooth muscle relaxation via cGMP-
regulate their function [4]. mediated signal transduction, mediates vascular endothelial
Low levels of NOS can impact male fertility by causing growth factor induced angiogenesis in coronary vessels, and
erectile dysfunction (ED) [46]. This is because NO is the pri- promotes blood clotting via platelet activation [51]. Inside the
mary biochemical way that an erection is stimulated via the muscle cell, NOS3 binds to guanylate cyclase, resulting in acti-
corpus cavernosum [47]. Phosphodiesterase 5 (PDE5) inhib- vation and, consequently, catalyzing the conversion of GTP to
itor medications such as Viagra® capitalize on this mecha- cyclic GMP. This process ultimately leads to the activation of
nism, though they were not originally designed for this cGMP-activated protein kinase and the subsequent attachment
purpose. In fact, it was not until Viagra® was used in a phase of a phosphate group to the inositol trisphosphate receptor
I clinical trial for the treatment of angina that the medica- (IP3), which then results in a decrease in calcium in the muscle
tion’s “side effect” of penile erection was discovered [15]. cells’ cytoplasm [52]. This is the mechanism by which NO
Viagra® allows for blood vessels within the erectile tissue to results in arterial relaxation. Key variants include rs1800783
vasodilate in response to released NO as well as for the acti- (A6251T), rs3918188 (C19635T), rs7830 (G10T), rs1800779
vation of guanylate cyclase (cGMP). Viagra® inhibits break- (G6797A), and rs2070744 (T786C) (. Fig. 18.7).
 

down of cGMP causing increased and sustained levels of Interestingly, manganese appears to be another nutrient
cGMP, thus causing vasodilation in erectile tissue [4]. that can be used to regulate NO production [53]. This is
There are three different forms of nitric oxide synthase related to arginine’s ability to be converted into either orni-
(NOS 1–3). All three enzymes catalyze the conversion of thine or citrulline to produce urea and nitric oxide, respec-
arginine to nitric oxide using NADPH and NADP+ as cofac- tively [11]. If you inhibit production of ornithine via the
tors [44]. This reaction also creates the byproduct citrulline enzyme arginase (converts arginine and water to ornithine
[11]. It is possible to test NOS activity via urinary organic and urea), it will increase nitric oxide production and decrease
acid testing, specifically looking for increased levels of citrul- urea production. Since manganese is the cofactor for arginase,
line. NOS1 encodes neuronal nitric oxide synthase (nNOS) decreasing manganese intake may allow for increased nitric
and is found in nervous tissue and skeletal muscle where it is oxide production that could allow for vasorelaxation. This
involved in cell communication [48]. Key variants include could have positive implications for childhood asthma [11].
rs7298903 (A57373G), rs3782206 (G59494A), and rs2293054
18 (T2202C). NOS2, or inducible nitric oxide synthase (iNOS),
is considered a reactive free radical involved in neurotrans- 18.8 Final Thoughts
mission along with antimicrobial and antitumor activities
[48]. In this way, it may be induced by lipopolysaccharides Methylation has far-reaching implications and plays a central
and cytokines, allowing it to serve as an immune activator to role in metabolism. Methylation contributes to epigenetic
help defend against pathogens. Found in both the immune activation via turning “on” and “off ” genes, synthesizes neu-
and cardiovascular systems, elevations are commonly found rotransmitters, and is required for the production of glutathi-
in inflammatory disorders [49]. one required for detoxification. Understanding the nutritional
Via iNOS, NO may play a role in cancer, though this mech- implications of genetic SNPs while validating these altera-
anism is not well understood. It may have the potential to tions by correlating it to laboratory evaluations allows medi-
stimulate tumor growth, development, and progression as well cal and nutrition professionals to directly influence
as angiogenesis [49]. Due to the precursory nature of arginine methylation-related biological processes that may, in turn,
to NO, a low arginine diet has been suggested as a means of improve the health of the patient. This may then help prevent
controlling cancer progression [50]. Key variants include and treat a host of chronic disease states as we are learning
rs2297518 (C1823T), rs2248814 (T32235C), and rs2274894 that all diseases are a confluence of nature and nurture or
(T836165G). Endothelial nitric oxide synthase (eNOS) is what we now call epigenetics . Table 18.2.
 
Nutritional Influences on Methylation
279 18
..      Fig. 18.7 Guanosine
triphosphate Protein kinase
inactive

Guanylate
Guanosine cyclase
triphosphate Protein kinase/
cGMP cGMP (activated)
(GTP)

PPi

Copyright © 2019 NGI, LLC

..      Table 18.2  Single-nucleotide polymorphisms (SNPs), cofactors, and functional markers

SNPs Cofactors Organic acids Amino acids/other rs Numbers

tests/interventions

Methylation, transsulfuration, and one- 7 www.­snppros.­com

 

carbon metabolism

DHFR NADPH, BH4 ↑FIGLU; ↓HVA, Restricted rs1643649, rs1643659,

Dihydrofolate reductase re-coupling ↓VMA neurotransmitters, rs1677693, rs1650697
Codes the enzyme dihydrofolate (BH4 requires ↓tyrosine, ↓trypto-
reductase used in conversion of magnesium) phan; restricted
dihydrofolate and folic acid into one-carbon
tetrahydrofolate metabolism,
↓methionine

MTHFR C677T Riboflavin, ↑FIGLU, ↑Homocysteine; rs1801133

Methylene tetrahydrofolate reductase NADH, and ↑glutaric acid correct B12 status to
Catalyzes the conversion of ATP avoid folate
5,10-­methylenetetrahydrofolate to trapping
5-methyltetrahydrofolate, a co-substrate
for homocysteine remethylation to
methionine; folate trapping may
increase homocysteine levels and
deplete cellular folate concentrations

MTR/MTRR B12, SAM, ↑MMA ↓Methionine, rs1801394, rs1802059, rs162036

Methionine synthase/ methionine zinc, heme ↑↓homocysteine –
synthase reductase MTR cofactor: Check other
Responsible for B12 recycling and Zinc, blocked homocysteine
converting adenosyl-cobalamin into by lead, catabolism SNPs like
methyl-cobalamin as needed for aluminum, CBS and BHMT
methylation and mercury
MTRR
cofactors:
SAM,
(continued)
 280 J. M. Pizano and C. B. Williamson

..      Table 18.2 (continued)

SNPs Cofactors Organic acids Amino acids/other rs Numbers

tests/interventions

FAD, NAD,
zinc, blocked
by lead

AHCY NAD, SAM SAH regulator; ↑Methionine, rs121918607

Adenosylhomocysteinase SAH blocks ↑homocysteine
Regulates intracellular COMT and is
S-­adenosylhomocysteine (SAH) considered
concentration and assists with inflammatory
methionine catabolism

SHMT P5P, SAM ↑FIGLU Potential abnormali- rs9909104 rs1979277

Serine hydroxymethyl-transferase ties in glycine and
Catalyzes the reversible, simultaneous serine
conversions of L-serine to glycine and
tetrahydrofolate to
5,10-­methylenetetrahydrofolate
(requires SAM); also catalyzes conversion
of 5,10-methenyltetrahydrofolate to
10-formyltetrahydrofolate

CBS C699T P5P, ↑Xanthurenate ↑Cystathionine, rs234706

Cystathionine beta synthase magnesium, ↑cysteine, ↑cystine,
Converts homocysteine to cystathio- blocked by ↓homocysteine,
nine; sulfur sensitivity lead ↑glutamate,
↑ammonia (depletes
BH4)

CBS A360A P5P, ↑↓Xanthure- ↑Homocysteine, rs1801181

Cystathionine beta synthase magnesium, nate ↓cystathionine,
Converts homocysteine to cystathio- blocked by ↓cysteine, ↓cystine,
nine; cardiovascular complications lead ↑NO

CGL (CTH gene) P5P, NADH ↓↑Xanthure- ↑Homocysteine, Primary: rs1021737

Cystathionine gamma lyase nate, alpha-­ ↑cystathionine,
Associated with cystathioninuria; ketobutyrate, ↓cysteine, ↓cystine,
converts cystathionine to cystine; alpha-­ ↑ammonia
limiting enzyme for glutathione hydroxybutyrate (depletes BH4)
synthesis

PEMT SAM, choline, ↓SAM: SAH; ↓Phosphoethanol- rs12325817, rs7946,

Phosphatidyl-ethanolamine folate potential ↑ in amine, potentially ↓ rs46464006, rs4244593
N-­methyltransferase hydroxyproline phosphatidyl-serine
Required in choline synthesis, hepato- (membrane and ↓phosphatidyl-­
cyte membrane structure, bile secretion, fluidity) choline; pathway
estrogen degradation and VLDL requires magnesium
18 secretion

BHMT Zinc, TMG; N/A ↓Methionine, rs3733890

Betaine homocysteine methyltransferase blocked by Consider RBC ↑homocysteine
Supplies a methyl group to convert glucocorti- zinc
homocysteine back to methionine and coids
betaine to dimethylglycine (DMG)

SUOX Molybdenum, ↑sulfate, ↓Homocysteine, rs705703

Sulfite oxidase hydroxo-­ ↑pyrogluta- ↓cystathionine,
Is a mitochondrial enzyme; catalyzes the cobalamin, mate, ↓cysteine, ↑taurine
oxidation of sulfite to sulfate, the final vitamin E potentially
reaction in the oxidative degradation of ↑alpha hydroxy-
the sulfur amino acids cysteine and butyrate
methionine
Nutritional Influences on Methylation
281 18

..      Table 18.2 (continued)

SNPs Cofactors Organic acids Amino acids/other rs Numbers

tests/interventions

Neurotransmitters

NOS1 NADPH and ↑Orotate, Potential abnormali- rs7298903, rs3782206, rs2293054

Nitric oxide synthase 1 NADP+ ↑citrate, ties in arginine,
Catalyzes the conversion of arginine to ↑isocitrate, citrulline, nitric
nitric oxideAlso creates the byproduct ↑cis-aconitate oxide
citrulline

NOS2 Manganese ↑Orotate, Potential abnormali- rs2297518, rs2248814, rs2274894

Nitric oxide synthase 2 ↑citrate, ties in arginine,
Inducible nitric oxide synthase (iNOS); ↑isocitrate, citrulline, nitric
considered a reactive free radical ↑cis-aconitate oxide; responds to
involved in neurotransmission along antioxdiation
with antimicrobial and antitumoral
activities

Found in the immune and cardiovascu-

lar systems; involved in immune defense
against pathogens; maybe induced by
lipopolysaccharides and cytokines;
commonly found in inflammatory
disorders

NOS3 Manganese ↑Orotate, Potential abnormali- rs1800783, rs3918188, rs7830,

Nitric oxide synthase 3 ↑citrate, ties in arginine, rs1800779, rs2070744
Endothelial nitric oxide synthase (eNOS); ↑isocitrate, citrulline, nitric
involved in vasodilation, vascular ↑cis-aconitate oxide
smooth muscle relaxation via cGMP-­
mediated signal transduction pathway;
mediates vascular endothelial growth
factor (VEGF)-induced angiogenesis in
coronary vessels; promotes blood
clotting via platelet activation

PAH BH4, Fe+3 ↑Phenylacetic ↑Phenylalanine, rs62507347, rs10860936,

Phenylalanine hydroxylase Acid, (poten- ↓tyrosine rs3817446, rs1722387,
Converts phenylalanine to tyrosine; tially) rs5030858, rs1522305,
associated with PKU ↓HVA, ↓VMA rs2037639, rs1718301,
rs1522296, rs2245360,
rs1801153, rs772897,
rs1722392, rs1042503,
rs5030849, rs1522307,
rs11111419, rs10778209,
rs1718312

TH BH4, Fe+3 Potentially ↑Tyrosine, ↓DOPA rs28934581, rs28934580,

Tyrosine hydroxylase ↓HVA, ↓VMA

Converts tyrosine to L-DOPA rs2070762, rs7483056, rs6356

TPH BH4, P5P, B2, ↑5-HIAA, ↓Tryptophan rs623580

Tryptophan hydroxylase copper ↑Glutaric acid
Converts tryptophan to 5-HO-RP, a
serotonin precursor

DBH Copper, ↓VMA, ↑HVA ↑↓Dopamine rs1611115 rs1108580

Dopamine beta hydroxylase vitamin C
Converts dopamine to norepinephrine;
may be associated with schizophrenia or
depression
(continued)
 282 J. M. Pizano and C. B. Williamson

..      Table 18.2 (continued)

SNPs Cofactors Organic acids Amino acids/other rs Numbers

tests/interventions

MOA-A FAD Upregulation: Potential ↓ in Upregulation: rs6323

Monoamine oxidase A ↓5-HIAA, tryptophan, Downregulation: rs5906883,
Catalyzes the deamination of the amines ↑glutaric acid phenylalanine, and rs5906957, rs909525, rs9593210,
dopamine, serotonin, epinephrine, Downregula- tyrosine rs2072743
norepinephrine tion: ↑5-HIAA,
Metabolizes the xenobiotic amines: ↑glutaric
Heterocyclic amines (meat), tyramines Acid
and histamine
MAO-A preferentially oxidizes serotonin
and noradrenaline

MOA-B FAD Upregulation: ↓Tyrosine, rs1799836, rs10521432,

Monoamine oxidase B ↑HVA, ↑VMA, ↓dopamine rs6651806
Catalyzes the oxidative deamination of ↑glutaric acid
biogenic and xenobiotic amines (i.e.,
histamine and tyramine); part of the
metabolism of neuroactive and
vasoactive amines in the CNS and
peripheral tissues; preferentially oxidizes
dopamine; associated with depression

COMT Catechol-O-methyltransferase Magnesium, Downregula- N/A rs4680, rs769224, rs4633

Transfers methyl group from SAM to the SAM tion: ↓VMA, Consider RBC
catecholamines ↓HVA magnesium
Upregulation:
↑HVA, ↑VMA

Breaks down dopamine, epinephrine,

and norepinephrine; transfers a methyl
group from SAM to catechols from foods
(green tea, potatoes), antioxidants
(quercetin), and hormone catechols
(estrogen)

Glutathione

GSS Magnesium Potential ↑ in Potential abnormali- rs22273684, rs6088659,

Glutathione synthase pyroglutamate, ties in glutamate, rs2236270, rs28936396,
Found within the gamma-glutamyl alpha-­ cysteine, glycine rs6060124
cycle; aids in the production of hydroxybutyr-
glutathione ate and
alpha-­
ketobutyrate

GSTT1Del 1200 mg Potential ↑ in Potential abnormali- rs796052137, rs796052136

Glutathione S-transferase theta 1 vitamin C/day pyroglutamate, ties in glutamate,
18 Conjugates reduced glutathione; has alpha-­ cysteine, glycine
many exogenous and endogenous hydroxybutyr-
hydrophobic electrophiles ate, and
alpha-­
ketobutyrate

GSTM1 Vitamin C Potential ↑ in Potential abnormali- rs2740574, rs4147565,

Glutathione-S-transferase pyroglutamate, ties in glutamate, rs4147567, rs4147568,
Mu 1 alpha-­ cysteine, glycine rs1056806, rs12562055,
Conjugates reduced glutathione; hydroxybutyr- rs2239892
functions in the detoxification of ate, and
electrophilic compounds including alpha-­
carcinogens, therapeutic drugs, ketobutyrate
environmental toxins, and products of
oxidative stress
Nutritional Influences on Methylation
283 18
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18
 285 19

The Immune System:

Our Body’s Homeland
Security Against Disease
Aristo Vojdani, Elroy Vojdani, and Charlene Vojdani

19.1 Introduction – 286

19.2 The Mucosal Immune System: The First Line of Defense – 286
19.2.1 I ntestinal Permeability to Large Macromolecules – 287
19.2.2 Diagnostic Features of the Mucosal Immune System – 287

19.3 An Innate Immune System – 288

19.3.1 Diagnostic Features of the Innate Immune System – 292

19.4 Acquired or Adaptive Immunity – 292

19.4.1  rimary and Secondary Immune Response – 293
P
19.4.2 IgE and Allergic Reactions – 294
19.4.3 Diagnostic Features of the Adaptive Immune System – 295

19.5  he Three Major Mechanisms of Protection against

T
Autoimmunity – 295
19.5.1  ral Tolerance – 295
O
19.5.2 Central Tolerance – 297
19.5.3 Peripheral Tolerance – 298

19.6 Dietary Intervention – 299

19.7 Conclusion – 300

References – 300

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_19
 286 A. Vojdani et al.

Learning Objectives molecules, the mucosal immune system is ready to launch an

55 The mucosal immune system as the first line of defense, effective immune response against harmful environmental
our homeland security against invading pathogens and factors, including infections by viruses, bacteria, parasites,
diseases. and fungi, as well as toxic chemicals and dietary proteins and
55 The importance of innate immunity in inflammation and peptides [1]. Mucosal immunity protects the epithelial bar-
autoinflammation. rier by eliciting pro-inflammatory responses against patho-
55 The role of adaptive or acquired immunity in health and gens or mucosally induced oral tolerance toward food
disease. antigens and components of commensal microbiota.
55 The three tolerance mechanisms that protect the body Secretory immunoglobulin A (SIgA), which is in all mucous
against immune disorders: The central, oral, and secretions – including milk, saliva, and tears – as well as in GI
peripheral tolerance mechanisms provide an umbrella of secretions, the respiratory epithelium, and the genitourinary
protection against immune disorders. tract, plays a crucial role in the maintenance of immunologi-
cal tolerance and protection against allergies and other
inflammatory diseases [2]. This is done by inhibiting bacte-
19.1  Introduction rial and fungal adhesion to the epithelial cells and neutraliz-
ing the viruses, antigens, enzymes, and toxins (see . Fig. 19.1).
 

An immune system is a collection of organs, tissues, cells, The role of the mucosal immune system in the body’s
and humoral factors that protects a living organism. The health is so important that an entire society is dedicated to
immune system shields the body against external harmful the promotion of its research, advancement, and literary and
influences by developing several levels of protective weapons. educational aspects. Part of the mission statement of the
The three major protective layers of the immune system Society for Mucosal Immunology (SMI) states: “While gen-
are: eral immunologists typically study immune responses in the
1. The mucosal immune system or surface factors. spleen, lymph nodes or peripheral blood, mucosal immu-
2. Innate immunity. nologists focus on the sites at which most antigens enter – the
3. Adaptive or acquired immunity. mucosal surfaces of the gastrointestinal, respiratory, and uro-
genital tracts … Equally important is the study of the disease
states that result when the mucosal immune system’s ability
19.2   he Mucosal Immune System:
T to distinguish pathogens from innocuous antigens fails;
The First Line of Defense examples include inflammatory bowel disease and food
allergy.”
The mucosal immune system is our body’s first line of IgA plays a critical role in mucosal immunity. Produced
defense. It allows the absorption of nutrients from our gas- in the mucosal linings, more IgA is generated than all the
trointestinal tract while at the same time maintaining a con- other antibodies combined. About 3–5 g are secreted into the
stant alertness to a large number of harmful pathogens and intestinal lumen daily [3, 4]. It is therefore the most abundant
antigens by using its antenna-like molecules or Toll-like immunoglobulin in all mammals, secreted mostly via the
receptors (TLRs) or antibodies such as immunoglobulin A mucous membranes, protecting us against the unceasing
(IgA) or immunoglobulin M (IgM). Using these and other assault of pathogens and commensal microbes. The induc-

a b c Pathogen Bacterial
toxins

19

..      Fig. 19.1  The major antibody isotype present in the lumen of the through epithelial cells at the base of the crypts. b Polymeric IgA binds
gut is secretory polymeric IgA. a Secretory IgA is synthesized by plasma to the mucus layer overlying the gut epithelium and c acts as an
cells in the lamina propria and transported into the lumen of the gut antigen-specific barrier to the pathogens and toxins in the gut lumen
The Immune System: Our Body’s Homeland Security Against Disease
287 19
tion of IgA occurs via both T-dependent and T-independent teins into the submucosa and regional lymph nodes and into
mechanisms. After dendritic cells have sampled a tiny frac- the circulation. The ensuing immune response against these
tion of the intestinal antigens, IgA specifically is produced invading antigens results in the formation of polymeric IgA
against the commensal microbes and food antigens. and immune complexes, which bind to the mucosal layer to
In one study [5], IgA and IgG antigens specific to ovalbu- protect against greater damage. However, these immune com-
min, β-lactoglobulin, or gliadin were measured in serum, plexes, along with inflammatory cytokines, can lead to fur-
saliva, colostrum, and breast milk from 40 healthy breast-­ ther increased gut permeability and to the entry of dietary
feeding women, and specific IgA reactivity was found in all proteins and peptides into the bloodstream and formation of
the samples analyzed. Levels were found to be highest in antibodies against these antigens. Circulating memory B lym-
colostrum and milk, followed by saliva, and then in serum. phocytes that have previously been exposed to these antigens
Despite inclusion in the testing of three unrelated food anti- upon repeated exposure to the same antigen(s) will cause the
gens (gliadin, albumin, lactoglobulin), a correlation between formation of plasma cells with J chains to produce antibodies
the levels of specific IgA was found in the saliva, colostrum, in the blood in a much shorter period of time than the pri-
and milk samples of all 40 subjects [5]. mary immune response. A J chain is a protein component
In individuals with IgA deficiency, a compensatory that acts like a “glue” in IgA and IgM antibodies. When these
increase in secretory IgM has also been detected [6]. These antigens and peptides are presented to APCs, T cells, and B
findings together support the importance of measuring IgA cells for the first time, the plasma cell formation can result in
and IgM antibodies against different components of gut the production of both IgG and IgA against dietary proteins
microbiome and food antigens. and peptides in the blood within 15  days. If these antigens
Furthermore, the increased production of IgA antibody share homology with different tissue antigens, they can initi-
in the blood, which is measured against food antigens and ate an autoimmune disease in different organs, such as the
bacterial toxins, is the spillover from increased mucosal IgA kidneys, liver, brain, skeletal muscles, and others [9, 10].
production. In this process, naïve B cells generated in the
bone marrow migrate to the inductive sites of mucosal
immunity represented by the gut-associated lymphoid tis- 19.2.2   iagnostic Features of the Mucosal
D
sues (GALT or Peyer’s patches; lymphoid follicles of the large Immune System
bowel) or bronchus-associated lymphoid tissues, where they
are stimulated by antigen-presenting cells (APCs) and cog- The importance of measuring the total and specific SIgA is
nate T-helper cells. Antigen-stimulated B and T cells migrate well established in different disorders.
out through the draining lymph nodes and lymphatics and For example, testing for SIgA helps in determining:
enter the bloodstream. During this process, a subset of these 55 If the mucosal immune system is in a healthy and
cells remains in the blood in the form of memory cells that balanced state. Normal levels of SIgA may indicate a
recognize food antigens. The stimulated cells finally relocate healthy mucosal immune system; very high or low SIgA
or “home in” to the effector sites (including the lamina pro- may indicate inflammation, autoimmunity, and immu-
pria) of the gastrointestinal, respiratory, and genital tracts nodeficiency.
and various endocrine glands, where they secrete a signifi- 55 Elevated total SIgA with elevation of IgA or IgM
cant amount of IgA antibody. This spillover from IgA pro- antibodies against oral pathogens may indicate chronic
duction in saliva can be detected in the blood using different infection in the oral cavity.
immunological assays. 55 Elevated total SIgA with elevation of IgA or IgM
Although production of IgA antibody in the secretion is antibodies against bacterial cytotoxins and tight junction
considered protective, in the case of oral tolerance failure, the proteins may indicate intestinal barrier dysfunction to
overproduction of IgA against food antigens and bacterial large molecules, irritable bowel syndrome, and small
toxins may result in IgA immune complex formation. This intestinal bacterial overgrowth (SIBO).
may be followed by the production of pro-inflammatory 55 Elevated total SIgA with elevation in IgA or IgM
cytokines, all of which can lead to increased intestinal per- antibodies against a variety of food antigens may
meability and increased antigen exposure. This will then lead indicate breakdown in oral tolerance, enhanced intesti-
to increased IgA and IgM production against dietary proteins nal permeability, food immune reaction, and possibly
and bacterial antigens in the blood [7, 8]. autoimmunities.
55 Elevated total SIgA with elevation in IgA or IgM
antibodies against gliadin and transglutaminase-2,
19.2.1  I ntestinal Permeability to Large actomyosin, Saccharomyces cerevisiae, and/or calprotec-
Macromolecules tin may indicate the possibility of non-celiac gluten
sensitivity (NCGS), celiac disease (CD), and its overlap
A number of conditions and environmental triggers can with Crohn’s disease and ulcerative colitis.
result in damage to the intestinal barrier and increased per- 55 Elevated total SIgA with elevation in IgA and IgM
meability to large macromolecules, leading to the loss of antibodies against different parasitic antigens may
mucosal immune tolerance and the passage of dietary pro- indicate parasitic infection [11–20].
 288 A. Vojdani et al.

This is why the textbook of Food Allergy and Intolerance

[21] states that: “Mucosal production of IgA and IgM anti-
bodies to dietary antigens, and particularly to gliadin, appears
to be an early event in the gluten-sensitive enteropathy but
does not initially cause a flat lesion.”

19.3  An Innate Immune System

The mucosal immune system of higher mammals is covered

by a single layer of epithelium, which secretes antimicrobial
peptide and is topped by a thick layer of mucus. This system
is fortified by both innate and adaptive immune responses to
protect the host against the harsh environment of bacteria,
toxins, antigens, and a variety of food components that varies ..      Fig. 19.2 Monocytes
from person to person. This interrelationship between the
mucosal immune system and gut bacteria is bidirectional.
For example, bacteria flourish on food components, such as
carbohydrates, proteins, and vitamins, and in return reward
the microbiota by developing oral tolerance and natural
immunity through regulatory T cells (CD4+ cD25+) and
regulatory cytokines (TGF-β and IL-10). Moreover, the host
microbiota influences the development and maturation of
lymphoid cells involved in mucosal immunity [22–24].
The innate immune system acts as the “first responders”
against pathogens such as bacteria, viruses, fungi, and protozo-
ans. This system is not unique to mammals; even invertebrates
possess the ability to protect themselves against invaders. From
an evolutionary point of view, this ancient mechanism was
developed to protect multicellular organisms. However, start- ..      Fig. 19.3  Dendritic cell
ing with the fish, and going through amphibians and birds and
all the way to mammals, the innate immune system provides cytes, dendritic cells, macrophages, innate lymphoid cells,
this frontline barrier or defense. It very wisely stops the enemy natural killer cells, mast cells, basophils, neutrophils, eosino-
to provide the required time for action by the adaptive immune phils, epithelial cells, and paneth cells [26].
system and the development of specific antibodies against the Monocytes are produced by the bone marrow (. Fig. 19.2).
 

pathogens, which requires about 2 weeks [25]. Think of it as the The largest type of leukocyte, they are recognizable by their
frontline soldiers fighting a heroic holding action against the distinct kidney-shaped nucleus. They circulate in the blood-
assaulting forces to give their reinforcements enough time to stream for 1–3 days before moving into the tissues through-
prepare the necessary weapons and bring them to the battle. out the body and differentiating into macrophages and
The innate immune system in the mucous membranes myeloid lineage dendritic cells. Half of the body’s monocytes
consists of several physiologic, anatomic, and cellular com- remain stored in the spleen as a reserve. Monocytes and their
ponents. The anatomical aspects include mucosal surfaces of macrophage and dendritic cell descendants have three main
the skin, lungs, mammary, and gastrointestinal and urogeni- functions in the immune system: phagocytosis, antigen pre-
tal tracts. Secretion of hydrochloric acid and digestive sentation, and cytokine production.
19 enzymes is a major physiologic function that – in collabora- Dendritic cells (DCs) are antigen-presenting cells (APCs)
tion with gut barrier structures – prevents the entry of food that act as messengers between the innate and adaptive
antigens, bacterial toxins, and whole pathogens into the immune systems (. Fig. 19.3). Their main function is to pro-
 

body. Complement proteins and some cytokines are also cess antigenic material and present it on their cell surfaces to
considered components of innate immunity. Innate immu- T cells. They can be found in the tissues that come in contact
nity as a whole is a nonselective, nonspecific immune system with the external environment, such as the skin, the inside of
and does not modify itself based on the type of invaders. For the nose, the lungs, the stomach, the intestines, and, in an
example, most food antigens are digested by digestive immature state, in the blood. When activated, they migrate
enzymes and, other than H. pylori, most pathogens cannot to the lymph nodes where they interact with B cells and T
withstand the low pH of the stomach. cells to craft the adaptive immune response. They grow the
However, the cellular component of innate immunity is projections or dendrites that give them their name.
more selective and constantly modifies itself to efficiently Macrophages are the junkyard dogs of the human body
combat the enemy. The cellular component consists of mono- (. Fig.  19.4). They are found in virtually all tissues, where
 
The Immune System: Our Body’s Homeland Security Against Disease
289 19

..      Fig. 19.4 Macrophage

..      Fig. 19.6  NK cell

..      Fig. 19.5  Innate lymphoid cell

they patrol for potential pathogens such as cellular debris,

foreign substances, microbes, cancer cells, and anything else
that they don’t identify as a healthy body cell. When they find
..      Fig. 19.7  Mast cell
an object that they identify as alien or harmful, they become
true to their name (which means “big eater”), engulfing and
digesting the offending antigen and presenting the digested much faster reaction time and makes them the only protec-
bits to T cells. They have various forms and various names to tive immune cell that can detect and destroy harmful cells
go with them. M1 macrophages encourage inflammation, that are missing MHC markers. They use perforin and gran-
whereas M2 macrophages decrease inflammation and zyme B to kill their targets.
encourage tissue repair. Macrophages can also decrease Mast cells (mastocytes, labrocytes) are granulocytes derived
immune reactions through the release of cytokines. from the myeloid stem cell (. Fig. 19.7). They contain many
 

Innate lymphoid cells (ILCs) are a group of innate immune granules rich in histamine and heparin. Best known for their
cells derived from a common lymphoid progenitor (CLP) role in allergies, mast cells can bind to the fragment crystalliz-
(. Fig.  19.5). They are identified by the absence of an
  able (Fc) region of IgE, causing them to release histamine and
antigen-­specific B- or T-cell receptor because they lack the other inflammatory mediators. However, they also play an
recombination-­activating gene (RAG). They have various important protective role and are critically involved in wound
physiological functions and have an important role in protec- healing, angiogenesis, immune tolerance, anti-pathogen
tive immunity and the regulation of homeostasis and inflam- defense, and the blood-brain barrier function.
mation. Their dysregulation can lead to immune disorders Basophils are the least common but largest of the granulo-
and even autoimmune disease. cytes (. Fig.  19.8). They are responsible for inflammatory
 

Natural killer cells (NK cells) are a type of cytotoxic lym- reactions during immune response and for the formation of
phocyte (. Fig.  19.6). Their main function is to kill tumor
  acute and chronic allergic diseases such as anaphylaxis,
cells and virally infected cells. They are to the innate immune asthma, atopic dermatitis, and hay fever. On the protective
system what cytotoxic T cells are to the adaptive immune sys- side, they can perform phagocytosis and produce histamine
tem. Normally, protective immune cells do their job by and serotonin to reduce inflammation and heparin to pre-
detecting the major histocompatibility complex (MHC) pre- vent blood clotting. They were once thought to be mast cell
sented on infected cell surfaces, which cause them to trigger precursors, but no longer. They have a distinct two-lobed
cytokine release and cause lysis or apoptosis. NK cells are nucleus surrounded by cytoplasmic granules.
unique in that they have the ability to recognize stressed cells Neutrophils or neutrocytes are the most abundant of the
even in the absence of antibodies or MHC. This gives them a granulocytes and are an essential part of the innate immune
 290 A. Vojdani et al.

..      Fig. 19.10 Eosinophil
..      Fig. 19.8 Basophil

..      Fig. 19.11  Epithelial cells

..      Fig. 19.9 Neutrophil

system (. Fig.  19.9). Formed from stem cells in the bone

 

marrow, they are short-lived and highly motile and can enter
parts of tissue that other cells or molecules can’t. During the
starting phase of inflammation, neutrophils are one of the
first responders to migrate toward the trouble site, reaching it
within minutes following the causative trauma. They are the
predominant cells in pus and account for its whitish/yellow-
ish appearance. They are part of the polymorphonuclear cell
family along with the mast cells, basophils, and eosinophils.
Eosinophils are one of the immune system’s components
responsible for combating multicellular parasites and certain
19 infections in vertebrates (. Fig. 19.10). They are granulocytes
 

that develop during hematopoiesis in the bone marrow ..      Fig. 19.12  Paneth cells
before migrating into blood. Like mast cells and basophils,
they control mechanisms associated with asthma and allergy. body. Epithelial cells come in different shapes, depending on
Their granules contain many chemical mediators that are where in the body they’re found; the three basic shapes are
toxic to both parasite and host tissues. They are unique gran- called squamous, cuboidal, and columnar. Structurally, ECs
ulocytes in that they can survive for extended periods of time rest on a basement membrane and are interconnected by cell
after maturation, persisting in the circulation for 8–12 hours junctions. The functions of ECs include secretion, selective
and in tissue an additional 8–12 days without stimulation. absorption, protection, transcellular transport, sensing, and
Epithelial cells (ECs) are one of the most important cells maintaining the integrity of the gut barriers.
found in the human body. They are the first type of cells to Paneth cells are found at the bottom of the intestinal
encounter external stimuli (. Fig. 19.11). They line the cavi-
  crypts in the small intestine (. Fig. 19.12). They are the key
 

ties and surfaces of blood vessels and organs throughout the effectors of innate mucosal defense, producing large amounts
The Immune System: Our Body’s Homeland Security Against Disease
291 19
..      Fig. 19.13  How mammalian
cells via the recognition of Environmental stressors
different patterns detect the Monocyte
presence of invading triggers. activating
Environmental triggers bind to Flaggelin lipopeptide ssRNA
TLRs (1–11) present on the Molds, Yeast,
Mannan, LPS ssRNA
surface of macrophages and CpG
neutrophils. This initiates PolyIC, DNA
activation of inflammasomes and mRNA
Molds, Yeast,
initiation of the autoinflamma- 6 ?
Bacteria, PGN, 5 7
tory process. Inflammasomes 4 8
LTA, LPS STRESSED
activate the inflammatory 9 Uropathogenic
Spirochetes 3 HOST
cytokines, causing systemic 10 E. coli
OsPA
inflammation and induction of

2
programmed cell death of tissues NLRP

11
1
that were affected by environ-
mental stressors. PGN peptido-
glycan, LTA lipoteichoic acid, LPS
Inflammasome activation
lipopolysaccharide, OsPA outer and autoinflammation
surface protein A
Production of IL-b, IL-6, IL-18, NF-kB
and other proinflammatory cytokines

Systemic inflammation

Programmed cell death or

apoptosis of damaged cells

Apoptotic fragments
Antigen presentation
and autoimmunities

of α-defensins and other antimicrobial peptides, such as lyso- The exogenous factors that induce inflammation-­
zymes and secretory phospholipase A2 (sPLA2). These sub- associated diseases are:
stances are stored in secretory granules and released into the 55 Dietary components: gluten, casein, lectins, agglutinins,
intestinal lumen upon stimulation with bacterial antigens other food antigens, glucose, cholesterol.
such as lipopolysaccharide (LPS) and muramyl dipeptide 55 Toxic chemical exposure: drugs, smoking, pollution,
(MDP). plasticizer, adjuvants, pesticides, herbicides.
This cellular component of innate immunity identifies 55 Infections and their antigens: bacteria, viruses, yeasts,
foreign materials by the previously mentioned antenna- molds, parasites, spirochetes.
like structures known as TLRs. Because pathogens contain
molecules such as lipoteichoic acid, lipopolysaccharides The endogenous inflammation includes autoinflammation
(LPS), and others which are not found on mammalian and autoimmune inflammation. Inflammation underlies a
cells, the innate systems are able to recognize and detect wide variety of physiological and pathological conditions.
the invading pathogens. These molecules are called patho- 55 Autoinflammatory diseases are diseases of innate
gen-associated molecular patterns (PAMPs). The binding immunity.
of PAMPs on the pathogens to TLRs on macrophages and 55 Autoimmune diseases are diseases of both innate and
neutrophils initiates the killing mechanism. An additional adaptive immunity.
component of the innate system is an intracellular compo-
nent known as the inflammasome. Inflammasomes are Inflammation is the immune system’s natural response
NOD-like receptors (NLRPs) which detect intracellular to infections, tissue damage, or metabolic disorders. The
PAMPs after phagocytosis. This causes the release of pro- purpose of the inflammatory activity is to kill pathogenic
inflammatory cytokines from the activated cells and activa- microbes, repair injured tissue, and remove harmful metabo-
tion of the inflammasome. lite deposits. Normally, tissue homeostasis is restored once the
The cytokines plus activated inflammasomes induce the inflammation has done its work and run its course. However,
apoptosis and death of infected cells. This way, cells that are the incomplete resolution of inflammatory responses along
heavily infected with pathogens are cleared from the system with chronic effects of immune stressors is known to be an
[27] (see . Fig. 19.13). Overall, the inflammatory reaction is
  important trigger of tissue pathology in numerous diseases,
divided into exogenous and endogenous inflammation, both such as atherosclerosis, rheumatoid arthritis, psoriasis, and
of which are associated with diseases: diabetes. When this happens in the brain as a result of astro-
 292 A. Vojdani et al.

cyte activation and astrocyte reaction to infectious agents 5. Disturbance in cytokine signaling. Given the importance
(amyloid plaque formation), it is called neuroinflammation. of cytokines in immunity, it is not surprising that
Neuroinflammation could result in a decline of neurologic erroneous cytokine signaling can lead to autoimmune
function. It accompanies a variety of neurodegenerative dis- disorders. One such example is cherubism, a relatively
eases, such as dementia, Alzheimer’s, or Parkinson’s; it has newly recognized autoinflammatory disorder of the
become increasingly evident that in many, or perhaps even bone. It is caused by mutations in an SH3-binding
all of these, neuroinflammation is not only a consequence but protein, which in animal models leads to heightened
could also be a pathologic trigger. In many neurodegenera- responsiveness to the cytokines M-CSF (macrophage
tive pathologies, various triggers of inflammation are found colony-stimulating factor) and RANKL (receptor
and can actually be used as biomarkers for the particular activator of NF-kappaB ligand), and increased osteoclas-
disease. Therefore, rather than a late consequence, immune togenesis.
activation could be an early cause in neurodegenerative dis- 6. Macrophage activation syndrome. This syndrome is a
eases; this suggests that anti-inflammatory therapies could be common factor among many autoinflammatory disor-
a promising treatment approach [28]. ders, such as Chediak-Higashi syndrome, familial
Both inflammatory and autoimmune diseases are very hemophagocytic lymphohistiocytosis, and atherosclero-
complex, and for their investigation, high-throughput meth- sis. Among its causes are loss-of-function lesions in the
ods are needed. For example, C-reactive protein (CRP) or adaptive immune system, the activation of effector cells
sedimentation rate is not sensitive enough, but mediators in the innate immune system, and the elaboration of a
such as IL-1β, TNF-α, IL-6, NF-κB, and other cytokines are pro-inflammatory cytokine milieu.
very sensitive biomarkers. Furthermore, the study of the
function of effectors such as T cells, B cells, NK cells, macro-
phages, neutrophils, epithelial cells, and endothelial cells 19.3.1   iagnostic Features of the Innate
D
helps in the investigation of the pathways involved in the Immune System
physiological role of inflammatory pathophysiology [29].
The exact endogenous stimuli that induce autoinflammatory 55 Macrophage/monocyte function
disorders is not known yet, but six different molecular mech- 55 Neutrophil function (immune complexes), CD116/
anisms in the development of autoinflammatory diseases CD18
have been described [30]. 55 Acute phase proteins and inflammation: CRP, serum
1. IL-1β activation disorders or inflammasomopathies. The amyloid A, fibrinogen, other clotting factors, vasoactive
inflammasomes or NLRPs are the guardians of the body amines such as histamine and serotonin
and are part of the inflammation engines. These engine- 55 Complement hemolytic activity and complement
like materials are involved in the proteolytic activation of components
pro-inflammatory cytokines such as IL-1β and IL-18. 55 Pro-inflammatory cytokines and proteins: IL-1β, TNF-α,
One such disorder in which inflammasome activation is IL-6, NF-κB, MCP-1, IL-17A–IL-17F, INF-γ
involved is gout, which could be initiated by dietary 55 Natural killer cytotoxic activity
components (e.g., chicken), bacteria (such as S. aureus),
viral DNA, toxic chemicals, skin irritants, UV, adjuvants,
or food additives [27–30]. 19.4  Acquired or Adaptive Immunity
2. NF-κB activation syndromes. Loss-of-­function mutations
can cause dysfunctions in NF-κB’s response to intracel- The adaptive immune system is known as the second arm of
lular microbial products, leading to pro-­inflammatory immunity. It is characterized by cellular immune reaction
diseases. against different antigens and production of specific antibod-
3. Protein misfolding disorder. These mishaps in the cells of ies against them. During this process, the pathogens, because
the innate immune system can have biological conse- of their large size, are phagocytosed and digested into very
19 quences. Generally speaking, misfolding disorders can small pieces by macrophages and dendritic cells. These
trigger the wrong responses and cause inappropriate digested pieces of pathogens, which are named antigens, are
cytokine secretions. For instance, in TNF receptor- then presented on the surfaces of antigen-presenting cells
associated periodic syndrome (TRAPS), missense substi- (APCs) to T-helper cells (Th cells) (see . Fig. 19.14). The Th
 

tutions in the p55 TNF receptor lead to misfolding and cells secrete different cytokines to communicate with B cells,
ligand-independent activation of kinases and aberrant stimulating them to go through blastogenesis, B-cell expan-
cytokine production. sion, plasma cell formation, and the production of IgM fol-
4. Complement regulatory diseases. Complements are key lowed by IgG antibodies.
components of innate immunity, and deficiencies in Simultaneously, Th cells in response to interleukin-2 will
complement regulatory factors can lead to a classical develop into cytotoxic T lymphocytes, which express anti-
autoimmune lupus-like picture, producing an autoin- bodies on their surface, guiding them to go after cells infected
flammatory phenotype such as age-related macular with pathogens, such as a virus. This way, the body gets rid of
degeneration and atypical hemolytic uremic syndrome. both pathogens and cells infected with pathogens [26].
The Immune System: Our Body’s Homeland Security Against Disease
293 19
..      Fig. 19.14  The adaptive
immune system. Invading
pathogens are phagocytosed
into smaller manageable pieces E. coli APC Th Th
and presented by APCs to Th H. pylori cell cell IL-2
cells, causing them to secrete
cytokines and undergo Bacterial cross-linking
differentiation and other and phagocytosis
processes involved in immune B7
CD28
response, including the Th Th
Activated Th cell cell
production of different
B cell cell
phenotypes of immunoglobulin
antibodies CD40 CD40L IL-2 IL-2 IL-2
In the presence of IL-2
proliferating cytokines IL-4
IL-5 T
G1 G1 cell
M S M S
G2 G2

IFN-g TGF-b IL-4 IL-2, IL-4, IL-5

Cytotoxic
Iymphocyte

IgG2a, IgG3 IgG2b, IgA IgG1, IgE IgM

19.4.1   rimary and Secondary Immune

P
IgG
Response
Primary and
secondary
When an antigen comes into contact with the immune sys-
response against
Ig Concentration

tem for the first time, our body’s response is to activate the T-dependent
primary immune response. At this time, the immune system antigens
IgM IgM
still has to learn all it can about the invading pathogen so it
can make the proper antibody against it. The lag time to form
the response may take a while, from 4 to 7 days to sometimes IgG
even weeks or months, so that immunity takes longer to
establish. The “first responders” to this antigenic attack are
the effector cells, relatively short-lived cells designed for an
initial response. Effector B cells or plasma cells secrete anti- Primary response Secondary response
bodies; effector T cells include cytotoxic T cells and helper T
cells, which carry out cell-mediated responses. The first anti-
..      Fig. 19.15  IgM and IgG response. Th cells produce an immune
bodies produced are mainly IgM, although small amounts of response first in the form of IgM antibodies and then IgG antibodies
IgG also occur (see . Fig.  19.15). The amount of antibody
 

produced depends on the antigen but is typically low. The

level of antibody peaks in 14 days and declines rapidly. The strategy used to defeat the pathogen the first time it was
affinity of the antibody produced at this time for its antigen is encountered. Once the immune system recognizes its old
lower. This primary antibody response appears mainly in the enemy, it fires up the memory cells for a fast and powerful
lymph nodes and spleen. secondary immune response. Thus, the response time is
The secondary immune response is launched upon the much shorter, from 1 to 4 days. This means that immunity
immune system’s second and subsequent exposure to the takes a shorter time to establish. Primarily IgG antibody is
same previously encountered antigen. When the immune produced, with some small amounts of IgM occasionally
system first encounters the invading antigen, some of the occurring as well (see . Fig. 19.15). IgA and IgE are also pro-
 

responding naïve B cells and T cells become memory cells. duced. Usually 100–1000 times more antibodies are pro-
Memory T cells and B cells are immune cells that are longer-­ duced in the secondary response than in the first. The level of
lived than the other initial responder cells. They remain in antibody peaks in 3–5  days and remains high for a longer
the body after initial infection and retain a memory of the period. The affinity of the antibody for its antigen is much
 294 A. Vojdani et al.

Allergen IgE
IgE
FceR CD80/
T cell CD28 B cell
MHCII CD86
TCR IgM
CeGLT
IL-4 IgE

CD4 CD3
CD40L CD40 IL-4R

Dendritic cell IL-4

..      Fig. 19.16  Production of allergen-specific IgE by receptor leads to the production of more IL-4. The IL-4 binds to the IL-4 receptor
upregulation in collaboration with dendritic cell, T cell, B cell, and on B cells and activates the transcription factor, causing class-switch to
plasma cell. Allergens are taken up by DCs and presented to T cells, IgE and the production of significant amounts of IgE, releasing the
stimulating the upregulation of CD40 ligand expression. This in turn mediators involved in classical allergy
stimulates the expression of CD80/CD86, which binds to CD28 and

greater and therefore more effective. The secondary immune results in IL-4 binding to IL-4 receptor on B cells, signaling the
response appears mainly in the bone marrow, followed by the activation of the transcription factor in B cells. Enhancement
spleen and lymph nodes. of transcription factor and activation-induced cytidine deami-
Antibodies or immunoglobulins (Ig) take a variety of nase causes IgE class-switch recombination and the produc-
forms or isotypes. The most common Ig isotypes are IgG, tion of significant amounts of IgE (see . Fig.  19.16). The
 

IgA, IgM, and IgE, or the easily remembered acronym binding of IgE to IgE receptor on mast cells and its bridging by
GAME.  IgM, known as acute antibodies, are the first to the allergens result in the release of mediators that are involved
arrive. The IgM antibodies are relatively low-affinity, pro- in the classical allergy symptomologies [26].
duced rapidly in order to control infection. IgG is the more
specific isotype, consisting of IgG1, IgG2, IgG3, and IgG4 sub-
classes. For the production of IgG, additional time is required, 19.4.2  IgE and Allergic Reactions
and it appears in the blood when IgM levels are in the process
of decline. IgG antibody levels peak at about 30 days and stay Distinctions should be made between sensitivities and
in the body for several months in order to protect it from allergies. True allergic reactions are triggered when aller-
future possible infections (. Fig.  19.15). The production of
  gens cross-link preformed IgE bound to the high-affinity
IgG, IgA, IgM, and IgE depends on the cytokine environ- receptor FcεRI on mast cells. Mast cells line the body sur-
ment. For example, after collaboration between Th cells and faces and serve to alert the immune system to local infec-
B cells in the presence of proliferating cytokines, such as IL-2, tion. Once activated, they induce inflammatory reactions
IL-4, and IL-5, and of differentiation cytokines IFN-α and by secreting chemical mediators stored in preformed gran-
TGF-β, the plasma cells produce IgG2, IgG3, and IgA. With ules and by synthesizing leukotrienes and cytokines after
the help of IL-2, IL-4, and IL-5, the activated cells may pro- activation occurs. In allergy, they provoke very unpleasant
duce IgM, and in the presence of Th2 cytokine IL-4, the reactions to innocuous antigens that are not associated with
plasma cells may produce IgG and IgE. The production of the invading pathogens that need to be expelled. The conse-
19 IgE isotype of antibody, which is involved in allergy, depends quences of IgE-­mediated mast-cell activation depend on
on the cellular interactions that are important for IgE class the dose of antigen and its route of entry, with symptoms
switch recombination. During this process, the uptake of ranging from the irritating sniffles of hay fever when pollen
allergens such as peanut or house dust mites by dendritic is inhaled to the life-­threatening circulatory collapse that
cells allows antigenic presentation to the T cells. Stimulation occurs in systemic anaphylaxis. A more sustained inflam-
of specific helper cells by these antigens or allergens leads to mation known as the late-phase response follows the imme-
the production of Th2 cytokines (IL-4) and the upregulation diate allergic reaction caused by mast-cell degranulation.
of CD40 ligand expression by the T cells. This late response involves the recruitment of other effector
Binding of CD40L to CD40 on the B-cell membrane cells, notably Th2 lymphocytes, eosinophils, and basophils,
upregulates the expression of costimulatory molecules and which contribute significantly to the immunopathology of
CD80/CD86, which binds to CD28 receptor to stimulate fur- an allergic response.
ther production of IL-4. This binding of CD 40 L to CD40 and Most antibodies are found in body fluids and engage
CD28 to CD80/CD86, and the production of more IL-4, effector cells, through receptors specific for the Fc constant
The Immune System: Our Body’s Homeland Security Against Disease
295 19
regions, only after binding to a specific antigen through the flora, gut barriers, and oral tolerance to human health and
antibody variable regions. IgE, however, is an exception, as it disease. The specific mechanisms of action that separate
is captured by the high-affinity Fcε receptor in the absence of tolerance from effective immunity against various food and
bound antigen. This means that IgE is mostly found fixed in bacterial antigens have yet to be fully explored and are the
the tissues on mast cells that bear the Fcε receptor, as well as subject of ongoing research.
on activated eosinophils and circulating basophils. The liga- When these different mechanisms of action fail to control
tion of cell-bound IgE antibody by specific antigen triggers ingested antigens, the first result can be a breakdown in tol-
the activation of these cells at the site of antigen entry into the erance to soluble antigens, which then triggers active secre-
tissues. The release of inflammatory lipid mediators, cyto- tory and systemic immune responses against food antigens.
kines, and chemokines at the sites of IgE-triggered reactions Indeed, individuals in whom the immune exclusion mecha-
results in the recruitment of eosinophils and basophils to nism does not function may experience chronic hyperab-
augment the type I response. sorption of macromolecules and the tendency to develop
When the humoral and cellular components of adaptive autoantibodies and even autoimmune disease [33, 34].
immune response fail, the results could be allergies and auto-
immunities. 19.5.1.1   xclusion of Various Antigens by
E
Secretory IgA and IgM Antibodies
to Modulate or Inhibit Colonization
19.4.3   iagnostic Features of the Adaptive
D
of Bacteria and Yeast and Dampen
Immune System
Penetration by Dangerous Soluble
55 Immunoglobulins and immunoglobulin subclasses Luminal Agents
55 Immune response to vaccination or antigenic A child at birth has almost no protective immune system
challenge other than passive immunity and maternal transfer of IgG
55 Antibody titers, ANA, RF, ssDNA, and other tissue-­ against various food antigens and infectious agents. Although
specific antibodies against self-antigens (multiple born practically germ-free and with no microbiota in the
autoimmune reactivity screen) gastrointestinal (GI) tract, the child’s mucosae are immedi-
55 Lymphocyte subpopulation including regulatory ately assaulted after birth by a motley horde of microorgan-
T cell isms originating, first, from the mother; secondly, from the
55 T- and B-cell function (antigen/mitogen stimulation) air in the delivery room and the doctor and nurses present;
55 Monitoring cell death (apoptosis) thirdly, from breast milk or baby formula; and, lastly, from
55 Cytokine production after antigen challenges exposure to various food antigens upon the introduction of
solid food. This is why the mucosal immune system has
evolved into the two arms of defense, innate immunity and
19.5  The Three Major Mechanisms adaptive immunity, to handle these challenges [35].
of Protection against Autoimmunity Maternally acquired immunity is essential for the survival
of newborns until endogenous immunity develops. These
Oral tolerance, central tolerance, and peripheral tolerance are exogenous antibodies are acquired both prenatally through
the three major mechanisms that protect the body against transplacental transfer and postnatally via breast-­feeding and
autoimmunities. Breakdown in any of these three mecha- colostrum [36]. In fact, when breast-fed infants were com-
nisms, especially failure in oral tolerance, can result in food pared with formula-fed babies, a more rapid increase in
immune reaction and associated autoimmunities [31]. SIgA1, SIgA2, and total salivary IgA was observed during the
first 6 months [37]. Furthermore, breast-fed infants also pro-
duce higher levels of SIgA in urine than formula-­fed infants.
19.5.1  Oral Tolerance Therefore, the importance of infant feeding practices cannot
be underestimated, since there is significant association
The gut mucosal immune system has to keep an intricate between feeding patterns, bacterial colonization, and immu-
immune homeostasis by maintaining tolerance to harm- nological maturation – in particular with respect to IgA- and
less or even beneficial molecules in the gut while mounting IgM-containing plasma cells in the gut lamina propria. This is
an effective immune defense against pathogens [32]. The why intravenous-fed fully developed infants lack these IgA-
unresponsiveness to food antigens with subsequent down-­ and IgM-producing plasma cells in their gut tissue, while the
regulation of systemic immune response is what is charac- orally fed individuals have adult proportions of these immu-
terized as oral tolerance. The failure of this system results in nocytes [38]. Furthermore, the initial bacterial colonization
immune reactivities to the food we eat, sometimes with life- and subsequent antigenic challenge in the GI tract differ
threatening consequences such as allergies and autoimmu- between breast-fed and formula-­fed infants. In addition to
nities [32]. The revolutionary developments in the fields of providing secretory IgA and IgM, breast milk reinforces
mucosal immunology and microbiology of the gut in recent mucosal defenses by delivering antigens, immune complexes,
years are the best indication of the importance of commensal regulatory cytokines, growth factors, and peribiotics such as
 296 A. Vojdani et al.

oligosaccharides that promote the proliferation of friendly

bacteria, which are part of the neonatal intestinal microbiota.
Environment, Nutrients, Infection
This could be an explanation for the protective role breast-
feeding plays when inflammatory bowel disease develops
ONATAL WINDOW
later in life. This emphasizes the impact of perinatal immune THE NE
development, in particular IgA and IgM antibodies, on
mucosal homeostasis and chronic inflammation [39–41].
Before pregnancy After birth
Oral tolerance to dietary proteins is crucial to prevent the • Healthy sperm
• Healthy egg
• Prudent vaccination schedule
• Breast feeding vs formula
development of food immune reactivity. The mode of antigen • Mother’s lifestyle
• Mother’s diet (peanuts &
(vitamin A & D, probiotics)
• Knowledgeable pediatrician
uptake in the gut and different regulatory immune cells plays other allergens)
During pregnancy
• Supplementation with
probiotics, Vitamin D,
a role in its maintenance. In addition to the intestinal epithe- • Mother’s lifestyle
• Mother’s diet
Vitamin A
• Weaning and time of solid

lial cells acting as nonprofessional APCS, DCs, CD8+ cells, • No implants

• No toxic chemicals
food introduction
• Child’s exposure to natural

and a variety of regulatory CD4+ cells – namely, TR1, Th3, or • No medications

• No stress
environment (farm vs city)
• Raw milk consumption
• Happy pregnancy
CD4+ CD25+ cells – play an important role in maintaining
• Infection control measures
Birth • Minimal antibiotic use
• Healthy birth (no C section)
oral tolerance to low doses of antigen through suppression of • No vaccination at birth

immune responses. Other mechanisms are important in

response to high antigen doses, including induction of lym-
phocyte anergy or deletion.
This induction of oral tolerance to soluble antigens is not
..      Fig. 19.17  The neonatal window of opportunity. Early-life
limited only to the intestinal mucosa but can involve the entire exposure to environmental triggers before birth, during birth, and after
body. The explanation for this is that through oral exposure, birth sets the foundations of the immune system to come
an antigen can gain access to the blood via the lymph. Indeed,
food protein can be detected in the blood of mice and humans
soon after eating [42]. This entry of undegraded food proteins circulatory-­induced tolerance appears to prevent intestinal
into the circulation at low levels is a normal process, but in the disorders such as inflammatory bowel disease, food immune
presence of inactive enzymes or resistance of some dietary reactivity, and organ-specific and nonspecific autoimmuni-
proteins to degradation, the level of dietary proteins in the ties. This process is carried out by a very special population
blood is enhanced. Of course, this presence of food antigen in of dendritic cells found in the microenvironment of mesen-
the blood does not go unnoticed by the immune system. If the teric lymph nodes. The presence of antigen-specific T cells
antigen is taken up by the blood antigen-presenting cell, the and nodes and cytokines such as TGF-β and IL-10 induces
result could be IgG or IgA antibody production. the generation and differentiation of these DCs into FOXP3+
regulatory T cells (Tregs). These committed Tregs home back
19.5.1.2   actors Involved in the Induction or
F to the intestinal lamina propria, where some of them may
Disturbance of Oral Tolerance exit from the mucosa via the lymphatic system or blood-
stream and disseminate throughout the immune system,
Several factors affect the induction of oral tolerance to a
promoting systemic oral tolerance [45]. The ability of oral
dietary antigen. Some are antigen-related, namely, the doses
tolerance to maintain an inhibitory environment by the Treg
and nature of the antigen. Other factors are inherent to the
cells and the production of noninflammatory IgA against
host, including age, genetics, intestinal flora, diet, medica-
both dietary proteins and microbiota can prevent hyperim-
tion, and more. Epidemiological studies have revealed that
mune reactivities in the mucosa and in circulation [46, 47].
there is one factor of particular importance in the develop-
The perinatal period is therefore crucial for the establishment
ment of oral tolerance [43, 44]. This is the period surround-
of oral tolerance and for the induction of food immune reac-
ing a child’s birth. Early-life exposure to environmental
tivities [48]. Food immune reactivities can result from many
triggers before birth (through the mother), during birth, and
environmental factors that can disturb the homeostasis of
19 after birth acts as a priming period that shapes the future
the immune system, resulting in the penetration of dietary
enteric microbiota and the innate and adaptive immune sys-
proteins and non-tolerogenic peptides to the submucosa. To
tems, which reach a lasting homeostatic equilibrium shortly
avoid immune reactivity to food antigens, the body employs
after a child is born [43, 44]. This period could be called the
the inflammatory immune defenses, including secretory
neonatal window of opportunity (see . Fig. 19.17).
IgA (SIgA) antibodies and hyporesponsiveness to innocu-
 

ous agents, particularly dietary antigens and the commensal

19.5.1.3   reach in Oral Tolerance and Its
B gut microbiota [49, 50]. The induction of these homeostatic
Association with Food Immune mechanisms depends on exogenous stimuli, and the neonatal
Reactivities period is particularly critical to this end. Both the intestinal
Oral tolerance is induced by multiple cellular and molecu- surface barrier with its reinforcement by SIgA and the immu-
lar processes to ensure lack of immune reactivity to harm- noregulatory network require adaptation.
less intestinally derived antigens both in the mucosa and in In most cases, this adaptation is remarkably successful in
the systemic immune system [45]. Together, mucosal and view of the fact that a ton of food, perhaps including 100 kg
The Immune System: Our Body’s Homeland Security Against Disease
297 19

Food antigens

Microbes Microbes

Food
antigens

M cell FAE

CD8+
TEFF
Subepithelial dome DC CD4+
TEFF
B TH TREG
cell
CD103+
CCR7+
Mf APCs in TREG
steady-state
(quiescent)

Mesenteric
lymph node
Lamina propria
vessel
TREG
TREG
Peripheral blood
Periphery

..      Fig. 19.18  The immunoregulatory network. Some antigen-­ lymph nodes where they either mature to become active APCs that
presenting cells extend their dendrites between epithelial cells to stimulate TEFF for productive immunity or become conditioned for
sample luminal antigens. Such dendrites can also be seen in the tolerance via the generation and/or expansion of TREG cells. These
follicle-associated epithelium (FAE) of gut-associated lymphoid tissue inductile TREG cells migrate via efferent lymph to peripheral blood and
(GALT). Subepithelial APCs, mainly CD103 + CCR7+ dendritic cells (DCs) then to the mucosa or the periphery where they exert anti-inflamma-
with captured antigen, migrate via draining lymph to mesenteric tory control of CD4+ and CD8+ TEFF cells

of proteins, may pass through the gut of an adult human this chapter shows that intranasal administration of either
being every year without causing adverse reactions. Food substance can be effective in reestablishing oral tolerance and
immune reactivity reflects a lack of such homeostasis, either either preventing or curing type 1 diabetes and other autoim-
due to retarded immunological development with immatu- mune diseases in which food antigens play a role.
rity of the intestinal surface barrier or a persistently imbal-
anced immunoregulatory network. Both homeostatic
deficiencies may be associated with immune reactivity, in 19.5.2  Central Tolerance
particular IgA and IgG production against innocuous anti-
gens, such as food proteins [51]. Central tolerance refers to the tolerance established by cer-
The mechanism of oral tolerance to food antigens and tain events that occur in the early development stages of a
microbiota is shown in . Fig. 19.18.
  lymphocyte. These events serve to focus these agents of the
Understanding the mechanisms responsible for the immune system onto pathogens (non-self) and away from
induction of oral tolerance [52–54] is helpful in the design innocent healthy tissue (self). This tolerance toward self is
and introduction of vaccines for autoimmunities. For exam- induced at the primary sites of lymphocyte development.
ple, tolerance can be restored by sublingual immunotherapy For B cells, this is the bone marrow and lymphoid organs,
[33, 55, 56], by a rush program of specific oral tolerance while for T cells, it is the thymus [61, 62]. In these sites,
induction [57], and by introducing the triggering antigen maturing lymphocytes are exposed to self-antigens pre-
nasally [58]. In a study on diabetes, intranasal administration sented by medullary thymic epithelial cells and thymic den-
of insulin, GAD-65, and even gliadin to 4-week-old, non- dritic cells, or bone marrow cells. Self-antigens are present
obese, diabetic (NOD) mice significantly reduced the diabe- due to endogenous expression, importation of antigen from
tes incidence and lowered the insulitis. Likewise, another peripheral sites via circulating blood, and –in the case of
study [59] demonstrated that intranasal administration of thymic stromal cells – expression of proteins of other non-
glutamic acid decarboxylase 65 (GAD-65) could prevent thymic tissues by the action of the transcription factor
murine, insulin-dependent diabetes in NOD mice. named autoimmune regulator (AIRE). The lymphocytes
It is interesting to note that gliadin has been shown to be will be unable to develop tolerance unless they encounter
cross-reactive to GAD-65 [60]. The information collected in these antigens.
 298 A. Vojdani et al.

19.5.3  Peripheral Tolerance

Differentiation
a Foreign
antigen
promoting
factor
Peripheral tolerance describes the mechanisms that take
TCR place outside of primary lymphoid tissues to prevent lym-
cTEC T cell phocytes from initiating potentially dangerous immune
Differentiation
responses against the body’s own tissues or against other
CD4
or CD8
harmless materials, such as food or commensal organisms. It
Self
Apoptosis takes place in the immune periphery after the T and B cells
b antigen
promoting
migrate from the primary lymphoid organs. Its main purpose
factor

TCR
is to ensure that self-reactive T and B cells that escaped the
T cell purging of central tolerance do not cause autoimmune dis-
cTEC
ease [61, 65].
CD4 Peripheral tolerance is established by different but
or CD8
somewhat overlapping mechanisms that mostly involve T
cells, in particular CD4+ helper T cells, which coordinate
immune responses and give B cells the confirmatory signals
..      Fig. 19.19  How presentation of a foreign antigen or a self-antigen
can lead to differentiation or cell death. a The cortical thymic epithelial they need in order to produce antibodies, as already men-
cell (cTEC) presents a foreign peptide antigen to a T cell’s TCR, sending tioned above [33, 59]. T cells that have left the thymus are
signals that lead to differentiation. b Presenting a self-antigen peptide relatively but not completely safe; unwarranted immune
sends signals that lead to the T-cell lymphocyte’s apoptosis or cell response toward normal self-antigens that were not elimi-
death
nated in central tolerance can still occur. Some of the
mature T cells may have receptors (TCRs) sensitive to self-
When a cortical thymic epithelial cell (cTEC) presents an antigens present in such high concentration outside the
antigen peptide, some lymphocytes have receptors that bind thymus that they can bind to “weak” receptors. Alternatively,
strongly to self-antigens, making them potentially strongly the T cell could react to a self-antigen it had not previously
reactive to self-tissue. These autoreactive lymphocytes are encountered in the thymus (tissue-specific molecules such
removed before they develop into fully immunocompetent as those from the islets of Langerhans, brain, or spinal cord
cells, for the most part by induction of apoptosis of the auto- not expressed by the AIRE transcription factor in the thy-
reactive cells (clonal deletion) and to a lesser extent by induc- mic tissues).
tion of anergy (a state of non-activity), or even receptor These self-reactive T cells that escaped clonal deletion in
editing [61] (see . Fig. 19.19).
 
the thymus can inflict cell injury to self-tissues unless they
The affinity of the peptide-MHC complex ligands also are eliminated or effectively neutralized in the peripheral
plays a role. If the peptide-MHC complex has low-affinity tissue, chiefly by the previously mentioned nTreg cells
ligands, the T-cell receptor complex (TCR) will deliver [64, 65].
signals that will promote the T cell’s differentiation. However, Appropriate reactivity toward certain antigens can also
if the peptide-MHC complex has high-affinity ligands, the be quieted by induction of tolerance after repeated expo-
TCR will deliver signals that promote the T cell’s apoptosis sure, or exposure in a certain context. In these cases, there
(see . Fig. 19.19).
 
is a differentiation of naïve CD4+ helper T cells into induced
The deletion threshold is much stricter for T cells than for Treg cells (iTreg cells) in the peripheral tissue or nearby
B cells. This is because T cells alone can cause direct tissue lymphoid tissue (lymph nodes, mucosal-associated lym-
damage, while B cells need costimulatory signals from T cells phoid tissue, etc.). This differentiation is mediated by IL-2
as well as a recognized antigen to proliferate and produce produced upon T-cell activation and TGF-β from any of a
antibodies [63]. It is also more advantageous for the immune variety of sources, including tolerizing dendritic cells
system to let its B cells recognize a wider variety of antigens
19 so it can produce antibodies against a greater diversity of
(DCs), other antigen-­presenting cells, or in certain condi-
tions, surrounding tissue [66].
pathogens [64]. This process ensures that T and B cells that Adaptive Foxp3  +  CD4+ regulatory T cells, otherwise
could initiate a potent immune response to the host’s own known as induced or iTreg cells, develop outside the thymus
tissues are eliminated while preserving the ability to recog- under subimmunogenic antigen presentation, during chronic
nize foreign antigens. inflammation, and during normal homeostasis of the gut.
Weakly autoreactive B cells may also remain in a state of They are essential in mucosal immune tolerance and in the
immunological ignorance, simply not responding to stimu- control of severe chronic allergic inflammation [66].
lation of their B-cell receptor. Alternatively, some weakly The Foxp3+ iTreg cell repertoire is drawn from naive con-
self-­recognizing T cells are differentiated into natural regu- ventional CD4+ T cells, whereas natural Treg (nTreg) cells
latory T cells (nTreg cells), which act as sentinels in the are selected by high-avidity interactions in the thymus [67].
periphery to calm down potential instances of T-cell autore- There are other regulatory immune cells aside from Treg
activity. cells that mediate peripheral tolerance. These include T-cell
The Immune System: Our Body’s Homeland Security Against Disease
299 19
subsets similar to but phenotypically distinct from Treg cells, NK cells and CD8+ T cells. Vitamin B9 is essential for the
such as TR1 cells that make IL-10 but do not express Foxp3, activation of Bcl-2, the anti-apoptotic molecule that acts as a
TGF-β-secreting TH3 cells, and other less well-characterized brake in cell survival; in the absence of vitamin B9, naïve T
cells that help establish a local tolerogenic environment [68]. cells can differentiate into Treg cells but are unable to survive
B cells also express CD22, a nonspecific inhibitor receptor for a long period of time [77].
that dampens B-cell receptor activation, and a subset of B Vitamin C, or ascorbic acid, has been shown to be impor-
regulatory cells makes IL-10 and TGF-β [69]. Some DCs can tant in immunoregulation. Vitamin C deficiency can disrupt
make indoleamine 2,3-dioxygenase (IDO), which depletes T- and B-cell function and NK cytotoxic activity [78–80]. A
the amino acid tryptophan needed by T cells to proliferate, decrease in vitamin C may result in immune suppression
thereby reducing immune responsiveness. Additionally, DCs [81]. Studies indicate therapeutic possibilities with vitamin C
have the capacity to directly induce anergy in T cells that rec- for the enhancement of NK-cell, T-cell, and B-cell function,
ognize antigens expressed at high levels and thus presented at as well as for immunoregulation and the induction of toler-
steady state by DCs [70, 71]. ance to autoantigens.
Vitamin D or 1,25-(OH)2D3 promotes the generation of
tolerogenic or semi-mature DCs with a reduced ability to
19.6  Dietary Intervention process and present the antigens of food and friendly bacte-
ria to T cells. Vitamin D3 also promotes a general suppres-
It is basic knowledge that eating bad food, the wrong food, sion of immune response and protects against various
can make us sick. Nowadays we can elaborate about sensi- autoimmune disorders while enhancing the antimicrobial
tivities and immune reactivities and autoimmunities, but the properties of monocytes and macrophages and increasing
easiest way to put it is: Bad food makes you sick. The con- the body’s defense against invading microorganisms. It also
verse is equally easy to understand; good foods, or the right enhances the production of Toll-like receptors (TLRs) and
foods, make you healthy. To elaborate on this in turn, the triggering receptors expressed on myeloid cells (TREMs).
right foods can not only keep you healthy but can actually Vitamin D has the potential to restore antigen-specific
help to reestablish tolerance and fix or repair deficiencies or immune tolerance by inhibiting the maturation of dendritic
dysfunctions in your health and immune system. cells or locking the cells in a semi-mature state so as to
Vitamins are pretty much taken for granted. Everyone deprive them of their capacity to activate autoreactive T cells.
knows they’re generally good for you, but so what? People Treatment with vitamin D is a promising tool for restoring
who consider themselves healthy don’t think twice about not the balance between immunogenicity and tolerogenicity in
taking any vitamins at all. However, accumulated evidence many autoimmune diseases [82, 83].
shows that a healthy diet containing phytochemicals, fatty Aryl hydrocarbon receptor (AhR) is a ligand-activated
acids, and vitamins such as A, C, and D have a direct effect on transcription factor that is a crucial regulator in maintain-
the maintenance of our long-term health [72]. ing the number of intraepithelial lymphocyte (IEL) cells in
We have previously discussed innate lymphoid cells the intestine. AhR is found in cells that are important in the
(ILCs). They are essential for orchestrating immune responses defense against intestinal and extracellular pathogens and
and discriminating between friendly bacteria, harmless food also helps in gene transcription and maintaining homeo-
particles, and harmful food antigens. The binding of these stasis in the immune system. It stands to reason that any
cells to vitamins and their metabolites contributes signifi- food that helps AhR do its job is a food that’s good to eat.
cantly to immune homeostasis [73, 74]. Cruciferous vegetables such as broccoli, cabbage, cauli-
Vitamin A or retinoic acid (RA) is an important requisite flower, kale, Brussels sprouts, and watercress, which con-
in the conversion of naïve CD4+ cells into iTregs [75]. tain indole-3-carbinol, are a major source of AhR ligands
Metabolites of vitamin A, in particular all-trans RA, are an [84]. Plant-derived nutrients like indole-3-carbinol can
important determinant in mucosal immune homeostasis and work with AhR to shape the intestinal immune defenses
the maintenance of oral tolerance. RA is key in the mainte- and have an impact on the control of microbiota and over-
nance of mucosal immune homeostasis mediated by TGF-β1 all immunity and health. However, if you’re feeling dismay
and the IL-10 expression of T cells, which prevents immune that your parents were right after all (they were) and you
reaction to normal food antigens and the development of gut should be eating vegetables (you should), here’s a bit of
inflammatory disorders [76]. uplifting news.
Vitamin B comprises eight different members involved in Tryptophan is an essential amino acid that plays an
various biochemical pathways in cell metabolism. Vitamin important role in immune function. Yes, that tryptophan, the
B6 influences cell growth and differentiation by enhancing stuff in turkey that people blame when they feel sleepy after
the metabolism of amino acids, nucleic acids, and lipids. gorging themselves on Thanksgiving. Tryptophan in fact is
Vitamin B6 deficiency can lead to impairment of immune found not just in turkey but in many plant and animal pro-
function, and, conversely, its supplementation can repair and teins, including chicken, beef, pork, fish, cheese, seeds, nuts,
even enhance weakened immune response. Vitamin B9, also and beans [85, 86]. It is able to influence the immune system
known as folic acid, is essential for protein and nucleic acid when it is converted into metabolites by the enzyme indole-
synthesis. Low levels of this vitamin can alter the activity of amine 2,3-dioxygenase (IDO). This enzyme converts dietary
 300 A. Vojdani et al.

tryptophan to kynurenine, hydroxykynurenine, and xanth- 19.7  Conclusion

urenic acid; these metabolites can regulate immune function,
inducing Treg cells to produce IL-10, thereby preventing The three major protective layers of the immune system
asthma and allergy. (mucosal, innate, and adaptive) work together to protect an
Tryptophan metabolites and naturally occurring com- individual from the assault of environmental triggers such as
pounds found in fruits and vegetables, such as resveratrol in infections, toxic chemicals, and immune-reactive foods. The
grapes and quercetin in apples, can act on the AhR on mechanisms of the immune system comprise highly complex
intraepithelial lymphocytes, innate lymphoid cells, Treg cells, processes and myriad cells with a variety of functions, mak-
and Th17 cells, thereby controlling their functions. ing it all too easy for an environmental trigger to cause a mis-
Probiotics are defined by the World Health Organization step or hiccup in the system.
as live bacterial species that confer a health benefit when As knowledge grows, the information gained is eventu-
administered in adequate amounts [87]. These are com- ally put to use. The information we have presented here is
mensal bacteria among the gut microbiome’s bacterial gradually being applied in clinical practice. Such therapeutic
population that have been identified to provide their hosts interventions focused on the cells, molecules, and mecha-
with many health benefits, including intestinal homeosta- nisms of the immune system can have far-reaching benefits
sis, and blocking the harmful effects of other microbiota. for a patient’s immune system and health.
They directly compete with pathogens for various nutrients, We now know that things as basic to life as foods are not
stimulate innate and adaptive immune responses, and pro- to be taken for granted and that they can either help or hin-
mote tolerance. der our immune system and, therefore, our health.
Good bacteria can convert fiber-containing molecules Understanding how the immune system works and how
such as starch pectins, fructan, and cellulose into three the mechanisms and components of the mucosal, innate, and
major fatty acid metabolites: acetate, butyrate, and propio- adaptive immune systems all work together can help us to
nate. These metabolites or short-chain fatty acids (SCFAs) design modalities for the maintenance of immune homeosta-
act as ligands for the GP43 receptor (GP43R) on Treg cells. sis and the prevention of many immune disorders, including
They activate the Treg cells into expanding and producing autoimmunities [89].
a significant amount of IL-10 and TGF-β, which do not
only enhance the oral tolerance mechanisms but can also Acknowledgments  We would like to acknowledge Joel Bautista
control inflammatory immune responses in the gut. for the preparation of this manuscript for publication and for
Dietary intervention with probiotics could be used for the the execution of the figures.
prevention and alleviation of food immune reactivity,
intestinal barrier dysfunction, and even autoimmunities
(see . Fig. 19.20) [88].
 
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19
 303 20

Nutritional Influences
on Immunity and Infection
Joel Noland and Diana Noland

20.1 Introduction – 305

20.2 Impact of Infection on Health and Disease – 305

20.3 Key Metabolic Mechanisms for Defense and Repair – 306

20.4 Insults to Our Defense and Repair Systems – 306

20.4.1 Increased Toxin Load – 306

20.5 Antimicrobial Resistance (AMR) – 306

20.6 Gastrointestinal Dysbiosis: From Mouth to Anus – 306

20.7 Stressors – 306

20.8  alnutrition, Inflammation, and the Infectious

M
Processes – 307

20.9  iagnosis of Nutrition Status and Infection-Related

D
Diseases – 309

20.10 Differential for Nutritional Infection Risk – 310

20.10.1 Look for Evidence of Infections – 310

20.11 Chronic Diseases, Nutrition, Microbiome, and Infection – 311

20.11.1 L aboratory – 311
20.11.2 Assessment Laboratory and Clinical Tools – 313
20.11.3 Key Nutrients Influencing the Risk of Infectious
Disease (. Fig. 20.8) – 315
 

20.12 Homocysteine Catabolism (. Fig. 20.9) – 315  

20.12.1 F olate Metabolism – 315

20.12.2 Methionine Metabolism – 316

20.13 K
 ey Lifestyle Factors Influencing the Risk of Infectious
Disease – 316
20.13.1 Sleep (see 7 Chap. 45) – 316
 

20.13.2 Stress (see 7 Chap. 47) – 316

 

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_20
20.14 Movement (see 7 Chap. 36) – 316
 

20.14.1 E xamples of Chronic Disease Connections

with Infectious Disease – 316
20.14.2 Vaccination – 317

20.15 Conclusion – 318

References – 319
Nutritional Influences on Immunity and Infection
305 20
Learning Objectives trained practitioner assesses an individual to identify where
55 Impact of infection on health and disease malnutrition may be present and develops an intervention
55 Malnutrition, inflammation, and the infectious processes with early delivery of essential nutrients in an effective and
55 Chronic diseases, nutrition, microbiome, and infection comprehensive manner. Healthcare practitioners are often
challenged to understand the importance of adequate nutri-
tional support in the prevention and treatment of infection,
20.1 Introduction multiple organ failure, and most life-threatening systemic
sepsis [3].
The complex nutrition-immunity-microbiome-infection- The aim of this chapter is to provide the current science
genomic connection is presented in this chapter, bringing for and a description of the interaction between nutritional
their relationship together in an integrated view with a focus status of an individual and immunological susceptibility to
on the role of nutrients in maintaining the integrity of the infection, as well as integrative and functional approaches
immune system. Infection has been a primary challenge to to interventions that may be considered to restore immune
human health and disease throughout history. It is now rec- integrity and restore wellness. There will not be an in-depth
ognized that an individual’s vulnerability to infection is asso- review of immune function. Please refer to the excellent
ciated with nutritional status. Malnutrition increases the risk presentations of the immune system by Dr. Vodjani in
of infection and immune system compromise. The past cen- 7 Chaps. 19 and 49.
 

tury’s renaissance of nutrition science has supplied the This chapter is divided into three sections.
increasing evidence for the roles that essential nutrients, 1. Impact of infection on health and disease
dietary intake, environmental exposures, and nutrigenomic 2. Malnutrition, inflammation, and the infectious processes
influences play in the ability of the immune system to respond 3. Chronic diseases, nutrition, microbiome, and infection
and resolve infectious insults. The recognition of the impor-
tance of nutrition within the scope of assessment and inter-
vention, which is often overlooked in healthcare, is presented 20.2 I mpact of Infection on Health
as having an overall impact on outcome. The current knowl- and Disease
edge of the role of nutrients and their interrelationships with
the immune system and chronic disease provides scientific Until the beginning of the nineteenth century and the
support for the nutritionally trained practitioner. This chap- industrial revolution, illness was primarily impacted by
ter will describe some of the key mechanisms and nutrient physical injury and acute infections related to poor sanita-
influences on the immune response as well as dietary and tion practices that allowed a higher prevalence of infection.
lifestyle considerations for treatment. Throughout thousands of years of history, the human body
Nutritional deficiencies and insufficiencies have has survived through the strength of several defense mecha-
known associations with increased susceptibility to infec- nisms, including an alert immune system, the impermeable
tious disease. Infection can also increase requirement for skin membrane, and gut barrier, and the more recently rec-
nutrients and produce further undernutrition, infection, ognized microbiome that shields all body orifices. It has
and compromise of the immune system, setting up a been well established, even by Hippocrates almost 3000
vicious cycle between malnutrition and infection [1, 2]. years ago, that these mechanisms are dependent on an opti-
Malnutrition is the primary global cause of immunodefi- mal nutritional status in order to maintain health and to
ciency for all age groups, especially for infant mortality prevent infection.
with poor nutrition promoting underweight, weak, and
vulnerable children. Optimum nutrition status allows the
metabolic function defense and repair mechanisms to Illnesses do not come upon us out of the blue. They are
increase immune integrity. developed from small daily sins against Nature. When
Optimal nutritional status contributes to health mainte- enough sins have accumulated, illnesses will suddenly
nance and the prevention of infection. The function of appear. –Hippocrates (c. 460 – c. 370 BC)
healthy cells is maintained by adequate nutrition, movement,
and sleep routines. Primary and secondary malnutrition
may occur when each individual lacks the available clean During the nineteenth century, outstanding scientific discov-
food, nutrients, and water that are required. The healthy eries occurred and changes in philosophy took place regard-
immune system enables the body’s ability to adapt, recover, ing the biological functions within the human body, enabling
and survive. When there is disruption in the nutrient intake, greater appreciation of the fact that when the biochemical
the malnutrition that ensues contributes to a cascade of mechanisms of our defense system are disrupted, it increases
adverse metabolic events leading to illness. The nutritionally vulnerability to infectious disease.
 306 J. Noland and D. Noland

20.3  ey Metabolic Mechanisms for Defense

K saliva digestives, and endocrine immune glands (parotid,
and Repair tonsils, adenoids) preparing food that enters the gut for
digestion and absorption. The next step is the pH 1–3 acid
55 Enterohepatic circulation (see 7 Chap. 16)
 
bath the bolus of food passes through in the stomach with
55 Phase I and phase II biotransformation/detoxifica- antimicrobial action suppressing any pathogens traveling in
tion (see 7 Chap. 14)
 
with your food. The small intestine is the next pass, bathing
55 Gastrointestinal, lung and skin/barrier integrity/ the bolus in bile, pancreatic digestive enzymes, and bicarbon-
membrane integrity (see 7 Chap. 12)  
ate, ready for the serious work of digestion. This is the loca-
55 Mitochondrial function tion where the gut houses more than 70% of our body’s
55 Methylation (see 7 Chap. 18) 
immune tissue (lymphoid tissues) and, when compromised
55 Hormonal function (see 7 Chap. 32)
 
by insults, we become more vulnerable to infection weaken-
55 Autophagy (see 7 Chap. 51.2.6)
 
ing our immune integrity. Those lymphoid immune cells also
55 Happiness (see 7 Chaps. 6 and 30)
 
depend on a healthy microbiota’s symbiotic relationship to
optimally function. The gut is frequently referred to as “the
second brain” [5] because of its generous secretion of neu-
20.4 I nsults to Our Defense and Repair rotransmitters and direct connections to and from the brain,
Systems the enteric nervous system. When insults like antibiotics,
emotional upsets, stress, infection, chemicals, or toxic metals
20.4.1  Increased Toxin Load enter the gut, the gut barrier breaks down and suffers intesti-
nal permeability (“leaky gut”) that allows for non-desirable
As the industrial revolution evolved, increased toxin expo- molecules to be absorbed and enter the blood and lymphatic
sure accumulated from the discovery and use of petroleum systems, triggering an immune response of loss of self-­
which released petrochemicals and mercury into the air, the tolerance, or an antigenic response against one’s own tissue
discovery of mercury (e.g., used in making the British top [6]. Once someone experiences a “leaky gut,” a pro-­
hat), the common use in dentistry of mercury (comprising inflammatory cascade initiates, adding a burden to the
about 50% of dental amalgam material), and pollution from immune system and increasing vulnerability to infection.
industrial practices into rivers and the resulting contami-
nated water supply. The trend for increased environmental
toxin exposure has continued to grow, so that at the time of 20.7 Stressors
this publication there have been more than 80,000 chemicals
created with relatively few tested for safety. A most pervasive Stress can insult our defense and repair in several forms: bio-
and hazardous pesticide toxin, glyphosate, is now used nearly logical, emotional, and energetic stressors. As stressors
universally in agriculture, thereby ending up in our water increase, there is a resulting biological stress, along with a
and food supplies. concurrent increase in nutritional requirements. If the food
intake cannot keep up with meeting the nutritional needs
under stress, malnutrition ensues. Unfortunately, with the
20.5 Antimicrobial Resistance (AMR) increased consumption of the standard American diet
(S.A.D.), the population eats more calorie-dense, nutrient-­
There has been continuous improvement in sanitation prac- depleted, processed, and high-sugar foods. A majority of the
tices, perhaps too robustly going beyond the abilities of US population does not have the available nutrients to meet
human and animal life to balance with the microbial world to the essentials of a generally more stressed society [7]. One of
avoid development of “superbugs” that have become resis- the most prevalent nutrient deficiencies and insufficiencies in
tance to antibiotics. The challenge of acute infections is of the USA from NHANES studies are “40% deficient in Vitamin
great concern to public health because of antimicrobial resis- A, C, D & E, calcium or magnesium deficient and >90% do
tance (AMR) and the rise of “superbugs” that are considered not get enough choline, fiber & potassium.” [6] (. Fig. 20.1).
 

the biggest threats to modern healthcare [4]. The primary About 65% of the population does not even meet the rec-
20 driver of AMR is thought to be the overuse of antibiotics in ommended daily allowance (RDA) for magnesium [8, 9].
humans and agricultural animals and overuse of antibacte- More than two-thirds of the US population are either over-
rial hand soaps and gels. weight or obese. This population subgroup has a higher risk
of several chronic diseases.
Early in the twentieth century, great trust and hope were
20.6  astrointestinal Dysbiosis: From Mouth
G generated by Alexander Fleming’s discovery of penicillin and
to Anus the world of antibiotics [10], with the anticipation of ending
uncontrolled bacterial infection. Now in the twenty-first cen-
The two largest defense barriers to infection are the skin and tury, as science looks back on the use of antibiotics, recogni-
the gastrointestinal tract (gut). The mouth and oral cavity tion is increasing that the overuse of antibiotics is enabling
provide the beginning of defense and repair by mastication, the development of what are now termed “superbugs.”
Nutritional Influences on Immunity and Infection
307 20
..      Fig. 20.1  NHANES 2001–
2008 micronutrient deficits. 100
Percentage of the adult
population (aged 19 years) with
vitamin and mineral intakes 80

% Population Below EAR

below the EAR for individuals
(data from NHANES 2001–2008).
Usual intakes from foods were 60
estimated by using the National
Cancer Institute (NCI) method [8].
(Reprinted from Agarwal et al. [8]. 40
With permission from Taylor &
Francis)
20

0
Ri min

Se rus
n

um

nc
Th A

ta FE

m 6
Vi B12

Vi in C

Ca E

er

ne n
os m
n

Co m
ta n B
Fo aci

ag Iro
vi

in
in

pp

Ph siu
u
in
D

Zi
o
fla

lci

ni
m
m
m

ia

m
Ni

in

ph
i
te
m

le
bo

ta
ta
ta

ta
la

Vi
Vi

Vi

M
Vi
..      Fig. 20.2  HPV lifespan
spectrum [12]. (Reprinted from
Burger et al. [12]. With permis- Acquisition Clinical
sion from Oxford University of causal detection
Press) HPV infection* of cancer

No/latent HPV Persistent HPV High-grade precancerous lesion Invasive cancer

*Age (years) for all high-risk HPV genotypes, stratified by HPV-16, and other non-HPV-16 genotypes

Superbugs are beginning to threaten the success of medicine With nutritional status being a major factor affecting host
and pharmacology. The antibiotics have weakened the resistance to infection, this chapter focuses on how to assess
defense mechanisms of the microbiome shield that humans a chronic disease sufferer’s “infection load” or “infection sta-
have depended on throughout history. Public health con- tus” using an integrative and functional lens, searching for
cerns are increasing that the overuse of antibiotics in humans the disease etiology and impaired resolution of inflammation
and animal husbandry, along with antimicrobial antiseptics, (resolution biology) [19]. This assessment of infection status
has become a health threat through the weakening of the should become part of the nutritional and metabolic assess-
microbiome protection of the population. ment differential. It rules out, or identifies, if infection is part
The discovery of subclinical unresolving infections that of the etiology and pathophysiology of a disease condition.
are associated with many of the chronic diseases is beginning Once identified, targeted intervention proceeds to improve
to be appreciated by the global medical community. Infection successful outcomes of restoring wellness (. Fig. 20.4).
 

increases infection-related morbidity and mortality [11].

Subclinical-level long-latency infections often go unnoticed
while they alter and sometimes mutate tissue cells over time, 20.8 Malnutrition, Inflammation,
leading to an acute disease. Examples of infection connec- and the Infectious Processes
tions to chronic disease are:
55 HPV virus causal of cervical cancer and neck/head Infection, as well as trauma or excessive visceral fat, appro-
cancers [12] (. Fig. 20.2)
  priately perturbs the immune system into secretion of
55 H. pylori increased risk of gastric cancer [13] (. Fig. 20.3)   inflammatory molecules like cytokines, acute phase reac-
55 HSV-1 increasing risk of Alzheimer’s disease [14] tants, and others [11]. It is not possible to cover the scope of
55 Klebsiella pneumoniae association with rheumatoid the physiology of the immune system and inflammation in
arthritis [15, 16] this space; the focus of this chapter is to describe how malnu-
55 EBV and CMV combo-viral increasing risk of various trition and insufficiencies of specific nutrient groups can per-
cancers [17] petuate compromising the immune system and the
55 Chlamydia pneumonia and atherosclerotic plaque microenvironment, so the natural immune mechanisms of
­formation [18] defense and repair from infection are weakened (see 7 Chaps.  
 308 J. Noland and D. Noland

..      Fig. 20.3  H. pylori increased

risk of gastric cancer [13]. Determinants of H. pylori-induced gastric carcinogenesis
(Reprinted from Kim et al. [13].
With permission from Elsevier)
1 1. Host genetic polymorphisms
2. H. pylori virulence factors
3. Host immmune response
4. Bone-marrow derived cells in
tumor micro-environment
5. Gastric acidity

5
2

..      Fig. 20.4  Key nutritional,

lifestyle, and environmental
influences on infection Chronic
inflammation Antigens
Stress
Sedentary
Immune-
compromising
toxin exposure
Poor sleep

Communicable Nutritional
disease health
exposure geography
Infection

Nutrient Nutrigenomics
deficiency

20
19 and 50). Inflammation almost always accompanies infec- time can result in a loss of self-tolerance and perturb meta-
tion and, when prolonged, sets up susceptibility for all bolic mechanisms toward diseased tissue that can lead to any
chronic diseases. of the chronic diseases. The inflammatory load of an indi-
For acute infections, this inflammatory response is a vidual should be assessed for each chronic disease and infec-
critical part of tissue healing, with increased blood flow and tion ruled out as a potential contributor to total body
heat. Increased heat can involve local tissue or produce sys- inflammation [20].
temic natural hyperthermia with fever. If infection continues Tuberculosis (TB) is a leading cause of death worldwide,
to be unresolved, it can produce a prolonged state of inflam- despite being preventable and often curable [21, 22]. It is prev-
mation with continuing subclinical infection(s) that over alent in malnourished populations with poor sanitation [20].
Nutritional Influences on Immunity and Infection
309 20
Schwenk states that TB, also called “consumption,” is predis- linolenic acid (GLA), di-homo-gamma-linolenic (DGLA),
posed by a state of macro- and micronutrient deficiencies. eicosapentaenoic acid (EPA), and docosahexaenoic acid
There is a complex relationship between tuberculosis and (DHA) reveals where there may be an underlying imbalance
malnutrition, in that TB can increase nutrient requirements directly related to what they eat. Developing a diet plan to rid
and lead to a worsening of nutritional status. In high-TB rate intake of inflammatory foods and get foods that are anti-
countries, vitamin A, carotenoids, and vitamin D levels are inflammatory is a desirable goal. (see 7 Chap. 43). Key foods
 

found to be low and deficient. Nutritional correction of mal- include therapeutic use of food oils that can modulate a per-
nutrition factors is considered part of the best approach to son’s fatty acid status and provide ability to control inflamma-
the treatment of tuberculosis [20, 21]. tion. Phytonutrients rich in the variety of colorful fruits and
vegetables have powerful anti-inflammatory action. Some
herbs have excellent evidence of anti-­inflammatory support
20.9  iagnosis of Nutrition Status
D with successful practice-based experience.
and Infection-Related Diseases
Anti-inflammatory foods, herbs, and dietary
There is much evidence for association or causal nutritional supplements targeted recommendations based on
insufficiencies or deficiencies increasing the risk of someone patient assessment
becoming infected. Once infected, levels of tissue inflamma- Foods
tion increase until clinically observable (see . Fig. 20.2) and
 
Whole-foods, pesticide-free, vegetable, and fruit
may linger long term unless resolved back to wellness. If the variety of color, adequate protein, healthy fats and oils,
infection continues even at a subclinical level, it can continue foods-rich in herbal components, and hydration;
to weaken the host integrity of the immune system [11]. minimize or avoid processed and high-sugar foods and
Inflammation is the body’s normal response and protects beverages; avoidance of identified antigenic foods.
the body from infection from pathogens like bacteria or (see 7 Chap. 43)
viruses, as well as injury. Inflammation can be acute, which
 

Herbs
should be short-lived as the body resolves an infection or 55 Turmeric/curcumin
injury, or chronic and long term and can be destructive, lead- 55 Resveratrol
ing to chronic diseases. Examples of chronic diseases that can 55 Boswellia
develop from a long-latency infection are periodontitis, 55 Artemisinin
asthma, inflammatory arthritis, and inflammatory bowel 55 Garlic
­disease. 55 Quercetin (suppresses mast cells)
Conventional therapies for chronic inflammation use 55 Proteolytic enzymes: bromelain, papain, trypsin, etc.
anti-inflammatories primarily from two categories of phar- (contraindicated for alpha-1-antitrypsin deficiency+
maceuticals: steroids and nonsteroidal anti-inflammatory genetics)
drugs (NSAIDs). NSAIDs counteract enzymes and prosta-
glandins. NSAID use of more than 10 days is not desirable, Dietary supplements
due to increased risk of stomach ulcers and gastrointestinal 55 Vitamin C (contraindicated for hemochromatosis+
bleeding and sometimes adverse effects like worsening of genetics)
asthma or kidney problems. 55 Adequate methyl nutrients
55 Vitamin D3 (if indicated per personalized assessment)
Cardinal signs and physiology of inflammation 55 Vitamin A (if indicated per personalized assessment)
Rubor (redness): increased blood flow
Tumor (swelling): exudation of fluid
Infectious processes are biological stressors that alter the
Calor (heat): exudation of fluid, increased blood flow,
requirement of an individual metabolism beyond the RDA/
release of inflammatory mediators
RDI recommendations. Recognition of this principle drove
Dolor (pain): chemical mediators; inflammatory exudates
the emergence of the field of orthomolecular nutritional
stretching pain receptors and nerves
therapy early in the twentieth century, leading to provision
Functio laesa (loss of function): pain, fibroplasia, metapla-
of the right nutrients at a molecular and cellular level.
sia, disruption of structure
Under high-stress conditions, micronutrient requirements
are altered [23]. For example, vitamin C requirements as a
For the IFMNT practitioner, changing the patient’s dietary primary cellular antioxidant vary for an individual depend-
intake and use of dietary or herbal supplements to correct ing on the stress load, diet, gastrointestinal function, and
nutrient deficits or excesses can support the underlying sys- genomics [24] as stated by Dr. Tim Spector, “there is a lot of
tems promoting the inflammation. For instance, NSAIDs act variability in the ways in which healthy people react to
on suppressing eicosanoid and prostaglandin metabolites. food (and nutrients)” [25].  With the recognition of how
Assessment of blood RBC fatty acids (linoleic (LA) and unique and diverse individual physiologic immune
alpha-linolenic acid (ALA) and their metabolites, gamma- responses are to food and lifestyle, the inclusion of a per-
 310 J. Noland and D. Noland

..      Fig. 20.5  Protein energy

malnutrition increases preva-
lence of infection, leading to
Malnutrition
energy loss for the individual [2].
(Reprinted from Schaible and
Socioeconomic &
Kaufmann [2]. With permission
Impaired child development political instability
from Creative Commons License)

Impaired development of
Compromised immunity
education and health system

Infection Poverty

Disease Reduced productivity

Energy loss

son’s nutrition status as part of their differential exam for 2014, the results of one of the first clinical trials for IV ascor-
development of a comprehensive treatment plan is of bic acid at Division of Pulmonary Disease and Critical Care
utmost importance. Medicine, Department of Internal Medicine, School of
Over human history, many cultures have evolved food Medicine, Virginia Commonwealth University were pub-
traditions to meet specific health needs such as pregnancy, or lished.
infection, or child development. Records from Hippocrates The conclusion of the n = 26 human trials with severe
describe specific foods to treat various disease conditions. In sepsis and a variety of diagnoses of cancer, respiratory failure,
the Middle Ages, eggs were soaked in vinegar to dissolve the and others was that infusion of intravenous ascorbic acid was
eggshell, rich in calcium and minerals, to be given to a preg- safe and may positively influence patients when challenged
nant woman. Various herbal teas were given for various with severe sepsis with multi-organ failure. The study showed
types of infections and many other conditions. Besides food improved lower biomarkers of inflammation, C-reactive pro-
being a source of nutrients, herbal and nutraceutical oral tein (CRP), and procalcitonin (PCT) that correlate with the
supplementation became prevalent in the eighteenth cen- overall extent of infection. Higher levels of both have been
tury. In 1831, the first intravenous (IV) technology was biomarkers linked to higher incidences of organ injury and
attempted for treatment of cholera by a Scottish doctor, Dr. death in the critically ill. These two biomarkers proved accu-
Thomas Latta. It took another 100 years for further develop- rate to assess effectiveness of the IV ascorbic acid.
ment of intravenous therapies and only became commonly Thrombomodulin (TM) was the biomarker used to measure
available clinically by licensed practitioners in the 1960s. endothelial injury status and showed similar improvement
Once determined safe and clinically feasible, it was embraced . Fig. 20.5.
 

by many medical specialties where patients were impacted

by compromised gastrointestinal function and malnutrition
20 [26]. Today, many hospital and clinic infusion centers 20.10 Differential for Nutritional
administer IV vitamins, mineral and nutrient cocktails, and Infection Risk
intramuscular (IM) nutrients to support nutritional status of
individuals seeking prevention, or as prescribed due to com- 20.10.1  Look for Evidence of Infections
promised oral dietary intake. IV treatments can provide
nutrients for individuals with increased nutrient require- Toolbox to identify infectious relationship with nutrition
ments, especially with the biological stressors presented by ­status:
acute or chronic infections. 55 Nutrition physical exam (see 7 Chap. 40)
 

One of the most life-threatening infectious conditions is 55 Medical history: diagnosis, medical event history,
severe sepsis [27] with no effective treatment options. In infectious history, residential location
Nutritional Influences on Immunity and Infection
311 20
55 Signs and symptoms: medical symptoms questionnaire
(MSQ)
55 Laboratory and procedural testing (basic nutrition-­ Inadequate
related and, if applicable, for disease-specific and Dietary
intake
sometimes patient-specific markers)
55 Bioelectrical impedance analysis (if available)
55 Laboratory nutrition status and infection-related Appetite loss Weight Loss
biomarkers (. Table 20.1 and . Fig. 20.6).
   
Nutrient Loss The Malnutrition Growth faltering
Malabsorption Infection Cycle Lowered immunity
Altered metabolism Mucosal damage
The nutrients most studied regarding immunonutrition that
should be considered in the assessment are listed in
. Table 20.2 and will be discussed below.
 
Disease:
incidence
duration
severity
20.11  hronic Diseases, Nutrition,
C
Microbiome, and Infection
..      Fig. 20.6  The “vicious cycle” of malnutrition and infection. Spiral of
All chronic diseases have associations with acute or sub- malnutrition and infection [28]. (Adapted from Katona and Katona-
clinical infections as potential etiologies for a chronic dis- Apte [28]. With permission from Oxford University Press)
ease individual. Infections are caused by the exposure to
such pathogens as virus, bacteria, parasites, fungi, or
prion. Many chronic diseases have known nutrient-micro-
biome-infection interactions [57]. When completing an
..      Table 20.1  Immunonutrition assessment investigation tools
initial assessment differential consideration of an
­infectious component of any patient presenting with a
Test Type Practitioner options chronic disease, it should be part of an initial assessment
differential to identify if infection could be part of the
Imaging Diagnosis-­ Radiology pathophysiology.
related
Malnutrition, altered microbiome, and infection inter-
Functional Digestive Functional medicine act to influence health and disease in the developed and
testing Hormonal Endocrinology developing world. Infectious morbidity is significant in the
Organic acids MD, DO, ND, LAc, RD, CNS, RN,
Structural NP, PA DC, DO, PT-classical
malnourished, whether nutrient insufficiencies or overnu-
trition. Infections significantly compromise utilization of
Mind-body Psychology MD, psychologist, family oral nutrition and the immune lymphoid tissue in the gas-
counselor therapist
trointestinal tract disturbing the microbiome. Malnutrition
Initial Follow-up Initial practitioner predisposes a person to infection, and restoring the injured
assessment nutritional status improves immune integrity. Improving
and
nutritional status reduces risk of infection, and when one
monitoring
does contract infection, there may be a reduction in the
BIA All; equipment required severity of systems.
MSQ All Nutritional assessment currently makes use of many
new technological modalities. The Integrative and
Monitoring All
Functional Medical Nutrition Therapy assessment model
abnormal test
results identification of “root cause(s)” of a condition starts by
hearing the patient’s story (see 7 Chap. 39). When was the
 

Nutrition All; more expanded with

last time they felt well? Family history? Signs and symp-
physical exam integrative and functional
nutrition-trained practitioners toms? Diet history? Medications? Supplements? Toxin
exposure? Other issues? The model explores the question of
Oxygen satura- All how a person’s metabolism evolved to the current disease
tion monitor
condition.
Thermometer All; nutrition-trained
practitioners will use
temperature to consider
thyroid functional status
20.11.1 Laboratory
maintaining body tempera-
ture; rule out infection; With laboratory data to  examine, a diagnostic profile
begins to emerge to clarify the priorities of core physiological
 312 J. Noland and D. Noland

..      Table 20.2  Key immuno-nutrient insufficiencies/deficiencies associated with or causal for subclinical or acute infections; key
immune-nutrients foundational for healthy immune endogenous defense

Nutrient Infection: deficiency Reference Symptoms Testing to

­connection consider

Immune modulators

Vitamin D Immune modulator [29–31] Mood disorders; Vitamin D25OH

bone loss; joint pain;
compromised
immunity

Vitamin A retinol Mucosal immunity [22, 24] Mucosal bacterial/ Vitamin A, retinol;
viral infections β-carotene

Phytonutrients [32, 33]

polyphenols

Rate-limiting cofactors

Folate NK cell activity [34] Fatigue Folate, serum

Cytotoxic cellular immunity Infection FIGLU
Modulate T cell responses Mood disorder

Zinc Regulates intracellular [34–36] Skin conditions Zinc, serum

signaling pathways in innate Poor smell
and adaptive immune cells Poor taste Zinc, RBC
Frequent illness
Nail spots

Magnesium >300 enzymes cofactor One of the most Magnesium, serum

Urine excretion under stress deficient minerals in RBC magnesium
the USA
Muscle tension
Cramps

Iodine Thyroid metabolism [37, 38] Cysts Urinary iodine

requirement UIC values Fibrocystic breasts concentration (UIC)
<20 μg/L (severe iodine Hypothyroid
Iodine, random
deficiency) In utero develop-
blood
20–49 μg/L (moderate mental
iodine deficiency)
50–99 μg/L (mild iodine
deficiency), 100–199 μg/L
(adequate iodine intake)
200–299 μg/L (more than
adequate iodine intake)
>300 μg/L (excessive iodine
intake)

Amino acids Nitric oxide (NO) Low grade evidence [39] Perturbed protein Plasma or urine
Arginine Gut barrier support Herpes Simplex [40] metabolism amino acid profile
Lysine Poor healing
Glutamine Express herpes
simplex skin rash
Poor gut barrier
20 repair

Antioxidants

Vitamin C Regulates cellular humoral [27] Connective tissue Blood

immune function; increase impairment Vitamin C
macrophage Skin conditions CPT 82180
Antihistamine requirements Poor wound healing
increase during infection
Antiviral
Nutritional Influences on Immunity and Infection
313 20

..      Table 20.2 (continued)

Nutrient Infection: deficiency Reference Symptoms Testing to

­connection consider

Vitamin E full-spectrum 4 tocopherols + 4 tocotrienols [29, 41] Oxidative stress Vitamin E

protective from oxidative Premature wrinkles (tocopherol)
stress/lipid peroxides Cysts CPT 84446
Leg cramps

Selenium Thyroid peroxidase metabo- [36, 41] Hypothyroid Blood

lism with vitamin E Low glutathione Selenium, RBC
Selenoproteins special effects blood levels Selenium
on cellular immunity Impaired detoxifica- CPT 84255
Resistance to viral infections tion

Gut secretions

Short-chain fatty acids Intestinal cells Anti-­ [42–47] Inflammation Fecal collection
(SCFA) inflammatory Perturbed uric acid
Microbiome-gut- brain axis cycle
via immune system/vagal Colon disease
nerve
Mucosal immunity

Bile acids Fat emulsification duodenum [48, 49] Perturbed fat Blood
Carrier of toxins/elimination digestion Bile acids, total
Suppressed CPT 82239 or fecal
detoxification collection
enterohepatic
circulation

Anti-nutrients

Endocrine disruptors Circadian rhythm disruption [50, 51] Hormonal imbalance Blood or urine
that can modulate immune Insomnia
function Cancer

Damaged food The damaged high-heat foods [52] Toxicity Blood or urine
components/Western diet Chemicals Symptoms vary
and food preparation Toxic metals ingested in
Trans fat foods and from food utensils
Oxidized fat during food preparation
Toxic metals
Toxic chemicals
“new-to-nature
molecules” (cookware,
pest control, pollutants,
processed, etc.)

Environmental toxins Neuropsychiatric immune [53–56] Toxicities Specialty labs

Mold/mycotoxins disruption Chronic kidney failure
Natural gas carcinogenic Vulnerable to infections Infertility
Chemical vapors increased risk for kidney Cancer
Pesticides failure, fertility problems, Developmental
cancer, birth defects Frequent infections

imbalances for nutrition and lifestyle therapy. When focus- 20.11.2 Assessment Laboratory
ing on assessing the existence of infectious activity, and the and Clinical Tools
priority within the etiology of a disease condition, consider-
ation of the three most likely physiological areas of immune 55 Comprehensive Digestive Stool Analysis (CDSA)
imbalances are defense and repair, assimilation, and structural various labs provide CPT
integrity (. Fig. 20.7).
 
55 Ova and Parasitology (2–3 samples) CPT Code(s) 87177,
87209
 314 J. Noland and D. Noland

..      Fig. 20.7 IFM Matrix:
physiology and function –
organizing the patient’s clinical Physiology and function: organizing the patient’s clinical imbalances
imbalances [58]. (Used with
permission from The Institute for Assimilation Defense & repair
Functional Medicine ©2015) (e.g., Digestion (e.g., Immune,
Absorption, Microbiota/Gl,
Respiration) Mental Emotional Infection/Microbiota)
e.g., Cognitive e.g., Emotional
Structural function, regulation, grief,
Energy
integrity perceptual sadness, anger,
(e.g., Energy
(e.g., From subcellular patterns etc.
Regulation
Membranes to Mitochondrial
Musculoskeletal Spiritual Function)
structure) e.g., Meaning &
purpose,
Communication relationship with Biotransformation
(e.g., Endocrine, something & elimination
Neurotransmitters, Immune greater (e.g., Toxicity
messengers)
Transport
(e.g., Cardiovascular, Lymphatic System)

55 Rule out other infections 55 high sensitivity CRP (hs-CRP)

55 Calprotectin, fecal CPT 83993 [fecal calprotectin (FC] High-sensitivity C-reactive protein (hs-CRP) is an
55 Clostridium difficile toxin/GDH with reflex to PCR (if acute-­phase-­reactant marker of systemic inflammation
diarrhea) most often promoted by bacterial infection, central adi-
55 Lactoferrin, fecal CPT 83631: leukocyte marker; posity, neoplastic activity, or traumatic injury. The ideal
intestinal inflammation level of hs-CRP is ≤0.6. hs-CRP elevation implies poten-
55 Differentiate IBD from irritable bowel syndrome (IBS) tial bacterial infection. The most common infections
55 Monitor patients with IBD for treatment response and with elevated  hs-CRP are periodontitis or necrosis of
relapse the jawbone. If an elevated CRP >1.0 and clinical oral
55 Diagnose inflammatory bowel disease (IBD) exam and report of bleeding upon flossing or brushing,
55 Occult blood, fecal appropriate referral to a biological dentist for evaluation
is warranted. If no dental/oral infection is identified,
Defense and Repair  Immune, Inflammation, and Infection/ further investigation as to the root cause of the elevated
Microbiota Assessment Biomarkers hs-CRP is warranted. It is important to rule out a recent
Blood traumatic injury that may be related, and hs-CRP should
55 Vitamin D 25-hydroxy be retested in a month or two to observe if injury
Vitamin 25-OH serum levels have been associated with sev- affected the hs-CRP.
eral comorbidities, such as infectious, autoimmune and neu- 55 CBC with differential
rological diseases, as well as neuromuscular disorders, which 55 Complete metabolic panel (CMP)
can lead to increased pain sensitivity [59–61]. Regarding the 55 Lipid panel
mechanisms of pain sensitization, vitamin D seems to stim- 55 Sed rate
ulate anti-inflammatory processes in some cases and thus to 55 TSH
relieve the painful sensation of many diseases [62–64]. 55 Bacterial/viral evaluation
55 CMV IgG Ab CPT 86644–0.5 ml red top serum
55 Vitamin A retinol [65] 55 CMV IgM Ab CPT 86645–0.5 ml red top serum
20 Vitamin A retinol  is increasingly recognized in experi- 55 Epstein-Barr virus (EBV) antibody panel ((IgM,
mental and human studies to suppress inflammatory VCA IgG, EBNA IgG) – CPT 86664, 86,665–1 ml red
reactions and plays a significant role in normal mucosal top serum
immunity, regulation of T cell-dependent responses, anti- 55 EBV early antigen D antibody (IgG) – CPT
viral activity [66], and cell trafficking. 86663–1 ml red top serum
Adequate vitamin A status, whether from intake of 55 Chlamydophila pneumoniae antibodies (IgG, IgA,
preformed retinol or β-carotene, is important for pre- IgM) – CPT 86631 86,632 1 ml red top serum
venting excessive or prolonged inflammatory reactions 55 Mycoplasma IgG/IgM – CPT 8673–86,738 – 1 ml red
and infectious events [66]. top serum
Nutritional Influences on Immunity and Infection
315 20
55 Herpesvirus 6 antibodies (IgG, IgM) – CPT 86790,
86,790 (×2)– 0.5 ml red top serum
55 ASO CPT 86060–1 ml SST Undernutrition Infection
55 ANA W/RFX – CPT 86038–1 ml red top serum
55 Immune function
55 Natural killer cells, functional – CPT 88184, 88,185–
10 ml (WB) green tube
55 Toxin load
Decreased
55 Heavy metals panel, blood – CPT 82175, 83,655, Impaired absorption
immune function
83,825 – (WB) royal blue EDTA • Innate
• Altered gut lumen
Includes: arsenic, lead, mercury • Mucosal injury
• Acquired
55 Cadmium, blood – CPT 82300 – (WB) royal blue
EDTA trace element (REF)
55 Fecal ..      Fig. 20.8  Interactions between malnutrition and infection [28].
55 Microbiology, fecal (Adapted from Katona and Katona-Apte [28]. With permission from
55 Ova and parasitology Oxford University Press)
55 Urine
55 Urinalysis (urine) worth noting in nature that vitamins D2/3 and A are found in
55 Organic acids (urine) their food-rich sources together (e.g., liver, caviar/roe, egg
55 Complete hormone panel yolk, etc.).
55 Saliva or blood Genomic testing
55 (saliva) Lipids  Phospholipids, oils, and fat foods – RBC fatty acid,
lipid panel tests. The phospholipids, sterols, and eicosanoid
Structural integrity  Membrane structure affects the func- fatty acids and their metabolites give structural and func-
tion of transport and communication at the cell membrane tional influences on cell signaling and prostaglandin
site and receptors; review if history of head/neck/dentition/ “hormone-­like” regulation to transport of components in
back injury may affect brainstem and vagal nerve immune- and out of the cell compartments to nourish and regulate
related function; structure, dysfunction occurs. Dietary immune response of inflammation, hormonal modulation,
intake of these lipid groups is reflected in their endogenous and other undiscovered functions. When there is poor struc-
structure and function [67]. ture, poor function follows (see 7 Chap. 10).
 

55 Cell membrane fluidity (BIA phase angle, fatty acid

status) Methyl nutrients  Vitamins B6, folate, B12, riboflavin, beta-
55 Structural: spinal alignment ine, biotin, choline, SAMe, and amino acids methionine, cys-
55 Dental: periodontitis – infection of the tissues that teine, serine, and glycine [70, 71].
surround the teeth Methyl nutrients support the process of methylation with
55 Cervical C1–C7 – brainstem and vagal assessment – many roles within human metabolism, with DNA methyla-
check vagal tone [68] tion being the underlying mechanism, and currently appear
55 Thoracic T1–T5 – stenosis or injury, increased pain to be the primary messengers of epigenetic expression (see
resulting in exaggerated immune inflammatory 7 Chap. 18) identified in the etiology of developing cardio-
 

response vascular, cancer, and neurological disease conditions. Methyl

55 Lumbar L1–L5 – stenosis or injury increased pain nutrients include vitamins (folate, riboflavin, vitamin B12,
resulting in exaggerated immune inflammatory vitamin B6, choline) and amino acids (methionine, cysteine,
response serine, glycine).
Methylation involves biochemical pathways where the B
vitamins and other cofactors like amino acids are rate-­
20.11.3  ey Nutrients Influencing the Risk
K limiting cofactors.
of Infectious Disease (. Fig. 20.8)  

20.12 Homocysteine Catabolism (. Fig. 20.9)  

20.11.3.1 Vitamin D, A, E [69]

These fat-soluble vitamins have many metabolic roles, but for 20.12.1  Folate Metabolism
the focus on the immune system in this chapter, the role of
immune modulation is discussed. The fat-soluble vitamins Folate is critical to many metabolic pathways like nucleic acid
function synergistically; even the vitamin D and A receptors precursors, several amino acids, and erythropoiesis, the pro-
share the RXR nuclear receptor influencing each other. It is cess in which new erythrocytes are produced. Elevated mean
 316 J. Noland and D. Noland

Iron  weaken cell-mediated immunity; decreases in neutro-

phil action

Magnesium  co-factor in >300 enzymes affecting all systems

20.13  ey Lifestyle Factors Influencing

K
the Risk of Infectious Disease

20.13.1  Sleep (see 7 Chap. 45)

 

..      Fig. 20.9  Homocysteine major metabolic pathways in humans

[72]. (Reprinted from Dudman et al. [72]. With permission from Oxford
University Press) Sleep and circadian rhythm have a great influence on the
integrity of the immune system. Much evidence has accrued
corpuscular volume (MCV)on a complete blood count  can over the past decades associating poor sleep quantity and
suggest folate deficiency. Folate deficiency can be part of the quality with weakening of the immune system, increasing
etiology of enlarged RBC, or megaloblastic anemia, from vulnerability to infection.
ineffective erythropoiesis. Vitamin B6 and B12 are cofactors
also involved in erythropoiesis [73].
20.13.2 Stress (see 7 Chap. 47)
 

Chronic stress impacts every biological and psychological

20.12.2 Methionine Metabolism system. The chemical microenvironment under long-term
stress pushes the immune system response into chronic
Methionine metabolism occurs predominantly in the liver
inflammation. The vicious cycle continues until the thresh-
tissue with two components: a  transsulfuration pathway,
old of resilience and adaptation is exceeded, leading to vul-
involving homocysteine reduction to glutathione, and a trans-
nerability to many chronic diseases including infection.
methylation cycle with folate and methyl nutrients producing
S-adenosylmethionine (SAMe). Thus, methionine metabo-
lism is dependent on dietary intake of vitamins B12, B6, and 20.14 Movement (see 7 Chap. 36)
 

folate. SAMe is key in regulating epigenetic expressions of

multiple pathways and, when deficient, leads to ramifications 20.14.1   xamples of Chronic Disease
E
of nutritional and immune injury [74] (see 7 Chap. 17).
 
Connections with Infectious Disease
20.12.2.1 Phytonutrients
20.14.1.1 Heart Disease/Cardiovascular
Inflammation: powerful pigment-rich polyphenols found in
Association with Infectious Processes
a variety of fruits, vegetables, grains, nuts, teas, herbal spices,
and legumes have anti-inflammatory properties. Plant chem- 55 Infectious risk: Chlamydia pneumonia, group A
icals include antioxidants and antibacterial and antiviral Streptococcus [77].
mechanisms. Even though phytonutrients are not considered 55 Dental: periodontitis, necrosis of the jaw.
essential nutrients, the evidence is mounting of their critical 55 Rheumatic heart disease: [78].
role health maintenance and anti-aging. 55 Bacterial endocarditis (cardiac inflammation and
Biomarkers of phytonutrient status: poor dietary intake scarring triggered by an autoimmune reaction to
of high polyphenol foods. Significant biomarkers for inflam- infection with group A Streptococci).
mation can be related to poor vegetable and fruit intake and 55 Pancarditis (involving inflammation of the myocardium,
lack of or imbalance in dietary intake of healthy fats and oils endocardium, and epicardium); follows pharyngitis
(see 7 Chap. 57).
 
infection without antibiotic treatment.
Resource: The Rainbow Diet. Color Can Heal Your Life [75] 55 Rheumatic chronic disease: mitral valve stenosis almost
20 always originates from rheumatic conditions and
20.12.2.2 Minerals: [76] expresses and perfusion insufficiency. Rheumatic
Zinc  critical role in the function of immune cells
conditions are highly associated with underlying
infection [79]. A previous infective endocarditis should
Potassium  principal intracellular cytosol electrolyte
be ruled out if there are symptoms of unexplained fever,
malaise, or weight loss [80].
Iodine  thyroid hormone structure, brain development
20.14.1.2 Oncology
Selenium  thyroid peroxidase metabolism with vitamin E,
Etiology of cancer can be related to infectious disease.
selenoproteins special effects on cellular immunity resistance
Viral  EBV, CMV. Herpes simplex, herpes zoster, HIV, HPV
to viral infections. Central to glutathione peroxidase structure
Nutritional Influences on Immunity and Infection
317 20
Bacterial  H. pylori, Mycoplasma pneumoniae 20.14.2 Vaccination
Fungal  Candida, mycotoxins During the twentieth century, the discovery and use  of
antibiotics began the breakdown of natural microbiota
Mycoplasma  M. pneumonia, M. genitalium, M. hominis, throughout the gastrointestinal tract and other microbi-
ureaplasma urealyticum, U. parvum ome-containing orifices. It is recognized at the time of this
publication that the current epidemic of “superbugs” has
Parasites  trichinosis [81], blastocystis hominis, tropical resulted from overuse and misuse of antibiotics and anti-
parasites microbials. After the discovery of antibiotics, more phar-
maceuticals were discovered to be  providing strong
20.14.1.3 Neurological manipulation of body systems and  perturbing nutrient
Alzheimer’s disease  Viruses of life-long carriage are typi- functions, such as steroid medications weakening connec-
cally asymptomatic, strongly associated immunologic, and tive tissue resulting in the increased need for vitamin C,
virologic characteristics with Alzheimer disease neuropa- biotin, and zinc. In addition, after World War II, there was
thology increasing ­amyloid plaque and neurofibrillary tan- the introduction of many “new-to-nature” molecules to
gles (NFTs): herpes simplex virus-1 (HSV-1), long-term agricultural practices and as  additives to the food supply
cytomegalovirus (CMV) [82]. [85]. All of these new introductions into the human envi-
ronment have altered the immune system, contributing to
Developmental plasticity  Due to fetal and early childhood weakening defense systems. The twenty-first century  is
metabolic plasticity influences by the environment, negative introducing even more organic and inorganic molecules
toxic exposures and infectious processes in utero or in child- that need more extensive investigation about their safety.
hood can influence the risk of later chronic adverse condi- Two examples of concern:
tions, especially noncommunicable disease (NCD). This fact 1. Fecal microbiota for transplantation (FMT) implanting
has driven the public health drive for vaccination programs foreign bacteria from a donor into the gastrointestinal
during the first year of birth [83]. The importance of mater- tract of a patient. The US Food and Drug Administration
nal health nutrition status and free from infectious disease (FDA) has not officially approved FMT procedures but
lays the foundation for fetal growth. Developmental epi- supports the area of scientific discovery. In 2019,
genetics studies provide insight into the importance of epi- implants performed for two immune-compromised
genetic marks occurring in utero and recognition of new patients from a single donor contained drug-resistant
biomarkers to provide interventions for prevention and organisms. One of the patients died. Clinical trials were
treatment [83]. suspended and the FDA has warned all fecal matter for
FMT should be tested for drug-­resistant bacteria [86,
20.14.1.4 Respiratory (see 7 Chap. 52)
 
87]. This event illustrates the potential risk of FMT as a
Acute respiratory infection can derive from viral, bacterial, source of life-threatening infections.
or mold/mycotoxin exposure. The risk for an individual can 2. Vaccinations have strong pro and con public opinion, but
be related to exposure environment and genotype (e.g., cystic all sides agree in vaccine safety monitored by the US
fibrosis, alpha-1-antitrypsin, Wegener’s granulomatosis). FDA and the Centers for Disease Control and Prevention
More extensive discussion on respiratory conditions and (CDC). The principle of vaccination is based on the
infection is presented in 7 Chap. 52.
 
body’s healthy adaptive immune response when exposed
to a pathogen to develop protective antibodies to the
20.14.1.5 Autoimmune (see 7 Chap. 49)  
pathogen. The most prominent concerns about vaccine
Autoimmune conditions are inflammatory. Ongoing research safety are the additives to the vaccine preparations for
has identified genetic relationships with susceptibility to preservation and effectiveness, the age at which vaccine
developing autoimmune conditions, but coexisting infec- is administered, and the number of vaccines given
tions can contribute to the etiology of an individual’s disease. simultaneously. The most commonly used preservative
The human leukocyte antigen (HLA) group of genes is highly adjuvants are aluminum, mercury-­containing thimerosal
associated with risk of developing autoimmunity. HLA DQ2 [88], and formaldehyde. These compounds have known
and HLA DQ8 reside within the HLA gene group, and are adverse effects. In 2011, the International Agency for
known risks for developing celiac disease [84]. Research on Cancer (IARC) named formaldehyde “a
known human carcinogen” [89]. The US FDA has a
Comprehensive Human Leukocyte Antigen Panel reporting site for Vaccine Adverse Event Reporting System
HLA DR1/3/4/5, DQ Intermediate Resolution CPT 81375 (VAERS) and Wide-ranging Online Data for
LabCorp Specialty Labs Epidemiologic Research (WONDER) to provide public
health information [90].
 318 J. Noland and D. Noland

Thimerosal contains mercury, of  which the World Health

Organization (WHO) says that exposure, even in small Several reports have shown that vitamin A deficiency
amounts, “may cause serious health problems and is a threat results in a poor response to immunization, with
to the development of the child in utero and early in life.” generally low antibody responses to immunization with
“Mercury is considered by WHO as one of the top ten chem- T cell-dependent antigens [93, 94].
icals or groups of chemicals of major public health concern”
[91]. Aluminum is a known neurotoxin and can play a sig-
nificant role in neurological diseases. Reported elevated lev-
els of aluminum found in Alzheimer’s patient brains increases 20.15 Conclusion
public concern. There is no evidence of harm for aluminum
content in single vaccines, but concern for the accumulation This chapter reviews the importance of considering infection
of total aluminum in multiple-dose vaccine vials is not as a potential contributor to the etiology of any of the chronic
known. diseases.
The use of vaccines has become a highly debated political Infection can contribute to each type of chronic disease.
issue with states overhauling fundamental changes in their Growing evidence is emerging that infections are most dam-
vaccine laws toward mandatory vaccination. Integrative and aging to tissues and metabolism when they have continued as
functional medical practitioners tend to embrace “first do no a prolonged burden on the immune system. Pathogens
harm” and at least recommend parents base their decisions are generally attracted to specific tissue types and the disease
with full knowledge of the pros and cons of vaccinations for that may develop for a unique individual may vary. Chronic
their individual child. There is no clear evidence of why some diseases are characterized as long-latency, lifestyle, and diet-­
children and adults have mild to life-threatening side effects related diseases. An acute infection may either be resolved by
after receiving a vaccine. a healthy immune system or survive and continue as a sub-
If there is a suspected reaction to a vaccine, the National clinical infection that is often not recognized but continues to
Vaccine Injury Compensation Program (NVICP) exists to wear on the immune system. Examples of commonly recog-
provide financial compensation to individuals who have nized subclinical infections that lead to increasing risk of a
documented injury [92]. serious chronic disease: HPV risk of cervical or head/neck
General considerations for parents that may increase vac- cancers, hepatitis C risk of liver cancer, Epstein-Barr virus
cine safety for a child: risk of non-Hodgkin’s lymphoma and some autoimmune
55 Is my child sick the day of a scheduled vaccine? If yes, conditions, and C. pneumoniae implicated in chronic ill-
best to reschedule. nesses, such as atherosclerosis, asthma, arthritis, multiple
55 Has my child had a reaction to any previous vaccina- sclerosis, and many others. This chapter has described the
tion? association between a person’s nutritional status and their
55 Do our family or I have a history of vaccine reactions, vulnerability to infection.  Individual nutritional status is a
neurological disorders, or immune system conditions determinant of how well their body can respond to and
like Sjogren’s, lupus, celiac, eczema, etc.? If yes, docu- resolve an infection, returning it to a state of wellness. The
ment your child’s personal and family history [90]. risk to get or not resolve an infection is greater from a com-
55 What are the vaccination laws in the state in which I promised immune system when nutrient tissue levels are not
live? optimized for an individual or able to provide adequate
nutrient metabolic cofactors. Healthy nutritional status
If agreeing to vaccination, recommend limiting vaccinations decreases risk of chronic diseases and vulnerability for long-­
to one vaccine administration at a time instead of multiple latency prolonged infection [1, 3].
vaccines. Single-use vials of vaccines, if available, can be con- The healthy human body is equipped with defense fea-
sidered  to reduce exposure to preservatives like thimerasol tures from conception throughout life to interact with the
(mercury-containing) and formaldehyde. environment to protect from infection. Much of the defense
Genomic counselors can be sought to discuss currently starts with the skin barrier and microbiome at all body ori-
identified single-nucleotide polymorphisms (SNPs) that may fices to protect from pathogens entering and infecting.
20 be associated with increased risk of vaccine reaction. Another key is keeping the stomach acid-neutralizing patho-
Ensure your child is in good nutrition status, eating a bal- gens or toxic organics from traveling further down the gas-
anced whole-food, low-pesticide, fruit- and vegetable-rich, trointestinal tract where they could cause havoc and alter the
low-sugar diet with adequate intake of vitamins D, A, and C, powerful GI microbiome. These defenses guard pathogens
essential fatty acids, and bioactive forms of B vitamins from and toxins from entering the blood and/or lymph circulation.
food or supplements if needed. Along with the internal milieu of the body, ethnic cultures
The US FDA has a reporting site for Vaccine Adverse have developed mores to support immune defense by tradi-
Event Reporting System (VAERS) and Wide-ranging Online tions of toileting, diet, sleeping, sanitation (especially for
Data for Epidemiologic Research (WONDER) to provide pub- food preparation and handwashing), and other complemen-
lic health information [90]. tary routines that minimize infection.
Nutritional Influences on Immunity and Infection
319 20
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 323 21

Body Composition
Sue Ward and Diana Noland

21.1 Introduction – 324

21.2 Body Composition Methods – 324

21.3 Field Methods – 324

21.4 Height, Weight, and Body Mass Index – 325

21.5 Girth Measurements – 325

21.5.1  aist Circumference (WC) – 326
W
21.5.2 Waist-to-Hip Ratio – 326
21.5.3 Waist-to-Height Ratio (WHR) – 326
21.5.4 Upper Arm Circumference – 326
21.5.5 Using Circumference Measurements to Calculate
Body Fat Percentage – 326
21.5.6 Skinfold Measurement – 327
21.5.7 Bioelectrical Impedance Analysis and Bioimpedance
Spectroscopy – 327

21.6  ioelectrical Impedance Analysis: Non-­body Composition

B
Parameters for Nutritional Assessment – 328

21.7 Intracellular Water (ICW)/Extracellular

Water (ECW) Hydration – 329

21.8 Basal Metabolic Rate Analyzers – 330

21.8.1 E lectrical Impedance Myography – 330
21.8.2 Consumer Apps for Smartphones – 330

21.9 Laboratory Methods – 331

21.9.1  ydrostatic Weighing – 331
H
21.9.2 Air Displacement Plethysmography – 331
21.9.3 Dual-energy X-ray Absorptiometry (DXA/DEXA) – 331
21.9.4 Medical Imaging – Computed Tomography (CT) and Magnetic
Resonance Imaging (MRI) – 332
21.9.5 Ultrasound – 332

21.10 Classification Based on Percent Fat – 332

21.11 Conclusion – 333

References – 333
© Springer Nature Switzerland AG 2020
D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_21
 324 S. Ward and D. Noland

21.1 Introduction Current methods for body composition assessment are

characterized from simple to complex and all have some
Anthropometric measurements, such as body size, weight, degree of measurement error. Some inherent problems with
and proportions, are often used to evaluate and monitor the assessment techniques occur with the methodology, inter-
effects of nutritional interventions as well as reflect an indi- pretation of data, and assumptions made with certain meth-
vidual’s overall growth and development. Body composition ods. The choice often depends on the intended purpose, cost,
is the proportion of fat, muscle, bone, and water that make up and available technology.
the human body and its measurement helps determine
excesses or deficiencies of a component that is related to
»» Although decreases in muscle and increases in fat mass
are considered part of the natural course of aging, to a
health risk. In the fitness and sports setting, body fatness is an great extent they’re probably the results of inactivity and
indicator of physical fitness and may be assessed by personal sedentary behaviors. – Melissa Benton [1]
trainers and athletic coaches since fat content can affect
sports performance. Nutrition practitioners often assess
body composition since certain proportions are associated 21.2 Body Composition Methods
with a variety of health problems. Obesity and the newer
identification of sarcopenic obesity of increased body fat per- There are a variety of techniques used to estimate body
centage and loss of muscle, independent of BMI, has been composition as part of a nutritional assessment in the clini-
associated with a number of diseases such as type 2 diabetes, cal setting. With all methods, strict adherence to the estab-
hypertension, heart disease, arthritis, autoimmunity, liver lished protocols must be followed to obtain the most
disease, cancer, and kidney disease. accurate results possible. Knowing the advantages and dis-
At the other end of the spectrum, too little body fat is advantages of each method will help the practitioner decide
often seen in those with eating disorders, oligomenorrhea, wisely when choosing a method for body composition
exercise addiction, and certain diseases such as cystic fibro- assessment.
sis, Crohn’s disease, and cancer. Since physiological dysfunc- One prevalent system of assessment is the two-com-
tion can occur with too much or too little body fat, sarcopenic partment model, which assumes the body is made up of fat
obesity and its distribution in the body, assessment and and fat-free compartments. The terms “fat-free mass” and
monitoring of body composition has become widespread “lean body mass” are often used incorrectly. Fat-free mass
and important for health practitioners (. Fig. 21.1).
 
does not contain lipids, whereas lean mass includes
approximately 2–3% for men and 5–8% for women. The
lipids contained in lean mass include essential fat that
a b serves as a structural component of cell membranes. Thus,
the fat-free compartment is primarily made up of bone,
muscle, other fat-free tissue, and body water. The water
content of fat-free mass is about 72–74%. Except for
cadaver studies, which provide a direct assessment of body
composition, the methods discussed in this chapter are
considered indirect measures and are appropriate for the
clinical setting.

21.3 Field Methods

Field methods are commonly used for assessing body com-

position in both sport and health settings. Health practitio-
ners use body composition in the assessment of nutritional
and growth status, as well as in disease states and their treat-
ment. Most measurements of body composition are made in
the field or clinic, while more expensive laboratory methods
21 are used primarily in research and for establishing the accu-
..      Fig. 21.1  Body Composition Changes with Sarcopenic Obesity. As racy of the field methods [2]. Selecting a method is often dif-
people age they lose the lean muscle mass gained in young adulthood a, ficult since practitioners want simple, inexpensive, and
resulting in a higher proportion of fat mass b, even if the absolute amounts non-invasive options to measure body composition, but not
of body fat remain constant. This can lead to sarcopenic obesity – a loss of
at the expense of accuracy. Clinicians need to consider all
muscle and a concomitant increase in fat, often while the body weight
remains stable or even decreases (Illustration by Anne Rains). (Reprinted factors and choose one or more methods that appropriately
from Benton et al. [1]. With permission from Wolters Kluwer Health) meet their needs.
Body Composition
325 21
21.4 Height, Weight, and Body Mass Index ..      Table 21.1  Body mass index

Since loss of height may indicate certain health problems, the Body mass index (BMI) = body weight (kg)/height (m)2
accuracy of the information on height is relevant for clinical To determine body mass index, measure height to the nearest
practice. Measure stature, or height, using a wall-mounted half inch and multiply by 0.0254 (to convert it to meters). Record
stadiometer, or height rod, rather than asking the person his weight to the nearest half pound and divide by 2.2 (to convert it
to kilograms).
or her height. The wall-mounted measuring devices are pre-
ferred to the moveable rod on a platform scale, which lacks BMI Classification
rigidity and can yield inaccuracy. Measurement of height can Under 18.5 Underweight
also be helpful in monitoring height loss in older individuals.
In a recent study, the best predictors of a height loss of 3 cm 18.5–24.9 Normal
or more were age, vertebral fractures, thoracic kyphosis, sco- 25.0–29.9 Overweight
liosis, back pain, and osteoporosis [3]. Height loss may also
30.0–34.9 Obesity – Class I
be a useful tool in detecting vertebral fractures, low bone
mineral density, and vitamin D deficiency [4]. 35.0–39.9 Obesity – Class II
Body weight should be measured using a standard physi- ≥40.0 Obesity – Class III (extreme obesity)
cian’s balance beam scale or a portable digital scale, which are
accurate and consistent [5]. There is some belief that strain Based on data from Ref. [9]
gauge scales may be more accurate than a conventional spring-
type scale that simply has electronics to convert the result to a
digital readout. Strain gauge scales use a strain gauge trans- are often used to track changes in body size during weight
ducer to measure weight and display it digitally. This type of loss interventions. There are also consumer apps available for
scale is inexpensive, accurate, reliable, and often portable. All smartphones that often use circumferences to estimate body
scales should be placed on a flat, hard surface and checked for fat, but these give little direction about how to accurately
accuracy two times per year by using standard weights or the measure. Some common circumference sites and measure-
manufacturer recommended calibration methods. ment tips are as follows:
From height and weight, body mass index (BMI), or 55 Wrist – Measure the minimum circumference of the
Quetelet index, can be calculated and is a widely used clinical wrist (the tape may need to be moved up and down to
assessment to determine appropriateness of a person’s body identify the minimum circumference).
weight. It is currently the accepted method for interpreting 55 Forearm – This girth is measured at the maximal
the height-weight relationship and is commonly used in obe- circumference of the forearm, usually closer to the
sity research. BMI is calculated by dividing the weight in elbow.
kilograms by height in meters squared. Although this is a 55 Upper arm – Measure at the midpoint between the
quick and easy method for classifying weight, it does not acromial (bony part of the shoulder) and the olecranon
assess actual body composition or distinguish between fat (bony part of elbow) process.
and muscle components. BMI tends to overestimate body fat 55 Waist – Measure at the midpoint between the lower
levels in lean, muscular, or large-framed individuals, classify- margin of the last palpable rib and the top of the iliac
ing them as overweight or obese [6]. A simple adjustment has crest.
been proposed that will allow the BMI of athletes to reflect 55 Abdomen – Measure the torso at the level of the
the adiposity normally associated with non-athletic popula- umbilicus.
tions and provide the clinician or researcher with greater 55 Hips – Measure the maximal circumference of the
confidence when using BMI [7]. Body mass index also may buttocks above the gluteal fold (measure from the
not accurately reflect obesity and health risk in people with person’s right or left side to better identify maximal
normal BMI values, but have a high percentage of body fat circumference).
and visceral fat, especially among different ethnic groups [8]. 55 Thigh – Measure the largest circumference of the right
Health practitioners should be aware of the limitations of thigh just below the gluteal fold.
using body mass index as the only assessment of body com- 55 Calf – Measure at the largest circumference of the calf.
position (. Table 21.1).
 

How to take measurements:

1. The person to be measured should wear minimal or
21.5 Girth Measurements tight-fitting clothing.
2. Take all measurements on the right side of the body
Several body and limb circumferences are often used to esti- when measuring limb circumferences.
mate body composition and describe body proportions. 3. Obtain the measurement with the tape in contact with,
These methods provide quick and reliable information and but not compressing, the skin.
 326 S. Ward and D. Noland

4. Take waist measurements at the end of a normal expiration. risks associated with central obesity [15]. The use of waist-­
5. Take hip, thigh, and calf circumferences from the left or height ratio in public health screenings, with appropriate
right side of the individual to ensure the tape measure is action, could help add years to life, according to a recent
horizontal and parallel to the floor. British study [16] and supports the simple message “keep
6. Record measurements to the closest line marking your waist circumference to less than half your height.”
(i.e., fraction of an inch/cm). Waist-to-­height ratio is a simple, quick, non-invasive method
7. Take each measurement is two times to ensure accuracy. of assessment using measurements in centimeters or inches.
The nutritionist should consider it as part of a standard
assessment.
21.5.1 Waist Circumference (WC) Waist-to-Height References (cm or inches)  –
7 omnicalculator.­com
 

The measurement of waist circumference assesses an indi- 55 Extremely slim – <0.34 both for men and women
vidual’s pattern of fat distribution and visceral fat. In fact, 55 Healthy – 0.43–0.52 for men and 0.42–0.48 for women
obesity defined by waist circumference may be a better pre- 55 Overweight – 0.53–0.57 for men and 0.49–0.53 for
dictor of coronary artery calcification than BMI according to women
a recent study [10] that also showed those with BMIs in the 55 Very overweight – 0.58–0.62 for men and 0.54–0.57 for
overweight range and waist circumferences in the obese range women
had the second highest risk. Typically, waist circumference 55 Morbidly obese – >0.63 for men and > 0.58 for women
greater than 35 inches (88 cm) in women and greater than 40
inches (102 cm) in men significantly increases the risk for
obesity-related diseases and may be a better predictor of the 21.5.4 Upper Arm Circumference
insulin-resistant phenotype and diabetes than BMI [11].
Recently, some studies have shown the association of dis-
ease, biochemical changes, and nutritional status with
21.5.2 Waist-to-Hip Ratio upper-arm composition [17], which may provide a better
assessment of muscularity and adiposity over other anthro-
Waist-to-hip ratio (WHR) helps determine an individual’s pometric measures, although it may not show short-term
pattern of fat distribution and whether or not that pattern car- alterations in body composition [18]. One study found the
ries additional health risks. An excessive amount of visceral fat combination of upper arm circumference and BMI good
(“apple-shaped” bodies) has been associated with disorders of indicators of adiposity and showed arm circumference as a
carbohydrate and fat metabolism and possible hypertension. single measurement as a practical and good choice, corre-
Waist-to-hip ratio is also a marker of insulin resistance and lating well with air displacement plethysmography [19].
hyperinsulinemia, which may assist the practitioner with rec- Another study showed favorable results when predicting
ommendations for further laboratory testing. High insulin has fat percentage using electrical resistivity of the upper arm
been associated with increased risk of breast cancer and poorer [20]. Further research is needed to develop reliable norma-
outcomes after diagnosis. Elevated waist-to-hip ratio has been tive data.
confirmed as a predictor of cancer mortality [12]. In one study,
waist-to-hip ratio was a better predictor of obesity-related gas-
troesophageal reflux disease, also known as GERD [13]. 21.5.5  sing Circumference Measurements
U
Waist-to-hip ratio appears to be a better indicator for central to Calculate Body Fat Percentage
body fat, regardless of waist circumference in patients with
non-alcoholic fatty liver disease [14]. Those individuals with a One older formula (Katch, McArdle 1983) can be used to
healthy BMI or body fat percentage, but a high waist-to-hip estimate body fat percentage if the clinician is looking for an
ratio should be advised to further reduce overall body fat. easy way to assess fat along with monitoring changes in cir-
Calculate waist-to-hip ratio by dividing the waist girth by cumferences. The formulas below are based on age and gen-
hip girth (waist ÷ hip). The World Health Organization der and can be adjusted for athletes. Although the “athletic”
(2008) has determined that a WHR of greater than 0.85 in adjustment was not defined for this formula, the practitioner
women and greater than 0.90 in men shows an increased risk can use the adjustment factor if the person regularly engages
21 of metabolic complications. in moderate to vigorous physical activity or strenuous sports.
55 Younger Women (17–26 years)
% Body Fat = (abdominal circumference × 1.34) + (thigh
21.5.3 Waist-to-Height Ratio (WHR) circumference × 2.08) – (forearm circumference ×
4.31) – 19.6
Recent research has identified waist-to-height ratio (waist 55 Older Women (over 26 years)
circumference more than half of your height) is considered % Body Fat = (abdominal circumference × 1.19) + (thigh
as a simpler and more predictive indicator of early health circumference × 1.24) – (calf circumference × 1.45) – 18.4
Body Composition
327 21
55 Younger Men (17–26 years) 21.5.7  ioelectrical Impedance Analysis
B
|% Body Fat = (upper arm circumference × and Bioimpedance Spectroscopy
3.70) + (abdominal circumference × 1.31) –
(forearm circumference × 5.43) – 10.2 Bioelectrical impedance analysis (BIA) is a non-invasive,
55 Older Men (over 26 years) useful tool for estimating body composition based on a two-
% Body Fat = (buttock circumference × 1.05) + or four-compartment model [22]. Numerous researchers
(­abdominal circumference × 0.90) – have conducted studies on bioimpedance analysis and its
(forearm circumference × 3.00) – 15.0 applications in estimation of body composition and evalua-
tion of clinical conditions [22]. This technique measures the
Athletic Adjustment Factor: Subtract 4.0 for males and 3.0 for resistance, called impedance, to a small electrical current as it
females from the percent body fat value. travels through the body’s water pool and is based on the
principle that lean tissue has a higher electrical conductivity
and lower impedance than fat tissue due to its electrolyte
21.5.6 Skinfold Measurement content relative to water. With this method, the instrument
generates an alternating electrical current, which is passed
Skinfold measurement, the thickness of a double fold of skin through the body via electrodes that are either placed on the
and compressed subcutaneous adipose tissue, is widely used body or built into a scale or handheld instrument.
in the clinical setting. The validity depends on the accuracy Bioimpedance spectroscopy (BIS) is known as full-body
of the measurement and the skill of the technician. An (hand-to-foot) multi-frequency BIA as it allows total body
improperly trained technician will introduce significant water to be differentiated further into intracellular and
measurement error. Skinfold calipers are used and a variety extracellular water compartments. This is useful when mon-
of measurements are taken from different sites on the body. itoring fluid shifts and hydration. BIS can also provide an
Common sites for measurement include the triceps, biceps, estimate of body cell mass (BCM), an important indicator of
subscapular, suprailiac, abdomen, upper thigh, and calf. nutritional status. BIS differs from the more widely recog-
There are several different protocols utilizing these sites that nized single-­frequency BIA and does not require the use of
yield an individual’s estimate of body fat percent. Though statistically derived, population-specific prediction equa-
skinfold measurement yields a percentage of body fat, the tions [23]. Some BIA instruments use the multi-segmental
individual site measurements may also be a good way to approach, which assumes the body is made up of a group of
monitor patient progress. It should be noted that this is a cylinders (left and right arms, left and right legs, and the
somewhat invasive measurement, since the fat must be total body) and are available in both single-frequency and
pinched and pulled away from the muscle. This can cause multi-frequency systems.
some discomfort and embarrassment in some patients and is The BIA is widely used in practice and body composition
inappropriate for those who are severely obese. Individuals research. Its benefits of BIA include its portability, ease of use,
will have variations in skinfold thickness, compressibility of low cost (depending on the instrument), and safety. It mea-
tissue, and hydration level, which is likely to affect the mea- sures impedance with high precision, does not subject the
surement. person to ionizing radiation, and requires minimal subject
There are many assumptions involved in using skinfold involvement. It is useful in the clinical setting provided the
measurement to predict body fat [21]: individual follows important pre-test instructions:
55 Skinfold compressibility is constant. 55 Avoid heavy exercise for 12 hours before testing.
55 Skin thickness is constant (subscapular skin thickness 55 Refrain from consuming caffeine and alcohol the day
was found to be greater than skin thickness at other before testing.
sites). 55 Maintain good hydration (dehydration will overestimate
55 Subcutaneous adipose tissue patterning is constant fat mass).
(there is variability reinforcing the importance of using
readings from multiple sites). Limitations of the BIA include poor accuracy in estimating
55 Variability in fat content of adipose tissue is constant fat-free mass and percent body fat, with the trunk being
(estimated to be 20%). under-represented and the limbs over-represented [24].
55 Internal and subcutaneous fat deposition is constant. Since BIA instruments rely on regression equations for their
calculations, the method is good only if the appropriate equa-
Biochemical individuality plays a major role in the accuracy tions are used. This is the reason why some instruments are
and reliability of this method. While skinfold measurement better than others ranging from inexpensive, portable BIA
is not the optimal method for body composition assessment scales to professional and expensive devices. These units can
when time and accuracy is a concern, practitioners should be range in price from $50 to $30,000 (. Figs. 21.2 and 21.3).
 

aware of this technique, which has been widely used in a vari- Bioelectrical impedance analysis has shown to be effica-
ety of health and fitness settings. cious in assessing body composition in patients with eating
 328 S. Ward and D. Noland

quadriplegic individuals and other special populations, espe-

cially when cognition or speech is impaired so a patient his-
tory cannot be reported for dietary and fluid intake.
Detection
electrode
21.6  ioelectrical Impedance Analysis:
B
Non-­body Composition Parameters
for Nutritional Assessment
Current
source In addition to body composition measurement, the bioelec-
electrode trical impedance analysis (BIA) is also an important func-
tional tool in evaluating the metabolic status of a patient. It
provides data about body cell mass, cell membrane fluidity,
and cell electrical potential.
Body cell mass (BCM) contains metabolically active com-
ponents of the body such as muscle cells, organ cells, blood,
and immune cells. BCM also includes intracellular water and
the active portion of fat cells, but not the stored fat lipids.
..      Fig. 21.2  Bioelectric Impedance Analysis standard placement of Since BCM is the functional mass of the body where most of
electrodes on hand-wrist-foot and ankle for tetrapolar single (SF-BIA) the metabolic work is done, it is an indicator of overall nutri-
and multiple-frequency (MF-BIA) BIA. (Reprinted from Kyle et al. [25]. tion status. In well-nourished individuals, the muscle tissue
With permission from Elsevier) accounts for approximately 60% of the body cell mass, organ
tissue for 20%, and the remaining 20% made up of red cells
and tissue cells. When the body cell mass increases, it indi-
cates an increase in muscle tissue. A body cell mass of about
Caregiver 40% is desirable.
Phase angle (PA) is a general indicator of overall health
and is a measurement of cell membrane integrity and often
X-ray arm
referred to as a marker of cell membrane fluidity. “Phase
angle (PA) is interpreted as an indicator of cell membrane
integrity and a prognostic indicator in some clinical situa-
tions [30].” Without universal references available, and
general recommendations developed from BIA research
and clinical observation, a PA of 6–8 is optimal. As the
membrane becomes rigid, receptor function and healthy
Table exchange between intracellular and extracellular compart-
ments decrease. Lower phase angles (<6.0) are consistent
with an inability of cells to store energy and can indicate a
breakdown in the permeability of cellular membranes.
Since cell membranes have a high lipid content, phase
angle provides an indication about lipid status. Low phase
angles may reveal insulin resistance, malnutrition, infec-
tion, chronic disease, cancer, perturbed fatty acid status,
reduced antioxidant status, and old age. Higher phase
..      Fig. 21.3  Bone densitometry scan. (Reprinted from 7 Blausen.­com
angles (>8.0) can be consistent with intact healthy cell
membranes and body cell mass. Frequent clinical observa-
 

staff [26]. With permission from Creative Commons License 3.0:

7 https://creativecommons.­org/licenses/by/3.­0/deed.­en)
  tion of higher phase angles is seen in those who exercise
and consume a healthy diet, including antioxidant-rich
21 fruits, vegetables, and healthy fats. Higher than 8 is excel-
disorders during the treatment period [27], since only assess- lent and 6 or lower can indicate a serious energy deficiency
ing weight changes does not reflect changes in various body or chronic disease state.
compartments. BIA was studied as a tool to measure fluid Body Capacitance (C) is an indicator of the cell wall
changes in obese patients after bariatric surgery, but research- ionic potential, the ability of the non-conducting object to
ers found it impractical in the clinical setting for extremely save electrical charges. All movement of energy and com-
obese patients due to individual variability [28]. pounds require biochemical ionic charge. This value is pri-
BIA can also yield very beneficial information when used marily dependent on nutritional influences of mineral
in wheelchair bound and bedridden [29] paraplegic and electrolytes and potential of hydrogen (pH) on establishing
Body Composition
329 21
the capacitance (C), which is the ability of the non-con- 21.7 Intracellular Water (ICW)/Extracellular
ducting object to save electrical charges. When capacitance Water (ECW) Hydration
or electrical charges are low, it has clinically been beneficial
to check the individual’s mineral status (serum electrolytes, The assessment of extra-, intracellular, and total body water
calcium, magnesium, and blood pressure). If the person’s (ECW, ICW, TBW) is important in many clinical situations
condition clinically supports low mineral status, consider [32]. For the nutritional perspective to be clinically useful, it
increasing dietary sea salt and magnesium, and reduce cal- is important to review the physiology of ICW and ECW. ICW
cium intake, if elevated. If capacitance is high, it is sug- is 97% potassium and ECW 97% sodium and calcium. The
gested to check serum calcium, electrolytes, blood pressure, homeostasis between the two compartments is regulated by
and dietary intake of calcium. Oxidative stress, free radical the action of the sodium-potassium pump (Na+/K+ pump)
damage, toxicity, and low antioxidant reserve also affect this that was discovered in 1957 by Danish scientist Jens Christian
result. Optimum numbers reflect a healthy cell. The body Skou. The pump is an active process driven by the energy of
capacitance number can move up or down rapidly. ATP with magnesium being the primary driver of the pump.
Optimum capacitance for males is about 1300 and for Thus, these three mineral-electrolytes become a focus when
females is about 900. assessing nutritional balance of the cellular compartments,
It is important to note regarding inverse relationships pumping potassium into cells while pumping sodium out of
with calcium and other nutrient minerals with RBC and cells against their concentration gradients. The Na+/K+ pump
urine excretion testing results. Calcium is primarily an extra- supports maintenance of the resting potential affecting trans-
cellular element because cells carefully regulate its entry into port between the compartments while regulating cellular
the cell. When BIA capacitance readings occasionally mea- volume. Magnesium status of an individual is an important
sure higher than optimum reference, it can be inferred that consideration in assessing a person’s nutrition status since
there may be a high calcium-to-magnesium and potassium magnesium is important to the function of the pump.
ratio. NHHANES studies have repeatedly identified that about
Total Body Water as a percentage of fat-free mass is a 80% of the U.S. population consumes less than the RDA of
marker of hydration. If this result is <69% the patient should magnesium (NHHANES).
be put on hydration protocol and retested in 24–48 hours as The Na+/K+ pump has many functions with some of the
values below this level indicate dehydration. This is an accu- most important the import of glucose, amino acids, and
rate indicator of hydration even when the person is signifi- other nutrients into the cell using the energy of the sodium
cantly overweight. gradient.
Total Body Water (TBW/total weight) as a percentage of Thus, the individual’s data of ICW and ECW from a BIA
total weight can show dehydration but is also related to per- measurement can be supportive of further investigation of
centage of body fat. If a person’s percent fat falls in the over- mineral-electrolyte status with biomarkers in blood testing
weight or obese categories, then consider the inverse like: RBC minerals (magnesium, calcium, potassium), elec-
relationship between total body fat and TBW (total body trolyte panel and urinalysis-specific gravity, along with nutri-
water may show lower values). This is due to lean body mass tion physical exam of skin assessing potential edema or
being approximately 70% water and body fat being around dehydration issues (see 7 Chap. 39). Assessing the dietary
 

10% water. This value may decline with age. history for intake of magnesium and potassium-rich foods,
Consumption of food or beverages in preparation is and salt and high-sodium food intake can provide guidance,
important to consider with the recommendations as food or if needed, to improve better balance of these mineral-rich
fluid intake before BIA measurement affects TBW and ECW foods. Assessing intake of fatty acids and phospholipid-rich
from studies in the 1990s. foods is also valuable to consider cell membrane fluidity
»» Significant alteration in body hydration, fluid influencing the activity of the Na+/K+ pump. During develop-
ment of the nutrition intervention plan for an individual,
distribution, and differences in the ratio of ECW to ICW
caused by a medical condition will affect impedance improving the dietary intake (food, fluids, and potential sup-
measurements. Among those conditions, the most plements) based on the hydration measurement markers of
significant confounding variable is edema of the distal the BIA ICW and ECW status can affect physiological func-
extremities, which is mainly caused by peripheral venous tion of all cells. Repeated BIA testing during monitoring and
insufficiency. This insufficiency may result from evaluation of a patient demonstrates if the nutrition interven-
congestive heart failure, cirrhosis, nephrotic syndrome, tion is effective in improving cellular hydration (. Fig. 21.4).
 

hypoalbuminemia, and lymphoedema [31]. Other Basal metabolic rate (BMR) represents the estimated
medical conditions, which affect BIA validity, include number of calories metabolized at rest during a 24-hour
cutaneous disease that may alter electrode-skin period. About 70% of a human’s total daily energy expendi-
electrical transmission in patients with amputations, ture is due to the basal life processes within the organs of the
poliomyelitis, and muscular dystrophies. These body. About 20% of one’s energy expenditure comes from
conditions will have significant effects on the application physical activity and another 10% from 7 thermogenesis.
 

of BIA in the clinical population [25]. BMR decreases with age and the loss of lean body mass and
 330 S. Ward and D. Noland

..      Fig. 21.4 Sodium-potassium
pump. The Na+/K+-ATPase, as
well as effects of diffusion of the
involved ions maintain the
resting potential across the
membranes. (Reprinted from
7 Blausen.­com staff [26]. With
 

permission from Creative

Commons License 3.0: 7 https://
 

creativecommons.­org/licenses/
by/3.­0/deed.­en)

increases as lean body mass increases, since lean mass is In addition to muscle quality, the device measures over-
metabolically active. The BMR value is important for provid- all fat percentage and local fat percentage in 24 different
ing patients with estimated daily calorie intake plus caloric areas of the body. The device was originally made to moni-
need adjustments for physical activity or energetic require- tor muscular degeneration disorders, but using a complex
ments (like infection). algorithm that does not require age, gender, or weight, the
device can estimate overall body fat percentage as well as
in  local areas. The company manufacturing the Skulpt®
21.8 Basal Metabolic Rate Analyzers device was founded in 2009 by Dr. Seward Rutkove, a
Harvard Medical School neurology professor, and Dr. Jose
55 Digital Calculator 7 calculator.­net/bmr-calculator
  Bohorquez, an electrical engineering graduate from
55 Ergospirometry Indirect calorimetry Massachusetts Institute of Technology (MIT). Most of the
55 PNOE cardio-metabolic analysis (AKA VO2max, research involves EIM’s use in neurodegenerative diseases
metabolic testing, Cardiopulmonary) such as amyotrophic lateral sclerosis (ALS) and muscular
55 KORR Metabolic Test Equipment 7 korr.­com
  dystrophy. Internal research by the manufacturer on body
55 MedGem / BodyGem Indirect Calorimeter 7 measurermr.­
  composition shows a high correlation when compared with
com dual-energy X-ray absorptiometry (DEXA) measurements.
55 Metabolic Cart – indirect calorimetry using a metabolic Since this is the only device on the market that measures
cart [33] muscle quality, it may have important clinical significance
for health practitioners. Although further research is
needed, practitioners may consider using this low-cost
21.8.1 Electrical Impedance Myography device (about $100) to monitor changes resulting from
weight loss and exercise interventions. The Skulpt® device is
Electrical impedance myography (EIM) is a technique for the designed to be used with smartphones or tablets and is
evaluation of neuromuscular diseases that may have future extremely portable.
significance for the measurement of body composition. EIM
technology is similar to bioelectrical impedance technology
in that it sends an electrical current into the limb (usually 21.8.2 Consumer Apps for Smartphones
arm or leg), but unlike BIA devices that send a current
21 through lean mass, EIM measures how current flows through There are a number of smartphone apps for consumers to
muscle and fat tissue. A new consumer product, Skulpt®, was assess body composition. Many use circumferences, skin-
recently introduced as a way to measure muscle quality along folds, bioelectrical impedance technology, or are an exten-
with body fat percent to help people monitor progress during sion of Wi-Fi-connected bathroom scales. Most allow users
exercise training. Muscle quality is defined as the force a to track body mass index (BMI). While many of these do not
muscle produces relative to its size and is a scientific metric provide a high degree of accuracy, the health practitioner
for the fitness of muscles. This could have clinical significance may find these useful for monitoring client progress. In addi-
not only for sports enthusiasts, but also for those with chronic tion, clients may find such apps motivational, which may
diseases. improve compliance with weight loss interventions.
Body Composition
331 21
21.9 Laboratory Methods Both air displacement plethysmography and hydrostatic
weighing correlate remarkably well with computed tomogra-
Laboratory methods for assessing body composition are used phy (CT) algorithms for measurement of body composition
often in research or when evaluating athletes, but vary in [36]. Of all the methods, air displacement plethysmography
their accuracy and precision [24]. Some of these methods are appears to be the best instrument for tracking body composi-
used as criterion to validate field methods. Health practitio- tion from infancy to adulthood, when compared to bioelec-
ners may consider selecting a laboratory method depending trical impedance, dual-energy X-ray absorptiometry,
on the size of the clinic and the demographics of patients. For hydrometry, and magnetic resonance imaging [37]. This is
example, a dual-energy X-ray absorptiometry (DXA/DEXA) likely because it is the only practical clinical tool available for
scanner may be chosen if the practitioner wants to assess and use in infants.
monitor bone mineral density in addition to body composi-
tion. The main disadvantage of laboratory methods is the
high cost of the equipment. 21.9.3  ual-energy X-ray Absorptiometry
D
(DXA/DEXA)

21.9.1 Hydrostatic Weighing Dual-energy X-ray absorptiometry (DXA/DEXA) was origi-

nally developed to assess bone mineral density and is cur-
A technique for determining whole body density is hydro- rently considered the gold standard technique for the
static, or underwater, weighing. This method is based on diagnosis of osteopenia and osteoporosis. Recently, it has
Archimedes’ principle, which states that the volume of an become a widely used approach for determining fat mass and
object submerged in water equals the volume of water it dis- fat-free mass. It uses a three-compartment model rather than
places. This method yields a more accurate estimation of body two-compartment measuring bone mineral density, fat, and
fat percentage and is considered the criterion method, but is fat-free soft tissue. DXA/DEXA is non-invasive, quick, and
impractical in a clinical setting. Hydrostatic weighing is based reliable, though the equipment is relatively expensive.
on the two-compartment model of body composition and The International Society for Clinical Densitometry
assumes that fat-free mass has a constant level of hydration (ISCD) recently developed official positions regarding the
and a constant proportion of bone mineral to muscle. Other use of the DXA technique for body composition analysis. The
studies have shown the density of fat-free mass is not constant report limited indications to three conditions: HIV patients
[34] and the variation in bone mineral density affects the den- treated with antiretroviral agents associated with a risk of
sity of fat-free mass. This technique also requires cooperation lipoatrophy; obese patients undergoing treatment for high
from the person being measured since he or she must be sub- weight loss; and patients with sarcopenia or muscle weakness
merged in water and remain still long enough for an accurate [38]. However, DXA/DEXA offers diagnostic and research
measurement to be taken. Hydrostatic weighing remains the possibilities for a variety of diseases and has the potential to
standard laboratory technique to which most other methods monitor body composition changes with various nutritional
for assessing body composition are often compared. interventions. The ongoing National Health and Nutrition
Examination Survey (NHANES) uses this technique for bone
density and body composition assessment.
21.9.2 Air Displacement Plethysmography As with most methods for assessment of body composi-
tion, DXA/DEXA has some disadvantages and limitations.
The fundamental principle behind the air displacement The radiation exposure from a whole-body scan ranges from
plethysmography (ADP) method for measuring body com- 0.04 to 0.86 millirem, an extremely low dose when compared
position uses the inverse relationship between pressure and to the exposure of a standard chest X-ray [39]. For this rea-
volume to measure total body densitometry. This method is son, repeated, frequent measurements are not recommended.
an alternative to underwater weighing and is better tolerated Other limitations include weight and height limits on the
by individuals. Air displacement plethysmography is deter- scanning bed with some units and the field of view cannot
mined by a commercially available product called the BOD accommodate large individuals. Differences in the hydration
POD®, which measures body composition in adults and chil- of lean tissue may affect the results as well as trunk or limb
dren. The PEA POD® has neonatal applications. One advan- thickness. Despite its limitations, some studies show it is
tage of this method is that it is more convenient and more accurate than densitometry methods [40], which has
comfortable than underwater weighing and more practical in led to the use of DXA/DEXA as a reference laboratory
the clinical setting. In general, the air-displacement plethys- method.
mography method shows agreement between two other cri- When DXA/DEXA was compared to air-displacement
terion methods (hydrostatic weighing and dual-energy X-ray plethysmography (BOD POD®), researchers concluded that
absorptiometry); however, some studies show significantly the BOD POD® was more accurate when measuring people
different estimates of body composition. According to a closer to a healthy BMI, but it was less accurate than DXA/
recent study, clinicians using this method should perform DEXA when it came to measuring lean individuals [41].
two trials and report the average result [35]. Those with low body fat percentages were more likely to get a
 332 S. Ward and D. Noland

higher percent fat reading from the BOD POD®, and people those most commonly used in fitness and are presented below. It
with higher body fat percentages were more likely to see a should be noted that a certain amount of fat is essential for nor-
lower result. Both techniques had smaller discrepancies in mal bodily functions. This is the fat in the bone marrow, heart,
normal weight and overweight individuals. lungs, liver, muscle, and lipid-rich tissues throughout the body,
including cell membrane. Essential fat in females is approxi-
mately 10–13% and in males is 2–5% (. Tables 21.2 and 21.3).
 

21.9.4  edical Imaging – Computed

M Some classifications have been presented that are adjusted
Tomography (CT) and Magnetic for age, since body fat often increases and lean mass decreases
Resonance Imaging (MRI) as part of the aging process. ACSM also offers age-adjusted
norms for body fat percent and are presented in . Table 21.4.  

Computed tomography (CT) scans are capable of estimating Once a person’s body fat has been determined, the clini-
subcutaneous and intra-abdominal fat and compare closely cian can use the following equation to predict a healthy
with direct measurements in cadavers [42]. The disadvan- weight based on body fat percent. This equation assumes that
tages of using CT for assessing body composition include the person’s lean mass remains the same.
high levels of radiation exposure, cost, and limited availabil-
Desired Weight = Current Fat - free Mass in pounds
ity of equipment. Magnetic resonance imaging (MRI) allows
both imaging of the body and in vivo chemical analysis with- / (1- desired % )
out ionizing radiation. It is a valuable tool for assessing
regional fat distribution and muscle mass, but it is a costly Example:
method for health practitioners. Therefore, neither CT or 55 Female with a current percent fat = 31% and body
MRI is practical for everyday body composition assessment. weight of 170 pounds.
55 170 × 0.31 = 52.7 pounds fat mass
55 170–52.7 = 117.3 pounds of fat-free mass
21.9.5 Ultrasound 55 Her desired percent fat is 25% – (1–0.25) = 0.75
55 Add to the equation:
Ultrasound technology is a widely used imaging method and 55 117.3 (current fat-free mass) divided by 0.75 = 156.4
has been studied as a possible tool in nutritional assessment. 55 156.4 would be her desired weight (25%) if her fat-free
It is a low cost, somewhat portable, alternative method for mass remains the same
assessing body composition. In a recent study, when a specific
regression equation was applied, ultrasound showed a strong ..      Table 21.2  ACSM body fat classifications
correlation with DXA/DEXA [31]. Ultrasound can provide a
similar degree of accuracy and reliability when compared ACSM Percent fat
with DXA/DEXA and air displacement plethysmography for
Body type Females (%) Males (%)
tracking group-based body fat changes over time [43, 44].
One advantage of ultrasound is that it can provide informa- Athlete <17 <10
tion about fatty liver disease in obese patients and shows a
Lean 17–22 10–15
high correlation with other markers such as waist circumfer-
ence, trunk fat mass, and intra-abdominal adipose tissue Normal 22–25 15–18
[45]. In addition to assessment of body composition, ultra- Above average 25–29 18–20
sound has also been suggested as a method for visceral fat
Over-fat 29–35 20–25
mass evaluation. Estimates of total body fat based on ultra-
sound will result in higher accuracies when compared with Obese >35 >25
skinfold measurements and bioelectrical impedance [24].
In the sport and athletic setting, ultrasound offers highly
accurate and reliable field measurement essential for protec-
..      Table 21.3  ACE body fat classifications
tion of the athlete’s health and optimizing performance [46].
One study showed the validity of a portable ultrasound ACE Percent fat
device questionable in female athletes, but due to its excellent
21 reliability, practitioners and coaches should consider this Body type Females (%) Males (%)
method for assessing body composition changes [47].
Essential fat 10–13 2–5

Athletes 14–20 6–13

21.10 Classification Based on Percent Fat Fitness 21–24 14–17

Acceptable 25–31 18–25

There are several different systems currently used for classifying
body fat percent. The American College of Sports Medicine Obese >31 >25
(ACSM) and American Council on Exercise (ACE) are among
Body Composition
333 21

..      Table 21.4  ACSM age-adjusted body fat classifications for fitness

Females Age

Fitness category 20–29 30–39 40–49 50–59 60+

Essential fat 10–13 10–13 10–13 10–13 10–13

Excellent 14.5–17 15.5–17.9 18.5–21.2 21.6–24.9 21.1–25

Good 17.1–20.5 18–21.5 21.3–24.8 25–28.4 25.1–29.2

Average 20.6–23.6 21.6–24.8 24.9–28 28.5–31.5 29.3–32.4

Below average 23.7–27.6 24.9–29.2 28.1–32 31.6–35.5 32.5–36.5

Poor >27.7 >29.3 >32.1 >35.6 >36.6

Males Age

Fitness category 20–29 30–39 40–49 50–59 60+

Essential fat 2–5 2–5 2–5 2–5 2–5

Excellent 7.1–9.3 11.3–13.8 13.6–16.2 15.3–17.8 15.3–18.3

Good 9.4–14 13.9–17.4 16.3–19.5 17.9–21.2 18.4–21.9

Average 14.1–17.5 17.5–20.4 19.6–22.4 21.3–24 22–25

Below average 17.6–22.5 20.5–24.1 22.5–26 24.1–27.4 25.1–28.4

Poor >22.6 >24.2 >26.1 >27.5 >28.5

21.11 Conclusion Bod Pod, and Pea Pod that are considered for larger clinics or
hospitals. The clinician should consider cost, ease of mea-
Body composition measurement helps determine excesses or surement, and ability to monitor progress in patients under-
deficiencies of components that relate to health risk. going interventions.
Significant changes in body composition are strongly corre-
lated with the pathophysiology of chronic diseases. The
importance of measuring body composition beyond height References
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6. Witt KA, Bush EA. College athletes with an elevated body mass index
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The field methods of body composition available are
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 335 22

The Therapeutic Ketogenic

Diet: Harnessing Glucose,
Insulin, and Ketone Metabolism
Miriam Kalamian

22.1 The Current Paradigm – 338

22.2 Factors in Choosing an “Ideal” Diet – 338

22.2.1  enetic and Epigenetic Influences – 339
G
22.2.2 The Inflammatory Response – 339
22.2.3 Insulin Resistance Adds Fuel to the Flames – 339
22.2.4 Anticipated Weight Loss – 339
22.2.5 Mitochondrial Health [13] – 340

22.3 Glucose and Insulin – 340

22.4 Ketogenesis – 340

22.4.1 S tep One [20] – 341
22.4.2 Step Two [20] – 341
22.4.3 Step Three – 342
22.4.4 Step Four – 342
22.4.5 Ketogenic Metabolic Pathway – 343

22.5 History of Use in Epilepsy – 343

22.6 Diseases of Insulin Resistance – 344

22.6.1  besity – 344
O
22.6.2 Diabetes – 344
22.6.3 Polycystic Ovary Syndrome – 345

22.7 Cancer – 345

22.7.1 Cancer Cells Are Reliant on Fermentable Fuels – 345

22.8 Neurodegenerative Diseases – 347

22.9 Risk/Benefit Analysis – 348

22.9.1  aseline Laboratory Evaluation – 348
B
22.9.2 Blood Panel – 348
22.9.3 Absolute Contraindications – 348
22.9.4 Relative Contraindications – 349

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_22
22.10 Macronutrient Calculations – 349
22.10.1  rotein Target – 349
P
22.10.2 Carbohydrate – 350
22.10.3 Fats – 350
22.10.4 The Question of Calorie Restriction – 350
22.10.5 Food Trackers and Meal Planners – 351

22.11 Food and Supplement Recommendations – 352

22.11.1 E liminate the Following – 352
22.11.2 Allowed Foods – 352
22.11.3 Diet Supplementation – 353

22.12 Variations of the Ketogenic Diet – 353

22.12.1 A tkins Diet [44, 67] – 354
22.12.2 Modified Atkins Diet – 354

22.13 Diet Ratio – 354

22.14 Diet Macros – 355

22.15 Short-Term Versus Long-Term Maintenance – 355

22.16 Transitioning to a Ketogenic Diet – 356

22.16.1 O ption #1: Fasting – 356
22.16.2 Option #2: A Rigorous Ketogenic Diet – 356
22.16.3 Option #3: A Slow Transition to Ketosis – 356

22.17 Potential Side Effects of the Transition – 357

22.17.1 Hunger and Cravings – 357
22.17.2 “Keto Flu” – 357
22.17.3 Hypoglycemia – 357
22.17.4 Acidosis – 357
22.17.5 Dizzy, Lightheaded, or Shaky – 358
22.17.6 Constipation – 358
22.17.7 Heart Rate or Rhythm Changes, Including Palpitations – 358
22.17.8 Change in Exercise Tolerance or Physical Performance – 358
22.17.9 “Keto Rash” – 358
22.17.10 Increased Risk of Kidney Stones and Gout – 358

22.18 The First Few Weeks: The “Make or Break” Period – 359

22.18.1 T esting Glucose and Ketones – 359
22.18.2 Testing Blood Glucose – 359
22.18.3 Ketone Testing Tools [73] – 360
22.19 Troubleshooting – 360
22.19.1  ngoing Flu-like Symptoms – 360
O
22.19.2 Hunger between Meals – 360
22.19.3 Food Cravings – 360
22.19.4 Unsustainable or Rapid Weight Loss – 361
22.19.5 Spikes in Glucose (a Rise of >25–30mg/dL) with a Meal or Snack – 361
22.19.6 Steroid Medications (e.g., Prednisone, Dexamethasone,
or Hydrocortisone) – 361
22.19.7 Dropping out of Ketosis – 361
22.19.8 Hidden Carbohydrates in Medicines, Supplements,
or Hygiene Products – 361
22.19.9 Nausea or Vomiting – 361
22.19.10 Dissatisfaction with Food Choices – 362
22.19.11 High Blood Glucose Levels – 362

22.20 Conclusion – 362

References – 363
 338 M. Kalamian

Learning Objectives Subsequent to that shift, the majority of tissue with high
1. Name at least two disease-promoting pathways that are energy needs, such as muscle, heart, and most brain tissue,
downregulated through implementation of a therapeutic will preferentially take up ketone bodies. During starvation
ketogenic diet. or with adherence to a ketogenic diet, ketone bodies are pro-
2. Describe the steps that characterize the metabolic shift to duced in sufficient amounts to easily meet more than 60% of
ketosis. the energy needs of the brain and CNS.  This amount was
3. Describe the rationale for use of a therapeutic ketogenic determined by a rigorous human fasting study conducted by
diet for expanded applications including (1) diseases of Dr. George Cahill and colleagues, published in 1967 in the
insulin resistance, (2) cancer, and (3) neurodegenerative Journal of Clinical Investigation [2]. Unfortunately, most
disease. conventional nutrition texts either imply or implicitly state
4. Know what demographic and health history information that the presence of more than trace amounts of ketone bod-
must be included in order to begin a risk/benefit analysis. ies reflects an invariably aberrant and potentially dangerous
5. Describe the calculations needed to develop an individu- metabolic state. This fails to acknowledge the science sup-
alized macronutrient prescription for a therapeutic keto- porting nearly a century of use of a therapeutic ketogenic
genic diet. diet as a medical nutritional therapy for epilepsy [3, 4].
The DRIs for glucose have been superseded by another
set of government guidelines from the Food and Nutrition
22.1  The Current Paradigm Board: the Acceptable Macronutrient Distribution Range
(AMDR). The AMDR recommends that carbohydrate-­
There is a pervasive belief that glucose is the optimal source containing foods make up 45–65% of total calories [5]: In a
of energy for the brain and central nervous system. However, 2000 calorie-per-day plan, that percentage translates to an
the reliance on glucose to meet brain and central nervous intake of 225–325 grams of carbohydrate, an amount far
system (CNS) energy requirements is only true if the intake greater than the DRI. As previously noted, this recommenda-
of dietary carbohydrates is sufficiently high to keep homeo- tion is not due to the need for carbohydrate as an essential
static control of glucose dependent on the opposing actions nutrient. Instead, it exists based on its role as a source of kilo-
of the hormones insulin and glucagon. When glucose avail- calories to maintain body weight [6]. In fact, science makes
ability is low—as it is during fasts or very-low-carbohydrate clear that there is no requirement for dietary glucose even in
diets—cerebral energy metabolism shifts to the efficient utili- populations with extremely high energy needs, such as ultra-
zation of ketone bodies. This makes evolutionary sense given athletes. A recent paper illustrates this point by stating: “less
the frequent disruption of the food supply that has marked appreciated is the perspective that there is no essential
most of human history prior to the transition from hunter-­ requirement for dietary carbohydrate because humans
gatherer to agrarian societies. possess a robust capacity to adapt to low carbohydrate
­
The brain and CNS of most adults requires the energy ­availability” [7].
equivalent of 130 g of carbohydrate per day. In a standard
diet, it is assumed that this need will be met through the
Key Point: Unlike Fat or Protein, Dietary Intake of
dietary intake of carbohydrates without considering the
Glucose Is Not Essential to Human Life
potential of ketone bodies as an energy source. This absolute
In the absence of sufficient dietary intake, glucose homeo-
requirement, designated as the Recommended Dietary
stasis is maintained at normal physiological levels primarily
Allowance (RDA), has been incorporated into a set of gov-
through gluconeogenesis: Glycerol backbones stripped
ernment guidelines known as Dietary Reference Intakes
from triglycerides as part of fatty acid oxidation become
(DRIs) [1]. However, signs are appearing that government
the major substrate with contributions from amino acid
nutrition authorities are beginning to recognize that essential
and the recycling of lactate through the Cori cycle.
glucose energy is still available during ketosis:
»» Diets contain a combination of carbohydrate, fat, and
protein, and therefore available glucose is not limiting to
22.2  Factors in Choosing an “Ideal” Diet
the brain unless carbohydrate energy intake is
insufficient to meet the glucose needs of the brain.
The ideal diet is one that ensures adequate nutrition, lowers
Nevertheless, it should be recognized that the brain can
inflammation, improves insulin sensitivity, and normalizes
still receive enough glucose from the metabolism of the
body weight. It must be sustainable long-term and flexible
glycerol component of fat and from the gluconeogenic
enough to accommodate food allergies, aversions, and intol-
22 amino acids in protein when a very low carbohydrate
erances. It must accommodate the fact that religious, cul-
diet is consumed [1].
tural, and personally held beliefs, such as the philosophical
This statement acknowledges the physiological fact that decision to avoid all animal products, will influence food
very-low-carbohydrate diets will shift metabolism away choices. Beyond the basics, though, there is no consensus as
from reliance on glucose obtained from exogenous sources. to what constitutes the ideal diet.
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
339 22
22.2.1  Genetic and Epigenetic Influences 22.2.2  The Inflammatory Response

Genetic variants can alter an individual’s response to foods, The production of inflammatory cytokines is an essential
even to those that are generally regarded as healthy. Traits component of the immune response, but prolonged overpro-
such as lactose intolerance or glucose-6-phosphate dehydro- duction of these proteins may result from repeated exposure
genase (G6PD) deficiency require the avoidance of certain to antigens [8]. Inflammatory cytokines are also secreted by
foods or beverages. For example, the diet for an individual insulin-resistant adipose tissue. This is increasingly being
with lactose intolerance would limit milk and a diet for an shown to play a critical role in obesity-related insulin resis-
individual with G6PD would exclude fava beans, sulfites, and tance, and it wreaks havoc in the form of chronic inflamma-
quinine. tion, a prime driver in many diseases. Chronic inflammation
Changes in gene expression also arise from epigenetic at any site damages cell membranes and DNA while simulta-
influences. Interactions of genes with the environment may neously altering normal cell molecular signaling and repair
include but are not limited to those induced by environ- mechanisms. The presence of ketone bodies lowers the levels
mental toxins (lead, smoke, radon, pesticides), lifestyle of some of these cytokines. [9].
impacts (night shift work, poor sleep hygiene, food
choices), and psychological stressors (chronic disease,
unrelenting stress). Complexity increases when age, gen- 22.2.3  Insulin Resistance Adds Fuel
der, nutritional insufficiencies, and comorbidities are fac-
to the Flames
tored into the situation. As a result, primary prevention
might dictate one set of rules while tertiary care demands
In individuals consuming a standard diet (with carbohydrate
another.
intake of 45–65% of total calories) each meal or snack results
Consuming certain foods can alter gene expression. The
in a significant rise in serum glucose, which in turn stimu-
constituents in a food can turn on or turn off the signaling
lates beta cells in the pancreas to secrete insulin. Over time, a
responsible for controlling vital activities at the cellular
persistent pattern of frequent spikes in glucose and insulin is
level. Research in the field of nutrigenomics is illuminating
likely to result in some degree of insulin resistance. Insulin
the impact of micronutrients and other food constituents
receptors become less responsive to insulin signaling so high
while inquiry into the impact of dietary manipulation of
levels of glucose remain in circulation for a longer period of
macronutrients arises primarily from the study of biochem-
time. High fasting blood glucose is one of the markers used
istry and physiology. One example is the abundance of
to diagnose diseases of insulin resistance, including predia-
research on the role of protein and constituent amino acids
betes, type 2 diabetes, and polycystic ovary syndrome. Insulin
in regulating cellular pathways such as the mammalian (or
resistance is also associated with obesity, which is a risk fac-
mechanistic) target of rapamycin (mTOR) (see below). In
tor in certain cancers, including (but not limited to) cancers
muscle, the presence of abundant amino acids (particularly
of the breast, prostate, and colon. More recently, insulin resis-
branched-­chain amino acids) generally signals muscle tissue
tance has also been identified as a risk factor in Alzheimer’s
to increase anabolic activities that stimulate the accretion of
disease [10–12].
muscle mass which is considered highly valuable. However,
those same signals are also known to stimulate growth and
proliferation in cancer cells characterized by upregulated
mTOR activity. Changes in protein intake and meal timing 22.2.4  Anticipated Weight Loss
are known to downregulate this activity but conventional
cancer researchers remain focused on the development of Weight loss is one of the most widely documented side
drugs intended to inhibit this pathway. Unfortunately, these effects of a ketogenic diet. Obviously, this is not always desir-
drug therapies, such as rapamycin, all have dire downstream able, especially for individuals who are malnourished,
effects. already below a desirable weight, or have health issues (such
It is understandable that the role of epigenetic influences as bowel disease or advanced cancer) that place them at high
in disease states is often overlooked as it involves the accu- risk for sarcopenia or cachexia. Although weight stabiliza-
mulation of numerous small changes occurring over years tion is often possible, weight gain on a ketogenic diet may be
or even decades. Yet it is increasingly clear that these difficult to accomplish unless the individual can promote
changes eventually tip the scales, causing an imbalance in muscle mass accretion through resistance training. There is
the system that manifests as disease. This appears to be the also speculation that weight gain may interfere with the
case with insulin resistance, cancer, and neurological dis- therapeutic impact of the diet in cancer. Accommodating
ease. As noted earlier, the interaction of genes with the envi- medical conditions like these underscore the need for
ronment is complex and multifactorial, which makes it trained nutrition and health professionals that can individu-
exceedingly difficult to isolate which factors exert the most alize the plan and closely monitor the impact of any nutri-
influence. tional intervention.
 340 M. Kalamian

22.2.5  Mitochondrial Health [13] facilitates the movement of glucose across the cell membrane.
GLUT4 is highly concentrated in muscle, cardiac, and adi-
Structurally and functionally healthy mitochondria are pose tissue, allowing for rapid uptake of glucose. However,
essential to maintaining health throughout the lifespan. It is persistently high levels of circulating insulin are known to
increasingly clear that mitochondrial health for most indi- contribute to insulin resistance of these tissues. Exercise can
viduals is determined by more than the genetic code handed improve insulin sensitivity and transport of glucose through
down at birth—instead, it is strongly influenced by epigenetic cell membranes thus reducing the amount of insulin needed.
changes, including those related to the type and timing of Glucose transporter 5 (GLUT5) is specific to fructose rather
food intake. Changes in the gut microbiome, in part altered than glucose and is active in skeletal muscle [16].
by food choices, can also influence how genes interact with Insulin is essential to human life [17]. Individuals who
the environment. There is an urgent need to discover new experience acute destruction of pancreatic beta cells, through
ways to push back against the rising tide of metabolic dis- an autoimmune reaction or potentially through certain
eases. Ketogenic metabolic therapy [14] offers great potential enteroviral infections, lose the ability to produce insulin and
here as an adjunct to the current standard of care, even in quickly progress to type 1 diabetes (formerly referred to as
treatment-resistant diseases, such as glioblastoma multi- “juvenile-onset diabetes”). Before Frederick Banting’s discov-
forme. Moving forward, it is essential that effective preven- ery of insulin in the 1920s, type 1 diabetes was inevitably
tion strategies incorporate sound nutrition science. fatal. In contrast, type 2 diabetes is most often characterized
by prolonged high levels of circulating glucose and insulin
due to insulin resistance, primarily in muscle, adipose, and
22.3  Glucose and Insulin liver tissue. This inability to move glucose into cells stimu-
lates secretion of glucagon (insulin’s counterregulatory hor-
Glucose is essential to human life and biology has developed mone) from alpha cells in the pancreas. Glucagon has several
a plethora of mechanisms to facilitate the movement of glu- actions, including mobilization of glycogen (glycogenolysis),
cose from the bloodstream into cells. Once inside the cyto- further compounding the problems associated with high
plasm of the cell, each glucose molecule is split into two blood glucose levels. In type 2 diabetes, beta cell function can
molecules of pyruvate in a process known as glycolysis. In also deteriorate over time as a result of a disease process that
normal cells, most of the pyruvate then crosses the mito- allows amyloid plaques to accumulate in pancreatic islets.
chondrial membrane where it is oxidized to generate energy Damage to cellular structure and metabolic function
within the Krebs cycle and electron transport chain. results in further dysregulation of regulatory and counterregu-
Glycolysis also converts nicotinamide adenine dinucleotide latory hormones that impact metabolism including (but not
(NAD) to its reduced form, NADH, a coenzyme needed to limited to) glucose homeostasis, fatty acid oxidation, and keto-
facilitate mitochondrial activities. genesis. Although the mechanisms for these degenerative
When blood glucose levels rise, beta cells in the pancreas changes are multifactorial, the expression of these genes can be
secrete insulin, which in turn facilitates the movement of glu- altered by lifestyle changes that serve to improve insulin sensi-
cose across cell membranes through membrane-embedded tivity, such as physical activity. It is now increasingly evident
protein transporters. Interestingly, changes at the cellular that the adoption of very-low-carbohydrate dietary patterns
level, including alterations in genetic expression, can alter the can also improve insulin sensitivity and glucose homeostasis
number of embedded glucose transporters as well as the while significantly reducing the need for drugs and insulin.
amount of glucose that is oxidized relative to the amount that Insulin also plays a role in cellular signaling though this is
is fermented. Most of these transporters are insulin-­ complex and still poorly understood. That said, it is well-­
independent, though some of their signaling may be acti- documented [18] that high carbohydrate intake and the asso-
vated through insulin-sensing pathways. Glucose transporter ciated rise in insulin initiates lipogenesis in liver and adipose
1 (GLUT1), present in most cells and highly expressed in tissue. These newly synthesized fatty acids are then converted
glucose-hungry erythrocytes and endothelial cells of the into triglycerides for transport and storage. Upregulation of
blood–brain barrier, allows insulin-independent facilitated this activity is known to contribute to a number of metabolic
diffusion across cell membranes based on the concentration diseases [19], including obesity, hepatic steatosis, diabetes,
gradient. Glucose transporter 2 (GLUT2) is highly expressed cardiovascular diseases, and the cluster of symptoms com-
in hepatic tissue as well as intestine, kidney, and pancreatic prising metabolic syndrome.
islet beta cells, where it acts as a glucose sensor to stimulate
insulin secretion. It is also expressed in neurons and astro-
cytes. Glucose transporter 3 (GLUT3), another insulin-­ 22.4  Ketogenesis
22 independent transporter, is essential to the movement of
glucose into neurons [15]. Ketogenesis involves the biosynthesis of small energy mole-
The presence of insulin, sensed through insulin receptors cules that can then be utilized alongside (or in place of) glu-
embedded in cell membranes, also stimulates the transloca- cose, fatty acids, and amino acids. Ketogenesis is a normal
tion of glucose transporter 4 (GLUT4) from cellular vesicles and natural adaptation that ensures a continuous supply of
within the cytoplasm to the surface of the cell, which in turn metabolic fuels during periods of limited food availability or
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
341 22

o o H H H H H H H H H
CoA + CoA 2 Acetyl-CoA O
H3C S H3C S H C C C C C C C C C C H
H C O
H H H H H H H H H
Thiolase
CoA-SH H H H H H H H H H
O
o o C C C C C C C C C C H
CoA Acetoacetyl-CoA
H3C S H C O
H H H H H H H H H
Acetyl-CoA
HMG-CoA synthase
CoA-SH H H H H H H
O H
OH CH3 O C C C C C C C C H
β-hydroxy-β-methylglutaryl- H
CoA H C O C
O S CoA H H H H H
OH
H C
(HMG-CoA) H H
H
HMG-CoA lyase
Acetyl-CoA

O O ..      Fig. 22.2  Schematic of triglyceride ester. (Reprinted from Bayly

Acetoacetate
H3C O–
[22]. With permission from Elsevier)
NADH + H+
Non-enzymatic D-β-hydroxybutyrate
decarboxylation NAD+ dehydrogenase
22.4.2  Step Two [20]
CO2
O OH O Depletion of liver glycogen stores, typically within
H3C CH3 O– 18–24 hours, upregulates gluconeogenic activity, primarily in
Acetone D-β-hydroxybutyrate hepatocytes but also in renal cortex. This endogenous pro-
duction of glucose replaces dietary intake as the major con-
tributor to blood glucose during periods of starvation or low
..      Fig. 22.1  Ketogenesis pathway [21]. The three ketone bodies carbohydrate intake. During the transition, low blood glu-
(acetoacetate, acetone, and beta-hydroxy-butyrate) are marked within cose levels also stimulate the production of steroid hormones
an orange box. (Reprinted with permission from 7 https://en.­
(primarily adrenaline and norepinephrine) which stimulate
 

wikipedia.­org/wiki/File:Ketogenesis.­svg)
an increase in gluconeogenic activity, thereby restoring glu-
cose levels to physiological norms. Starvation and fasting are
even frank starvation. However, the metabolic shift to ketosis
potent initiators but on a smaller scale, gluconeogenesis
is also possible in a well-fed state that limits carbohydrate
occurs many times throughout the day and during the over-
intake. The shift from a standard diet begins with either a
night fast, effectively maintaining glucose homeostasis.
short fast or a rigorous restriction in carbohydrate intake.
Depending on availability at any given time, lactate, amino
The change in energy substrates from “glucocentric” to “adi-
acids, and the glycerol backbones from triglycerides can all
pocentric” involves a series of predictable metabolic changes
be used in the endogenous production of glucose.
that accompany the adoption of a ketogenic dietary pattern
[20] (. Fig. 22.1).
 
22.4.2.1  Simple Schematic of a Triglyceride
Ester (. Fig. 22.2)
 

22.4.1  Step One [20]

A Closer Look at Gluconeogenesis
Carbohydrate restriction results in a drop in blood glucose Most textbook descriptions of the shift to ketosis point
levels which in turn reduces insulin secretion. Low glucose to muscle mass degradation as the main source of the
levels also stimulate the secretion of the hormone, glucagon, amino acids used in gluconeogenesis during fasting or
which stimulates glycogenolysis; specifically, the breakdown starvation. The amount of degradation has been quanti-
of glucose stored in the liver as glycogen which in turn liber- fied and, in total starvation, an estimate can predict how
ates approximately 100 g (400 calories) of stored glucose. long an individual can survive based solely on body fat
Glucose is also stored as glycogen in muscle tissue. Muscle stores. However, muscle mass degradation does not con-
glycogen consists of an additional 400–500 g of glucose tinue at that same unsustainable rate when dietary
(1600–2000 calories) but it can only be utilized by the muscle intake of fats and protein replace carbohydrates in a
tissue in which it is stored. In essence, muscle glycogen serves ketogenic fed state. In fact, the science suggests that
as reserve fuel for muscle which is crucial during activities ketone bodies spare both glucose and protein [23]. Fol-
that require a burst of energy, such as sprinting.
 342 M. Kalamian

lowing a few days of carbohydrate restriction, gluconeo- for example, many cancer cells are unable to upregulate
genesis shifts away from reliance on amino acids production of key ketolytic enzymes, one of the
obtained from muscle and instead uses the abundant ­characteristics that allow them to be targeted through a
supply of glycerol backbones stripped from triglycerides change in diet.)
(described in step 3 of this shift to ketosis). Limiting the
discussion to fasting or starvation points to a poor
understanding of the adaptations that occur in a very-
22.4.4  Step Four
low-carbohydrate (ketogenic) fed state.

There are limitations in the utilization of longer chain fatty

acids as a source of metabolic fuel for the brain and central
22.4.3  Step Three
nervous system: that is, they cannot cross the BBB, the semi-­
permeable protective interface of highly specialized endothe-
By itself, gluconeogenic activity cannot continue to meet the
lial cells with uniquely tight junctions that line the blood
energy needs of the system as this would be dependent on the
vessels leading to the brain. Fatty acids also cannot be utilized
unsustainable breakdown of lean body tissue. With contin-
by cells that lack mitochondria, such as mature red blood
ued low carbohydrate intake, even in a fed state, fatty acid
cells and lens tissue. For most other tissue, an evolutionary
oxidation is upregulated, flipping the metabolic switch to
adaptation fills the energy gap through the conversion of
reliance on energy stored as triglycerides in adipose tissue or
fatty acids to ketone bodies [28]; small water-soluble energy
provided through diet.
molecules that are biosynthesized primarily in hepatocytes
Lipases strip the backbone from triglycerides, releasing
and, to a lesser degree, the renal cortex. Certain amino acids
free fatty acids into the bloodstream where they are carried
can also be converted to ketone bodies. These include L-lysine
throughout most of the body. Exception: most long-chain
and L-leucine, which are exclusively ketogenic, along with
fatty acids cannot cross the blood–brain barrier (BBB). In a
five others that are conditionally ketogenic.
resting state [24], heart and skeletal muscle prefer fatty acids
Ketone bodies are preferentially taken up by heart and
over glucose: “Unlike skeletal muscle, heart muscle functions
muscle tissue but even more important, they readily cross the
almost exclusively aerobically, as evidenced by the density of
BBB, serving as the only metabolic fuel other than glucose
mitochondria in heart muscle. Moreover, the heart has virtu-
that can meet the high energy needs of normal brain and cen-
ally no glycogen reserves. Fatty acids are the heart’s main
tral nervous system tissue [29]. This shift to adipocentric fuels
source of fuel, although ketone bodies as well as lactate can
plays a critical role in mitochondrial energy metabolism by
serve as fuel for heart muscle. In fact, heart muscle consumes
reducing the demand for both glucose and protein during
acetoacetate in preference to glucose.” All but the most com-
periods of fasting, starvation, or very low carbohydrate intake.
promised individuals maintain fat stores that are adequate
enough to survive for weeks or months during periods of
total starvation [25, 26]. Glycerol released in this process is Is Ketosis Safe?
diverted to the liver and renal cortex where it is used primar- The level of ketosis achieved through adherence to a
ily as a substrate for gluconeogenesis. therapeutic ketogenic diet represents a normal and
desirable adaptation to low availability of dietary carbo-
Analogy to a Hybrid Engine hydrates. In contrast, dangerously high blood levels of
It is easy to lose sight of the fact that humans have his- ketone bodies seen in diabetic and alcoholic ketoacido-
torically experienced frequent disruptions in food sup- sis are the result of a metabolic derangement that is not
ply. In modern times and in affluent nations that shortfall associated with the change in diet. Differential charac-
has been reduced to a narrow window of time, usually teristics are described in the section on side effects.
limited to a few hours between meals or overnight.
“Hybrid engine” is often used as a metaphor in
describing the flexibility of evolutionary adaptations that Mitochondria in hepatocytes lack the enzyme needed to uti-
ensure utilization of energy reserves. Normal cells and lize ketone bodies [30]; therefore, virtually all of the ketones
tissue function like tiny hybrid engines maintaining the produced there are exported into the bloodstream for distri-
metabolic flexibility that allows for a seamless integra- bution throughout the body. As ketone bodies enter circula-
tion of fuels from a variety of sources. In that context, it tion, they are immediately taken up and utilized for energy
22 makes sense that a shortage of dietary carbohydrate by most normal cells that contain mitochondria. Most
would require both the endogenous production of new importantly, due to their size and solubility, ketone bodies
glucose and the breakdown of stored fats into free fatty readily cross the BBB, providing up to two-thirds [31] of the
acids and ketone bodies. (Accumulated mutations in brain’s ongoing energy needs. This represents roughly 20% of
cancer cells render them less metabolically flexible [27]; the body’s total energy needs. In a ketogenic diet, endoge-
nous ketone production relies on dietary intake of fats as well
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
343 22
energy needs of tissues and organs. Conventional nutri-
Fatty acids tion textbooks include information on ketone metabolism
but it is most often presented as a temporary state with the
sole purpose of providing energy during periods of starva-
tion. Another limitation of such descriptions is that they
typically blur the distinction between the physiologically
Acetyl CoA normal levels of ketones that result from intentional
dietary manipulation and the pathologically high levels of
ketones seen in aberrant metabolic conditions such as
H alcoholic or diabetic ketoacidosis [7]. This does not
CH3
acknowledge the unique nature of the ketogenic pathway:
HO C CH3 O C CH3
that is, as a stunningly sophisticated adaptation not only to
CH2 CH2 O C periods of prolonged fasting or frank starvation but also to
the voluntary restriction of carbohydrate intake that is
COO– COO– CH3 adopted as part of a ketogenic diet or other very-low-car-
3-β-Hdroxybutyrate Acetoacetate Acetone bohydrate pattern [7].
Utilization of newly synthesized ketone bodies begins as
soon as they enter the bloodstream. Beta-hydroxybutyrate
..      Fig. 22.3  Ketone bodies. (Reprinted from Laffel [31]. With and acetoacetate pass from the bloodstream into the cyto-
permission from John Wiley & Sons, Inc.) plasm of cells via monocarboxylate transporters. These same
transporters also allow passage of pyruvate and lactate (which
as robust lipolysis of triglycerides stored in adipose tissue. are also monocarboxylates). From the cytoplasm, ketone
There are three types of ketone bodies [31]: bodies then pass through the mitochondrial membranes
55 Acetoacetate is preferentially taken up by muscle tissue and where they are oxidized for energy [29, 35], generating less
oxidized as energy. The brain also uses acetoacetate for reactive oxygen species (ROS) than either glucose or fatty
energy [32, 33]. With keto-adaptation, most acetoacetate is acid metabolism. Next, a sustained rise in serum ketone lev-
converted (reduced) to D-beta-hydroxybutyrate, primarily els drives the upregulation of ketolytic enzymes which serve
by liver and muscle tissue, and returned to circulation. to oxidize ketone bodies within the mitochondria of nor-
55 D-beta-hydroxybutyrate (D-βHB) is initially produced in mally functioning cells.
almost equal proportions as acetoacetate. As the body In a standard diet, carbohydrate intake makes up more
adapts to ketosis, interconversion of acetoacetate favors than half of total calories, much of that coming from grains,
the production of D-βHB, a preferred fuel for heart, starches, and added sugars. In contrast, a classic ketogenic
muscle, and brain tissue. diet limits carbohydrate to an average of 6% of total calories
55 Acetone is usually produced from the spontaneous [36, 37]. With protein kept low (but adequate in meeting the
breakdown of acetoacetate. Only a small amount of body’s needs), the amount of fat in the diet can rise to over
acetone undergoes reactions that allow it to be used for 80% of calories [20, 37].
energy. Most of it is simply eliminated from the body as
fruity smelling “keto breath” (. Fig. 22.3).
 

22.5  History of Use in Epilepsy

Nutritional ketosis is defined as a metabolic state in which The ketogenic diet has a century-long history of use as a
beta-hydroxybutyrate (βHB) is present in the blood at a dietary therapy for intractable epilepsy. By the start of the
level between 0.5 and 5.0 mmol/L [29, 34]. This repre- twenty-first century, it had passed through the clinic trial
sents the body’s normal physiological response to a very-­ process, which led to greater acceptance as an evidence-­
low-­carbohydrate diet. If levels drop below this based treatment [36–38]. There is general consensus on the
threshold, people are no longer in a ketogenic state. Lev- initiation protocol for the classic ketogenic diet and nearly
els above 5.0 mmol/L are not usually seen in adults on 100 hospitals in the United States [37, 39] alone are staffed
standard diets except during fasting, intense exercise, or with professionals, including neurologists, epileptologists,
with exogenous ketone supplementation. and registered dietitians that are trained in diet implemen-
tation and support. However, significant barriers to
resources remain as most of the centers are concentrated in
22.4.5  Ketogenic Metabolic Pathway urban areas, leaving large regions of the country, including
the states of Alaska and Hawaii, without access to clinical
Adaptation to starvation, fasting, or a diet very low in car- services.
bohydrates involves the upregulation of activity in the Liberalized forms of the diet have emerged, including:
ketogenic metabolic pathway in order to meet the specific 1. Modified Atkins (no tracking of protein or fats)
 344 M. Kalamian

22.6.1  Obesity
..      Table 22.1  Macronutrients as a percentage of total daily
calories in a eucaloric ketogenic diet
The bias against ketogenic diet therapy in obesity medicine
Fat Protein Carbohydrate continues despite research showing a clear advantage for
(%) (%) (%) low-carbohydrate patterns in weight loss. In a 2007 paper
Standard diet (AMDR) 20–35 10–35 45–65
published in the Journal of the American Medical Association,
a randomized trial known as “The A to Z Weight Loss Study”
Ketogenic diet (rigorous 78–86 8–12 2–10 tested four dietary and lifestyle interventions: Atkins (“induc-
to moderate)
tion” at 20 g carbohydrate per day for several months then an
Based on data from Ref. [42] “ongoing weight loss” phase at 50 g/day), LEARN (standard
These percentages represent a typical range—individual guidelines plus lifestyle recommendations), Ornish (10% fat/
patterns may vary low-protein/very-high-carbohydrate and primarily plant-­
based), and Zone (40% carbohydrate/30% protein/30% fat)
[44]. At 2 and 6 months, weight loss was significantly greater,
2. Modified ketogenic diet (lower ratio of fat to carbohy- and, at the endpoint of 12 months, weight loss was still great-
drate/protein) est in the Atkins group. The authors also assessed other bio-
3. Low glycemic index diet (includes limited portions of markers of health, including those assumed to be negatively
carbohydrates, such as bread and pasta, with a GI index impacted by a very-low-carbohydrate diet, and the findings
of <50) did not confirm this bias:
4. Medium-chain triglyceride (MCT) oil diet (allows
greater portions of vegetables, berries, and protein given »» Many concerns have been expressed that
that ketosis is enhanced by the inclusion of ketogenic low-­carbohydrate weight-loss diets, high in total and
MCT oil) [34, 40] saturated fat, will adversely affect blood lipid levels and
cardiovascular risk. These concerns have not been
Although the level of ketosis is not as robust with liberalized substantiated in recent weight-loss diet trials. The recent
versions as it is with the classic ketogenic diet, long-term trials, like the current study, have consistently reported
adherence may be more realistic, especially in adolescents and that triglycerides, HDL-C, blood pressure, and measures
adults. The ratio of fat grams to carbohydrate/protein grams is of insulin resistance either were not significantly
lower in modified versions, thus reducing the number of calo- different or were more favorable for the very-­low-­
ries needed from fat [41]. Another benefit to liberalized plans carbohydrate groups. [44]
is that diet initiation is usually more gradual, reducing the Given the rising tide of obesity and an increase in obesity-­
incidence and severity of adverse effects such as nausea, hypo- linked comorbidities, there is an urgent need to act on the
glycemia, or mild metabolic acidosis that are commonly seen evidence that supports a sea change in obesity medicine
in patients who begin the diet with a fast. In fact, most adult guidelines and practice. Well-formulated and nutritionally
patients who opt for less rigorous versions are not routinely complete ketogenic diets, together with education and sup-
hospitalized at initiation which in turn has greater appeal to port provided by clinicians trained in proper implementa-
professionals, families, and insurers (. Table 22.1).
 
tion, are essential to moving ketogenic diets forward as the
As noted, the ketogenic diet has nearly a century of use as a preferred nutritional approach to obesity treatment. This
medical dietary therapy. There has recently been a surge in could include private models (i.e., corporate wellness pro-
research assessing the downstream metabolic effects of ketosis grams) as well as traditional reimbursement schedules
at both the system and cellular level, and a corresponding through private insurers.
surge of interest in widespread implementation of the diet as
an adjuvant or stand-alone treatment for a variety of seemingly
unrelated diseases. Further progress in exploring the diet’s 22.6.2  Diabetes
potential will most likely arise from the demand for nutritional
therapy from an informed and empowered public. Low carbohydrate and ketogenic diets have experienced a
recent resurgence as the preferred dietary pattern for individu-
als with diabetes. In fact, the evidence from decades of research
22.6  Diseases of Insulin Resistance is so strong that it has prompted a group of obesity medicine
researchers and clinicians to unequivocally support “the use of
Recent results from both preclinical and clinical research low-carbohydrate diets as the first approach to treating type 2
22 provide evidence to support prior speculation that diseases diabetes and as the most effective adjunct to pharmacology in
of insulin resistance can be successfully treated using keto- type 1,” even taking this a step further to state that “the burden
genic diet therapy [43–46]. Despite mounting evidence, the of proof rests with those who are opposed” [45].
majority of practitioners in the conventional medical and Results of a 10-week interventional trial aimed at reducing
nutrition communities still view ketogenic diets as a fad, hemoglobin A1c level, medication use, and weight in individ-
often labeling them as “too extreme” or “dangerous.” uals with type 2 diabetes [46]. In this study, researchers com-
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
345 22
pared an onsite program with remote means using an online
platform to deliver a comprehensive intervention that included Dr. Otto Warburg: Nobel Laureate
a ketogenic diet, behavioral counseling, digital coaching, and Otto Warburg was a prominent German biochemist of
physician-guided medication management. Results from both the early twentieth century with a special interest in
groups (totaling 238 participants) who completed the study the metabolism of cancer cells. His famous observa-
included a 1% reduction from baseline in HbA1c, mean body tion, now known as the Warburg effect, was that can-
mass reduction of 7.2%, and a reduction in the number and/or cer cells increase their rate of glycolysis even in the
dosage of diabetes medications in the majority of participants. presence of oxygen. Dr. Seyfried sums it up this way:
What is intriguing here is that these results support the devel- Warburg’s theory was based on his findings that all
opment of medically supervised programs that utilize digital cancer cells have some defect in their ability to use
coaching to expand the implementation of ketogenic diet oxygen to obtain energy through mitochondrial respi-
therapy beyond the geographical limitations imposed by reli- ration. As a result, cancer cells relied more on fermen-
ance on traditional brick-and-mortar clinics. tation than on respiration to obtain energy in order to
compensate for their defective respiration. The reliance
on fermentation even in the presence of sufficient oxy-
22.6.3  Polycystic Ovary Syndrome gen was referred to as the Warburg effect. [50]

Potential therapeutic applications of ketogenic diets include

polycystic ovary syndrome (PCOS). This is understandable
given the high prevalence of insulin resistance in this popula- In a review published in the journal Nutrition and Metabo-
tion (65–70% of all women with PCOS, rising to 70–80% of lism, Seyfried and Mukherjee presented a strong case in sup-
obese women with this disease). The authors of a review in port of Warburg’s central theory that cancer is the downstream
the European Journal of Clinical Nutrition stated that “although effect of damage to mitochondria [51]. They also describe the
we have only preliminary evidence…there are clear mecha- mechanism by which ROS from damaged respiration could
nisms that are consistent with the physiological plausibility of produce mutations in the nucleus. Put simply, inefficiencies
such dietary therapy” [47]. The preliminary evidence referred in cellular energy metabolism can be compensated for by an
to in this review included results of a pilot study of five obese increase in glucose fermentation and, if left unchecked, ulti-
or overweight women with PCOS who completed a 6-month mately transforms a normal cell into a cancer cell [51]. This
trial of a low-carbohydrate (20 g/day) ketogenic diet. When line of reasoning suggests that cancer is primarily a mito-
compared to baseline, there was a 54% reduction in fasting chondrial metabolic disease that can be targeted with thera-
insulin levels [48] with improvements in other markers of the pies, including ketogenic diet, that exploit this vulnerability.
disease as well. (Of note, two of the women became pregnant At the same time, Seyfried and Mukherjee also reiterated a
during this study despite a prior history of infertility.) fact well-known in cancer research and practice: namely, that
the amino acid glutamine is another primary source of fuel
that drives cancer progression.
22.7  Cancer Fermentation is a primitive process that meets bacteria’s
simple needs for energy. In humans, fermentation by itself
There is mounting preclinical evidence to support the use of usually contributes relatively little to overall energy produc-
a ketogenic diet as an adjunct in cancer treatment [49–51]. tion. That said, all cells ferment a small percentage of pyru-
Clinical trials are currently investigating the effects of com- vate, but the rate of glycolysis in cancer cells is typically 10–15
bining diet therapy with standard of care. Unfortunately, times the rate in a normal cell [52]. For this switch in the fate
most of these clinical studies are underpowered and poorly of glucose to occur, cells must also upregulate activities that
funded. allow more glucose to enter the cancer cell. This is accom-
plished through an increase in the number of glucose trans-
porters and insulin receptors on the cell’s surface.
22.7.1  Cancer Cells Are Reliant Fermentation produces lactic acid which, in large amounts, is
on Fermentable Fuels toxic to cells, so there are mechanisms in place in all cells to
quickly shunt lactic acid to the microenvironment. This
In 2005, biologist Dr. Thomas Seyfried and his colleague Dr. increased acidity in the microenvironment of cancer cells
Purna Mukherjee were leaders in reexamining a characteris- increases inflammation, which in turn facilitates both local
tic of most cancer cells: That is, to produce energy, they pref- progression and metastatic spread of the disease.
erentially ferment glucose in the cell’s cytoplasm even when Fermentation also results in many more ROS molecules
there is sufficient oxygen to support energy generation using which inflict further damage to already dysfunctional mito-
the more efficient mitochondrial pathway. This particular chondria leading to even more cellular disruption and dis-
characteristic of cancer is known as the “Warburg effect” ease progression. This effect of ROS is not specific to cancer
[49], named after German biochemist and Nobel laureate but instead is relevant in a wide array of other chronic and
Otto Warburg. degenerative conditions.
 346 M. Kalamian

Ketogenic diets also dampen spikes in glucose [53]. This cells, making IGF-1 a target of many cancer drugs. Ketogenic
not only reduces insulin levels but also lowers levels of an diets that are calculated to meet but not exceed protein
associated hormone, insulin-like growth factor 1 (IGF-1). requirements may influence epigenetic changes that lead to
IGF-1 and its cell receptor, IGF-1R, are upregulated in cancer the downregulation of activity in the mTOR pathway [54, 55].
and both can drive disease progression. In fact, activity in this This is significant given that upregulated mTOR in cancer is
pathway can be two to three times greater than in normal associated with disease progression (. Figs. 22.4 and 22.5).
 

Stress

Amino acids Energy levels

Oxygen Growth factors

Rapamycin mTORC1 mTORC2

Macromolecule Metabolism Cell survival

biosynthesis
Autophagy Growth Cytoskeletal
Cell cycle organization
progression

mTORC1 mTORC2

mTOR Serine/threonine kinase mTOR Serine/threonine kinase

raptor Scaffold protein regulating the assembly, raptor Scaffold protein regulating the assembly
localization, and substrate binding of mTORC1 and substrate binding of mTORC2

pras40 mTORC1 inhibitor mSin1 Scaffold protein regulating the assembly of

mTORC2 and its interaction with SGK1
deptor mTOR inhibitor protor Protor1 increases mTORC2-mediated
1/2 activation of SGK1
Unknown function, its loss does not affect
mLST8 mTORC1 activity towards known substrates deptor mTOR inhibitor

tti1 Scaffold proteins regulating the assembly and Unknown function, essential for mTORC2
mLST8
tel2 the stability of mTORC1 activity
tti1 Scaffold proteins regulating the assembly and
tel2 the stability of mTORC2

Rapamycin
FKBR12
pras40 raptor
deptor mLST8

tti1 ? mTOR
tel2 HEAT repeats HEAT repeats FAT domain FRB Kinase FATC
domain domain domain

22 protor
mSin1 rictor
1/2

..      Fig. 22.4  mTOR signaling in growth control and disease. (Reprinted from Laplante and Sabatini [55]. With permission from Elsevier)
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
347 22

1. Normal Cell 2. Tumor Cell 3. Normal Cytoplasm + 4. Tumor Cytoplasm

Tumor Nucleus + Normal Nucleus

Normal Cells Tumor Cells Normal Cells Tumor Cells/Death

..      Fig. 22.5  Cybrid diagram [56]. (Courtesy of Jeffrey Ling and Thomas N. Seyfried)

The Masino book also highlights and expands on earlier

Cancer as a Mitochondrial Metabolic Disease research pointing to therapeutic benefit of ketogenic thera-
Dr. Thomas Seyfried and colleagues describes some pies for neurodegenerative diseases, including amyotrophic
intriguing research involving nuclear cytoplasm trans- lateral sclerosis [59, 60], Parkinson’s disease [61], Alzheimer’s
fer experiments in a paper entitled Cancer as a mito- disease [62], and mild cognitive impairment [62]. It is impor-
chondrial metabolic disease published in Frontiers in tant to note that existing drug therapies offer only modest and
Cell and Developmental Biology and in Cancer as a temporary benefit in slowing disease progression and there is
Metabolic Disease [56, 57]. In nuclear transfer experi- no curative therapy for any of these devastating diseases.
ments, cytoplasmic hybrid cells (cybrids) were created Recently, another mechanism underlying improved cog-
by transferring tumor nuclei into cells with normal nition has been elucidated by research, that is, the under-
cytoplasm. The result was cells that replicated and sur- standing that a ketogenic diet and/or ketone supplementation
vived, despite having a nucleus with mutated spares NAD+ (the oxidized form of NAD) [63, 64]. This is
DNA. Other cybrids were created by transferring nor- significant given that cell senescence and degeneration is
mal nuclei into tumor cells containing cytoplasm that associated with a decrease in the NAD+ pool, which in turn
displayed the Warburg effect. These cells also replicated epigenetically impacts downstream cell signaling, particu-
but the majority did not survive. According to Dr. larly in activities related to SIRT1.
Seyfried: “The results suggest that nuclear genomic
defects alone cannot account for the origin of tumors,
and that normal mitochondria can suppress tumori- RECHARGE: Mild Cognitive Impairment and
genesis. In essence, the evidence is consistent with the Alzheimer’s Disease
theory that cancer is primarily a mitochondrial meta- Alzheimer’s disease is characterized as a disorder of
bolic disease.” [56]. impaired cerebral glucose metabolism. Ironically and
very tragically, the drug most commonly prescribed to
treat this disease targets that deficiency by making
even more glucose available to neurons. Instead, it
22.8  Neurodegenerative Diseases makes sense to investigate ways to reduce reliance on
glucose as the primary fuel by replacing glucose with
Ketone bodies, particularly beta-hydroxybutyrate and aceto- ketone bodies. Ketone bodies are preferentially taken
acetate, are a preferred energy metabolite for much of the up and readily metabolized by most normal brain tis-
brain and central nervous system, and a large body of evidence sue and there is a large body of evidence that clearly
combined with a century-long history of use have consistently demonstrates neuroprotective and neurotherapeutic
demonstrated neuroprotective and neurotherapeutic benefits properties. This could amount to a win/win/win in
of ketogenic diets in epilepsy [58]. Preliminary research indi- Alzheimer’s disease [64, 65].
cates that these benefits may extend to applications in other The MEND trial investigated the effects of changes
neurological diseases and disorders, including autism spec- in diet and lifestyle on symptoms of mild cognitive
trum disorder, traumatic brain injury, spinal cord injury, impairment and early Alzheimer’s in a small group of
mood disorders, and even migraines. Several of these studies older adults [65]. Interventions included (but were not
are included in a book edited by Susan Masino, PhD [59].
 348 M. Kalamian

result in a debilitating symptom such as fatigue if the under-

limited to) lowering the intake of grains and refined lying disorder is not addressed prior to initiation of a keto-
starches, adding MCT and coconut oil, optimizing genic diet. Other tests include but are not limited to ferritin,
sleep, practicing daily intermittent fasting, and reduc- uric acid, urine organic acids (Genova), comprehensive fatty
ing stress through mind/body practices. Subjects acid profiles (such as the one offered through Mayo Medical
could pick and choose from a smorgasbord of these Laboratories), and nutrient assessments including selenium,
options that as single therapies would have little total B12, methylmalonic acid, and folate [38].
impact on disease but taken together improved out-
comes for a majority of participants. This emphasis on
individualizing protocols has recently been rebranded 22.9.2  Blood Panel
as the Bredesen Protocol™ [63, 65].
Combination therapies rather than miracle drug sin- 55 Complete blood count (CBC)
gle agents have proven to be the solution for long-term 55 Comprehensive metabolic panel (CMP)
management of other diseases, most notably HIV- 55 Full thyroid panel (including reverse T3)
AIDS. It is worthy to note that the development of that 55 25-hydroxyvitamin D (optimal levels: 50–80 ng/dL)
successful protocol was not made within the context of 55 Red blood cell (RBC) magnesium
conventional medical model that tests one drug or 55 Selenium
therapy at a time in clinical trials. In fact, that model had 55 Vitamin B12, serum
hindered progress but was ultimately overshadowed by 55 Methylmalonic acid
a grassroots movement by impassioned researchers, 55 Folate
doctors, and the empowered lay people that combined 55 Thiamin
scientific research with political activism. 55 Riboflavin
55 Niacin
55 Pantothenate
55 Biotin
22.9  Risk/Benefit Analysis 55 Glycated hemoglobin (HbA1c)
55 Fasting insulin (as a baseline for comparison and to
It is essential to conduct a risk/benefit analysis before initiat- detect hyperinsulinemia)
ing a ketogenic diet. This includes assessment through an 55 Carnitine panel (vegans are at risk of low levels due to
intake that gathers information on the patient’s health his- the lack of dietary intake of carnitine; individuals
tory, including demographics, present and past diagnoses, experiencing catabolic events may also be low at
interventions, comorbidities, hospitalizations, clinical symp- baseline; high values for acyl/esterified are acceptable in
toms, lab results, and medications and supplements. A nutri- those who are already in ketosis)
tion intake should include information about current dietary 55 Advanced lipid panel (e.g., NMR) including particle
pattern and history of diets for weight loss or health improve- count and particle density
ment. It should identify conditions that may limit food 55 High sensitivity C-reactive protein (hsCRP)
choices, such as food allergies, intolerances, aversions, 55 Homocysteine (optimal level: low end of the normal
FODMAP issues, philosophy, and if applicable, religious range)
dietary laws. Potential impacts of any physical or cognitive
limitations, social environment, family responsibilities, Note that the ranges typically used in certain labs, such as
financial limitations, cultural influences, and level of support 25-hydroxyvitamin D and homocysteine, may not be opti-
need to be assessed as well. mal. Over time, levels of carnitine and insulin may drop
below the optimal range, so retesting at intervals is essential
to proper monitoring.
22.9.1  Baseline Laboratory Evaluation

At a minimum, the following labs should be drawn prior to 22.9.3  Absolute Contraindications
initiating a diet and the results evaluated alongside other
information used in the risk/benefit analysis. Disease-­specific In 2008, a special report was published entitled “Optimal
biomarkers, such as carcinoembryonic antigen (CEA) in clinical management of children receiving the ketogenic diet:
cancer or thyroid autoantibodies (anti-thyroid peroxidase Recommendations of the International Ketogenic Diet Study
22 and anti-thyroglobulin) in suspected autoimmune thyroid Group” [38]. The 24 authors identified a set of absolute con-
disease, should also be tested at baseline. Other labs may be traindications to the use of the diet. These should be ruled
ordered by the integrative or functional doctor to test for out during any risk/benefit analysis completed prior to initi-
metabolic issues that may impact implementation or compli- ating the diet. Absolute contraindications include:
ance. For example, an organic acids test may identify a pre-­ 55 Carnitine deficiency (primary)
existing, yet previously undiagnosed, problem that could 55 Carnitine palmitoyltransferase (CPT) I or II deficiency
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
349 22
55 Carnitine translocase deficiency 22.10.1  Protein Target
55 β-oxidation defects
55 Medium-chain acyl dehydrogenase deficiency Most estimates of protein needs are very broad and inclusive.
(MCAD) The Recommended Dietary Allowance for protein stands at 0.8
55 Long-chain acyl dehydrogenase deficiency g of protein per kilogram of body weight, an intake that the
(LCAD) Food and Nutrition Board of the Institute of Medicine has
55 Short-chain acyl dehydrogenase deficiency determined as adequate for over 97% of healthy Americans
(SCAD) [66]. However, there are other considerations, including: (1) this
55 Long-chain 3-hydroxyacyl-CoA deficiency amount was determined by studies of people following a stan-
55 Medium-chain 3-hydroxyacyl-CoA deficiency. dard diet, (2) this recommendation is based on actual body
55 Pyruvate carboxylase deficiency weight instead of ideal weight, and (3) protein needs are higher
55 Porphyria in subsets of the population including athletes and the elderly, as
well as individuals who are undergoing cancer treatment or
recovering from surgery. Women who are pregnant or lactating
How Common Are Contraindications? need to follow the medical and nutrition advice of their gyne-
With the exception of adult-onset porphyria, most of cologist. Aside from these exceptions, patients following keto-
these limiting conditions are identified in childhood genic diets may need to adjust protein intake to support tissue
[36]. However, secondary carnitine deficiency can repair and maintenance or to maintain muscle mass but there
develop in individuals due to an increase in the use of are simply too many variables here to come up with a single
carnitine predicated by a ketogenic diet as carnitine is recommendation that can be generalized to everyone in ketosis.
needed to support the activity of the mitochondrial
carnitine shuttle. It can also develop as a result of sur-
geries, serious injuries, or catabolic treatments, such as Variables to Consider in Setting a Protein Target
chemotherapy. Those who follow primarily plant- 55 Older adults may benefit from more protein as
based diets and those with genetic variants that nega- greater intake is associated with reduced mortal-
tively impact the biosynthesis of carnitine are also at a ity, but this may simply reflect confounders that
higher risk of deficiency. impact nutrient intake and digestion rather than
an increased need for protein.
55 Those who engage in moderate or vigorous
activity may benefit from a slight increase in
22.9.4  Relative Contraindications protein intake, especially in the form of branched-
chain amino acids before or during the activity.
In addition to absolute contraindications, there are a signifi- The needs of elite athletes should be calculated
cant number of diseases, conditions, and situations that pre- by a nutritionist that specializes in low carbohy-
clude or complicate initiation and compliance. The functional drate nutrition for this special population.
or integrative team should consider these in the planning 55 Excess protein is converted to glucose via
process [36–41]. gluconeogenesis. This can interfere with ketosis.
55 Conditions that require medical and nutritional moni- 55 Excess protein stimulates mTOR and IGF-1 activity
toring by a skilled integrative team which may be detrimental in individuals with cancer
55 Conditions that interfere with the ability to keep glucose [54, 55].
low and steady 55 Glutamine is fermented for energy in the mito-
55 Inability to comply with implementation guidelines chondria of many types of cancer cells.
55 A single high-protein meal can stimulate an insulin
Potential side effects also need to be addressed prior to initi- response sufficient to suppress ketogenesis. This is
ating the diet. These can be reduced in number and severity especially evident with dairy and egg protein.
by proactive education and support during the transition. 55 The RDA for protein for a 5′9″ individual weighing
These side effects are discussed in detail in the section on 220 lbs. (100 kg) is 80 g and the RDA for a 5′9″
transitioning to the ketogenic diet. individual weighing an ideal 154 lbs. (70 kg) is 56
g. Where is the evidence that a heavier person
needs an additional 24 g of protein to support
22.10  Macronutrient Calculations what is basically the same lean body mass? Some
may argue that more protein is needed to
The ketogenic diet specialist aids the integrative or functional maintain the muscle tissue needed to support the
medicine team in developing an initial macronutrient pre- extra weight, but realistically, the extra amount of
scription. At best, this should be viewed as simply an esti- protein—if needed at all—is likely to be very
mate of where to start. Expect to periodically review and small, perhaps a few extra grams per day.
refine this prescription.
 350 M. Kalamian

22.10.2  Carbohydrate concern over estrogen metabolites in dairy, particularly for

those with hormone-sensitive cancers.
Determining carbohydrate intake does not entail a calcula-
tion as there is no requirement for dietary intake. Instead, the Key Points
limit is based on an individual’s response to carbohydrate 55 Most protein- and fat-rich animal and plant foods
intake [47]. Most people are able to maintain nutritional contain a complex blend of fats and oils with
ketosis with carbohydrate intake between 20 and 50 net varying amounts of saturated and unsaturated fatty
grams. Adopting a target at the lower end of the range may acid chains
help to facilitate adaptation to the diet, particularly in the 55 The ratio of omega-6 to omega-3 intake appears
early days and weeks. to influence systemic inflammation: High ratios
Patients following the ketogenic diet should be counseled seen in most standard diets (i.e., 15:1) are
to eliminate non-foods like coffee creamers that contain pro- assumed to be pro-inflammatory [57]
cessed fats and to focus instead on consuming nutrient-dense 55 A subset of fatty acids referred to as essential fatty
non-starchy vegetables, nuts, and seeds that are high in fat and acids (EFAs) cannot be biosynthesized efficiently
fiber. Consider these factors in setting carbohydrate limits: in humans and need to be included in the diet.
55 The most rigorous ketogenic diets (i.e.. for epilepsy or
cancer) generally limit net carbohydrates (total carbohy-
drates minus fiber) to 12–16 g per day. . Table 22.2; Please see 7 Chap. 10.
   

55 Patients with thyroid disease or other hormone imbal-

ances may be more successful and feel better during the
transition if the carbohydrate limit is set at 20–25 g. 22.10.4  The Question of Calorie Restriction
55 Patients recovering from surgery, or those currently
receiving chemotherapy or radiation, may benefit from a The benefits of a calorie-restricted ketogenic diet include (1)
higher carbohydrate intake (20–40 g) to allow for a more intentional weight loss, (2) lower blood glucose and insulin,
liberal intake of nutrient dense foods. (3) more rapid transition to ketosis, (4) improved mitochon-
55 A more liberal intake of salad or sauté greens is not drial health, and (4) greater initial impact on disease-pro-
likely to interfere with ketosis, especially when con- moting pathways, such as angiogenesis, mTOR, and IGF-1 in
sumed with oil-based sugar-free dressings. cancer. That said, it is crucial to ensure that caloric restriction
does not provoke or worsen malnutrition. All factors that
impact GI functions must be evaluated and addressed prior
22.10.3  Fats to setting the diet prescription.
Weight loss is almost always present in the early days and
While protein targets and carbohydrate limits are likely to weeks of the diet as the switch involves removing approximately
remain stable over the early weeks and months of the diet, half of total calories previously consumed as carbohydrate-­
the amount of fat needed will increase or decrease in containing food. Most patients adapt slowly to this change; in
response to overall energy needs [38, 42, 47]. As stated ear- effect, they may inadvertently restrict calories. The integrative or
lier, the initial macronutrient prescription is only an esti- functional team needs to assess baseline body fat percentage and
mate based on patient demographics, level of physical lean body mass (via BIA, BodPod, DEXA/DXA, calipers) then
activity, and accommodations needed during active treat- carefully monitor weight loss to ensure that it is healthy and sus-
ment of specific disease such as cancer or diabetes. The tainable. Inadvertent weight loss is especially problematic in
amount and/or type of fat initially prescribed may also those who need to maintain or even gain weight during this
reflect initial patient tolerance to an intake that may be transition so once again, proactive measures need to be in place
roughly two-and-a-half times that of the baseline pattern. before the transition to a ketogenic diet. Variations in approach
Variation in intake is amplified in those with high energy to initiating the diet will be discussed in the following section.
needs as they may require up to 300 g of fat per day to It is important to note that many of the same benefits of
maintain current weight (if that is a goal). Comorbidities caloric restriction can be achieved—often without weight
such as gallbladder disease may also impact digestion and loss—through the use of a fasting regimen. One of the sim-
tolerance and should be addressed proactively. plest to initiate and maintain is daily intermittent fasting
Patient education should include information on which (referred to now as “time-restricted eating”). This is easily
fats and oils to include in the diet and which to eliminate. accomplished by avoiding all food for 3–4 hours prior to bed-
Patients may also need guidance on how to incorporate fats time and refraining from carbohydrate- or protein-­containing
22 and oils into meals and snacks. foods for the first few hours after awakening. Limited
Dairy fats have traditionally played a large role in keto- amounts of fats, such as MCT oil and/or ghee, are often con-
genic diets for children. However, many functional and inte- sumed in a morning beverage to help extend the modified
grative practitioners may suggest a dairy-free diet for their fast to 14–16  hours. This facilitates autophagy while also
dairy-sensitive patients, and this will require even more increasing morning ketone levels and simultaneously keep-
intensive support from the nutritionist. There is also some ing glucose low and steady.
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
351 22

..      Table 22.2  Table of fats and oils

Sources Choose most often Limited amounts Eliminate

Omega-3 (rich in EPA, DHA, ALA)

Animal Wild-caught cold-water fish including Fish high up in the food chain (high Farmed fish with heavy contamina-
sardines, mackerel, salmon, and trout (rich concentrations of heavy metals and low tion including tilapia, salmon, trout
in EPA/DHA) in EPA/DHA) tuna, swordfish, halibut

Plant Flaxseed, chia seed, hemp, walnut Flaxseed oil (easily oxidized) GMO flaxseed (due to crop handling
practices)

Omega- 6 (rich in LA, GLA)

Animal Fresh or frozen grass-fed pastured Processed animal products including Fresh/frozen/processed CAFO beef,
proteins/fats including beef, lamb, pork, deli meats (even from grass-fed and pork, poultry, eggs or questionably
poultry, dairy, properly sourced crusta- pastured sources) sourced crustaceans
ceans

Plant Small amounts of GLA-rich oils including Oils including cold pressed non-GMO Soybean, corn, and all other GMO
borage, black currant, evening primrose sunflower, sesame, canola heat-damaged, solvent refined oils

Other mono- and polyunsaturated oils

Animal Animal fat from responsibly raised animals n/a Fats and oils from animals and fish/
and fish oil from wild-caught (preferably) shellfish coming from CAFOs, fish
cold water fish and shellfish farms, and contaminated fisheries

Plant Nuts and seeds; oils including cold-­ Brazil nuts (concerns over radium and Hydrogenated lard
pressed and minimally refined olive and excess selenium)
avocado

Medium-chain triglyceride oils (uniquely ketogenic)

Animal Dairy fats from goats (when available) n/a n/a

Plant Coconut and palm oil (including red palm n/a Hydrogenated coconut and palm
oil) oils

Saturated fats (most often some combination of saturated and unsaturated fats)

Animal Animal and dairy fats from responsibly Caveat for individuals with hormone-­ Processed and packaged products
raised animals sensitive cancers: dairy products contain containing fats, starches, and sugars
estrogen metabolites

Plant See medium-chain triglycerides Same as above

Trans fats

Animal Small amounts naturally occurring in n/a Hydrogenated animal fats including
meat and dairy commercial lard

Plant n/a n/a Hydrogenated margarine and oils

(mostly found in processed foods)

Based on data from Ref. [66]

EPA eicosapentaenoic acid (omega-3), DHA docosahexaenoic acid (omega-3), ALA alpha-linolenic acid (omega-3), LA linoleic acid
(omega-6), GLA gamma-linolenic acid (omega-6), AA Arachidonic acid (omega-6), CAFO Concentrated animal feeding operation

22.10.5  Food Trackers and Meal Planners refine the plan. For example, Cronometer displays details on
essential amino acids, comparing actual intake to the
Trackers and planners are important tools to both practitio- RDA. At a glance, clients/patients can see if they are meeting
ners and clients/patients. When used properly, accountability that requirement. Meal planning tools are not as readily
for food choices is visible, which can help with compliance. available as trackers. Currently, the best and most accurate
There has been a rapid rise in the number and quality of food ketogenic meal planner is the KetoDietCalculator developed
tracking apps and patients should be encouraged to use some and maintained by The Charlie Foundation [39]. Although
method of recording intake (though some will still prefer to this is an important tool for dietitians and nutritionists who
use written food logs). Used properly, trackers can provide work with children, it is not used as frequently with adults
direct feedback to the client/patient that they can then use to given the additional steps needed to access it and the steep
 352 M. Kalamian

learning curve needed to work with this program. Accessing 55 Cabbage

a patient’s food records through one of these tools can help 55 Cauliflower
the practitioner spot areas of concern, such as inadvertent 55 Celery
non-compliance or a lack of variety in food choices. 55 Cucumber
55 Kale
55 Mushrooms
22.11  Food and Supplement 55 Salad greens
Recommendations 55 Sauté greens (such as chard, beet greens, mustard
greens)
22.11.1  Eliminate the Following 55 Zucchini
55 After keto-adaptation, expand the options:
55 Sugars 55 Eggplant
Read ingredient labels carefully. Eliminate agave nectar, 55 Garlic
honey, molasses, and evaporated cane juice. Many other sug- 55 Onions
ars can be identified by their “-ose” endings (sucrose, dex- 55 Peppers
trose, maltose). 55 Tomatoes
55 Turnips
55 Grains 55 Winter squash
Eliminate wheat, corn, oats, rye, barley, spelt, triticale, qui- 55 Fruits:
noa, and bulgur. 55 Apple (a few very thin slices)
55 Avocados (Hass)
55 Starchy Vegetables 55 Berries (keep it to <2 g of carb per meal)
Eliminate potatoes, sweet potatoes, yams, winter squash, 55 Grapefruit (a few sections)
peas, and root vegetables. 55 Olives (use more like a condiment)
55 Proteins:
55 Starchy or High-Glycemic Fruits 55 Beef
Eliminate bananas, citrus, pears, grapes, pineapple, and 55 Eggs (preferably from free-range hens)
watermelon. (Small amounts of most berries and a slice or 55 Lamb
two of some fruits can be keto-friendly if carbohydrate con- 55 Pork (including limited amounts of bacon and
tent is kept low.) sausage)
55 Poultry
55 Legumes 55 Seafood (wild-caught fish and shellfish)
Eliminate peanuts, soy, garbanzos, beans, dried peas, and 55 Wild game meats
lentils. (Low glycemic index or vegetarian plans may include 55 Dairy (limit in hormone-sensitive cancers):
legumes.) 55 Cheese (hard cheeses, such as cheddar or Parmesan
or soft, high-fat cheeses, such as Brie)
55 Milk – It contains milk sugar (lactose). 55 Full-fat “original” cream cheese
55 Eliminate trans fats, heat-extracted and solvent-refined 55 Heavy whipping cream
plant oils, and oxidized oils. 55 Sour cream (cultured, without added starches or
55 Sugar Alcohols fillers)
Eliminate polyol sugar alcohols in foods with ingredients that 55 Nuts and seeds:
ends in “-ol” (sorbitol, mannitol, maltitol). These interfere 55 Almonds (including almond butter, almond flour,
with ketosis. Exception: Small amounts of erythritol or xylitol almond milk)
are allowed. (Note that xylitol is toxic to dogs.) 55 Brazil nuts (rich in selenium—limit of two per day)
55 Chia seeds
55 Alcohol (during the Transition) 55 Coconut (including unsweetened meat, milk, cream,
After keto-adaptation, a single shot of straight spirits or a glass of or flour)
dry red wine may be well tolerated. Track its effect on ketones. 55 Flaxseed (rich in healthy omega-3s and fiber; may
not be advisable in some cancers)
55 Hazelnuts
22.11.2  Allowed Foods 55 Hemp hearts/seeds
22 55 Macadamias (good choice: high in healthy fat; low in
55 Vegetables (not a complete list): carbs and protein)
55 Asparagus 55 Pecans
55 Broccoli 55 Walnuts (good choice: fewer omega-6s than
55 Brussels sprouts most nuts)
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
353 22
55 Fats and oils: 22.11.3.3  Gut Health
55 Lard, tallow, or other saturated animal fats (such as As mentioned previously, comorbidities such as gallbladder
duck fat) disease, history of cholecystectomy or poor fat digestion
55 Butter or ghee (if including dairy fats in the plan) should be addressed proactively. At this time, there are few
55 Buttery spreads (such as Earth Balance or Melt if guidelines specifically addressing the use of prebiotics or
substitute for dairy fat is needed) probiotics or constipation for people following ketogenic
55 Coconut oil and MCT oil diets. Instead, each practitioner should address the needs of
55 Avocado or extra virgin olive oil (for dressings or the individual in determining recommended foods and sup-
homemade mayonnaise) plements. For example, clients/patients with insufficient
55 Omega-3 fish oils (either as fresh fish—e.g., wild-­ diamine oxidase enzyme may not tolerate certain histamine-­
caught salmon—or in purified supplements) producing species of bacteria. Risk/benefit assessment here is
55 Salad dressings and mayonnaise (organic or home- also crucial for those in active cancer treatment or with
made) impaired immune function.
55 Small amounts of other oils based on personal
preferences (e.g., almond, macadamia) 22.11.3.4  Digestive Aids
55 Natural sweeteners: Some individuals will need supplemental digestive enzymes
55 Stevia (liquid drops) to support fat digestion. For example, certain patients may
55 Monk fruit (also known as luo han guo) benefit from a pancreatic enzyme that is high in lipase or
from the inclusion of an emulsifier, such as non-GMO sun-
flower oil lecithin. Ox bile is another consideration for indi-
22.11.3  Diet Supplementation viduals post-cholecystectomy or with bile deficiency;
however, this may not be well-tolerated and should be moni-
Rigorous ketogenic diets (10–12 net grams of carbohy- tored for side effects. Other digestive aids are situation-­
drate) are known to be deficient in some nutrients. More specific: for example, some individuals may benefit from
moderate ketogenic diets may also fail to provide all the betaine HCl supplementation.
vitamins and minerals considered essential to health.
Nutritional sufficiency can be assessed with any number of 22.11.3.5  Herbs and Botanicals
tools used by the functional or integrative team. Each team Oversight by the functional or integrative team is essential
will have their own preferred system for optimizing health particularly if patients are working with multiple teams and
through supplementation. What follows are some general providers to address complex health issues. All contraindica-
guidelines: tions (including drug/herb and herb/herb interactions) also
need to be assessed and monitored at initiation and over
22.11.3.1  Vitamins time.
Ensuring adequate intake of fat-soluble vitamins A (retinol),
D3, gamma tocopherol vitamin E, and K2 is important in any 22.11.3.6  Antioxidants
diet. Serum levels of these and other vitamins can be included The ketogenic diet has unique anti-inflammatory effects that
in baseline assessments. Routine monitoring of serum levels should be considered when developing protocols using anti-
of 25-hydroxyvitamin D to ensure optimal (as opposed to oxidants. The ketogenic diet’s decreased fruit and vegetable
“sufficient”) levels is already included in most functional and intake presents a common lack of intake of phytonutrients,
integrative protocols. fiber, and vitamin C that should be considered when devel-
oping an intervention. Also, antioxidant supplementation
22.11.3.2  Minerals may be contraindicated in those undergoing pro-oxidant
Ketogenic diets have a diuretic effect and it is common, espe- cancer treatments.
cially in the early weeks and months, to note some disruption
in electrolyte balance. Calcium, magnesium, potassium, and
sodium may all need to be supplemented, preferably as food 22.12  Variations of the Ketogenic Diet
(e.g., salted bone broth). However, food sources may not pro-
vide sufficient intake. Consider supplementation after There are some scenarios where adopting a variation of the
screening an individual with blood tests: classic ketogenic dietary may better fit the patient’s needs,
55 Electrolyte panel especially when fat is not well-tolerated or weight loss is not
55 Calcium, serum desirable [67]. Patients should still be counseled to avoid sug-
55 Calcium, ionized ars and grains but may opt to include small portions of
55 RBC magnesium legumes, fruits, or root vegetables. Another approach to lim-
55 Parathyroid hormone (PTH)—If calcium is >10, iting weight loss is to allow a greater percentage of calories
consider PTH to rule out secondary or primary hyper- from protein (though this may not be recommended for
parathyroidism. patients with cancer). A liberalized plan may also be the best
 354 M. Kalamian

option for active or athletic individuals, especially if there is a question the safety of keeping carbohydrate intake low over
substantially higher energy requirement. Here, a moderate an extended period of time [67].
plan might include more protein and carbohydrate as well as Published data also indicates that blood glucose levels
more total calories as fats and oils at each meal. Commercial range higher and ketosis is not as strong when the diet is lib-
ketone supplements are another option, especially for athletes eralized to include more protein. This appears to improve
who need a high-calorie snack before an event or workout. compliance and has minimal impact on outcomes in adults
choosing this pattern as a dietary therapy for epilepsy. The
modified Atkins may also be a better choice than the classic
22.12.1  Atkins Diet [44, 67] ketogenic diet for those with compromised health status or
complex medical conditions that prevent them from adher-
The Atkins diet is a low-carbohydrate plan primarily aimed ing to a more rigorous plan. Less frequently used variations
at those who want to lose weight. In Phase I (Induction), net include low-glycemic and medium-chain triglyceride ver-
carbohydrate intake is kept at or below 20 total grams and sions of the diet (see 7 Sect. 22.4).
 

there is no requirement to divide that amount equally

between meals. Atkins provides a list of acceptable induction
The Cyclical Ketogenic Diet and Feast/Famine
foods. There are no specific guidelines for quantity or quality
Cycling [7, 69, 70]
of fat or protein intake although more recent iterations of the
There is a great deal of interest in this option, which is
diet do emphasize better quality choices. Despite detractors’
promoted primarily through online forums and books
claims that the Atkins plan is a kidney-damaging high-­
directed at athletes and fitness enthusiasts. Simply put,
protein diet, years of research suggest that most people do
the cyclical ketogenic diet is a technique to enhance
not consume significantly more protein than they do on a
muscle glycogen storage by maintaining a ketogenic
standard diet. The combination of carbohydrate restriction
diet during 5 days of intensive training then rebuilding
along with a moderate increase in fat and protein intake
stores with 2 days of carbohydrate-loading. Cycling may
results in a calorie deficit that most times leads to weight loss.
have merit for that application, but one possible down-
Since the diet also has a diuretic effect, weight loss in the first
side is that keto-adaptation may take months, and
few weeks can be exhilarating for people who have tried—
cycling in carbohydrates may interfere with this process.
and failed—other weight loss diets. It is important to note,
Cycling may also lower resolve and commitment to a
though, that most individuals following an Atkins pattern do
ketogenic plan.
not achieve the low glucose or insulin levels seen with a more
Feast/famine cycling has been proposed as an option
rigorous adherence to a ketogenic diet.
for individuals with metabolic disorders other than can-
cer, such as diseases of insulin resistance. This plan allows
a day or two every week of higher carbohydrate and pro-
22.12.2  Modified Atkins Diet
tein intake followed by a return to a low-­carbohydrate or
ketogenic plan. There is little agreement as to which
The modified Atkins is a version of the Atkins plan that was
foods—and in what amounts—should be included on
developed and is now promoted by Dr. Eric Kossoff, an epi-
feast days. One of the downsides of cycling is that it may
leptologist at Johns Hopkins Hospital [68]. He was respond-
disrupt the metabolic reprogramming associated with
ing to the growing demand for a simpler ketogenic plan that
keto-adaptation. It also has the potential to lower resolve
did not require children to be hospitalized or fasted during
and commitment to the ketogenic plan.
initiation of the diet. His plan is also more user-friendly with
adolescents and adults, few of whom were compliant to the
restrictions used with younger children. In this version, car-
bohydrate intake is still low—initially 10–15 g of carbohy- 22.13  Diet Ratio
drate per day [68]. There are no specific guidelines for either
fat or protein. This more relaxed approach to meal planning Ketogenic diets are calculated using either a macronutrient
also makes it easier for families to dine out and travel. The ratio or a macronutrient distribution. From the beginning of
modified Atkins for epilepsy is still viewed as a medical diet, its use in epilepsy, diet ratio reigned. Children were most
and as such it is overseen by a team of specialists that include often started on a classic 3:1 or 4:1 ketogenic diet, meaning
(at a minimum) a neurologist and a registered dietitian. that every meal was carefully planned so that the amount of
Over a decade of experience with the modified Atkins has fat grams was 3 or 4 times the number of combined
now shown it to be a safe and efficacious alternative to the carbohydrate-­plus-protein grams. [38].
22 classic ketogenic diet therapy in epilepsy [67]. A recent 4-year Diet ratio can be confusing, primarily because the ratio is
study describes the challenges as well as the side effects of based on a system—gram weights of macronutrients—which
therapeutic ketogenic diets, including the modified Atkins. is foreign to the public at large, which is more accustomed to
The authors concluded that these diets may be feasible, effec- thinking of diets in terms of calories, not grams. Diet ratio
tive, and safe as long-term therapies in adults, which was developed as a tool for registered dietitians to use in
addresses some of the concerns of medical professionals who ­calculating a ketogenic diet prescription for a child with
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
355 22
e­ pilepsy based on that child’s individual protein and energy
needs. Discussions of diet ratio migrated from the epilepsy include an experienced keto dietitian or nutritionist. A
world to scientific research where it is still sometimes used to specialized meal planning tool, the KetoDietCalculator
describe diets used in both animal models and humans. (KDC), developed by Beth Zupec-Kania, consultant
nutritionist for The Charlie Foundation, is available to
registered clinics and dietitian/nutritionists. Using
22.14  Diet Macros patient demographics, the KDC is used to calculate the
initial diet prescription. Other features include a moder-
More recently, another way of designating diet macronutri- ated helpline for questions from nutrition professionals,
ents has grown in popularity as use of the ketogenic diet has a vetted macronutrient database, lists of low- and no-
expanded to applications beyond epilepsy. In the fitness carb dietary supplements, a selection of standard keto-
world, macronutrients (or “macros” as they are more com- genic meals, and flexibility to create new meals and
monly called) quickly became the preferred way to describe meal plans based on a child’s individual needs. The
the distribution of macronutrients in low carbohydrate and dietitian or nutritionist overseeing the child’s diet can
ketogenic diets. In this model, macros are assigned a percent- grant access to the KDC to allow families to create their
age based on calories, not grams. For example, in a 1600 calo- own meals that adhere to the diet prescription. (Use of
rie ketogenic diet, carbohydrates typically make up 5% of the KDC has expanded to include adults.)
total calories (i.e., 80 calories, which represents 20 g). Obesity
medicine specialist Dr. Eric Westman, along with researchers
Eric Kossoff, Jeff Volek, and Stephen Phinney, refer to diet
macronutrients in grams [20, 38, 48, 53]. 22.15  Short-Term Versus Long-Term
Macronutrient distribution is most often viewed as more Maintenance
intuitive and user-friendly than diet ratio. Plus, the conven-
tional nutrition community was already familiar with the The clinical trials of the late twentieth century identified the
Acceptable Macronutrient Distribution Ranges (AMDR) potential side effects of the ketogenic diet when used for up
guidelines so it did not require further explanation to make it to 2 years in children with epilepsy [38]. (It is important to
understandable to the public. Having a common language note that a subset of children receive enteral nutrition with
also made it much easier to compare the standard distribu- commercial formulas rather than whole foods.)
tion with that of a ketogenic diet. Reported side effects include:
As illustrated above, each macronutrient is assigned a dis- 55 Minor metabolic abnormalities (hyperuricemia,
tribution range that represents its percentage of total calories hypocalcemia, hypomagnesemia, decreased amino acid
in the diet. For example, 80% fat in a 1500-calorie plan levels, acidosis)
amounts to 1200 calories (approximately 133 g of fat), while 55 Gastrointestinal symptoms (vomiting, constipation,
80% fat in a 2500-calorie plan is 2000 calories (approximately diarrhea, abdominal pain)
222 g of fat). Even though both of these diets are 80% fat, the 55 Carnitine deficiency
increase in calories in the latter requires another 89 g of fat— 55 Hypercholesterolemia
an increase of more than 6 tablespoons of fat per day. 55 Renal calculi
Protein as a percentage of the total calories may vary as
well, but the absolute amount is in a narrower range as pro- Other observations that may or may not be related to the diet
tein targets in a ketogenic diet are determined either by ideal include slowed linear growth in children, pancreatitis, and a
body weight or lean body mass, not on total energy needs. few reported cases of cardiomyopathy and elongated QT
Carbohydrates, as a percentage of the total calories, vary interval (associated with selenium deficiency) [71, 72]. There
depending on two factors: total calories and diet rigor. are also reports in the literature of side effects, including
osteoporosis, associated with long-term maintenance on the
Ketogenic Diet Therapy for Children and diet, but these are mostly associated with syndromes or
Adolescents inborn errors of metabolism, most of which limit physical
There is a large body of work, including a consensus activity or involve the use of medications that deplete or
statement [38–40], that sets clear guidelines and proto- interfere with mineral absorption. Food allergies to dairy
cols for initiation of the ketogenic diet for children and proteins would also limit the amount of calcium available
adolescents with intractable epilepsy. In the US, The through diet.
Charlie Foundation is the major online resource for The growing body of research encompassing preclinical
families and practitioners interested in working with and anecdotal reports suggests that the diet is safe in the
this very special population. In the UK, the partner short-term but research to examine long-term effects lags
­foundation is Matthew’s Friends. Implementation of the behind. In fact, the lack of research identifying effects and
diet for other applications requires cooperation and outcomes from long-term adherence is one of the main criti-
support of the child’s medical team which should cisms of the growing number of studies that show a clear
benefit to carbohydrate-restricted and/or ketogenic diets as
 356 M. Kalamian

treatment for type 2 diabetes and metabolic syndrome. testing or urine test strips. And finally, the patient needs to
Concerns about long-term side-effects of ketogenic diets have a plan in place to maintain ketosis once the fast has
have been raised and addressed in part by a long-term study ended.
conducted by physicians affiliated with the Johns Hopkins Despite the patient or practitioner’s enthusiasm for a fast,
University School of Medicine and the Johns Hopkins Adult there are medical reasons (such as gallbladder disease) why
Epilepsy Diet Center. Their findings that ketogenic and mod- fasting may be a poor choice. For example, fasting is not a
ified Atkins diets were safe, feasible, and efficacious in the viable option if the patient is older, in frail health, recovering
study population were published in the journal Epilepsy from surgery, or in need of medication that must be taken
Behavior [68]. More questions will be answered and others with food. Individuals should proceed cautiously if they are
will be framed within the context of studies similar to this already below normal weight or have experienced a recent
one. unintended weight loss. Consider also the risks for those
with a history of heart arrhythmia or palpitations, or if prior
drug therapies have caused an elongated QT interval, as fast-
22.16  Transitioning to a Ketogenic Diet ing can cause some initial disruption in electrolyte balance
and heart rhythm. Fasting should not be practiced by women
Adaptations to ketosis fundamentally alter the manner in who are pregnant or lactating. This is only a partial list—fur-
which the body processes nutrients. The impact of the transi- ther investigation into health history is strongly recom-
tion must be considered in light of each individual’s health mended.
history and current status. In order to ensure the best chance
of success, the nutritionist should counsel the patient prior to
initiating the diet and provide ready access to the team via 22.16.2  Option #2: A Rigorous Ketogenic
email, phone calls, texts, or other predetermined means of Diet
communication.
Although fasting is the quickest way to reach ketosis, starting
with a classic ketogenic diet will also facilitate a quick shift to
22.16.1  Option #1: Fasting ketosis [73]. The patient should be encouraged to eliminate
all non-essential carbohydrates from the diet in order to keep
Fasting has known therapeutic benefits that are beyond the net carbs at or below 16–25 g per day. Another factor in this
scope of this chapter. One such benefit is the reduction or decision relates to the glycemic index and glycemic load of
elimination of seizures in individuals with severe epilepsy. In the foods that the integrative or functional team is recom-
fact, a short fast was part of the original Wilder/Peterman mending. For example, most carbohydrates from leafy greens
protocol [73] developed in the 1920s for initiating the diet as and a few cruciferous vegetables, such as cabbage, have a neg-
a treatment for epilepsy. Although most ketogenic centers for ligible impact on glucose levels. In contrast, blueberries will
epilepsy no longer require a fast, it is still commonly used in elicit more of a glycemic response.
other applications of the diet, particularly for weight loss and The transition to the ketogenic diet will be smoother if
cancer. A fast quickly lowers serum levels of glucose and the patient is educated as to which foods are included in a
insulin while simultaneously upregulating fatty acid oxida- very-low-carbohydrate diet and which should be limited or
tion and ketogenesis. Fasts have a diuretic effect, which is eliminated entirely (see the food lists in 7 Sect. 22.11). Those
 

motivating to individuals with a weight loss goal. A fast can with prior experience in whole-food cooking will already
also help cancer patients retain or regain a sense of control have most of the skills needed to plan and prepare ketogenic
over a health crisis that is otherwise overwhelming. Engaging meals. Many favorite recipes can be modified by substituting
in an extended water-only fast may inhibit angiogenesis, keto-friendly ingredients for the more traditional
which may in turn slow progression of the disease. Modified carbohydrate-­loaded ones; for example, “riced” cauliflower
fasts are a less rigorous option and can include fluids such as can be used in place of traditional rice. Protein portions may
salted broth with added fats or oils. need to be tapered down during this transition. Tracking
The benefits of fasting need to be weighed against the food intake with an app or other diary is highly recom-
risks and potential downsides. The functional or integrative mended as the feedback this provides is invaluable to both
team needs to consider the patient’s health and nutrition sta- the patient and the practitioner. As with fasting, it is impor-
tus, contraindications, comorbidities, and social support tant to monitor blood glucose and track ketones.
before recommending a fast. Before initiating a fast, the
patient needs to be educated regarding what to expect and
22 how to interpret the physical symptoms that they are likely to 22.16.3  Option #3: A Slow Transition
experience. They should be counseled to end the fast if con- to Ketosis
tinuing would endanger themselves or a person under their
care, such as a child or disabled adult. They should also have Patients are often nutritionally compromised by their dis-
some prior practice in the use of a home blood glucose meter. eases or treatments or otherwise unable to make all the
Ketone levels can also be assessed, either with blood ketone changes needed in order to begin with a rigorous ketogenic
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
357 22
diet [73]. A slower transition may also be more appropriate if respond to this change by upregulating production of the
the patient is moving to a ketogenic plan directly from a stan- enzyme needed to metabolize ketone bodies for energy
dard diet that is heavily reliant on packaged, processed, or which in turn helps to resolve these symptoms.
pre-prepared foods. They will often need more time to prop-
erly stock their kitchen and pantry.
Patients can start by eliminating grains, starchy gluten- 22.17.3  Hypoglycemia
free flours, and added sugars of any kind. They should also
reduce portions and servings of starchy vegetables, legumes, Within hours of the last moderate- to high-carbohydrate
and fruits while simultaneously adding a tablespoon or two meal, a drop in blood glucose levels will stimulate glycoge-
of a healthy fat or oil to each meal. Once they are comfortable nolysis [23]. Once liver glycogen is depleted, glucose homeo-
with the added fats, they can begin to phase out other con- stasis is maintained by the endogenous production of glucose,
centrated sources of carbohydrates. This is also a good time mostly through gluconeogenic activity in the liver. Some
to introduce medium-chain triglyceride oil to the diet. people experience a transient dizziness or a lightheaded feel-
Protein targets should be clearly prescribed. With ongoing ing during the transition due to low blood glucose levels.
support and monitoring from the nutrition specialist, the Most often, glucose levels self-correct quickly. Patients should
patient is less likely to experience side effects that often inter- be provided with a blood glucose home testing kit (meter,
fere with compliance. strips, finger stick device, lancets) and instructed in best
practices for testing. A low glucose reading (50–60 mg/dL)
accompanied by symptoms such as shaking, sweating, or leth-
22.17  Potential Side Effects of the Transition argy can be treated by dosing with two tablespoons of apple
or orange juice. If low levels do not resolve in 30 minutes or
The integrative or functional medicine team should educate if symptoms persist, a second dose of two tablespoons may
each patient as to potential side effects of the transition. correct the problem. If hypoglycemia persists, the patient
Addressing these proactively can ease the burden of symp- should be seen by a physician to rule out acidosis or a previ-
toms and improve patient compliance to the program. ously undiagnosed metabolic disorder. (Readings of
50–60 mg/dL are virtually without symptoms once the brain
begins utilizing ketone bodies.) Be aware that children
22.17.1  Hunger and Cravings deplete glycogen reserves more quickly and are more likely to
be symptomatic. For this and other safety reasons, it is highly
One of the most vexing problems for people following stan- recommended that children starting therapeutic ketogenic
dard high-carbohydrate diets is the impact of hormonal sig- diets do not start with a fast or a sharp reduction in carbohy-
naling on appetite. This signaling is subjectively experienced drates unless they are under the watchful eye of a physician.
as hunger and cravings. However, a ketogenic diet is associ-
ated with changes in hormone signaling that effectively
One Essential Caveat for Those with Diabetes
dampen appetite, which greatly reduces these symptoms. If
Individuals with type 1 diabetes or poorly controlled
the patient is generally healthy and at (or above) a normal
type 2 diabetes, with or without frequent hypoglyce-
weight, this reduction in appetite is welcome. However, if
mic episodes, MUST NOT adopt a ketogenic diet unless
weight loss is contraindicated, efforts should focus on ensur-
they are under the supervision of an experienced keto-
ing an adequate intake of nutrients prior to Day One of the
genic team. Some diabetics may also be at a higher
transition to the diet.
risk of “hypoglycemic unawareness”—another reason
to work with a specialist.

22.17.2  “Keto Flu”

In the first few days or weeks, many people experience symp-

toms that are collectively (and vaguely) referred to as “keto 22.17.4  Acidosis
flu.” This usually involves some combination of headaches,
fatigue, lightheadedness, poor concentration, muscle cramps, Mild and temporary acidosis may occur during the transi-
body aches, insomnia, and constipation. At the system level, tion to a ketogenic diet, especially if it is initiated with a fast
the decrease in insulin alters the manner in which the kid- [7]. This is usually limited to a slight and easily reversible
neys handle sodium, which in turn leads to a greater loss of disruption in blood pH. This uncomplicated metabolic disor-
fluids and electrolytes in urine. Patients should be counseled der is not the life-threatening condition known as diabetic
to replace fluids and replenish electrolytes, especially sodium ketoacidosis (DKA), a severe derangement that manifests as
[74]. At the cellular level, epigenetic changes prompted by the extremely high blood glucose (usually well over 200 mg/dL)
shift to ketosis result in an increase in the number of trans- along with extremely high levels of blood ketones (exceeding
porter proteins that allow for a greater influx of ketone bod- 14 mmol/L). DKA most often results from a shortage of insu-
ies into the cytoplasm. Within days or weeks, mitochondria lin in people with type 1 diabetes or poorly controlled type 2
 358 M. Kalamian

diabetes [74]. Another type of metabolic acidosis is associ- choose foods that are naturally high in fiber. (Use caution
ated with the use of a class of diabetes medications called with fiber supplements.) Certain medications and nutritional
SGLT2 inhibitors (such as Invokana) which should be dis- supplements (such as calcium carbonate) can also contribute
continued—under medical supervision—prior to initiating to constipation, while other supplements (such as certain
any low-carbohydrate diet. In fact, practitioners managing a forms of magnesium) can ease symptoms by drawing more
patient with diabetes need to be fully informed about any water into the colon [75].
proposed change in diet.
Alcoholic ketoacidosis (AKA) is a form of metabolic aci-
dosis characterized by an elevated anion gap, elevated serum 22.17.7  Heart Rate or Rhythm Changes,
ketone level, and normal or low blood glucose levels [74]. Including Palpitations
Practitioners should screen for prior history of alcohol abuse
and/or AKA and advise against drinking alcohol during the A change in blood volume brought on by dehydration and the
transition. loss of electrolytes in urine may cause the heart to beat faster and/
Acidosis may also occur during the transition or at times or harder [76]. Salted broth and proper hydration can help to
of illness or other metabolic stress that results in a sharp replenish fluids and electrolytes. Dehydration and an imbalance
increase in ketones (above 5 mmol/L), usually accompanied in electrolytes can trigger an episode in those with pre-existing
by dehydration. High ketone levels by themselves may not heart disease or rhythm disorders, such as atrial fibrillation. Also,
indicate acidosis but should be suspected when seen concur- risk/benefit assessment should include a cardiac evaluation in
rent with symptoms that include extreme lethargy, nausea, individuals who have received medications known to prolong
vomiting, flushing, panting, and a rapid or irregular heart QT interval—this potentially fatal condition should be ruled out
rate. Mild acidosis can be treated with two tablespoons of before transitioning a patient to a ketogenic diet [71, 72].
apple or orange juice as well as ½ teaspoon of baking soda in
a glass of water. However, if symptoms persist, the patient
will need to be seen by a physician that can assess blood 22.17.8  Change in Exercise Tolerance or
chemistries, such as CO2 levels and anion gap. Physical Performance
As is the case with hypoglycemia, children are more likely
than adults to experience acidosis during the transition or as a Patients should be advised to limit physical activities until
result of loss of fluids (diarrhea or vomiting) during an illness transition symptoms have resolved. Instead of intense work-
[4, 37]. Parents should be educated about this and provided outs or training, they can stay active with gentle walking,
with a sick day protocol and an emergency phone contact. cycling, or lap swimming. However, some individuals will
choose instead to engage in more vigorous activity. For them,
the transition may be a source of frustration as their muscle
22.17.5  Dizzy, Lightheaded, or Shaky tissue adapts to the increase in fatty acid oxidation and the
availability of ketone bodies as a preferred metabolic fuel. Low
As noted earlier, these symptoms may indicate hypoglyce- carbohydrate and ketogenic diets appear to confer a metabolic
mia, but they can also be due to a drop in blood pressure edge in many sports, especially endurance events [7].
during the transition. Patients should be advised against
engaging in activities that require balance or a sudden
increase in effort, such as climbing ladders or working out 22.17.9  “Keto Rash”
with weights. If these symptoms persist for more than a few
days, a healthcare practitioner should assess blood pressure Pruritis pigmentosa, a.k.a. “keto rash,” is an uncommon and
[67, 72–74]. It is also crucial that medical professionals mon- poorly understood potential side effect of the diet. There is
itor all individuals who are taking medications to control some speculation as to cause—either acetone in sweat or a
high blood pressure. Another consideration: The diet has a change in the skin microbiome. Reducing the level of ketosis
diuretic effect which may overlap with the impact of diuretics or discontinuing the diet will resolve the symptoms [73, 74].
used to manage high blood pressure.

22.17.10  Increased Risk of Kidney Stones

22.17.6  Constipation and Gout

Most people have fewer bowel movements on a ketogenic There is an increased risk for certain types of kidney stones,
22 diet than they may have had previously. This anticipated especially for those with a personal or family history. This
change in what is known as “regularity” is not the same can be addressed prophylactically with a prescription medi-
health issue as true constipation (straining to pass hard cation containing citric acid and potassium citrate and
stool). That said, true constipation may worsen with the ini- dietary supplementation of magnesium citrate and vitamin
tiation of a ketogenic diet and must be addressed proactively. K2. However, there are many contraindications to use espe-
Patients should be counseled to stay well-hydrated and to cially for those with compromised renal function [76].
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
359 22
In the first few weeks or months of the diet, there may be 22.18.1  Testing Glucose and Ketones
a rise in uric acid levels due to competition between uric acid
and ketone bodies for excretion in the urine [77]. Although Testing blood glucose and ketones is strongly encouraged in
this is often expressed as a concern by physicians, there is no the first few weeks of the transition as it offers an objective
evidence that it will progress to gout in individuals without a and quantifiable means of assessing whether or not the
personal history of this disease [77]. patient is achieving the goal of lowered blood glucose and
elevated ketones. Glucose and ketone measures also help the
patient and practitioner to troubleshoot issues that arise [73].
22.18  The First Few Weeks: The “Make or
Break” Period
22.18.2  Testing Blood Glucose
The first few weeks of the ketogenic diet is often the “make or
break” period so it is crucial to foster a strong commitment at There are currently two methods of testing blood glucose:
the start. Along with commitment, the patient needs the fol- glucometers and continuous glucose monitors. By far, the
lowing tools and strategies that enhance both compliance least expensive and most convenient testing method is with
and accountability [73, 78]. Along with these items, an acces- the use of a glucometer, also known as a home blood glucose
sible nutrition coach can answer the questions that inevitably meter. Specialized testing tools, such as watches and contact
arise during this period. lenses, are currently in development and will reduce or elim-
inate the need for finger stick testing.
Keep It Simple
The transition to a ketogenic diet usually involves a
considerable amount of effort on the part of the Patient Instructions for Testing Blood Glucose in
patient. Changes can feel overwhelming at the start, the First Few Weeks of the Diet
so it is often best to offer simple recipes and meal Although blood testing of glucose and ketones is not
preparation tips that allow the patient to put a meal essential in every application of a ketogenic diet, the
on the table with a minimum amount of time and practitioner may still recommend testing as it provides
effort. Variety is not usually a priority in the first few clear, objective data. What follows is one recommen-
weeks and many people will opt to recycle the keto- dation for a testing schedule:
genic meals that they find most palatable and easiest 55 Using the blood glucose meter, test and record
to prepare. Ongoing education and support will help fasting blood glucose (FBG)
to move them toward more variety and better quality ȤȤ In these early weeks, expect fasting glucose
once they are comfortable with basic meal planning. measurement to be erratic
Patients can start with one fully ketogenic meal per ȤȤ Expect levels to become low and steady with
day and build from there. Most people find breakfast keto-­adaptation
the easiest meal to adapt; for example, eggs cooked in 55 Test and record blood glucose in the middle of
butter garnished with grated cheese and perhaps a the afternoon, either before a meal or least 2
strip or two of bacon served with a steamed or sau- hours after a meal
téed vegetable and a drizzle of added oil. 55 Test blood glucose before bedtime
55 If the glucose measurement is uncharacteristically
high or low, immediately retest using a new drop
Review the following actions: of blood
55 Have they completed a pantry sweep, removing or ȤȤ If the two measurements are close, take the
relocating non-keto foods? average
55 Did they buy new keto-friendly food staples? ȤȤ If the second measurement matches the
55 Have they obtained a blood glucose meter? If so, have general trend, record that one
they practiced with it yet?
55 What is the plan for testing glucose and ketones in these If using a proprietary drink formula with oils, fats,
first few weeks? and coffee to delay the first meal of the day:
55 Do they have a kitchen gram scale? If so, are they 55 Test and record fasting blood glucose then test
familiar with how to use it? again just before the first meal. Most likely, the
55 Do they have access to meal planning tools and recipe second measurement will be lower than FBG. If
resources? the pre-meal test is higher than FBG then the
55 If the idea of structured meal planning is likely to be too length of the fast may be too long. (Do not rely on
daunting at the moment, have they been provided with a a single day’s numbers: test several days before
simple meal template customized to their macronutrient making changes in meal timing.)
prescription?
 360 M. Kalamian

22.18.3  Ketone Testing Tools [73] able marker of ketosis. However, some of the ­first-­generation
devices may not be good tools for individuals whose lung
As described earlier, there are three types of ketone bodies: capacity is impaired by asthma, age, or disease.
beta-hydroxybutyrate (detected in blood), acetoacetate
(detected in urine), and acetone (detected in breath).
22.19  Troubleshooting
22.18.3.1  Blood Ketones
Testing blood levels of beta-hydroxybutyrate is the standard Challenges that arise in the first few weeks or months of the
used in research and this method has gained widespread diet need to be addressed on a case-by-case basis before they
acceptance in therapeutic ketogenic diets. This requires the become obstacles to compliance. What follows is an overview
use of ketone test strips that are paired with a meter that tests of the most common transition symptoms along with sug-
both glucose and ketones. gested actions.

22.19.1  Ongoing Flu-like Symptoms

Testing Blood Ketones
55 Test and record fasting ketone levels The decrease in insulin levels alters the way in which kid-
55 Also test ketones an additional two or three times a neys handle sodium, producing a diuretic effect and con-
week—either in the middle of the afternoon (before current loss of electrolytes [74]. Sodium and chloride can
a meal or at least 2 hours after a meal) or at bedtime be replenished by adding salt to homemade broth.
55 The threshold for nutritional ketosis is 0.5 mmol/L Potassium supplements, including potassium citrate, may
and the upper level is considered to be in the range also be used along with the broth but may not be appropri-
of 3–5 mmol/l ate for patients taking potassium-sparing drugs, such as
55 Levels at 5–7 mmol/L are associated with fasting or Lisinopril. Magnesium supplementation should be consid-
starvation ered for all patients but may be contraindicated in those
55 Levels above 7 mmol/L are not common in adults with certain kidney diseases [75, 76]. Also, ensure adequate
unless they are supplementing with exogenous intake of calcium, preferably through food.
ketones.

22.19.2  Hunger between Meals

22.18.3.2  Urine Testing
Hunger and craving are common in the first few weeks. If they
Urine test strips use nitroprusside to detect the presence of
continue, it may indicate that the patient is not yet in sustained
acetoacetate in the urine. Nitroprusside changes to a pink
ketosis. Increase the frequency of ketone testing to detect any
tone ranging from a blush of color to deep purple—the
drop in ketone levels below the threshold of 0.5 mmol/L. Hunger
darker the shade of purple, the more acetoacetate is present.
may also persist in those who are slower to adapt to the changes
Urine test strips are inexpensive, non-invasive, and easy to
in hunger signaling associated with keto-adaptation. Another
use. While urine ketones are not as accurate a measure of
common reason for persistent hunger is inadvertent non-com-
ketosis as blood testing, the strips can still be used to check
pliance to the diet. Review the food diary for sources of hidden
compliance and improve accountability. (Note that testing
carbohydrates especially in beverages and food-based supple-
within a few hours of vigorous exercise or when hydration
ments. Also confirm that protein intake is within the suggested
levels are either higher or lower than the norm may not
limits. Caloric restriction adopted along with a therapeutic
yield accurate results.) Results using urine strips are typi-
ketogenic diet may result in lingering hunger—ensure that
cally more valid in the early weeks and months, before keto-
adequate amounts of fat are included in the plan.
adaptation is complete.

22.18.3.3  Breath Analyzer 22.19.3  Food Cravings

Specialized breath analyzers can detect the presence of ace-
tone, another of the ketone bodies. This technology uses a Determine which foods the patient is craving. If it is a sweet
small handheld device which connects to a computer or other treat, provide suggestions for keto-friendly substitutes, such
USB-supported device. Although these devices are conve- as fat bombs or keto treats. If the craving is for salty or crunchy
22 nient and reusable, they do not always correlate with blood foods, suggest sour pickles, fried pork rinds, or keto-­friendly
levels of beta-hydroxybutyrate. The later iterations are more crackers with a crunch. Some people crave protein: recheck
precise tools though they are more expensive to maintain. macro calculations and food records to be sure that the pro-
Some people, notably athletes, prefer this type of testing as tein target is accurate and met through the diet. Protein
part of their biohacking routine as it is a somewhat quantifi- foods, especially protein in eggs and dairy, will also elicit an
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
361 22
insulin response even in the absence of carbohydrates. In but are known to raise blood glucose in some individuals)
some individuals, this response may be exaggerated enough [78, 80]. Sauces and dressings added to restaurant meals
to suppress ketone production. (Cravings specific to cheese often contain sugars or flours. Also, be wary of foods pro-
may be influenced by other factors, such as opiate-like recep- moted as “sugar-free” and marketed to people with diabetes,
tors for beta-casomorphins in the brain.) [79]. as these may not be keto-friendly.

22.19.4  Unsustainable or Rapid Weight Loss 22.19.6  Steroid Medications (e.g.,

Prednisone, Dexamethasone,
Weight reduction is a goal for many people who adopt a keto- or Hydrocortisone)
genic diet, but unsustainable or rapid weight loss is not the
goal of a therapeutic ketogenic diet [73]. Weight loss that is Prednisone and dexamethasone are commonly prescribed to
greater than two pounds a week, or weight loss of any amount control inflammation, and hydrocortisone may be prescribed
in someone who is already below ideal weight, must be as a replacement hormone if cortisol levels are low [81]. All
slowed or stopped. This is especially important post-surgery steroid medications cause a rise in glucose levels and should
or with metabolic dysregulation associated with sarcopenia only be used under the supervision of a medical doctor.
and cancer cachexia. Furthermore, any attempt to discontinue or wean from these
Resistance training is anabolic in working muscle. drugs must be done under the direction of the medical team.
Therefore, it is crucial to advise patients to consider some
type of strength training to preserve or build muscle mass
especially during periods of rapid weight loss. This may be as 22.19.7  Dropping out of Ketosis
basic as the use of resistance bands or light weights ideally
under the watchful eye of an experienced fitness trainer that Use of an online tracking tool, such as Cronometer, can help
can provide feedback as to proper form and ideal degree of patients with both compliance and accountability by identi-
resistance. Exercises may need to be modified to match them fying food choices or portion amounts that are not in keep-
to the energy level and current fitness of each individual. ing with their ketogenic plan. Check to be sure that
To slow weight loss (or encourage slight weight gain), con- macronutrient intake is divided fairly evenly between meals.
sider adding a small serving (50–60 g) of a low glycemic index Women may also drop out of ketosis during the menstrual
fruit or legume (GI less than 40) to one meal a day. The patient cycle due to normal shifts in hormones that may be associ-
should assess their glucose response to that meal by testing ated with transient insulin resistance [78].
blood glucose just before the meal and again 45 minutes to an
hour after the meal. Expect to see a rise in glucose of about
25–30  mg/dL—this should be sufficient to briefly stimulate 22.19.8  Hidden Carbohydrates in Medicines,
insulin. Most likely, this will temporarily reduce ketone levels, Supplements, or Hygiene Products
but this downside may be offset by the opportunity to preserve
fat stores, restore glycogen, or regain lost weight. If glucose A pharmacist can provide information about the carbohydrate
rises by more than 25–30  mg/dL, then reduce the portion content of medications. Also look for sugars, starches, and
slightly and test again on another day. Test only one meal a day. sugar alcohols (aside from xylitol or erythritol) in the ingredi-
This will have less of a detrimental effect on ketosis. ents list on food and supplement labels. Visit the Charlie
Weight loss may accompany reliance on MCT oil as a pri- Foundation website [39] and download their list of low-carb
mary source of dietary fats. MCT is readily converted to and carb-free supplements and personal hygiene products.
ketones but excess ketones are excreted in the urine which
reduces the energy value. If weight loss is too rapid or other-
wise undesirable, counsel patients to consider MCT oil as a 22.19.9  Nausea or Vomiting
supplement, or “bonus.”
Gastrointestinal diseases and disorders can trigger the release
of stress hormones that stimulate gluconeogenesis. If nausea
22.19.5  Spikes in Glucose (a Rise of or vomiting is due to cancer or cancer treatment, the doctor
>25–30mg/dL) with or oncology nurse is likely to prescribe antiemetics. However,
a Meal or Snack if nausea appears to be diet-related, reduce the amount of fats
and oils to a point that does not cause symptoms then gradu-
Check the labels on packaged foods or low-carb snack bars to ally increase the amount, perhaps adding a high-lipase pan-
identify any ingredients that might be causing glucose spikes. creatic enzyme, lecithin, and/or ox bile that will aid in
Look for sugars or problematic fibers, such as isomaltooligo- digesting fat. Other strategies include spreading fat intake
saccharides (these are often assumed to be indigestible sugars out over several small meals and snacks.
 362 M. Kalamian

22.19.10  Dissatisfaction with Food Choices that individuals taking Metformin may see a drop in
HDL cholesterol and serum levels of vitamin B12.)
Ketogenic diets are restrictive and patients often express 55 Is the patient consuming too few calories? Rapid weight
boredom or dissatisfaction with the limited choices, espe- loss (greater than 5–7 pounds in the first 2 weeks) can be
cially at breakfast. Remind patients that they are not limited a red flag that calorie intake is too low. This may trigger
to traditional breakfast foods; any keto meal can take its hormones that upregulate glycogenolysis or gluconeo-
place. Also, there are many keto cookbooks and online reci- genesis. Reassess the diet prescription calculations and/
pes that can spark new interest in those who are bored with or check the food diary to be sure that targets are being
current choices. met.
55 Is the patient waiting too long between meals? The ideal
window for time-restricted feeding varies widely among
22.19.11  High Blood Glucose Levels individuals. Some people can routinely fast for
16–18 hours a day while others may be physically
In the context of a ketogenic diet, fasting blood glucose levels stressed by periods greater than 12–14 hours. Even in
over 85 mg/dL, or random blood glucose levels that remain those who maintain a wider eating window, the length of
over 90 mg/dL several hours after finishing a meal are con- time between meals may stimulate the production of
sidered high. Work through these questions: hormones that contribute to a rise in glucose. To
55 Is it only fasting blood glucose that is high? This can determine the ideal amount of fasting, the patient should
simply be due to the dawn effect, the normal circadian be advised to take several blood glucose readings at
rise in cortisol that stimulates a release of glucose. various points in the day, preferably before meals, to
Another possibility, but one that is poorly understood, detect any trends related to meal timing.
may rest with what is referred to as physiological insulin 55 How well is the patient coping with stress? External
resistance (more recently referred to as adaptive glucose stressors directly and indirectly influence blood glucose
sparing). Put simply, low fasting insulin concurrent with levels. For example, fear activates the sympathetic
a rise in early-morning blood glucose may result in a nervous system which stimulates the production of
higher than expected fasting number. High fasting epinephrine and release of glucose through glycogenoly-
numbers due to either the dawn effect or physiological sis. Psychological stressors can raise cortisol levels which
insulin resistance typically drop within a few hours of then upregulate gluconeogenic activity. Indirect stress-
waking, especially if the first meal of the day is delayed, ors, such as poor sleep, can interfere with hormone
as in time-restricted feeding. If this is the case, then no regulation and insulin sensitivity. Physical activity, social
intervention is needed. However, high fasting glucose connectivity, reduction in exposure to stressful environ-
can also be due to consuming too much protein at the ments, improved sleep, and meditation/prayer can all be
evening meal, particularly if that meal (or other food) is effective ways to lower stress and improve blood glucose
eaten within a few hours of bedtime. control and insulin sensitivity.
55 Is the patient receiving chemotherapy or radiation, or
recovering from surgery? These are all systemic “injuries”
and the body’s response here is the same as for all other 22.20  Conclusion
illnesses or injuries. Expect glucose levels to be higher
than they would be in individuals who are not facing The development of the infrastructure needed to support
these additional challenges. Glucose levels will also be widespread application of metabolic therapies, including the
higher in individuals with extensive metastatic disease ketogenic diet, lags behind the science. Acceptance by a
in cancer—lactic acid produced as metabolic waste from broader contingent of medical professionals remains elusive
excessive fermentation of glucose is converted back into in large part due to the high cost of conducting human clini-
glucose by the liver. (High lactate also occurs in cal trials that form the basis of most medical practice guide-
non-­disease states; for example, as a byproduct of lines. As a result, insurance providers have been slow to
metabolizing muscle glycogen during intense anaerobic provide reimbursement for healthcare professionals who
activities.) offer these therapies. At the heart of this problem lies a per-
55 Does the patient have a history of insulin resistance? If so, vasive belief, even among integrative practitioners, that keto-
circulating levels of glucose and insulin might remain genic plans are inherently inferior to those that are viewed as
higher than expected because cells are still less sensitive a “balanced diet.” This current nutrition paradigm should be
to insulin. These individuals may take longer to adapt to re-evaluated within the context of the body of evidence
22 the diet. The chronic presence of insulin also suppresses pointing to an underlying mechanism common to most dis-
ketone production, creating a vicious cycle. (Metformin, ease states: specifically, that epigenetic changes in gene
a prescription medication that helps lower blood glucose expression induced by an overabundant supply of glucose
levels, also helps to restore insulin and is sometimes contribute to a broad spectrum of conditions, including obe-
used concurrent with a therapeutic ketogenic diet. Note sity, diabetes, cancer, and neurodegenerative disease.
The Therapeutic Ketogenic Diet: Harnessing Glucose, Insulin, and Ketone Metabolism
363 22
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 367 23

The GUT-Immune System

Elizabeth Lipski

23.1 Introduction – 368

23.2 The Digestive System – 368

23.3 The Digestive Process – 368

23.4 The Stomach and the Immune System – 369

23.5 Functional Laboratory Testing – 369

23.5.1  ey Dietary and Lifestyle Recommendations to Raise
K
Gastric Acid – 369

23.6 The GALT and the MALT – 370

23.6.1  ey Dietary and Lifestyle Recommendations to Raise IgA – 370
K
23.6.2 Key Dietary and Lifestyle Recommendations to Break Down
Immune Complexes – 370

23.7 Small Intestine – 371

23.8 The Gut Microbiota – 372

23.9 The Microbiome: Bacteria – 372

23.10 Biofilm Layer – 373

23.11 Healing the Gut: The 5R Protocol – 373

23.12 R
 ole of Nutrition in Balancing the Gut-­Immune System:
Therapeutic Diets – 373

23.13 Prebiotics and Benefits – 375

23.14 Selected Therapeutic Foods – 375

23.15 Therapeutic Role of Probiotic Supplements – 375

23.16 Conclusion – 376

References – 376

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_23
 368 E. Lipski

The gut immune system has the challenge of responding to mouth, teeth, tongue, parotid, and other salivary glands.
the pathogens while remaining unresponsive to food Food choices are related to lifestyle, personal values, and cul-
antigens and the commensal flora. In the developed world, tural customs. This is our first immune contact: Does the
this ability appears to be breaking down, with chronic food smell good, look good, and taste good? Is thorough
inflammatory diseases of the gut commonplace in the mastication occurring?
apparent absence of overt infections. –Thomas T. MacDonald/ Digestion occurs in the mouth, stomach, and small intes-
Giovanni Monteleone (2005). Immunity, inflammation, and tine and requires cooperation from the liver and pancreas.
allergy in the gut. Science, 307(5717), 1920–1925. Mechanically, foods are chewed in the mouth and churned in
the small and large intestine to break the foods into mole-
cules that can be absorbed into the bloodstream and cells.
23.1  Introduction The proper levels of hydrochloric acid, bile, enzymes, and
intestinal bacteria are critical for full digestive capacity.
The focus of this chapter is to explore the synergistic relation- Digestion can be supported with digestive enzymes, bitters,
ships, between the gastrointestinal system and the immune relaxation, and thorough chewing.
system, and their joint effects on systemic health and inflam-
mation. Research in these areas is mushrooming. Current
Secretion  Every day, the walls of the digestive tract secrete
research indicates that 70% of the immune system is located
about seven quarts of water, acid, buffers, and enzymes into the
in the gastrointestinal system (GIT) and in the cells in the gut
lumen (inside) of the digestive tract. Secretion occurs through-
lumen, which is the opening in the middle of the intestines
out the entire digestive tract. These secretions help maintain
[1]. This is called the gut-associated immune system (GALT).
pH levels and send water into the gut to lubricate and keep
Food plays an enormous role in our immune response.
things moving. They also provide enzymes to digest foods and
Matzinger’s Danger model of immunity states that the function
facilitate the digestive process. Hydration is essential for this
of the immune system is to distinguish between exposures that
phase of digestion to work properly.
are dangerous and safe. Our tissues have two main responses to
foreign exposures: to be tolerant or to send alarm signals. The
Motility  Whatever we eat is squeezed through the digestive
immune system is tolerant to exposures nearly all of the time, yet
system by a rhythmic muscular contraction called peristalsis.
when it determines that something is dangerous, it reacts [2].
Sets of smooth muscles throughout the digestive tract con-
Each day we eat pounds of food, which is a “foreign matter” to
tract and relax, alternately pushing food through the esopha-
the body. Therefore, the food we eat each day is a main driver of
gus to the stomach and through the intestines. Think of a
immune response. The typical Western diet is inflammatory and
snake swallowing a mouse. The process helps the food
begins the process of digestive imbalance.
become acidified, liquefied, neutralized, and homogenized
Digestion is the river of life. When we cannot digest,
until it’s broken down into usable particles. From the time
absorb, and utilize nutrients from food, all tissues are com-
you swallow, this process is involuntary and can occur even if
promised. Other players in the gut-immune system include
you stand on your head. Irritable bowel syndrome, small
the integrity of the gut barrier, the role of the gut microbi-
intestinal bacterial overgrowth (SIBO), and gastroparesis are
ome, the cascade of immune responses that signal for healing
examples of altered motility disorders. Ginger, fiber, garlic,
and inflammation, gut motility, and the ability of the liver,
and an herbal product called Iberogast all help to stimulate
gallbladder, and pancreas to perform. This review will pro-
motility.
vide a clinical introduction.
Absorption occurs in the small intestine. Digested food
molecules are taken through the epithelial cell lining of the
23.2  The Digestive System small intestine into the bloodstream and through the por-
tal vein to the liver, where it is filtered. From the blood-
The digestive tract is comprised of the mouth, esophagus, stream, it passes to the cells. Until food is absorbed, it is
stomach, gallbladder, liver, pancreas, small intestine, large essentially outside the body – it is in a tube going through
intestine, and anus. Its job is to take food we eat and to nour- it. If the gut is inflamed, as with gluten intolerance or celiac
ish each cell in the human body. This is a finely orchestrated disease, there can be malabsorption, which is typified by
process and, when working correctly, is something we pay anemia, diarrhea, an inability to gain weight, and a lack of
little attention. When out of balance, we experience distress growth in children. Absorption is enhanced by healing
in the form of pain, gas, distension, inflammation, changes in intestinal permeability and utilizing a low-antigenic, low-
bowel movements, and immune system activation. inflammatory therapeutic diet until this healing has
occurred.
Assimilation is the process by which fuel and nutrients
23.3  The Digestive Process enter the cells. The reason we eat food is to nourish each indi-
23 vidual cell. Diabetes is a condition of poor assimilation.
Eating, also called ingestion or the cephalic phase, is volun- Assimilation is also enhanced by healing intestinal permea-
tary when materials are put in the mouth. This is our portal bility and utilizing a low-antigenic, low-inflammatory thera-
for nearly all nutrients to enter the body and involves the peutic diet until this healing has occurred.
The GUT-Immune System
369 23
Elimination  In digestion, we excrete wastes by having bowel down the gastrointestinal tract, but alcohol, water, and cer-
movements (defecation). These wastes are comprised of indi- tain salts are absorbed directly from the stomach into the
gestible food components, waste products, bacteria, cells from bloodstream.
the mucosal lining being sloughed off, and food that has not
been absorbed. Constipation and diarrhea are both examples
of imbalanced elimination. Chronic diarrhea contributes to 23.5  Functional Laboratory Testing
malnourishment. Chronic constipation is a sign of poor motil-
ity and can increase levels of beta-glucuronidase, which implies 55 Heidelberg capsule test. This test is typically performed
impaired phase II liver detoxification. Hydration, exercise, in an integrative medicine clinic.
dietary fiber, probiotics, and prebiotics all enhance elimina- 55 Smart pill: This is typically performed by a gastroenter-
tion. ologist.
When microbes enter the digestive system, they are con- 55 Empiric testing: Utilize betaine HCl supplementation to
fronted with several nonspecific and antigen-specific defense see if it resolves symptoms (see below).
mechanisms (innate immune system) including peristalsis,
bile secretion, hydrochloric acid, mucus, antibacterial pep-
tides, and immunoglobulin A, also known as IgA. This stops 23.5.1  Key Dietary and Lifestyle
most microbes and parasites from infecting the body. Recommendations to Raise Gastric
Acid

23.4  The Stomach and the Immune System Betaine HCl  Begin with one capsule of betaine HCl with a
protein-­containing meal. Most people will respond with dis-
The stomach contains two main immune protective sub- comfort, burning, or warmth in their belly. Any sign of dis-
stances: gastric acids  – also called hydrochloric acid  – and comfort indicates that there is sufficient acid already. Stop the
pepsin. After ingestion of food, this becomes the second line experiment by neutralizing the acid with 1 tsp of baking soda
of immune defense. in water or milk. For people who experience no discomfort,
Protein molecules are composed of chains of up to 200 titrate the dosage up slowly to a maximum of 2500 mg of beta-
amino acids strung together. Hydrochloric acid (HCl), pro- ine HCl per protein-containing meal. Any sign of discomfort
duced by millions of parietal cells in the stomach lining, indicates too much acid, so you cut the dosage. If symptoms
begins to break apart these protein chains. HCl also digests resolve, this supplement can be continued. If symptoms do not
bacteria, fungi, and parasites that come in with our food, resolve, stop. Betaine HCl is an acid and can create an ulcer, if
effectively sterilizing the food bolus. HCl is so strong that it used improperly.
would burn our skin and clothing, if spilled. However, a thick
coating of mucus (mucopolysaccharides) protects the stom- Umeboshi plum  Umeboshi plums/apricots are a traditional
ach and keeps the acid from burning through its lining. condiment used throughout Japan, Korea, and China for their
Prostaglandins, small chemical messengers, help keep the health benefits, which include improvements in periodontal
mucus layer active by sending messages to replace and repair disease, improved motility, and inhibition of H. pylori. The ume
the stomach lining and provide a protective coating. When plum is picked unripe, dried in the sun, and then pickled in a
this mucus layer breaks down, HCl burns a hole in the stom- brine of sea salt and shiso leaves. The net result is a highly alka-
ach lining, causing a gastric ulcer. line, naturally fermented pickle that is rich in enzymes and
Stomach acid also provides our first defense against food probiotics and has high antioxidant and antibiotic properties. It
poisoning, Helicobacter pylori, and parasitic and other infec- has been used traditionally for hangovers, liver support, detox-
tions. Low levels of stomach acid, hypochlorhydria, have ification, nausea, bad breath, dysentery, typhoid, paratyphoid,
been associated with common health issues, including food appetite stimulant, and skin diseases such as eczema [4–8].
poisoning, small intestinal bacterial overgrowth (SIBO), and Umeboshi plums can be eaten in many ways. They are
small intestinal fungal overgrowth (SIFO). Stomach acid is used as a condiment on vegetables or rice. Plums are very
also necessary for absorption of many minerals, so mineral salty but can be eaten whole from the jar. Umeboshi vinegars
depletion may occur with hypochlorhydria. are also available for use in salad dressings or on rice or other
A normal stomach acid level is a pH of 1.5–2.5. As we age, grains. One can also take whole plums or umeboshi paste
the parietal cells in the stomach lining produce less hydro- and drink as a tea. Just let it steep in boiled water for 5 min-
chloric acid [3]. Use of acid-blocking medications increases utes and then drink. This is a very restorative tonic.
stomach pH to 3.5 or higher, decreasing mineral absorption
and opening us up to opportunistic infection. Increase acidity with diluted vinegar  Dilute 1 teaspoon of
The stomach also makes pepsin, a protein-splitting vinegar in 10 teaspoons of water and drink with each meal.
enzyme, that cuts the bonds between specific amino acids Gradually increase the amount of vinegar, up to 10 teaspoons.
and breaks them down into short chains of just 4–12. The If you experience burning, immediately neutralize the acid by
stomach also produces small amounts of lipase, enzymes that drinking a glass of milk or taking a teaspoon of baking soda in
digest fat. Most foods are digested and absorbed farther water.
 370 E. Lipski

Swedish bitters  Bitters are a long-standing remedy for poor 23.6.1.1  Dietary Supplementation
digestion in Europe. Combinations of herbs such as gentian, Recommendations
ginger, cinnamon, cardamom, and others stimulate produc- These are suggestions to consider, but avoid if an individual is
tion of HCl and bile, act as antimicrobials, and increase motil- sensitive or allergic to a product.
ity. Take bitters either in tablet or liquid form as needed. 55 Saccharomyces boulardii. Typical dosage 250 mg three
times daily [6–8, 11, 12].
Change your eating habits and reduce stress  Chew food 55 Vitamin A. Typical dosage 5000 IU daily. It is recom-
thoroughly and eat small meals frequently. Small meals are mended to obtain a baseline vitamin A retinol blood
easier to digest. Avoid drinking liquids with meals because flu- level before beginning vitamin A retinyl palmitate
ids dilute stomach acid. Regularly practice stress management supplementation to ensure it is indicated for an indi-
by decluttering your calendar, meditating, receiving acupunc- vidual. Avoid recommending dosages of retinol if a
ture or massage, or doing tai chi or qigong. person already has a high-end or elevated vitamin A
retinol, because vitamin A supplementation above
10,000 IU daily can be toxic; monitor serum retinol
23.6  The GALT and the MALT
(vitamin A) levels every 2–3 months when supplement-
ing.
Throughout our digestive systems, we have immune tissue
55 Bovine colostrum: Typical dosage 500–2000 mg daily.
called gut-associated lymphoid tissue (GALT) and, in the
55 Transfer factor: Dosage 12.5–75 mg.
mucosal lining of the digestive lumen, the mucosal-­associated
55 Medium chain triglycerides (MCT oil): Typical dosage up
lymphoid tissue (MALT). The MALT also encompasses your
to 2 tbsp. Daily. MCT oil is available as C8, C8–C10, oil,
nose, bronchia, and, in women, the vulvovaginal areas.
and powder; or eat coconut or drink coconut milk or
Altogether, 70% of your immune system lies within the GALT
fresh coconut juice [8, 9, 13].
and digestive MALT, which protect us from antigens and
other foreign invaders. The tonsils, appendix, and the Peyer’s
patches within the small intestine are examples of GALT.
Secretory IgA (sIgA) is the primary way that the MALT con- 23.6.2  Key Dietary and Lifestyle
veys the message of immune assault. Secretory IgA are antibod- Recommendations to Break Down
ies – sentinels on constant alert for foreign substances present in Immune Complexes
the gut mucosa. When challenged by foreign molecules, sIgA
forms immune complexes with allergens and microbes [4, 5, 9]. 23.6.2.1  Dietary Supplementation
Immune complexes are clumps of IgA or IgG antibodies that Recommendations
signal the immune system to respond. If these immune com- These are suggestions to consider, but avoid if an individual is
plexes get deposited in organs, they can cause disease themselves. sensitive or allergic to a product.
Some IgA-associated diseases are IgA nephropathy, vasculitis, Proteolytic enzymes are taken between meals to increase
lupus, rheumatoid arthritis, scleroderma, and Sjogren’s syn- absorption to assist autophagy processes to break down the
drome. Immune complexes signal cytokines to begin the inflam- blood-clotting enzyme, fibrin, decreasing hypercoagulation,
matory process designed to rid our bodies of antigenic materials, and cleaning up cell debris. Protease enzymes taken between
a response of the adaptive immune system. Without sufficient meals can lessen food reactions and decrease systemic
sIgA, the MALT cannot work properly [5, 6, 10]. inflammation.
Secretory IgA response is the initial protective antibody 55 Porcine proteolytic enzymes: Contain chymotrypsin and
which comprises 80% of those in the gut. It is a protective trypsin along with other combinations of proteolytic
“scout” that signals trouble. Deficiency of sIgA is the most enzymes
common immunodeficiency. IgA can be assessed in serum 55 Vegan proteolytic enzymes: Most commonly contain
and stool. Low levels of sIgA make us more susceptible to vegan sources of bromelain (pineapple) and papain
infection and may be a fundamental cause of asthma, auto- (papaya), along with other enzymes combinations
immune diseases, candidiasis, celiac disease, chronic infec- 55 Nattokinase enzyme: Speeds up biochemical reac-
tions, food allergies, and more. In other words, if the sentry tions; extracted from fermented soybeans with a
isn’t standing at the gate, anyone can come in! bacterium Bacillus natto. Used commonly for
cardiovascular heart and circulatory system diseases
at 540 FU (fibrinolytic units) dosage providing the
23.6.1  Key Dietary and Lifestyle ability to break down the blood-clotting enzyme
Recommendations to Raise IgA fibrin
55 Boluoke and lumbrokinase oral enzymes: Derived from
23 Rest and relaxation  Ask your clients to rest for 2 hours dur- earthworms; fibrin-dissolving enzyme used commonly
ing daylight every day. Typically, within a few weeks, they are for heart disease and hypercoagulation of cancer, as well
beginning to feel amazingly better. as general inflammation
The GUT-Immune System
371 23
23.7  Small Intestine allows nutrients to pass into the bloodstream while blocking
the absorption of foreign substances found in chemicals, bac-
The small intestine is hardly small. If this coiled-up garden terial products, and other large molecules found in food. If
hose were stretched out, it would average 15–20 feet long. If maintenance is delayed due to stress, injury, infection, toxic
spread flat, it would cover a surface the size of a tennis court. exposure, medications (such as antibiotics steroids, oral con-
In the small intestine, food is completely digested and nutri- traceptives), or illness, there will be increased intestinal per-
ents are absorbed through cells called “enterocytes.” The meability, also called “leaky gut.” When this occurs, large
enterocytes are covered with hundreds of small fingerlike molecules such as toxins, microbes, chemicals, and molecules
folds called villi, which in turn are covered by millions of from food enter the bloodstream, triggering an immune sys-
microvilli. Think of them as small loops on a velvety towel tem reaction (. Fig. 23.1).  

that then have smaller threads projecting from them. The Leaky gut syndrome puts an extra burden on the liver. All
enterocyte layer is only one cell layer thick, but it performs foods pass directly from the bloodstream through the liver
multiple functions of producing digestive enzymes, absorb- for filtration. The liver “humanizes” the food and either lets it
ing nutrients, and blocking absorption of substances that are pass or changes it, breaking down or storing all toxic or for-
not useful to the body. The enterocytes are coated with a eign substances. Water-soluble toxins are easily excreted, but
mucous layer called the “biofilm.” the breakdown of fat-soluble toxins is a two-stage process
The enterocyte lining is semipermeable. The spaces that requires energy. When the liver is bombarded by inflam-
between the cells are called “tight junctions” and are regu- matory irritants from incomplete digestion, it has less energy
lated by occludens and zonulin. Absorption of nutrients and to neutralize chemical substances. When overwhelmed, the
substances into the bloodstream typically occurs through liver stores toxins in fat cells to deal with later. If the liver has
each cell; some occurs between the tight junctions. Zonulin is time later, it can deal with the stored toxins, but most com-
a molecule that opens the gates between the tight junctions. monly it is busy processing what is newly coming in and
To date, there are two known activators of zonulin: gluten-­ never catches up. These toxins provide a continued source of
containing grains in people who have celiac disease and lipo- inflammation to the body. Increased intestinal permeability
polysaccharides from gram-negative bacteria (LPS). High is the driving factor in liver diseases, such as cirrhosis and
levels of zonulin have been reported in autoimmune disease, nonalcoholic fatty liver disease (NAFLD) [29–32].
lung conditions, cancers, and neurological conditions such as Stop the mediators that perpetuate the problem:
multiple sclerosis and schizophrenia [14–16]. When you 55 Excess stress. Create the space in your life to relax and
have high levels of LPS, it is called “endotoxemia.” LPS parti- renew every day. Nap; meditate; do abdominal breathing
cles are released from mostly gram-negative bacteria as they exercises, tai chi, qigong, or a hobby; or watch birds in
die and go into circulation, binding to TLR-4 receptors on your yard. You choose, but do choose.
muscles and organs. This triggers inflammatory molecules 5 5 Poor sleep. Your body needs 7–9 hours of sleep each
such as IL-6 and inflammatory cytokines, ultimately damag- night. When healing, often more. Go to bed early
ing tissue. Elevated LPS has also been associated with changes enough to achieve this. It is hard to heal when you are
in tryptophan metabolism, increasing quinolinic acid, kyn- sleep-­deprived.
urenine, cortisol, and inflammation with simultaneous 5 5 Pain medications that injure GI lining, such as nonsteroi-
decreases in insulin sensitivity, thyroid function, melatonin, dal anti-inflammatories (NSAID), i.e., ibuprofen and
and glutathione. aspirin.
The intestinal lining repairs and replaces itself every 5 5 Use of birth control pills, steroid medications.
3–5 days. The intestinal lining has a paradoxical function: it 5 5 Environmental contaminants.

..      Fig. 23.1  Increased intestinal

permeability associated with Increased Intestinal Permeability Associated with Many Health Conditions
many health conditions. (Based
on data from Refs. [14, 17–28]) Acute pancreatitis Chronic Fatigue Kidney Stones
Asthma Syndrome Migraines
Autism Eczema Multi-Organ Failure
Autoimmune hepatitis Food Intolerances Multiple sclerosis
Autoimmune disease Fibromyalgia Non-Alcoholic Liver
Bechet’s disease IgA nephropathy Disease
Burn patients Inflammatory bowel Primary biliary cirrhosis
diseases Primary sclerosing
Celiac Disease
Irritable Bowel Syndrome cholangitis
Psoriasis
 372 E. Lipski

55 Overconsumption of alcohol. 23.8  The Gut Microbiota

55 Poor food choices.
55 Treat infection. One of the newest discoveries in the digestive system is the
microbiome. Each of us has 2–7 pounds of microbes in our
Diet: digestive system, about the size of the brain or liver. While these
55 Avoid foods that you are sensitive to. live throughout the entire digestive tract from the mouth to the
55 Eat gut-healing foods. Homemade chicken stock, beef anus, the great majority live in the colon and large intestine.
stock, and fish stocks are inexpensive and contain These microbes are comprised of bacteria, beneficial
nutrients, such as gelatin, glucosamine, and chondroitin, viruses known as bacteriophages or phage, fungi, archaea,
that help heal leaky gut better than anything else. It’s a and parasites that constitute more than 99% of the DNA in
food, so consume to taste. the human body [35]. This is a complex community that
functions to stabilize overall health and keep us robust. We
Supplements: Can be found individually or in combination have as many bacteria in our microbiome as cells in our body
products. [36]. Viruses equal or outnumber bacteria in the microbiome
55 L-glutamine (glutamine): Dosages vary 1–30 g daily. and regulate cell signaling of interferons and cytokines [37,
Begin with 1–3 g daily. Heat destroys its properties, so 38]. The mycobiome are the fungi in our microbiome; they
take with cold or cool beverage. Best on empty stomach. have not been well-studied as of this writing. Saccharomyces
Many people find that glutamine enhances their muscle boulardii is the best-studied of the beneficial fungi. It is typi-
endurance, which is a lovely side benefit. Too much cally used as a prebiotic and to treat diarrhea from all causes
glutamine can be constipating, so use that as an indica- [39–43]. Current research suggests that imbalances in this
tor. Occasionally glutamine makes someone feel wired “organ” enhance nutrient absorption; synthesize vitamins;
or anxious. If so, stop taking it; it is not for you. If you and drive obesity, type 2 diabetes, nonalcoholic fatty liver
have kidney disease, be cautious in taking more than disease, mental health issues, drug and toxin metabolism,
1–3 g daily. Caution when recommending glutamine for and intolerance to pain (. Fig. 23.2).
 

oncology patients, especially later-stage progression as

some cancers use glutamine as a fuel, along with glucose
[33, 34]. 23.9  The Microbiome: Bacteria
55 Zinc or zinc carnosine: Typical dose 75 mg of zinc
carnosine twice daily (totals 34 mg of zinc) or 25–50 mg Of microbes, there are many families and phyla, with the phyla
of other type of zinc. Bacteroidetes and Firmicutes predominant. These families are
55 Aloe vera. Dosage varies. If utilizing fresh aloe, use one comprised of hundreds of subfamilies and types of bacteria.
to two pieces the size of a thumb. Peel and utilize only No matter their names, they fall into three categories: symbi-
the inside pulp. otic bacteria, commensals, and pathogens. Symbiotic bacteria
55 Colostrum: 1000–3000 mg daily. provide a benefit to the host, such as Lactobacilli and
55 Probiotics. Lactobacillus plantarum is specifically Bifidobacterium species. When used in supplemental form, we
soothing to the small intestine. Take 1 daily. call these symbiotic microbes “probiotics.” Commensals
55 Quercetin. Dosage: 500–3000 mg daily. enhance digestion of fats, proteins, and carbohydrates and
55 Digestive enzymes with meals synthesis of SCFA and vitamins. They also aid detoxification
and protect us from pathogenic microbes [44]. As more is
Optional supplements: learned about the specific roles of each commensal, many will
55 Gamma oryzanol. Dosage 100 mg three times daily be recategorized as symbiotic. Pathogens, which have gathered
55 Fish peptides. Brand: Seacure. Six capsules daily in the most attention because of their devastating effects, com-
divided doses. Keep in freezer to make it more prise a smaller group of disease-causing microbes. In a healthy
palatable. human gut, these live in balanced communities. When out of
55 Vitamin A. 5000 IU of preformed vitamin A: retinol. Do balance, we call this “dysbiosis,” which is a general disordered
not take >5000 IU if you are pregnant or planning to microbiome rather than an infection with a specific pathogen.
become pregnant. Best to test vitamin A retinol status In the digestive system alone, you have many different
before determining need for supplementation. microbiomes. For example, your gingiva, tonsils, tongue,
55 Increase antioxidants. Vitamin C: dosage 500–10,000 mg teeth, and saliva each have their own microbiomes. If you
daily, and/or a full-spectrum antioxidant supplement. kiss someone, do you collect some of their microbiota?
55 Deglycyrrhized licorice. Dosage two tablets between Research indicates you receive 80 million bacteria for every
meals as needed, up to four times daily. 10 second kiss [45]!
55 Phosphatidylcholine. 2000–4000 mg daily. The microbiome begins to develop in the womb and
23 55 Herbal blends with combinations of marshmallow root, matures during the first 3 years of life. Research indicates that
slippery elm, arabinogalactan, ashwagandha, ginger, this development is associated with how well our immune
MSM, etc. usually powdered or capsules. system and metabolism function. This process can be
The GUT-Immune System
373 23
..      Fig. 23.2  The microbiome in
health and disease The Microbiome in Health & Disease
IN HEALTH OUT OF BALANCE / DYSBIOSIS
• Digestive Health: motility, function, • Atopic Illness
digestion • Autoimmune Disease
• Drug Metabolism • Cancers
• Heavy Metal Detoxification • Cardiovascular disease
• Increased nutrient absorption: fats,
• Chronic kidney disease
protein, minerals
• Dermatological issues
• Metabolism
• Modulate Immunity /Inhibit Pathogens • Diabetes
• Overall Health • Digestive Conditions
• Production of Short-Chain-Fatty Acids • Heart Failure
(SCFA) • Liver diseases
• Synthesis of vitamins: biotin, folate, • Mental Health: Depression,
B1, B2, B3, B6, B12, and K. Schizophrenia, Anxiety, Autism, ADHD
• Obesity
• Pain Tolerance
• Sleep disruption

enhanced with vaginal delivery and breastfeeding, having a 55 Remove: Remove stressors such as infection, toxins,
furry pet in the home [46], playing outdoors in dirt, and hav- foods that provoke reactions, processed foods, refined
ing older siblings. This development may be hampered by sugars, nonessential medications, and molds.
birth by C-section, bottle-feeding, antibiotics, and use of 55 Replace: Enhance digestion by utilizing digestive
other medications [47–49] (. Fig. 23.3).
  enzymes, betaine hydrochloride, and bile salts when
needed. Replace an inflammatory Western diet with a
whole-food diet or gut-healing therapeutic dietary plan.
23.10  Biofilm Layer 55 Reinoculate: Eat probiotic- and prebiotic-rich foods.
Take probiotic and/or prebiotic supplements containing
The gut microbes live in communities called biofilms. The immune-regulating species such as L. acidophilus, L.
biofilm layer contains antibacterial proteins and acts as a pro- reuteri, Bifidobacterium, Streptococcus thermophilus, and
tective barrier for the microbial communities, protecting the Bacilli species.
gut lumen. Mucin proteins contain glycosylated carbohy- 55 Repair: Eat gut-healing foods such as bone stock and
drates that are used as fuel by commensal and symbiotic vegetable broths. Eat at least nine servings (4.5 cups) daily
microbes, converting them into SCFA, which provide energy of vegetables and fruit. Polyphenols and plant bioactives
for the enterocytes. regulate inflammatory mediators. Increase dietary intake
When the microbial communities are out of balance, of gut-healing nutrients such as zinc, L-glutamine,
infection can set in the biofilm layer and also in the epithe- vitamin A, and omega-3 fatty acids. Utilize nutritional
lium to which they adhere. Commensal and pathogenic supplementation as discussed for increased intestinal
microbes typically stay inside the gut lumen, yet this is an permeability: aloe vera, quercetin, colostrum, etc.
imperfect system and some continuously make their way into 55 Rebalance: When someone is ill and improves, they will
the gut-associated lymphatic tissue (GALT), triggering an come to a “new normal” which may be healthier or less
immune and inflammatory response. robust than before becoming ill. This may affect posi-
Although we have no real research on protection of the tively or negatively what one can achieve in a day, week,
biofilm layer, gut-soothing foods and herbs have been used or year and will require adjustment. Examine lifestyle
traditionally to enhance mucus production and soothe the issues, such as sleep, exercise, and stress management.
gut. In herbal medicine, these are called “demulcents.” These
include licorice, slippery elm, marshmallow root (Althaea 23.12  Role of Nutrition in Balancing the Gut-­
officinalis), fenugreek tea, figs, almonds, oats, and okra. Immune System: Therapeutic Diets
Utilizing a gut-healing therapeutic dietary approach will also
be of benefit. (See later section in this chapter.) Research also indicates that changing what we eat has the
greatest impact on our microbiome [50, 51]. Food can have
both inflammatory and healing effects. In your initial assess-
23.11  Healing the Gut: The 5R Protocol ment, you will look for macronutrient, micronutrient, fiber,
and hydration adequacy through a food diary and any avail-
The 5R protocol is widely utilized in integrative and func- able clinical assessments. If someone is fatty acid- or protein-­
tional medicine. insufficient, digestion and absorption will not be optimized.
 374 E. Lipski

KINGDOM BACTERIA FUNGI

Glabella Site characteristic

Front Back
Oily Moist Dry
External
auditory canal
KINGDOM BACTERIA FUNGI

Retroauricular
Nare
crease

Manubrium Occiput

Antecubital
Back
fossa

Volar
forearm KINGDOM BACTERIA FUNGI
Bacteria Propionibacterium Malassezia
Eukaryota Corynebacterium
Hypothenar Viruses Staphylococcus
palm

Inguinal Toenail
crease

Plantar
Toe web heel
space

..      Fig. 23.3  Microbiome sites: the microbiota composition of each from Creative Commons Attribution: 7 https://creativecommons.­org/
 

tissue is unique. (Reprinted from: 7 https://commons.­wikimedia.­org/

  licenses/by/2.­0/)
wiki/File:Microbiome_Sites_(27058471125).­jpg. With permission

Recommendation of an anti-inflammatory, low-antigenic sive elimination diet, FODMAP diet, and the specific carbo-
food plan can decrease inflammation better than medica- hydrate diet. Although prebiotic, probiotic, and high-fiber
tions. The standard Western diet is inflammatory, so begin foods are health-promoting when we are healthy, these foods
with a whole-food, low-processed elimination diet protocol. feed the microbial imbalance when we have dysbiosis.
Utilizing a therapeutic elimination diet is simple: Avoid foods Therefore, avoiding them for a period of time helps starve out
that potentially cause inflammation and eat only foods that the problematic microbes. These are therapeutic diets and
have a low possibility of provoking a reaction. This is a thera- not meant to become a lifestyle. It’s important to heal the
peutic approach and used for a minimum of 2  weeks to a other underlying factors, so that people can begin eating
maximum of 3 months with a reintroduction phase to deter- more normally again. One caution, is that these diets can
mine which foods provoke reactivation of symptoms. In feed into disordered eating patterns. So, good counseling
some cases, some people may need to stay on a modified about their temporary nature is important. Diet, along with
therapeutic dietary program for up to 2  years until the gut herbal or pharmaceutical treatment for dysbiosis, and heal-
heals completely. Often the foods people react to are the ones ing permeability, provides a synergistic approach for healing.
that we least want to live without. If a patient says “I just For people in whom inflammation, pain, and/or mental
couldn’t live without dairy,” dairy may be that patient’s prob- health issues dominate, try a comprehensive elimination diet. For
lem food. The food groups with the most common reactions people with dysbiosis or those who feel worse eating any carbo-
include refined sugar of all types, gluten-containing grains, hydrates, eating a low-carbohydrate, low-starch diet works best.
dairy products, soy-containing foods, and eggs. Examples of this include the candida diet, body ecology diet, and
There are many types of elimination diets. What they the gut and psychology syndrome diet (GAPS), although cur-
have in common is that they are based in whole foods and rently we have no published research on the benefits.
have the effect of enhancing digestion and absorption, reduc- While many foods may be unmasked during the elimina-
23 ing inflammation, helping to balance the microbiome, tion/provocation challenge, others may remain hidden. To
increasing intestinal permeability, and reducing toxic bur- enhance this process, you may also want to have a blood test
den. Many also restrict carbohydrates. The best studies and for food sensitivities, allergies, and intolerances. Looking at
most frequently utilized approaches include the comprehen- antibodies is examining the adaptive/acquired immune sys-
The GUT-Immune System
375 23
tem. IgG, IgG4, IgA, and IgM tests report on food ­sensitivities, 23.14  Selected Therapeutic Foods
although IgG or IgG4 are most common. IgE testing reports
on true allergic reactions. Testing for lactose, fructose, and Kefir: Supports immune health with a variety of prebiotics
celiac disease reports on enzymatic insufficiencies. Tests such and probiotic microbes. Research reports that it supports
as the MRT-LEAP and ALCAT tests report on the adaptive gut-immune health, improves lactose digestion, has cancer-­
immune process. There is no standardization of food sensi- protective properties, and has been used to heal peptic and
tivity testing; yet, any of these tests can be clinically useful by duodenal ulcers [55]. Kefir can be made from animal milk
lowering the threshold of activation. (cow, goat, sheep, buffalo, yak) or nondairy liquids such as
Sensitivities are rated from normal to severe reactions. In water, nut milk, or seed milk.
addition to a detailed readout documenting individualized Kimchi: Reported to help regulate bowel movements,
reactions, most laboratories also include a list of foods which improve metabolism and weight, reduce high-serum choles-
contain hidden sources of the offending foods, a rotation terol levels, provide anticancer nutrients, promote immune
menu, and other educational material to help patients in the and brain health, and reduce fibrinogen levels [56].
healing process. Ginger: Ginger has been reported in many papers to be
effective for digestive conditions including colic, nausea,
appetite stimulation, and digestion enhancement. It is used
23.13  Prebiotics and Benefits as a prokinetic to enhance motility in small intestinal bacte-
rial and fungal overgrowth [57–59].
Prebiotics are food for the microbes of the microbiome. The Cabbage juice: Research reports that cabbage juice is an
average person today eats few prebiotic-rich foods, although effective immune modulator of peptic ulcers, diabetes, cirrho-
historically we ate many. The definition of a prebiotic is: “A sis, arthritis, and cancers [60]. It has also been reported to
substrate that is selectively utilized by host microorganisms enhance motility and gastric secretion. It contains the nutrients
conferring a health benefit” [52]. In other words, prebiotics glutamine, methionine, and sulforaphanes. The dosage utilized
are food for the symbiotic and commensal microorganisms was a quart of fresh cabbage juice daily for 7–10 days in divided
of the microbiome. Typically, they are “eaten” by the microbes disease. The taste is not pleasant, so diluting it with cherry or
which activates the bioactive food components. They con- pomegranate or other juice may be beneficial for compliance. It
tribute to colon health by synthesizing short-chain fatty is also effective as a dried powder in capsules [61–67].
acids: butyrate, valerate, and propionate. Prebiotics have
been reported to have many benefits (. Fig.  23.4). Some
 

diets, such as the low-FODMAP diet, temporarily restrict

many prebiotic-rich foods. 23.15  Therapeutic Role of Probiotic
Breast milk is a rich source of prebiotics and helps to Supplements
establish the infant microbiome. Common prebiotic foods
include kitchen herbs and spices, legumes, pulses, jicama, The definition of a probiotic is: “live microorganisms that,
Jerusalem artichoke, onions, chicory, garlic, leeks, plantain, when administered in adequate amounts, confer a health
unripe bananas, fruit, burdock root, asparagus, radishes, benefit on the host” [68]. Probiotics from food and supple-
dandelion root, peas, honey, green tea, black tea, cultured ments modulate immune and inflammatory responses.
dairy products, artichoke, tomatoes, beets, and whole grains Probiotics also improve lactose tolerance, enhance metabo-
such as rye, barley, and sprouted wheat. lism, regulate serum lipids, enhance digestive function,

..      Fig. 23.4  Prebiotic benefits.

(Based on data from Refs. Prebiotic Benefits
[52–54])
• Improved bowel function • > bone density (+ calcium)
• Promote growth of Bifidobacteria, • > serum cholesterol and
• Lactobacilli and other beneficial triglycerides
microbes • Cancer protective
• Colon pH • Used in treatment of
• Protect against negative effects of atherosclerosis
bile acids • Immune function
• Substrate for SCFA • Neural and cognitive function
• Improves intestinal permeability • Skin
• Improved Metabolism of • > insulin sensitivity & glucose
microbiota regulation (in all and Type 2 DM)
• Adds sweetness to food • > mineral absorption
• > Satiety • Small but sig. effects body weight
• Stimulates neurochemical
production in the gut
 376 E. Lipski

help control inflammatory bowel disease and irritable 7. Tamura M, Ohnishi Y, Kotani T, Gato N.  Effects of new dietary
bowel syndrome, improve innate immunity, inhibit infec- fiber from Japanese Apricot (Prunus mume Sieb. et Zucc.) on
gut function and intestinal microflora in adult mice. Int J Mol Sci.
tion, and balance the microbiome [69]. Probiotic supple- 2011;12(4):2088–99.
mentation has demonstrated benefits in virtually all health 8. Enomoto S, Yanaoka K, Utsunomiya H, Niwa T, Inada K, Deguchi H,
conditions. They have been shown to be of benefit in diges- et al. Inhibitory effects of Japanese apricot (Prunus mume Siebold
tive and immune conditions including celiac disease, para- et Zucc.; Ume) on Helicobacter pylori-related chronic gastritis. Eur J
sitic infection, H. pylori infection, inflammatory bowel Clin Nutr. 2010;64(7):714–9.
9. Lord RBJ, editor. Laboratory evaluations for integrative and func-
disease, bariatric surgery, irritable bowel syndrome, cardio- tional medicine. 2nd ed. Duluth: Metametrix Institute; 2009.
metabolic syndrome, allergy, lupus erythematosus, rheu- 10. Grethlein SJ, Besa EC.  Mucosa-associated lymphoid tissue.

matoid arthritis, and lower serum cortisol levels. They can Emedicine [Internet]. 2008. [cited assessed 29 Jan 2010]. https://
also help protect from a variety of cancers. What is less emedicine.medscape.com/article/207891-overview.
exactly known is what strains, dosages, and timing of spe- 11. Jahn HU, Ullrich R, Schneider T, Liehr RM, Schieferdecker HL, Holst H,
et al. Immunological and trophical effects of Saccharomyces bou-
cific probiotics to use in specific people at a specific moment lardii on the small intestine in healthy human volunteers. Digestion.
in time. Dosages range from millions of colony-forming 1996;57(2):95–104.
units (CFU) daily to trillions of CFU of supplemental pro- 12. Buts JP, Bernasconi P, Vaerman JP, Dive C.  Stimulation of secre-
biotics daily. tory IgA and secretory component of immunoglobulins in small
intestine of rats treated with Saccharomyces boulardii. Dig Dis Sci.
1990;35(2):251–6.
13. Kono H, Fujii H, Asakawa M, Maki A, Amemiya H, Hirai Y, et  al.
23.16  Conclusion Medium-chain triglycerides enhance secretory IgA expression
in rat intestine after administration of endotoxin. Am J Physiol
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JJ, et  al. Zonulin as prehaptoglobin2 regulates lung permeability
clinical pearls to direct the nutrition care process. Research
and activates the complement system. Am J Physiol Lung Cell Mol
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temic balance and disease, and the role of food, nutrition, 15. Fasano A. Intestinal permeability and its regulation by zonulin: diag-
and lifestyle is ballooning exponentially and will continue to nostic and therapeutic implications. Clin Gastroenterol Hepatol.
evolve. Common themes for balancing the gut-immune sys- 2012;10(10):1096–100.
16. Fasano A. Zonulin and its regulation of intestinal barrier function:
tem include stress management, increases in dietary poly-
the biological door to inflammation, autoimmunity, and cancer.
phenols and plant bioactive components, use of digestive Physiol Rev. 2011;91(1):151–75.
healing therapeutic dietary approaches, and inclusion of pro- 17. Fasano A. Zonulin, regulation of tight junctions, and autoimmune
biotic- and prebiotic-rich foods and supplements to modu- diseases. Ann N Y Acad Sci. 2012;1258:25–33.
late immune expression and promote health. Of critical 18. Hunt PW.  Leaky gut, clotting, and vasculopathy in SIV.  Blood.

2012;120(7):1350–1.
importance is optimizing barrier function of the enterocytes
19. Lee SH. Intestinal permeability regulation by tight junction: impli-
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Diet and lifestyle play a major role in maintaining gut-­ 20. Lerner A, Matthias T.  Possible association between celiac disease
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21. Li X, Atkinson MA. The role for gut permeability in the pathogen-
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 379 24

Centrality of the GI Tract

to Overall Health
and Functional Medicine
Strategies for GERD, IBS,
and IBD
Ronald L. Hoffman

24.1 Impact of the GI Tract on Immunity – 380

24.2 GI Impact on the Brain – 381

24.3 GI Endocrine Effects – 381

24.4 GI Impact on Metabolism – 381

24.5 GERD – 382

24.6 Diet for GERD – 382

24.7 Supplements for GERD – 383

24.8 Irritable Bowel Syndrome – 383

24.9 GI-IBD – 385

References – 387

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_24
 380 R. L. Hoffman

“All disease begins in the gut.” This quote is frequently attrib- programmed; its proper acquisition is encouraged by inocu-
uted to the ancient Greek physician Hippocrates nearly lation via vaginal birth and supported by humoral factors
2500 years ago. Traditional medical systems acknowledged the secreted in breast milk. Western lifestyle is thought to pose
primacy of the gut as many remedies for systemic disorders serious challenges to the integrity of the microbiome (see
involved purgatives to expel toxins and pernicious humors. . Table 24.1, “Factors that undermine the microbiome”).
 

With the Scientific Revolution, the emergence of a ratio- To turn the conventional paradigm on its head, the GI
nalistic model ushered in insights about the process of diges- tract is not merely a conduit for feces, but rather a carefully
tion and nutrient assimilation. This resulted in a more engineered housing for the microbiome, which itself may
reductionist model of the “alimentary canal” as a food tube well deserve the status of an organ, with multiple functions.
with little function except as a mere conduit for nutrients and
waste products (see . Fig. 24.1).
 

Nevertheless, the early twentieth century saw a reinstate- 24.1  Impact of the GI Tract on Immunity
ment of a more global appreciation of the role the GI tract
plays in overall physical and mental well-being [1, 2]. The intestinal microbiota are important constituents of the
The pioneering work of Eli Metchnikoff highlighted the human immune system and are essential for protection against
involvement of intestinal microbes in promoting or attenuat- pathogens. Evidence supporting this comes from studies show-
ing “autointoxication.” This was accompanied by popular ing that animals bred to be germ-free are highly susceptible to
reform movements, such as that of John Harvey Kellogg call- infection. The presence of commensal microbes provides nec-
ing for enemas, fiber, and fasting to avert “toxemia.” Radical essary stimulation to the intestinal immune system which, via
surgeons even proposed colectomies to abrogate the “autoin- structures like Peyer’s patches, regulates local and systemic
toxication” that was a presumed cause of “melancholia.” [3] immune responses via the elaboration of immunoglobulins [5].
The pendulum soon swung back with a firm repudiation
of intestinal toxicity as an imaginary hypothesis. In 1912,
famed pediatric surgeon Hastings Gilford stated that “autoin-
toxication, the term as we commonly use it, is significant of Nutrient
Assimilation
nothing but a sort of mental flatulency on the part of the user
as a substitute for thought.” [4]
Consequently, investigation of the role of the GI tract as a Immunity Metabolism
determinant of overall health was kept in abeyance for much
of the twentieth century, until a recent resurgence of interest
in the microbiome led to a greater appreciation of its role in
mediating metabolism, immunity, brain health, and endo- GI Tract
crine function.
Microbiota lie within the anatomical gut. They consist of
communities of bacteria, fungi, and viruses. Rather than being
casual colonizers, the constituents of the microbiome elabo- Brain Endocrine
rate essential nutrients, provide immunological signaling,
perform detoxifying functions, influence metabolism, and
­
influence neurotransmitters and hormones (see . Fig. 24.2).
 
Detoxification
The essentiality of intestinal flora that makes up the
microbiome has been underscored by experiments in which
germ-free animals encounter numerous liabilities. The com- ..      Fig. 24.2  Broader understanding of the GI tract’s bidirectional
position of the microbiome is, to some extent, genetically systemic relationships

..      Fig. 24.1  Mechanistic model

of GI tract

Nutrients

Waste
Nutrition Alimentary Canal
Products

24
Centrality of the GI Tract to Overall Health and Functional Medicine Strategies for GERD, IBS, and IBD
381 24
Clinical studies in humans suggest a robust effect of pro- 24.3  GI Endocrine Effects
biotic supplementation on infectious disease susceptibility.
Frequency and duration of upper respiratory infections were The GI tract influences endocrine function in many ways.
reduced with oral probiotic administration [6]. The systemic immune dysregulation that underlies celiac dis-
It has also been demonstrated that human microbial dys- ease—and even non-celiac gluten sensitivity—has been
biosis is associated with production of pathogenic cytokines, shown to be associated with thyroid autoimmunity, with
which suggests a causative role in inflammatory and autoim- consequent hypothyroidism [15]. In a reciprocal fashion, the
mune disorders [7]. Researchers revealed that the presence of intestinal stasis that is sometimes a feature of hypothyroid-
filamentous bacteria in young mice with an engineered pre- ism has been demonstrated to reinforce small intestinal bac-
disposition to autoimmunity caused spontaneous generation terial overgrowth (SIBO), perpetuating a vicious cycle
of antibodies to cell nuclei – a feature of autoimmune disor- wherein dysbiosis generates pathological cytokines that pro-
ders like lupus and systemic sclerosis [8]. Multiple sclerosis mote thyroid autoimmunity.
patients were found to have reduced levels of good bacteria Bacterial action is, in part, responsible for conjugation
ordinarily derived from diets high in healthy fiber [9]. and enterohepatic processing of endogenous sex hormones
Children with MS had different intestinal bacteria than those and xenobiotics (sometimes referred to as “gender benders”).
without MS [10]. Hence, dysbiosis may be linked to such conditions as estro-
gen dominance, menstrual abnormalities, and reproductive
system cancers [16]. The impact of the microbiome may
24.2  GI Impact on the Brain account for the demonstrated ability of oral administration
of fiber and especially lignans from flax and other plant
The gut-brain connection is now the subject of intense inves- sources to attenuate hormone imbalances.
tigation. A well-acknowledged example of the impact of the Lipopolysaccharides (LPS) from bacteria have also been
GI tract on brain function is the phenomenon of hepatic shown to inhibit growth hormone (GH), which may help
encephalopathy in patients with advanced liver cirrhosis. account for the growth retardation seen in children with
Asterixis and delirium are relieved by administration of an inflammatory bowel disease—which is sometimes treated
osmotic laxative (lactulose) and luminally active antibiotics with growth hormone injections.
(neomycin and more recently rifaximin). Lately, probiotics It is even thought that the intestinal microbiome exerts an
have been shown to prevent hepatic encephalopathy in cir- effect on skeletal fitness via its impact on sex hormones, glu-
rhotics [11]. cocorticoids, serotonin, PTH, and cytokines [17].
Speculation has arisen over the relationship between
­dysbiosis and neurodevelopmental disorders like autism. It
has been demonstrated that children with autism have dif- 24.4  GI Impact on Metabolism
ferent bacteria and that their microbiota may modulate
behavioral and physiological abnormalities [12]. While psy- In a series of remarkable experiments, it was demonstrated
chological stress has been found to alter the microbiome, that propensity to obesity can be transferred from a fat rodent
the authors conclude that bacterial anomalies are the cause, to a thin rodent via fecal inoculation; the converse also occurs
not the consequence of, behavioral disorders [13]. when flora from lean animals are transferred to fat animals
Additional evidence has been adduced for the role of the [18]. This underscores the notion that disruption of normal
microbiome in Parkinson’s disease, Alzheimer’s disease, intestinal flora (dysbiosis) can predispose to metabolic
depression, and anxiety. In fact, clinical trials of probiotic derangement—even diabetes and associated comorbidities.
administration have been demonstrated to impact mood [14]. There is evidence that the relative balance of two major
bacterial phyla within the digestive tract—Firmicutes and
Bacteroidetes—is a determinant of susceptibility to weight
..      Table 24.1  Factors that undermine the microbiome gain [19]. This has prompted speculation that the global obe-
sity epidemic is fueled not just by caloric excess and sedentary
Antibiotics, antimicrobials (intentionally Artificial ­sweeteners lifestyle but also by harmful environmental influences on the
administered or from food or water) microbial diversity that characterizes a healthy microbiome.
Chlorinated, fluoridated water Drugs (PPIs, H2 While this phenomenon has not been definitively con-
blockers) firmed in humans, there are anecdotal accounts of individu-
als who have received fecal transplants for Clostridium
C-section Stress
difficile infections and became overweight after the donors
Lack of breastfeeding Sedentary lifestyle were not properly screened for obesity [20].
Refined carbohydrates Western hygiene Additionally, while it was once thought that the weight
loss in gastric bypass surgery was mechanistically attributable
Inadequate fiber and polyphenols GMOs?
to deliberately induced malabsorption and/or reduced gastric
Chemicalized food (e.g., emulsifiers) volume, new evidence has emerged that alterations in the GI
microbiome may be, at least in part, responsible for altered
 382 R. L. Hoffman

metabolic disposition of consumed nutrients. Transfer of gut

microbiota from Roux-en-Y-treated mice resulted in weight Box 24.1  Conditions associated with chronic proton
loss in surgically naive mouse recipients, suggesting a robust pump inhibitor use
effect of microbial alteration on weight [21]. 55 Nutrient deficiencies
55 Osteoporosis
How does the microbiome exert its influence on metabo- 55 Susceptibility to gastroenteritis and Clostridium difficile
lism? For one, nutrient extraction may be dependent on 55 Coronary artery disease/MI
microbiota composition. For another, byproducts of micro- 55 Stroke
bial degradation of nutrients may play a role in signaling 55 Dementia
complex regulatory pathways, promoting or attenuating 55 Pneumonia
55 Irritable bowel syndrome
appetite and weight gain via insulin, adiponectin, leptin, or 55 Nausea, rash, headache
intestinal peptides [22]. Additionally, the presence of certain
organisms may promote inflammation, an acknowledged
contributor to metabolic syndrome [23].
The relationship of the microbiome to metabolism is now
the subject of intense research. NIH funds were recently autho- 24.6  Diet for GERD
rized for a study to see if the microbiome is linked to diabetes
risk in Hispanic Americans, a population that has seen obesity Lifestyle interventions have long been fundamental to manage-
rates skyrocket secondary to cultural changes [24]. ment of GERD symptoms. Patients are exhorted to lose weight,
per likelihood that intra-abdominal pressure associated with
excess girth may prompt reflux. They should eat smaller meals
24.5  GERD and refrain from eating before recumbency at bedtime. They
should elevate the head of their beds, but not simply use extra
For nearly 80 years, it has been unchallenged scientific dogma pillows, which can increase pressure on the abdomen. Tight,
that heartburn (more recently dubbed gastroesophageal constricting clothing should be avoided. Smoking is discour-
reflux disease or GERD) is a matter of unchecked acid secre- aged. Use of aspirin and NSAIDs, which have an erosive effect
tion. Tens of millions of Americans have chewed calcium on the esophageal lining, is to be minimized.
pills, quaffed first-generation acid blockers (Tagamet, Zantac, Traditional GERD diets entail elimination of classic food
Pepcid), and now are reliant on even more powerful proton and beverage precipitants:
pump inhibitors (PPIs) like Prilosec, Prevacid, Nexium, 1. Acidic foods and beverages like coffee, citrus, tomatoes,
Aciphex, and Protonix. and vinegars
But according to a revolutionary new study, we may have 2. Carbonated beverages, which induce belching
been barking up the wrong tree: GERD is now thought to be 3. Fried and fatty foods, which delay gastric emptying
caused by inflammation, not just hyperacidity. Researchers at 4. Spicy food
the University of Texas Southwestern Medical Center and 5. Peppermint candies or gum, which relax the lower
Dallas VA Medical Center have proven that GERD is actually esophageal sphincter
an inflammatory response prompted by the secretion of pro-­ 6. Alcoholic beverages
inflammatory cytokines [25].
Researchers “burned” the intestinal linings of mice with But, in clinical practice, these measures often fail to curtail
acid equivalent to the pH of refluxed gastric juice. They dis- GERD symptoms. The reason may be that some patients
covered that the resulting damage was not consistent with the have idiosyncratic reactions to specific “innocuous” foods,
typical pathology of GERD.  Rather, the acid triggered a like dairy, wheat, or eggs. These intolerances are unlikely
­slow-­developing inflammatory cascade that took weeks to to be revealed by allergy skin testing or the IgE
resemble the usual findings of GERD. RAST. Rather, they must be unmasked via elimination and
This doesn’t mean that acid suppression is without value reintroduction.
in treating GERD. But it does suggest that targeting inflam- Additionally, many patients with GERD react to the ubiq-
mation would be a better way of treating and preventing it, uitous food additive MSG, often overlooked as a harmless
especially since long-term PPI use has so many side effects “natural flavoring” in processed foods. MSG provokes gastric
(see 7 Box 24.1).
  acid hypersecretion [26].
Additionally, many GERD patients obtain only incom- A promising avenue for patients unresponsive to the
plete or partial relief from their antacid drugs. Why should usual diet measures for GERD is the very low-carbohydrate
this matter to the estimated 20% of Americans suffering from (VLC) diet. In a small sample of patients, the VLC diet dem-
upper GI pain? While acid blockers offer temporary relief, onstrated symptom relief and reduced distal esophageal acid
they don’t get to the bottom of the problem. Additionally, exposure [27]. While the authors claim the mechanism for
chronic use may engender rebound hyperacidity. Therefore this improvement is unknown, it is likely that carbohydrate
millions of Americans remain reliant on them, sometimes for restriction reduces microbial proliferation in the gut, as in
24 their entire lifetimes. IBS.
Centrality of the GI Tract to Overall Health and Functional Medicine Strategies for GERD, IBS, and IBD
383 24
24.7  Supplements for GERD tional digestive aids, Iberogast promotes optimal gastric
emptying and intestinal transit, alleviating the stuck feeling
DGL (Deglycyrrhizinated Licorice)  While DGL has not been that many GERD sufferers experience. Due to its dual anti-
formally studied for GERD, studies in the 1980s demonstrated bacterial and pro-motility effects, Iberogast is ideal for suffer-
its curative effects in gastritis. While licorice has demonstrable ers of SIBO (small intestinal bacterial overgrowth), a frequent
anti-inflammatory effects, it contains a substance, glycyrrhet- contributor to the reflux and sour eructation of heartburn
inic acid, which can cause pseudoaldosteronism, a condition sufferers.
where the body retains sodium, loses potassium, and accumu-
lates fluid volume, sometimes resulting in edema and hyper- Aloe  Another traditional remedy for gastrointestinal ail-
tension. ments, aloe is most familiar as a home first-aid treatment for
burns—hence its application to esophageal inflammation.
Melatonin  Considerable research validates the benefits of For aloe to work best, it is preferable to use the gel form,
melatonin in GERD. Melatonin [28] is best known as a sleep in generous amounts, away from food. I generally suggest ¼
aid and circadian rhythm regulator. In the body, it is manufac- cup of a purified aloe gel product or fresh aloe juice 3 or 4
tured by the pineal gland, located deep within the brain. Often times daily away from meals.
overlooked is that the gastrointestinal tract contains up to 400 In a recent study, aloe syrup was found to be comparable
times more melatonin than is secreted by the pineal gland. to Zantac and Prilosec in relieving symptoms of GERD and
Research demonstrates that melatonin has the ability to sup- was well tolerated [31].
press excess acid production. It also shields the GI lining from
the destructive effects of free radicals caused by stress, toxic Probiotics  No formal studies have been done on administer-
agents, or ulcer-causing drugs like NSAIDs. ing probiotics for GERD.  But it stands to reason that easing
A recent study showed that melatonin outperformed dysbiosis might relieve out-of-control bacterial proliferation
famotidine and boosted the effectiveness of omeprazole in which can lead to upper intestinal gas and upward reflux of
alleviating symptoms and preventing tissue damage in patients stomach contents.
with GERD [29]. The researchers summarized: “From the
results of our study, it can be concluded that melatonin could Acidify  Among the more controversial theories about GERD
be used in the treatment of GERD, either alone or in combina- is that it may be the paradoxical result, not of too much stom-
tion with omeprazole. The combination therapy of both mela- ach acid, but of too little. This condition, called hypochlorhy-
tonin and omeprazole is preferable, as melatonin accelerates dria, is known to be common in individuals over 50, especially
the healing effect of omeprazole and therefore shortens the women.
duration of treatment and minimizes its side effects.” The sug- According to this theory, popularized by Jonathan
gested dose of melatonin for GERD is 3–6 mg at bedtime. Wright, MD, and others, lack of stomach acid results in poor
motility, and incompletely digested food remains in the
Mucilaginous Substances  Marshmallow, plantain, and apple stomach, causing reflux [32]. This theory seems logical, as
pectin are mucilaginous substances that soothe the esophageal adequate acidification of the stomach can be a signal for gas-
mucosa; they belong to a category of herbs known for demul- tric emptying, enabling food to transit to the small intestine.
cent properties. On the other hand, the strategy can backfire: Some GERD
sufferers report worsened pain when they take acid supple-
Limonene  While its method of action is poorly understood ments like betaine hydrochloride as a digestive aid prior to
and there is a dearth of human clinical studies, d-limonene, a meals. Therefore, a cautious empirical trial of a capsule or
terpene extract of citrus fruit, has been advanced as a potential two of betaine HCl prior to meals (some patients prefer a
ameliorant for GERD [30]. tablespoon or two of apple cider vinegar) might be warranted
in some cases of GERD, if it eases symptoms.
Alginate  A “raft-forming agent” in the presence of gastric
acid, alginate forms a gel. In the presence of bicarbonates added
to the formula, alginate forms a pH buffer layer that offers pro- 24.8  Irritable Bowel Syndrome
tection to the esophageal mucosa.
Irritable bowel syndrome (IBS) was once thought to be
STW 5 (Iberogast)  A popular German formulation used mostly psychogenic in origin, because there were no sero-
extensively in Europe for treatment of dyspepsia, Iberogast is a logical markers or definitive pathological changes to set it
liquid combination of the herbs Iberis amara, Angelica, cham- apart from distinct organic conditions like inflammatory
omile, caraway fruit, St. Mary’s thistle, balm leaves, peppermint bowel disease (IBD). We now know that there are a variety of
leaves, celandine, and licorice root. Together, they exert anti-­ measurable factors that characterize it.
inflammatory, antibacterial, and pro-motility effects. While essentially a diagnosis of exclusion in the absence
The latter makes Iberogast particularly helpful for of other disease entities deemed more “serious,” IBS can
GERD.  By including certain herbal “bitters” that are tradi- roughly be categorized into diarrhea predominant (IBS-D)
 384 R. L. Hoffman

or constipation predominant (IBS-C), with a considerable D. One reason for the embrace and commercialization of this
proportion of cases occupying the middle ground where paradigm has been the introduction of the luminally active
diarrhea may alternate with constipation with associated antibiotic rifaximin, which can curtail bacterial proliferation
bloating, urgency, tenesmus, mucus in the stool, and colicky in the small intestine. But results can be temporary and
pain (mixed type or IBS-M). equivocal, especially if patients do not address dietary pre-
Recently, considerable interest has been generated about cipitants of IBS.
a subtype of IBS, dubbed postinfectious, which may be the Of course, celiac disease must be ruled out, but even in
long-term sequel to a bout of gastroenteritis. Symptoms per- the absence of serological markers or biopsy-proven ana-
sist, despite resolution of the initial infection, with no dis- tomical changes to the villi, non-celiac gluten sensitivity can
cernible traces of the implicated pathogen. The theory is that be a major contributor to IBS [34]. While gluten elimination
the infection may set the stage for prolonged dysbiosis; alter- is mostly helpful for IBS-D, the presence of opiate-like glia-
natively, there may be low-grade microscopic colitis, with dorphins in gluten may sometimes account for stubborn
lymphocyte aggregations seen on biopsy, but without the cases of constipation. Similarly, casomorphins from dairy
characteristic ulcerations or granulations pathognomonic of products can trigger mu receptors in the colon, slowing
IBD. Indeed, a new blood test has been introduced to identify intestinal transit.
postinfectious IBS [33]. Another way of defining optimal diets for IBS sufferers is
Much has been written about visceral hypersensitivity, by means of allergy testing. Conventional skin testing and
genetically determined or acquired, in which feedback from IgE RAST testing are not useful for identifying food precipi-
the enteric plexus is amplified by aberrant brain circuits. tants of IBS, but one study has demonstrated utility of IgG
From a conventional medicine standpoint, this argues for the food allergy testing [35].
use of bowel antispasmodics or antidepressant/anxiolytic A useful accoutrement to antimicrobial treatment of
medications. On the other hand, adopting a holistic perspec- SIBO, as well as a worthwhile starting point to test the effi-
tive, natural modalities such as yoga, relaxation and medita- cacy of an elimination diet for IBS symptoms even prior to
tion, biofeedback, hypnotherapy, and acupuncture might be initiation of antimicrobial therapy, is the low-FODMAP
invoked. (fermentable oligosaccharides, disaccharides, monosaccha-
Fiber is often tapped by gastroenterologists as a panacea rides, and polyols) diet. Rather than a diet per se, it proposes
for IBS, but it is uncertain whether refined forms of soluble or a trial elimination of potentially problematic carbohydrates
insoluble fiber confer the benefits of plant polyphenols, pres- and sugar alcohols (see . Table  24.2) [36, 37]. These are
 

ent in fresh fruits and vegetables and even coffee, chocolate, thought to provoke symptoms due to partial indigestibility
spices, and tea, which may be vital substrates for cultivation (e.g., disaccharide intolerance), osmotic laxative action (e.g.,
of a healthy intestinal flora. For many Westerners on diets ­polyols), or as a substrate for gas-generating fermentation. A
bereft of fiber, adding dietary or supplemental fiber may go a recent study confirmed that IBS-D patients assigned to a
long way toward resolving digestive issues. On the other low-­FODMAP diet for 4 weeks obtained statistically signifi-
hand, overzealous fiber replacement may exacerbate IBS cant symptom relief [38].
symptoms. The low-FODMAP diet is not meant to be a lifelong pre-
Of late, the concept of SIBO (small intestinal bacterial scription that requires rigid adherence; rather, it is a means
overgrowth) has been popularized as way of addressing IBS-­ for patients and nutritionists to identify potential food pre-

..      Table 24.2  Common foods high in FODMAPs

Fructose Lactose Fructans Mannitol Sorbitol Galactans

Fruit: Apples, Dairy (cow, Fruit: Custard apples, white Fruit: Stone Fruit: Apples and Legumes: Chickpeas,
mango, pear, goat, peaches, nectarines, fruits, peach, stone fruits; lentils, legumes (e.g.,
watermelon sheep) persimmon, watermelon watermelon sugar-free candies kidney beans, soy
Vegetables: Vegetables: Artichokes, Veggies: and gum beans)
Asparagus, garlic, leek, onion, spring Cauliflower, Others: Sorbitol
artichokes, sugar onion (white part only), mushrooms,
snap peas shallot snow peas
Others: Agave, Grains/cereals: Barley, rye, Others: Mannitol
high-fructose corn wheat-based food products
syrup, honey Nuts and legumes: Cashews,
pistachios, chickpeas,
legumes, lentils
Others: Fructo-­
oligosaccharides, inulin

24 Based on data from Refs. [36, 37]

Centrality of the GI Tract to Overall Health and Functional Medicine Strategies for GERD, IBS, and IBD
385 24
cipitants. Foods originally proscribed on the low-FODMAP studies have supported benefits of lactobacilli as well as the
diet that are well tolerated may be reintegrated. probiotic “cocktail” VSL#3® [42].
Natural antimicrobials have applicability to SIBO because For acute diarrhea, the use of the soluble fiber pectin,
of their broad spectrum of action that discourages antibiotic along with adsorbent clays like kaolin, may rid the intestine
and fungal resistance, their tolerability, relative affordability, of irritating bacterial endotoxins.
and potential for long-term administration. These include New discoveries have led us to appreciate the role that
berberine from Oregon grape root; aromatic oils from oreg- histamine may play in provoking intestinal symptoms. The
ano, thyme, sage, and rosemary; olive leaf polyphenols; gen- intestinal lining is richly populated with mast cells that
tian; and allicin-rich garlic extracts. release histamine in combination with zonulin, a substance
Enteric-coated peppermint oil is well studied for reliev- that disrupts gap junctions of intestinal epithelial cells and
ing the symptoms of “spastic colon,” a term formerly used for alters permeability. This may account for extraintestinal
a common manifestation of IBS.  In time-release form, the manifestations of not just celiac disease but also other less
peppermint is released past the gastroesophageal junction, classic forms of food intolerance or dysbiosis.
where it might exert a relaxing effect, prompting reflux. Just as it does in the nasal passages, histamine produces
Instead, the peppermint acts on the intestinal smooth mus- hyperemia, swelling, mucous secretion, and pain in the GI
cle, where it slows peristalsis by delaying the action potential tract. Histamine-mediated intestinal symptoms may be
of muscle fibers. In addition, peppermint has broad-­spectrum attenuated by a low-histamine diet and by administration of
antimicrobial effects, helping to alleviate SIBO. diamine oxidase (DAO), now available as an OTC supple-
Certain botanical agents possess pro-motility effects, which ment. DAO, normally produced by the intestinal epithelial
can overcome constipation, but also relieve the stasis which cells, acts to metabolize excess histamine. The bioflavonoid
perpetuates colonization of the small intestine via transloca- quercetin also can attenuate the histamine response.
tion of inappropriate colonic bacteria. These include the carmi- Since microscopic colitis is implicated in certain subtypes
native oils which are said to soothe the gastrointestinal tract, of IBS, it has been proposed that IBS sometimes represents a
stimulate appetite and the release of digestive enzymes, and forme fruste of IBD; therefore some of the following strategies
promote peristalsis and gastric emptying. They include fennel, employed for IBD may be equally warranted for stubborn
cardamom, cumin, caraway, lemon balm, as well as many other IBS symptoms.
herbs that are said to possess carminative properties.
Chamomile has a long tradition of use in treatment of
gastroenteritis and especially IBS-D. It is thought to impart 24.9  GI-IBD
soothing and antispasmodic effects, with a mild CNS seda-
tive component [39]. The term “colitis” comprises several types of inflammatory
A formula consisting of nine herbs (including some of the intestinal disorders, as distinguished from irritable bowel
aforementioned), STW 5 (Iberogast®), has been approved syndrome (IBS), a “functional” disorder of motility in which
and used safely for five decades in European countries for the gross pathological changes are not apparent. The main types
treatment of functional dyspepsia and IBS [40]. For constipa- of colitis are ulcerative colitis (UC) (and its subtype ulcer-
tion, a gradual ramp-up of magnesium citrate can prove ative proctitis) and Crohn’s disease (CD), which have differ-
helpful without the dependency of herbal laxatives that con- ent characteristic appearances and radiological and blood
tain anthraquinones. Prebiotics from kiwi fruit, acacia, and testing presentations. They are collectively referred to as
fructo-oligosaccharides (FOS) may help to alleviate consti- inflammatory bowel disease (IBD).
pation, but care must be taken lest they produce uncomfort- There is now evidence that, on closer examination, a
able gas and bloating (they are specifically contraindicated fairly high percentage of IBS patients actually have “micro-
on the low-FODMAP diet). scopic colitis” in which intestinal surface cells show signs of
Hydrochloric acid and digestive enzymes may play a role damage, helping us to appreciate that the colitis spectrum
in relieving IBS symptoms by facilitating complete break- may be wider than previously thought.
down of food constituents. In addition, while CD and UC have not generally been
Administration of certain strains of probiotics is docu- thought of as infectious diseases, one form of colitis, pseudo-
mented to alleviate IBS-C [41]. Less consistent results have membranous colitis, is known to be caused by a bacterium,
been seen in IBS-D. In the latter, it may be that certain spe- C. difficile.
cies exert competitive inhibition or possess antimicrobial More researchers are coming to accept that imbalances in
properties that discourage the proliferation of harmful flora. intestinal flora may be at the root of IBD [43]. Immune cells
Alternatively, probiotics may exert a direct or indirect ame- in the walls of the intestinal tract are engaged in continual
liorative effect on low-grade chronic intestinal immune acti- “cross-talk” with the trillions of bacteria that inhabit our gut.
vation that characterizes some forms of IBS. A recent pilot When beneficial bacteria are suppressed and harmful bacte-
study showed alleviation of each of the cardinal symptoms of ria proliferate, the intestinal defense system may go into
IBS (abdominal pain/discomfort, distention/bloating, and “overdrive,” resulting in an exaggerated immune response
difficult defecation) with Bifidobacterium infantis; other and triggering autoimmunity and consequent inflammation.
 386 R. L. Hoffman

This disordered state of intestinal microbes is sometimes This has led some to propose a return to a “paleo diet” to
referred to as “dysbiosis.” Evidence that dysbiosis might be a ameliorate the symptoms of IBD [48]. This ancestral diet
contributing factor in IBD comes from several sources. highlights organic or grass-fed meat, chicken, and eggs; fish
Frequent administration of antibiotics is known to be a risk and shellfish; fresh, organic fruits and vegetables; and nuts
factor for IBD, and UC and CD patients sometimes suffer and seeds. Conspicuously absent are grains, dairy products,
exacerbations of their disease after antibiotics are prescribed legumes, nightshade family vegetables, processed and refined
for other conditions. foods, and sugar.
Also, use of powerful acid-blocking medications increases Alternatively, some advocate the specific carbohydrate
the risk for IBD, probably because it alters the intestinal flora. diet (SCD) for IBD. This grain-free, animal protein, and
Breastfeeding, perhaps because of its “priming” effects on the fruit/vegetable diet has many similarities to the paleo diet,
intestinal immune system, appears to be protective against except that it more stringently emphasizes starch avoidance
IBD [43]. while permitting fermented dairy products for those not spe-
In some studies, probiotics appear to ameliorate the symp- cifically intolerant to cow’s milk [49] (see 7 Boxes 24.2 and
 

toms of IBD [44], but no one is yet sure which probiotics work 24.3). The goal of the SCD is to “break the vicious cycle” of
best, or in what form or dosage. Promising research [45] sug- microbial proliferation by denying pathogenic bacteria their
gests that fecal flora harvested from healthy donors can help preferred substrate of partially indigestible carbohydrate—
sufferers of IBD, but human trials are carefully regulated by much the same as the rationale for the low-FODMAP diet,
the FDA and results have been mixed, with case reports of with which the SCD shares similarities.
adverse consequences such as inadvertent transmission of
cytomegalovirus resulting in acute exacerbation [46].
Commonly used medications sometimes play a role. Box 24.2  Specific carbohydrate DIET (SCD)
Nonsteroidal anti-inflammatory drugs (NSAIDs) may set the 55 No disaccharides: lactose, sucrose, high-fructose corn syrup
stage for IBD by damaging the intestinal surface. 55 No grains
55 No agar, carrageenan, or seaweed derivatives
Additionally, stress provokes IBD.  Anxiety and depres-
55 No starchy legumes (some permitted)
sion are associated with increased CD activity, and signals 55 No starchy vegetables (potatoes, sweet potatoes,
from the brain have been shown to influence inflammation parsnips, corn, etc.)
by altering intestinal barrier function and even leading to 55 No processed meats
changes in the composition of intestinal flora. 55 Based on data from Ref. [49]
Whether because of overdependence on pharmacological
drugs, refined foods, or other factors, IBD incidence is on the
rise in developed countries, affecting as many as 1.4 million
Americans, nearly 0.5% of the population. Some point to the Box 24.3  Foods allowed on SCD
“hygiene hypothesis,” which proposes that our conquest over 55 Unprocessed meats, eggs, poultry, fish
unsanitary conditions has increased the likelihood that our 55 Most non-starchy vegetables
55 Most fruits and juices
idle immune systems will inappropriately target our own tis-
55 Plain yogurt and lactose-free natural cheese
sues in a misguided attack. Supporting this notion is research 55 Nuts and nut flours for baked goods
suggesting that introduction of the nonpathogenic helminth 55 Pulses, navy, string, lima beans
Plasmodium ovale into the GI tracts of IBD sufferers can 55 Oils, light tea and coffee, distilled alcohols, honey
induce remission via immunological “decoying” [47]. 55 Based on data from 7 www.­scdiet.­org
 

The role of diet cannot be underestimated. Major changes

in the Western diet have accompanied unprecedented rises in
the incidence of IBD over the last 75 years. Introduction of A recent first-of-its-kind study validated the benefits of the
refined and sugar- and chemical-laden foods has probably SCD in children with ulcerative colitis and Crohn’s disease.
fueled the epidemic. Globalization of the food supply has At the end of 12 weeks of strict adherence to the SCD, 8 of 10
rapidly introduced dairy products, cereal grains, potatoes, patients who finished the study showed significant improve-
tomatoes, legumes, and other novel dietary items into the ments and achieved remission from the dietary treatment
diets of populations not accustomed to these foods. alone [50]. On the other hand, stringent limitation of oligo-
Ubiquitous trans fats and refined omega-6 vegetable oils are saccharides may, at least in theory, have adverse conse-
thought to promote inflammation. quences for IBD sufferers. The selfsame banned fermentable
Certain food additives have been implicated in the causa- starches, upon bacterial degradation, yield beneficial short-
tion and perpetuation of IBD. “Microparticles,” such as tita- chain fatty acids (SCFAs) like butyrate, which nourish colonic
nium dioxide, are frequently added to food and have mucosa [51]. Indeed, some human trials have shown benefits
razor-like effects on the intestinal lining. Carrageenan, a of rectal instillation of sodium butyrate for proctitis and
“natural” seaweed derivative frequently added to foods to topical application for pouchitis.
improve texture and “mouth feel,” has been shown to inflame Administration of oral butyrate supplements seems to be
24 the intestinal lining in susceptible persons. Emulsifiers have less efficacious than encouraging endogenous production via
recently been implicated. diet. Prebiotics that promote SCFAs include resistant starches
Centrality of the GI Tract to Overall Health and Functional Medicine Strategies for GERD, IBS, and IBD
387 24

..      Table 24.3  Nutraceuticals for IBD

FODMAP Curcumin EGCG (green tea polyphenol)

Boswellin N-acetyl glucosamine (NAG)

Conjugated linolenic acid (CLA) Melatonin

Allergy SCD
Phosphatidylcholine Propionyl-L-carnitine (GPLC)

Fish peptides Omega-3

Paleo Aloe
Resistant
starch

A traditional naturopathic remedy for bowel disorders is

Bastyr (Robert’s) Formula B, consisting of marshmallow,
..      Fig. 24.3  GI diet similarities wild indigo, geranium, goldenseal, slippery elm, ginger, okra
powder, niacinamide, and duodenum powder.
Probiotics may play a role in ameliorating IBD.  Long-­
like cooked, then re-cooled potatoes and unmodified potato
standing European experience with Escherichia coli Nissle
starch powder (see . Fig. 24.3).
1917 (Mutaflor®) suggests benefits, but the formulation is not
 

There is no question that nutritional deficiencies play a

approved for importation to the United States. VSL#3®, a
prominent role in IBD.  Malabsorption, diarrhea, and GI
high-potency probiotic mixture, has been the object of sev-
blood loss are common features of IBD, and therefore defi-
eral trials, including some that were double-blind placebo-­
ciencies of B vitamins, fat-soluble vitamins, and essential
controlled, with significant impact on improved stool
fatty acids—and key minerals such as magnesium, zinc, and
frequency, self-reports of pain, physician assessment, and
selenium—are extremely common.
endoscopic scores [65].
But supplementation is not just a matter of repletion of
Comfrey, a once-preferred gastrointestinal healing herb,
missing nutrients in IBD; certain vitamins and minerals have
has now fallen into disfavor because of its high content of
therapeutic effects beyond just staving off deficiency. One
hepatotoxic pyrrolidine alkaloids.
such nutrient is fish oil, which some studies indicate may
While there is evidence that administration of a wide
suppress intestinal inflammation [52]. High doses are
variety of oral supplements and nutraceuticals may be justi-
required, up to 9 g per day, delivered via enteric-coated cap-
fied in IBD, caution must be exercised. Many patients suffer
sules that open downstream to deliver omega-3 fatty acids
from chronic diarrhea, cramping, and abdominal pain, or
directly to the intestinal epithelium.
may have narrowing of segments of the intestine. A gradual
Another is vitamin D, which studies suggest might be
introduction may be warranted, with supplements added
therapeutic at doses higher than required to simply ward off
only as tolerated.
deficiency [53]. One clue comes from the finding that IBD is
As documented above, GI disorders are exceptionally
less commonly found at equatorial latitudes, where plentiful
amenable to natural interventions. These functional medicine
sun exposure seems to confer protection via production of
strategies possess several advantages: (1) Preferential use of
vitamin D in the skin by UV rays. While a dose of 400 inter-
diet modification and nutraceuticals in lieu of pharmaceuti-
national units has traditionally been used to supplement vita-
cals generally minimizes serious side effects. (2) By compre-
min D, doses in the thousands seem to be required to rein in
hensively addressing the causes of GI complaints, natural
inflammation and autoimmunity.
approaches provide more than just transient, symptomatic
Iron is frequently low in patients with IBD because of
relief. (3) Because of the centrality of the microbiome to over-
malabsorption and gastrointestinal blood loss.
all health, and its role in the pathogenesis of what were previ-
Gastroenterologists, therefore, frequently prescribe potent
ously thought to be “remote” diseases, functional medicine
iron supplements to their patients. But concern has arisen
strategies contribute to long-term overall health optimization.
over the potentially pro-inflammatory and constipating
It is high time that such approaches take their rightful
effects of common iron supplements like ferrous sulfate [54].
place in modern medicine’s armamentarium. The pace of
Where possible, iron repletion via iron-rich foods like red
ongoing research guarantees that there will be an ever-­
meat and organ meats is preferable; if refractory to replace-
expanding evidence base rationalizing their deployment.
ment with diet, parenteral iron may be indicated.
Natural products that have documented efficacy in IBD
included curcumin [55], Boswellin [56], conjugated linolenic
acid (CLA) [57], phosphatidylcholine [58], fish peptides derived
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 391 25

The Microbiome
and Brain Health
Sharon L. Norling

25.1 Introduction – 392

25.2 Dysbiosis – 392

25.3 Probiotics – 393

25.4 Second Brain – 394

25.5 Mood Disorders – 395

25.6 Schizophrenia – 396

25.7 Bipolar Disorder – 396

25.8 General Discussion of Mood Disorders – 396

25.9 Psychobiotics – 397

25.10 Brain-Derived Neurotrophic Factor (BDNF) – 398

25.11 Neurological Disorders – 399

25.12 Alzheimer’s Disease – 399

25.13 Autism – 400

25.14 Parkinson’s Disease – 400

25.15 Aging – 400

25.16 Fecal Transplants – 402

25.17 Food Sources – 402

25.18 Summary – 403

References – 403

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_25
 392 S. L. Norling

25.1  Introduction [12–14]. However, a Westernized diet high in fat and sugar
25 has also been shown to cause a more porous intestinal lining,
Strange but true, our bodies have more bacteria than we have the consequences of which include systemic access to food
human cells. The microbiome is inhabited by 100 trillion antigens, environmental toxins, and structural components
microorganisms, about 10 times the number of cells in the of microbes, such as lipopolysaccharide endotoxin (LPS)
human body. Of note, it weighs 2–6 pounds. A dysfunction [15]. The latter agent, LPS, is particularly important regard-
in this system significantly affects mental, emotional, and ing depression; even relatively small elevations in systemic
physical health [1]. It is estimated that the microbiome con- LPS levels have been shown to provoke depressive symptoms
tributes 150–360 times more bacterial genes than human and disturb blood glucose control [16–22]. Endotoxins such
genes [2, 3]. as LPS can decrease the availability of tryptophan and zinc,
The word microbiome is defined as the collection of thereby negatively influencing neurotransmission [23, 24].
microbes or microorganisms that inhabit an environment. It Moreover, systemic LPS can elevate inflammation and oxida-
includes communities of symbiotic, commensal, and patho- tive stress. Traditional dietary practices have completely
genic bacteria, fungi, and viruses. The clusters of bacteria divergent effects of blood LPS levels; significant reductions
from different regions of the body are known as microbiota: (38%) have been noted after a one-month adherence to a
skin microbiota, oral microbiota, vaginal microbiota, and GI prudent (traditional) diet, while the Western diet provokes
microbiota. Scientists have recently come to understand that LPS elevations [25]. These and other findings help establish
our GI microbiota, as a whole, determines whether patho- mechanisms whereby the LPS-lowering, antioxidant, and
gens in the gut coexist peacefully or cause disease [4]. anti-inflammatory properties of broad traditional dietary
Bacteria are distributed throughout the intestine, with the practices, as well as specific components within them, can
major concentration of microbes and metabolic activity help provide mood support. Indeed, when the limitation of
found in the large intestine: It is commonly known as the intestinal absorption is overcome, individual phenolic struc-
intestinal microbiome. The intestinal microbiota are made tures have been shown, at least experimentally, to curb the
up of 1000 species comprised of up to 130 trillion microbes, breakdown of central neurotransmitters, mimicking the pro-
70% of which cannot be cultivated in a microbiology labora- posed mechanistic properties of some primary antidepres-
tory [5, 6]. sant medications [26, 27].
The gut microbiome is essential for the host for digestion,
including the breakdown of dietary fibers and complex car-
bohydrates, the synthesis of vitamins, and the production of 25.2  Dysbiosis
short-chain fatty acids. The balance and makeup of the
microbiota play a critical role in metabolic functions [7]. The The term “dysbiosis” refers to situations where microbial
intestinal microbiota is essential to nutrient metabolism, composition and functions are shifted from their normal
opportunistic pathogen defense immune system develop- beneficial state to another that may be harmful to one’s
ment, and intestinal barrier function. About 70% of our health. The microbiota dysbiosis may negatively impact CNS
immune cells reside in the GI tract. The development of the functioning through various pathways known as the brain-­
intestinal immune system is largely dependent upon expo- gut axis [28–30]. The brain-gut axis is impacted by intestinal
sure to microorganisms. permeability. Another name used for intestinal permeability
Scientists are conducting research which documents the is leaky gut (see 7 Box 25.1).
 

significant impact of the gut on brain health. The National

Institutes of Health devote millions of research dollars to
understand these complex interactions. More than 90% of Box 25.1  Intestinal Permeability (Leaky Gut)
over 4000 articles on the microbiome were published in 55 Modulation of local and systemic inflammation
PubMed in the past 5 years [8]. While some physicians and 55 Decreased digestion and absorption of nutrients
55 Decreased brain-derived neurotrophic factor (BDNF)
scientists see probiotics as the “new magic medicine,” it is far
55 Increased small intestinal bacterial overgrowth (SIBO)
from new. Élie Metchnikoff received the Nobel Prize in
Physiology or Medicine in 1908 for his work in discovering
probiotics and phagocytes.
In the exciting area of research, one of the open questions Dysbiosis of the gut microbiota has profound effects on
is how chronic inflammation might be initiated and main- immune function and leads to inflammation. One common
tained in illnesses such as depression, and what the gut has to cause of dysbiosis is the Western diet as it affects both
do with this. Emerging studies show that the normally very immune homeostasis and the gastrointestinal tract. For
selective intestinal barrier may be compromised in depres- example, a high-sugar-content diet allows for the overgrowth
sion (and in numerous conditions where depression is often of Clostridium difficile and Clostridium perfringens by
a hallmark symptom) [9–11]. increasing bile secretion. This dysbiosis can lead to metabolic
Psychological stress and exhaustive exercise have been syndrome, diabetes, obesity, celiac disease, inflammatory
shown to increase the permeability of the intestinal barrier bowel disease, and irritable bowel syndrome.
The Microbiome and Brain Health
393 25
One of the most important roles of the microbiota is the the microbiome in the colon where they germinate, prolifer-
development and sustainment of local and systemic immu- ate, and then resporulate [39–45].
nity through homeostasis of its environment. This has been Studies have shown that orally ingested B. subtilis spores
demonstrated in studies showing the expansion of T and B are immunogenic and can disseminate to the Peyer’s patches
cells in mesenteric lymph nodes and Peyer’s patches, includ- and mesenteric lymph nodes [46–52]. In this way, they offer
ing CD4+ cells and FOXP3 Treg cells [31, 32]. An altered gut some advantages over the more common Lactobacillus. The
microflora has been reported in patients with rheumatoid average over-the-counter probiotic typically has Lactobacilli
arthritis and other autoimmune diseases as well as in allergic and Bifidobacter organisms in various amounts, with some
disease, implying that the normal gut microflora constitutes trying to outdo the other with larger and larger amounts of
an ecosystem responding to inflammation in the gut and organisms. The gastric survival of these has been shown to be
elsewhere in the human body. low as many are not acid-stable. The probiotic paradox is that
dead cells can generate responses from the GIT, mainly
immunomodulatory rather than antimicrobial [53].
25.3  Probiotics The GI tract, with changes in pH, bile salts, and digestive
enzymes, may require large numbers of probiotics to be con-
Gut microbiota may be modulated with the use of probiotics, sumed so that adequate numbers reach the lower GI tract.
antibiotics, and fecal microbiota transplants as a prospect for Most probiotics today emphasize the number of live bacteria.
therapy in microbiota-associated diseases. Probiotics can sta- Lahtinen [54] suggests a product of fermentation may not
bilize the gut microbiota and the intestinal permeability bar- require the probiotic to be viable when consumed and the
rier, and they can improve the degradation of enteric antigens probiotic will still be beneficial.
and alter their immunogenicity by countering the progres- There is no consensus to the minimum number of bacte-
sion of inflammation. ria needed to produce a beneficial effect on health. Studies
In addition, probiotics can improve the immunological such as McNulty and colleagues have shown that probiotics
barrier, in particular the intestinal immunoglobulin A need to be consumed every day because they do not colonize
response. They are also able to mediate the balance between the gut [44].
pro- and anti-inflammatory cytokines, thereby quelling the Probiotics reinforce the various lines of gut defense:
inflammation [33–36]. Probiotics can decrease inflammation. immune exclusion, immune elimination, and immune reg-
Probiotics are on a dramatic growth curve. Probiotics ulation. Probiotics also stimulate nonspecific host resis-
are live microbial food supplements or components of bac- tance to microbial pathogens and thereby aid in their
teria, which have been shown to have beneficial effects on eradication. There is evidence for the use of probiotics for
human health. It is estimated that the global probiotics reducing anxiety in individuals with altered GI function, in
market will exceed $46 billion by 2022 [37]. We are addition to lowering systemic inflammatory cytokines and
undoubtedly in an exciting period for probiotics. Probiotic decreasing oxidative stress [55]. Messaoudi et  al. found
products are entering the marketplace in all shapes and Lactobacillus helveticus combined with Bifidobacterium
forms including yogurt, juices, and even chocolate. longum decreased anxiety in humans accompanied with a
Probiotics are being adapted to almost everything that is reduction in urinary free cortisol in treated humans [56].
ingestible. This raises the question as to whether or not Lactobacillus rhamnosus has been found to decrease anxiety
these new food sources are just trendy or if they can effec- and alters expression of GABA receptors in the brain, a
tively provide benefit. In terms of labeling probiotic prod- receptor known to play a role in anxiety disorders [57].
ucts, the only standard required by the FDA for foods, Probiotics have also been promising as a potential preven-
supplements, and medical foods is that the labeling be tative strategy for depression in human trials [58]. Moreover,
truthful and not misleading. Sometimes, there is a discon- there is evidence that the concentration of fatty acids,
nect between what’s studied in published papers and what is namely, arachidonic acid and docosahexaenoic acid, is
actually available commercially on the market, but there are increased in mice that received a strain of Bifidobacterium
some well-validated, properly labeled products out there breve [59]. It is known that both fatty acids contribute to
and those are the ones that should be utilized [38]. several neurodevelopmental processes, including neuro-
A probiotic should be able to survive the gastric barrier genesis and neurotransmission, and can impact such cogni-
and bile acids to make it through the gastrointestinal tract tive functions as learning and memory [60].
(GIT) and reach the colon. It should have the ability to colo- There is quite an amount of research evidence supporting
nize the intestinal tract to perform its functions as a probi- the effectiveness of probiotics; however, the mechanisms of
otic. A probiotic should be able to improve mucosal immunity action are less clear. They may competitively exclude gut
and support barrier function. It should be able to competi- pathogens by repairing leaky gut or producing antimicrobial
tively exclude pathogenic microbes. Bacillus subtilis are properties. Additionally, they may stimulate the immune sys-
spore-forming bacteria and is one of the species of the tem by increasing the production of anti-inflammatory cyto-
Bacillus genus that fit these criteria; these spores survive kines [61]. They also communicate with the CNS via the
the transit through the stomach and small intestines to reach vagus nerve and impact brain function.
 394 S. L. Norling

Probiotics protect the inflamed intestinal epithelium.

25 Competition for binding sites and inhibition of pathogen Box 25.2  Gut Brain
growth stimulate the immune system, including the stimula- 55 Influences from the gut affecting the brain
tion of anti-inflammatory cytokines and enhancement of 55 Dysbiosis
55 Antibiotics and infections
barrier function [62]. 55 Environmental influences:
Regardless, multiple studies confirm the presence of a 55 Toxins
microbiota-gut-brain axis, and thus it is clear that probiotics 55 Food and gluten sensitivities
can modulate aspects of brain function and brain health. 55 Genetic predisposition
Further research is needed to identify additional organisms 55 Nutrition and physical activity
55 GI neurotransmitters
and elucidate the underlying mechanism of actions. 55 Inflammatory cytokines
While the focus of this chapter is intestinal microbiome, 55 Mode of delivery at birth
many different health targets have been studied with probiot-
ics. One probiotic should not be expected to do all of these
things, however. In general, the best evidence for probiotic It is clear that the gut microbiota can be a key regulator of
health effects is in the area of decreasing duration or inci- mood, cognition, pain, and obesity [67]. The microbiota-gut-­
dence of certain diarrheal diseases and in immune enhance- brain (MGB) axis and the neuroimmune system provide
ment. Emerging evidence exists for probiotics in the areas of understanding and management of anxiety, ADHD, autism,
dental caries; prevention of allergy, intestinal infections, cytokines, depression, stress, and neuroimmune conditions
vaginal infections, and colds and respiratory infections; [68]. Major depression and anxiety states are common in
improved growth parameters in undernourished children; patients presenting with IBS.
and improvements in quality-of-life indicators [63]. Immune cells produce neurotransmitters. There are sev-
eral mechanisms that facilitate neuroimmune interactions
and the bidirectional communication. These include the ana-
25.4  Second Brain tomical proximity between immune cells and nerve cells, the
receptors for neurotransmitters on immune cells, and for
People may refer to the enteric nervous system (ENS) as an immune mediators on nerves and the intracellular signaling
intuitive feeling, describing its actions as a “gut response” or pathways that modulate nerve and immune phenotype
“gut decision.” So it is no surprise to find that the GI tract expression and function [69]. Chronic active inflammation
releases neurotransmitters that affect brain health and in the GI tract leads to neuroimmune plasticity, resulting in
decision-­making. The ENS is embedded in the wall of the remodeling of both the neural and immune systems.
digestive tract and is localized by the myenteric plexus and Gut microbiota and some probiotics can regulate immune
submucosal plexus. This system contributes to GI motility, functions. Benefits may be anti-inflammatory actions of cer-
nutrient handling, gastric acid secretion, and immune tain bacteria and a capacity to affect HPA axis activity. Most
function. physical and mental diseases have inflammation as their root
As researchers gain a deeper understanding of ENS, this cause. Much of our immune system, about 70%, is located in
second brain located in the GI tract, it is clear that it is filled the gut microbiome [68].
with neurotransmitters [64]. Together, the gut-brain connec- When food enters the mouth and passes through the
tion significantly determines mental states and plays key digestive system, it sends the brain a multitude of interacting
roles in certain diseases throughout the body. While the sec- signals that are filled with sensory, nutritive, and other infor-
ond brain has an important role in brain health, it does not mation. According to Cenit [70], gluten sensitivity is a result
appear to participate in conscious thoughts or decision-­ of dysbiosis, not a genetic disorder. This may explain, in part,
making. “The second brain does not help with the great why patients who test positive for the celiac gene may not be
thought processes…religion, philosophy, and poetry is left to gluten-sensitive while those patients who test negative for the
the brain in the head,” says Michael Gershon, chairman of the celiac gene may have a gluten sensitivity. Dysbiosis is most
Department of Anatomy and Cell Biology at New  York– prominent in the digestive tract or on the skin, but it can also
Presbyterian Hospital/Columbia University Medical Center, occur on any exposed surface or mucous membrane.
an expert in the field of neurogastroenterology, and the Dysbiosis creates inflammatory factors responsible for devel-
author of the Second Brain [64]. oping insulin resistance and body weight gain [70] (see
A dysfunction in the gut-brain axis is linked to neuropsy- . Fig. 25.1). These conditions, in turn, create inflammation
 

chological, metabolic disorders such as obesity, immune, and which can affect brain function and brain health.
endocrine disorders [65]. Dysbiosis has been linked to depres- Most information received by the brain relating to GI
sion and autism spectrum disorder (ASD) and GI disorders contents and activity is generally transmitted via vagal affer-
including IBD and IBS [66] (see 7 Box 25.2).
  ent feedback. The other enteric nervous system source is the
The Microbiome and Brain Health
395 25
..      Fig. 25.1 Gut–brain
interactions
Dysbiosis
Balanced Microbiota
Gut Dysfunction
HPA Normal Gut Function
Inflammation
Neuropeptides Healthy Immune System
Tissue Damage
↓
↓
Homeostasis
Disease

Brain

Balanced HPA Axis

Dysfunction HPA Axis
Normal Behavior
Mood Disorders
Emotional Well-Being
Altered Behavior
Normal Nociceptor
Increased Pain
Normal ENS/CNS
Obesity
Interactions

Food & Gluten

Toxins Sensitivity
Altered Brain
Peristalsis Neurotransmitters

Inflammation
Genetics
& Cytokins
Gut
Microbiota
Diet Probiotics

Antibiotics Mode of Delivery

at Birth

spinal cord afferents, which mediate GI pain rather than pro-

viding feedback to the brain relating to nutrient contents. Box 25.3  Brain Gut
55 Influences from the brain affecting the gut microbiota [72]
55 The hypothalamus-pituitary-adrenal (HPA) axis
25.5  Mood Disorders 55 The CNS regulating areas of satiety
55 Neuropeptides released from sensory nerve fibers

Conversely, visceral pain can affect central pain perception,

mood, and behavior. Communication between the central
nervous system (CNS) and ENS involves neural pathways Chronic psychological stress is associated with a greater risk
as well as immune and endocrine mechanisms [71] (see of depression, cardiovascular disease, diabetes, autoimmune
7 Box 25.3).
  diseases, upper respiratory infections, and poorer wound
 396 S. L. Norling

healing [73]. Stress induces leaky gut and increases mucosal tion by pro-inflammatory cytokines is involved in the
25 immune response, which in turn alters the composition of pathogenesis of schizophrenia [74]. Chronic macrophage
the microbiome and leads to enhanced HPA drive. The hypo- activation and secretion of interleukin-­2 and interleukin-2
thalamus is an integral part of the limbic system referred to as receptors have been proposed as the basic biological mech-
the “emotional” brain. The limbic system anatomically con- anism of schizophrenia in earlier papers [74]. For example,
sists of the hypothalamus, amygdala, medial thalamus, and the protozoa Toxoplasma gondii is known to cause major
anterior cingulate cortex (ACC). Psychosocial factors can perturbation to the gut microbiota and is a recognized
influence digestive function, symptom perception, illness environmental risk factor for schizophrenia [74]. More
behavior, and outcome [74]. recently, a chlorovirus (family Phycodnaviridae) has been
Lackner and colleagues [75] reported a series of six indi- identified in humans that affects cognitive function relevant
viduals with irritable bowel syndrome (IBS) and six controls. to schizophrenia in animal models [74].
Patients with IBS were treated with a 10-week course of cog-
nitive therapy. Treatment was associated with a significant
reduction in anxiety and digestive symptoms. PET scans Box 25.5
showed reduced activity in the region of the left amygdala Inflammation Cytokines HPA Mood disorders
and right ACC following therapy [75].

N-methyl-D-aspartate (NMDA) receptor hypofunction is

25.6  Schizophrenia believed to be central to the pathophysiology of schizophre-
nia, as NMDA receptor antagonists produce schizophrenia-­
The development of schizophrenia can be linked through the like symptoms while agents that enhance NMDA receptor
role of microbiota in regulating brain development, immune (R) function reduce negative symptoms and improve cogni-
function, and metabolism. The evidence suggests possible tion [74]. Variation in brain-derived neurotrophic factor
microbiota alterations in schizophrenia resulting in struc- (BDNF) expression is believed to play a role in the molecular
tural damage to the GI tract, and a heightened immune mechanism underlying cognitive dysfunction in schizophre-
response to infections, food antigens, and gluten sensitivity nia [74]. Given that normal development of the microbiota is
(see 7 Box 25.4). Evidence that patients with schizophrenia
 
necessary to stimulate brain plasticity through the appropri-
may have altered microbiota [76]: ate expression of BDNF and NMDA receptors, it is possible
that altered microbiota may contribute to the NMDA recep-
tor dysfunction seen in schizophrenia [74].
Box 25.4  Altered Microbiota in Psychiatric Disorders
55 Structural damage to the GI tract in schizophrenia
55 Abnormal response to infections pathogens in
schizophrenia 25.7  Bipolar Disorder
55 Abnormal response to food antigens in schizophrenia
55 Sensitivity to gluten and bovine casein Severance and colleagues [80] recently measured serological
surrogate markers of bacterial translocation (soluble CD14
(sCD14) and lipopolysaccharide binding protein (LBP)) in
A recent study on the oral microbiome and schizophrenia bipolar subjects and schizophrenia subjects compared to
has shown large differences between case and control indi- controls. In bipolar disorder, sCD14 levels were significantly
viduals in terms of bacterial, viral, and fungal composition correlated with anti-tissue transglutaminase IgG (r2 = 0.037,
[77]. Schizophrenics had increased levels of lactic acid bacte- P < 0.001). The authors concluded that these bacterial trans-
ria. Individuals with schizophrenia had decreased levels of location markers produced discordant patterns of activity
many nonpathogenic bacteria and increased levels of intesti- that may reflect an imbalanced, activated innate immune
nal immune activation as indicated by antibodies to food and state. Whereas both markers may upregulate following sys-
intestinal antigens. The microbiome was significantly altered temic exposure to gram-negative bacteria, autoimmunity,
by probiotic therapy with a tendency toward normalization and non-lipopolysaccharide-based monocyte activation, and
in the case individuals following treatment. metabolic dysfunction may also contribute to the observed
Major depressive disorders, bipolar disorder, and marker profiles [80].
schizophrenia have been associated with immune
responses, supporting the concept that mood disorders are
related to inflammatory cytokines (see 7 Box 25.5). The
  25.8  General Discussion of Mood Disorders
findings from clinical studies demonstrate an upregulated
immune and inflammatory status in patients with schizo- Poor mental health has been associated with an increased like-
phrenia [78] and a correlation between the level of inflam- lihood of eating unhealthy foods [81]. Different diets create
matory markers and severity of clinical symptoms [79]. It different gut flora. One study showed that rural African chil-
has been suggested that the uncontrolled neuroinflamma- dren eating a polysaccharide-rich diet had more Bacteroidetes
The Microbiome and Brain Health
397 25
and diversity than European Union children eating the sants, mirtazapine (Remeron) and fluoxetine (Prozac), are
Western diet [82]. In a 2014 study in Nature, it was indicated linked to a nearly 50% increased risk for CD infection [92].
that these changes can happen in the human gut—within three Stress induces a dysbiosis, which in turn can trigger
or 4 days of a big shift in what one eats! [83] A variety of popu- anxiety and depression [93–95]. Commensal bacteria
lation studies have linked traditional dietary patterns with modulate brain biochemistry and behavior through the
lowered risk of anxiety or depression [74]. More recent pro- vagus nerve , affecting neurotransmitters. Prolonged stress
spective investigations have shown that traditional healthy triggers unfavorable shifts in bacterial composition and
dietary patterns are associated with a 25–30% lower risk of diversity. Populations of beneficial microbes die off and
depression [84, 85]. dysbiosis flourishes [93–95]. More than one-third of peo-
Microbes produce neurotransmitters and the gut micro- ple with depression have “leaky gut,” the permeability of
biota produces three-fourths of the neurotransmitters in the gut lining that allows bacteria to enter the bloodstream
the body. More than 50% of the body’s dopamine and 95% (see 7 Box 25.7).
 

of your body’s serotonin are produced in your gut, along

with about 30 other neurotransmitters [86, 87]. These mol-
ecules are critical for signaling between cells of the nervous Box 25.7  Serotonin’s Role in the Gut [96]
system. Dopamine and serotonin in the brain and the GI 55 Motility patterns and gastric emptying
have both been shown to be involved in the regulation of 55 Secretion
eating behavior [88]. 55 Immune system
A decade ago, prior to the scientific hypothesis of Logan 55 Pain and discomfort
55 Nausea and vomiting
et al., the notion that the intestinal manipulation of the gut 55 Alters microbiome
microbiota could provide therapeutic value to relieve depres- 55 Circulating 5-HT has the potential to impact many other
sion and fatigue was, at the very least, outlandish [89, 90]. tissues
The mechanisms of probiotics and fermented foods are com- 55 Promotes homeostasis
plex and may be related to their role in making neurotrans- 55 Influences bone development
55 Receptor sites on immune cells B and T lymphocytes
mitters, decreasing oxidative stress, or improving cellular 55 Mast cells, macrophage, and T-cells synthesize 5-HT
repair [91]. How can this happen? 7 Box 25.6 shows mecha-
 

nisms proposed by Logan and others that have been subject

of study [89–91].
25.9  Psychobiotics

Box 25.6  Association of Gut Microbiota The close relationships between gut microbiota, health, and
and Therapeutic Value in Mood Disorders disease have led to a great interest in using probiotics and/or
55 Direct protection of the intestinal barrier prebiotics to prevent or treat disease [97]. The influence of
55 Influence on local and systemic antioxidant status, probiotics on moods is significant. Psychobiotics is an emerg-
reduction in lipid peroxidation ing class of probiotics of relevance to psychiatry and mood
55 Direct, microbial-produced neurotransmitter production,
for example, gamma-aminobutyric acid (GABA)
disorders. A psychobiotic is a live organism that produces a
55 Indirect influence on neurotransmitter or neuropeptide health benefit in patients suffering from mood disorders.
production Such mind-altering probiotics act via their ability to produce
55 Prevention of stress-induced alterations to overall various biologically active compounds [98].
intestinal microbiota Moreover, preliminary placebo-controlled human studies
55 Direct activation of neural pathways between gut and
brain
have shown that oral probiotic microbes can decrease anxi-
55 Limitation of inflammatory cytokine production ety, diminish perceptions of stress, and improve mental out-
55 Modulation of neurotrophic chemicals, including look [99]. Michael Messaoudi and colleagues from France
brain-derived neurotrophic factor (BDNF) evaluated Lactobacillus helveticus and Bifidobacterium
55 Limitation of carbohydrate malabsorption longum combination probiotic, which was orally adminis-
55 Improvement of nutritional status, for example, omega-3
fatty acids, minerals, and dietary phytochemicals
tered for 1 month in a one-month placebo-controlled study
55 Limitation of small intestinal bacterial overgrowth [100]. Among the otherwise healthy adults, significant
55 Reduction of amine or uremic toxin burden improvements in depression, anger, anxiety, and lower levels
55 Limitation of gastric or intestinal pathogens (e.g., of the stress hormone cortisol versus placebo were noted.
Helicobacter pylori) Bacteria are capable of producing and delivering GABA
55 Analgesic properties
and serotonin, which are on the brain-gut axis [101].
Microbes that actively secrete GABA in the gut are strains
of Lactobacillus and Bifidobacterium. Psychobiotics pro-
Microbiota influence brain chemistry and consequently duce psychotropic effects on behavior, affecting the HPA
behavior. Clostridium difficile (CD), the hospital-based gut axis and neurochemicals in the brain [98]. As cited by John
infection that kills 14,000 people each year in the USA, is asso- F.  Cryan, PhD, “two varieties of Bifidobacteria were more
ciated with depression and dementia [92]. Two antidepres- effective than escitalopram (Lexapro) at treating anxious
 398 S. L. Norling

and depressed behavior in a lab mouse strain known for Accumulating evidence from experimental studies sup-
25 pathological anxiety” [98]. ports the hypothesis that—via affecting inflammation, endo-
Alterations in microbiota influence stress-related behav- crine system, and neurotransmission—the gut microbiome
iors. GI tract bacteria, including commensal, probiotic, and takes a crucial role in the CNS function [107]. Accordingly, it is
pathogenic bacteria, can activate neural pathways and CNS suggested that dysfunction of the neuroendocrine system,
signaling systems [102]. The MGB axis may provide novel behavior, and cognition is correlated with gut microbiota
approaches for prevention and treatment of mental illness, dysbiosis [74]. These considerations led to establishing the
including anxiety and depression [102]. term “psychobiotics” to highlight the potential effects of
Tests revealed that chronic ingestion of probiotic probiotics in treatment of mental disorders [107].
Lactobacillus plantarum significantly reduced anxiety-like Consistently, in a meta-analysis study, Kasińska and
and depression-like behaviors [103]. It also reduced Lambert- Drzewoski [108] reported a reduced homeostatic model of
Eaton Myasthenic Syndrome-induced elevation of serum assessment for insulin resistance (HOMA-IR) and insignifi-
corticosterone. cant fasting plasma glucose (FGP) in probiotic-treated sub-
Lactobacillus plantarum also reduced inflammatory cyto- jects [107]. Mazloom and colleagues [109] also reported
kine levels and increased anti-inflammatory cytokine levels that probiotic supplementation had no significant effect on
in the serum. Furthermore, the dopamine levels in the brain fasting blood glucose, markers of insulin metabolism, and
were significantly increased. The psychotropic properties of lipid profiles [107]. Consumption of symbiotic bread con-
certain bacteria have great potential for improving stress-­ taining the heat-resistant probiotic Lactobacillus sporogenes
related symptoms [103]. (1 × 108 CFU/g) for 8 weeks also decreased the serum tri-
Lactobacillus rhamnosus is a bacterial strain that has been glyceride and VLDL concentrations in patients with type 2
shown to reduce anxiety and depression in anxious mice diabetes [107]. Probiotics have been shown to modulate
[104]. L. rhamnosus markedly increased GABA levels. A num- many chronic illnesses. Decreasing inflammation and
ber of microbes can produce other neurotransmitters, such as improving chronic disease have a significant impact on
norepinephrine, serotonin, and dopamine. Bifidobacterium brain health.
infantis, taken as a probiotic, alters serotonin levels just like
Prozac but without the undesirable side effects [105].
The National Institute of Mental Health labels anxiety as 25.10   rain-Derived Neurotrophic Factor
B
a learning deficit because the brain is unable to learn to dis- (BDNF)
criminate between dangerous and benign situations [106].
Recent research has led scientists to believe that the protein In the past, it was believed that the brain was hardwired
is an essential ingredient in combating anxiety. Scientists with a finite number of neurons. If a brain was damaged or
think this is due to the fact that it helps the brain learn to diseased, there was little that could be done to reverse the
essentially work around the fear and create positive memo- injury. However, today we know that the brain is neuroplas-
ries. In addition, higher levels of the protein ramp up levels tic and significant regeneration can occur with a wide vari-
of serotonin, which calms the brain down and increases the ety of therapies. Brain-derived neurotrophic factor (BDNF)
sense of safety [106]. is a protein produced inside nerve cells [106]. Although
Numerous studies have shown capability of bacteria in neurotransmitters like dopamine and serotonin are impor-
producing neurotransmitters and neuromodulators, includ- tant in helping the brain function because they carry the
ing gamma-aminobutyric acid (GABA), norepinephrine, signals of neurons, the protein BDNF builds and maintains
serotonin, dopamine, and acetylcholine [107]. Further, find- the brain circuits which allow the signals to function [106].
ings from germ-free animals indicated a decreased level of Therapies that may be used include treating the root cause,
brain-derived neurotrophic factor (BDNF), important neu- cytokine signaling, increasing BDNF, lifestyle factors, and
rotrophic factor in neuronal growth and survival, and a suppressing inflammation in the body. Increasing the
reduced expression of some subunits of N-methyl-D-­ expression of BDNF in the brain can be done by supple-
aspartate (NMDA) receptors involved in most abundant menting the excitatory neurotransmitter, glutamate, and
neurotransmission in the brain. The glutamatergic NMDA increasing physical activity [106].
receptors, involved in excitatory neurotransmission of brain BDNF improves the function of neurons, encourages their
waves, engage the neural circuits involved in learning and growth, and strengthens/protects them against premature cell
memory [107]. GABA is the major inhibitory neurotransmit- death [106]. It also binds to receptors at the synapses to
ter in the CNS. Dysfunctions in GABA signaling are linked improve signal strength between neurons. Essentially, the
to anxiety and depression, defects in synaptogenesis, and more BDNF in the brain, the better the brain works. Exposure
cognitive impairments [107]. From these considerations, it to stress and the stress hormone cortisone and depression
can be concluded that, at least through contributing in neu- have been shown to decrease the expression of BDNF. Various
rotransmitter synthesis or receptor expression, probiotics studies have shown possible links between BDNF and condi-
might adjust the brain activity. tions such as depression [110, 111], schizophrenia [63], obses-
The Microbiome and Brain Health
399 25
sive-compulsive disorder [64], Alzheimer’s disease [65], “microRNA-155,” is responsible for cleaving epithelial cells to
Huntington’s disease [66], Rett syndrome [67], and dementia create microscopic gaps that let material through [40].
[68]. Ratey pointed out that a study of 30 depressed people
found they all had low levels of BDNF [106].
25.12  Alzheimer’s Disease

25.11  Neurological Disorders The microbiota is a dynamic ecosystem which is influenced

by several factors including genetics, diet, metabolism, age,
Encased in bone— our skull—the brain is our most protected geography, antibiotic treatment, and stress [46]. In addition,
organ. It weighs 3 pounds (1.36 kg), or approximately 2% of animal studies imply the necessity of an optimal function of
our body weight, yet it uses 20% of our body’s oxygen and what is known as the microbiome-gut-brain axis (MGB) in
calories. Within the brain are approximately 100 billion neu- the behavioral as well as electrophysiological aspects of brain
rons, with approximately 1000 synaptic connections per cell. action [47].
In the visual cortex, there are approximately 12,000 synapses There are correlations between microglial immunoreac-
per cell, and in the prefrontal cortex, this increases to 80,000 tivity and neuronal viability in Alzheimer’s disease (AD)
synapses. The transmission speed along axons is measured at brain tissue. Immunohistochemical analysis demonstrated
200 miles per hour (322 km/h) [116]. AD brain tissue expressed areas of diffuse fibrinogen indica-
Coursing throughout the brain to reach each neuron are tive of a weakened BBB [41].
capillaries, more than 400  miles (644  km) of them. These More than 40 million individuals throughout the world
capillaries are not your ordinary ones; these are lined with suffer from Alzheimer’s, a disease for which there is no spe-
specialized endothelial cells (ECs) and tight junctions, form- cific treatment. We know that Alzheimer’s is an inflamma-
ing the blood-brain barrier (BBB). The BBB functions to help tory disease. It is also known that gut bacteria can increase
vital brain nutrients pass into the brain, protects the brain inflammation and probiotics can decrease inflammation.
from plasma components, preserves the homeostasis of the Alzheimer’s disease (AD) is recognized as one of the most
brain, and directs inflammatory cells in response to an intra- common forms of senile dementia [43]. AD begins with
cerebral event [74]. memory loss of recent events (short-term memory impair-
Where there is an intracerebral hemorrhage, ischemic ment) and finally robs patients of their sense of self [44].
injury, trauma, or neurodegenerative progression, plasma Increased biomarkers of oxidative stress [74], inflammation,
components, including red blood cells and leukocytes, cross and chronic neuroinflammation are reported to be associ-
the BBB and produce neurotoxins that may lead to abnormal ated with many neurodegenerative disorders of the central
synaptic and neuronal functions [74]. Tight junctions help nervous system (CNS) including AD [45]. See 7 Box 25.8 for
 

the BBB’s permeability to blood-borne solutes, which is emerging information on promotion of AD [43–45, 74].
dependent on their molecular weight and lipophilic and
hydrophilic characteristics.
The consequences of central nervous system (CNS) Box 25.8  Emerging Information on Promotion
inflammation are increased permeability of the BBB and leu- of Alzheimer’s Disease
kocyte infiltration of the brain, both found in multiple sclero-
sis (MS). Major factors in the progression of MS are CD4+ Toxins
interleukin-17 (IL-17)-producing T lymphocytes (Th17) with Too much sugar
IL-17 known to disrupt tight junctions in the ECs [66].
Too many antibiotics and given too young = leaky gut
Further, T lymphocyte cerebral infiltration has been
shown in patients with Alzheimer’s disease (AD) and C-sections, no breastfeeding, no skin-to-skin contact with
Parkinson’s disease (PD). These again increase the permea- parents
bility of the BBB [62, 99, 103–105]. Mounting evidence, both Too many medications = leaky gut
clinical and experimental, demonstrates the importance of
Low-fat diets
BBB and any abnormalities of its functions, as well as their
role in contributing to the progression of a number of inflam- Amalgam fillings
matory, infectious, and neurodegenerative diseases, espe- Genetically modified organisms/GMO = leaky gut
cially in our aging population.
Acute stress increases GI and BBB permeability through Poor methylation = epigenetics
activation of mast cells (MCs), which express high-affinity
receptors for cortisol-releasing hormone (CRH). Chronic
stress disrupted the intestinal barrier through MC activation
and permitted penetration of luminal antigens, microflora There is a preliminary research on the effect of probiotics on
metabolites, toxins, and lipopolysaccharide (LPS) in the sys- the prognosis of cognition [48]. However, data on the effects
temic circulation and the CNS [39]. A molecule, called of probiotics on improving cognitive disorders are scarce
 400 S. L. Norling

[49]. Gareau reported that intestinal dysbiosis in germ-free in the brain are involved in the alimentary synapse forma-
25 animals (containing no microbiota), bacterial infection tion. “If these genes are affected in autism,” he says, “it could
with an enteric pathogen, and administration of probiotics explain why so many kids with autism have GI motor abnor-
can modulate cognitive behaviors, including learning and malities” in addition to elevated levels of gut-produced sero-
memory [50]. tonin in their blood [64]. About 95% of serotonin is produced
Postmortem analysis has shown lowered levels of BDNF by probiotics in the GI tract.
in the brain tissues of people with Alzheimer’s disease, Food allergies, eczema, and asthma are associated with
although the nature of the connection remains unclear. behavioral problems and neuropsychiatric disorders, includ-
Studies suggest that neurotrophic factors have a protective ing ADHD. Many children with autism spectrum disorders
role against amyloid beta toxicity [112]. (ASD) present with GI systems and altered GI flora. ASD
Researchers took a group of elderly Alzheimer’s patients may involve brain inflammation. About 30% of children with
and studied them for 12 weeks [113]. Each participant under- ASDs have autoantibodies against brain proteins [42].
went a test for mental function called the mini-mental status
exam (MMSE), a standardized cognitive assessment used
worldwide. They also underwent a blood test called highly 25.14  Parkinson’s Disease
sensitive C-reactive protein (hs-CRP), a powerful marker of
inflammation. These tests were then repeated after 12 weeks. A high incidence rate of constipation is found in Parkinson’s
The results were impressive [113]. The placebo group disease (PD) patients. Constipation can precede the onset of
showed an increase in the inflammatory marker by 45%, motor symptoms by more than 10 years [74].
while the probiotic group decreased the CRP by 18%. Over Probiotics can efficiently reverse the impaired spatial
the 12 weeks, the placebo patients declined mentally. Their learning and memory as well as synaptic transmission in dia-
MMSE dropped from 8.47 to 8.00. The probiotic group betes mellitus [51]. It is demonstrated that other brain-related
improved their MMSE scores from 8.67 to 10.57. This study disorders, such as multiple sclerosis [52] and stress, are also
demonstrated that the probiotic administration for 12 weeks influenced by probiotics [53]. In the levels of molecular
has favorable effects on mini-mental state examination mechanism, the microbiome is known to play a pronounced
(MMSE) score, malondialdehyde (MDA), serum high-­ role in synaptic transmission. Numerous studies have shown
sensitivity C-reactive protein (hs-CRP), markers of insulin capability of bacteria in producing neurotransmitters and
metabolism, and triglyceride levels of the AD patients. These neuromodulators including gamma-aminobutyric acid
considerations led to establishing the term “psychobiotics” to (GABA), norepinephrine, serotonin, dopamine, and acetyl-
highlight the potential effects of probiotics in the treatment choline [54]. Further, findings from germ-free animals indi-
of mental disorders [60]. Consistently, in a meta-analysis cated a decreased level of brain-derived neurotrophic factor
study, Kasińska and Drzewoski [60] reported a reduced (BDNF), important neurotrophic factor in neuronal growth
homeostatic model of assessment for insulin resistance and survival, and a reduced expression of some subunits of
(HOMA-IR) and insignificant fasting plasma glucose (FGP) N-methyl-D-aspartate (NMDA) receptors [55]. GABA is the
in probiotic-treated subjects. Mazloom et  al. [109] also major inhibitory neurotransmitter in the CNS. Dysfunctions
reported that probiotic supplementation had no significant in GABA signaling are linked to anxiety, depression, and
effect on fasting blood glucose, markers of insulin metabo- defects in synaptogenesis and cognitive impairments [57].
lism, and lipid profiles. Also, the glutamatergic NMDA receptors are involved in the
The message here is that inflammation, which initiates or most important excitatory neurotransmission in the brain
exacerbates all chronic illnesses including Alzheimer’s dis- [58] and are engaged in the neural circuits involved in learn-
ease, is dependent on the diversity and health of our gut bac- ing and memory. From these considerations, by contributing
teria. This, in turn, has major implications for brain health in neurotransmitter synthesis or receptor expression, probi-
and function. otics might adjust the brain activity.
Accumulating evidence from experimental studies sup-
ports the hypothesis that via affecting inflammation, endo-
25.13  Autism crine system, and neurotransmission, the gut microbiome
takes a crucial role in the CNS function [59]. Accordingly, it
Autism is a condition in which intestinal microbiota is impli- is suggested that dysfunction of the neuroendocrine system,
cated. The onset of autism is often accompanied by intestinal behavior, and cognition is correlated with gut microbiota
dysfunction [79–81]. The first description of an association dysbiosis [74].
between autism and gastrointestinal syndrome began in
1971, with a report that 6 out of 15 autism patients had
changed fecal character and defecation frequency [81]. 25.15  Aging
Serotonin seeping from the second brain might even play
some part in autism, the development disorder often first We all know the brain changes as we age, as does the gastro-
noticed in early childhood. Gershon has discovered that the intestinal tract. These changes, as well as a modification in
same genes involved in synapse formation between neurons lifestyle and decreased nutrition, increase the risk for infec-
The Microbiome and Brain Health
401 25
tions, mental changes, physical impairments, and diminished inflammatory cytokines, as detected in long-stay hospital
cognitive abilities. The compromised microbiota in the patients, were linked to increased frailty.
elderly is associated with increased inflammation, also called There is a decline in immune function in aging, and so
inflammaging [11, 56, 74]. Inflammaging can also lead to microbiota-brain communication may be altered in the
decreased gut motility and constipation. Studies have illus- elderly, leading to changes in behavior. Supporting this is the
trated an association between gut flora composition and cog- fact that behavioral changes are observed in those with sys-
nitive processes, such as learning and memory. Additionally, temic infections as, similar to the gut, there is reciprocal
intestinal microbiota contributes to the early development of communication between the CNS and the immune system
normal social and cognitive behaviors [74]. [65]. Moreover, effects of gut microbiota and probiotics on
Changes occurring in the microbiota during aging can inflammatory cytokines can have a direct effect on the brain.
have an impact on host health [74]. Notably, there is correla- Research groups have shown that gut microbes can also
tion between the relationship of falling microbial diversity regulate the permeability of the blood–brain barrier (BBB), a
and worsening frailty scores in elderly individuals. highly selective barrier essential in protecting the brain from
Additionally, drugs such as antibiotics, antacids, and H2 potential toxins [68]. Given that the function of both the BBB
receptor blockers can have profound negative effects on gut and microglia may deteriorate through age, these mecha-
microbiota [74], all of which are more commonly used in the nisms are particularly relevant with regard to the role of
elderly as compared to a younger population. More than microglia in elderly cognitive decline [69, 70]. Several epide-
three-­quarters of those aged 65 or older use at least one pre- miological studies in elderly subjects have found links
scription medication, which can lead to unfavorable side between diet and cognitive function [100]. In addition,
effects on the GI tract [52]. For example, the use of opioids is chronic inflammation and a transformation in gut microbi-
linked to constipation [53], and the use of nonsteroidal anti-­ ota through age parallel a decline in cognitive function. The
inflammatory drugs is linked with dysfunction in the GI development of therapeutic strategies for diseases character-
defense system [54]. Furthermore, proton pump inhibitors, ized by cognitive decline through alteration of the microbiota-­
which are used to treat peptic ulcers, can trigger bacterial gut-­brain axis is an appealing possibility, particularly in the
overgrowth of the upper GI tract through changes in the pH context of a global aging population [115]. However, much
[17]. The use of broad-spectrum antibiotics can cause wide- work still remains before this becomes a reality.
spread disturbance in gut microbial composition and increase Decreased microbial diversity correlated with increased
risk of Clostridium difficile infection, which in turn can frailty, decreased diet diversity, health parameters, and
reduce the biodiversity of gut microbiota [55]. As such, these increased levels of inflammatory markers. Individuals liv-
medications can have implications on the microbiota-gut-­ ing in a community had the most diverse microbiota and
brain-axis and influence CNS function. were healthier as compared to those in short- or long-term
Immunosenescence with chronic low-grade inflamma- residential care [74]. Firmicutes population drops with
tion is characteristic in older age. This phenomenon, known aging, while Bacteroidetes become the new dominant pop-
as inflammaging, is distinguished by inflammation mediated ulations [74]. With a decline in Firmicutes, an increase in
by NK-kB and a loss of naïve CD4 T cells [56, 115]. A weak- inflammatory diseases is found; this decline causes a
ening of cell-mediated responses and reduction of the T-cell decrease in immune response and reduced efficiency to
receptor repertoire have been shown in animal models upon digest. It was found that people at age 70 on average are still
aging [57]. In addition, clonal expansion of specific immune seen to have a similar biome of that of a 20- to 30-year-old;
cells is impaired due to compromised cell division caused by substantial changes are only seen within people who are
a progressive shortening of telomeres through aging [58]. older than 80 [74].
Notably, the GI microbiota of the elderly express a pro-­ Deterioration in dentition, salivary function, digestion,
inflammatory phenotype, as evidenced by a reduction in and intestinal transit time may affect the intestinal micro-
vitamin B12 synthesis and microbial reductase activity biota with aging [74]. Aging is seen to negatively impact the
together with an increased incidence of DNA damage and microbiome, and the microbiome must be consistently
immune compromise [50]. maintained with a healthy diet to minimize the effects of
Indeed, inflammation is associated with a number of age-­ aging [74].
related diseases and neurodegenerative disorders, such as In aging, BDNF is important as neuron morphology is
Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, critical in behavioral processes like learning and motor skills
and motor neuron disease [60]. Claesson et al. showed that development [74]. BDNF levels have been shown to decrease
gut microbial composition and inflammation are directly in tissues with aging [74]. Studies using human subjects have
linked to health outcomes [49]. They analyzed the microbiota found that hippocampal volume decreases with decreasing
composition and health outcomes in 178 patients living in plasma levels of BDNF [74]. Like many other chemicals in
different residences. Statistical analysis illustrated a clear dif- the human body, aging decreases BDNF levels. This is why it
ference in the microbial profiles depending on residence takes the elderly longer to do complex tasks.
location, which significantly correlated with measures of The relationship of BDNF to chronic illnesses and aging
nutrition, inflammation, frailty, and comorbidity. A decrease can be modified through a wide range of activities, nutri-
in community-associated microbiota and an increase in pro-­ tion, a healthy microbiome, and probiotics. Perlmutter rec-
 402 S. L. Norling

irritable bowel syndrome (IBS), and ulcerative colitis, all of

25 ..      Table 25.1  Strains of probiotics and which foods contain
them
which affect brain health [117]. Additionally, FMT has been
linked to normalization of multiple sclerosis symptoms and
Lactobacillus Sauerkraut, pickles, brined olives, kimchi, improvement of chronic fatigue syndrome [74]. Neurological
plantarum Nigerian ogi, sourdough, fermented sausage, improvement was reported in one patient with Parkinson’s
stockfish, and some cheeses (such as cheddar) disease [74].
Lactobacillus Yogurt kefir, miso, and tempeh
acidophilus

Lactobacillus Pickles, sauerkraut, and beer hop

25.17  Food Sources
brevis
Mood disorders can make everything in life seem impossible.
Bifidobacte- Yogurt, miso, tempeh, pickled plum, pickles,
Mood-altering pharmaceutical drugs are frequently pre-
rium lactis kimchi, and many other forms of fermented
scribed. One out of every five adult Americans now uses
and pickled fruits/vegetables that have not
these drugs in spite of their side effects and addictive proper-
gone through the manufacturing process
ties [74].
Bifidobacte- Yogurt, milk, fermented dairy foods,
rium longum sauerkraut, and soy-based products
It is important to look at other natural options that are
effective to balance neurotransmitters and improve brain
health. The microbiome and probiotics have been discussed.
Removing sugar, refined grains, and processed foods is a
ommends five strains of probiotics to increase BDNF levels good beginning. Specific tests for food allergies and gluten
in the brain: Lactobacillus plantarum, Lactobacillus aci- sensitivities are important to identify which foods need to be
dophilus, Lactobacillus brevis, Bifidobacterium lactis, and eliminated from the diet to decrease inflammation and the
Bifidobacterium longum [114]. . Table  25.1 lists the com- risk of autoimmune disease.
 

mon foods to find these strains. Eating fresh, organic, non-GMO whole foods are essen-
tial to a healthy diversified microbiome and brain health.
Adding fermented foods is beneficial. As Hippocrates
25.16  Fecal Transplants famously said, “Let food be thy medicine and medicine be
thy food.” The diversity of whole foods containing phyto-
While probiotics and antibiotics are generally known and chemical, antioxidants, and anti-inflammatory properties
available to treat gastrointestinal dysbiosis, fecal microbiota has a significant impact on the gut microbiome and brain
transplantation (FMT) has been rediscovered as a “new” way health. The lipopolysaccharide endotoxin (LPS) is particu-
to restore gut microbiota. FMT is the administration of a larly important in provoking depressive symptoms and dis-
solution of fecal matter from a donor into the intestinal tract turbing blood sugar control [118]. Traditional dietary
of a recipient in order to directly change the recipient’s gut practices have shown a 38% reduction of LPS after 1 month,
microbial composition and confer a health benefit [74]. An while the Western diet increases LPS elevation [70]. The
early version of this practice was first documented in fourth-­ health benefits of eating live beneficial bacteria are becoming
century China as “Yellow Soup.” In some countries, maternal more evident. Foods are now being produced that contain
feces is inserted into the newborn’s mouth to “jump-start” probiotic bacteria.
the colon. On June 17, 2013, the FDA approved FMT proce- Fermentation of foods and beverages is an ancient prac-
dures for recurrent Clostridium difficile infection (CDI). tice. Superficially, it would seem obvious, given the brain’s
There were zero documented serious side effects and there dependence upon nutrients for its structure and function
was a 92–95% success rate [74]. This strong interest is par- (including the micronutrients and non-nutrient dietary anti-
ticular to patients with chronic gastrointestinal infections oxidants), that nutrition should be a target of research in
and inflammatory bowel diseases. Carefully screened donor mental health [66].
stool is mixed with a saline solution. The solution is intro- Fermented foods and foods that contain live bacteria
duced into the GI tract via an NG tube, fecal enema, or oral have been used throughout the world for centuries. Foods are
capsules or during a colonoscopy. The “good” bacteria multi- fermented to extend shelf life, improve taste, and increase
ply and help flush out the C. diff. Bacteria. FMT reestablishes nutrient value. Fermented foods are known to increase spe-
a balanced intestinal microbiota and results in impressive cific nutrients and the phytochemical content of foods.
cure rates in patients with recurrent CDI. Standardization of Research consistently shows that a diet consisting of tradi-
FMT protocols and a randomized controlled trial are needed. tional whole foods improves mental health. Fermented foods
FMT is likely to achieve widespread therapeutic benefit for a also support the growth of microbes such as Bifidobacteria
variety of diseases in the future [74]. and Lactobacillus sp. which, by themselves, have been shown
FMT is currently approved by the FDA for the treatment to produce neurotransmitters [66, 115].
of Clostridium difficile infection (CDI) with an IND Traditional fermented whole foods are instrumental in
(Investigational New Drug) application. FMT has also shown the complex systems of mental, emotional, and brain health
benefit in treatment of inflammatory bowel disease (IBD), [66]. Research has shown this influence may be by virtue of
The Microbiome and Brain Health
403 25
microbial actions, antioxidant and anti-inflammatory activ- that is needed is the dose and the timing of probiotics and
ity, reduction of intestinal permeability and decreasing LPS, food. Carefully designed longitudinal clinical studies exam-
improved glycemic control, nutritional support, lifestyle ining the microbial profiles of phenotype patients through-
changes, and minimizing environmental toxins. out life and the long-term effects of factors disturbing its
In addition to probiotics and fermented foods, other compositions (e.g., via probiotics, antibiotics, dietary inter-
foods have also shown antidepressant properties, such as soy ventions) will be of great value to expand our knowledge of a
foods, cocoa, turmeric, green tea, coffee, blueberries, pome- promising area of research.
granate, and honey [29–38]. Specific nutrients, such as mag- In 1907, Élie Metchnikoff probably never knew how
nesium, zinc, vitamin C, folic acid, and vitamin B12, have exciting his discovery of the beneficial bacteria and phago-
shown to decrease depressive symptoms [39–42]. Probiotics cytes would be. Future research holds the potential of uncov-
and the overall profile of the intestinal microbiota can influ- ering the intriguing connections between the gut microbiota
ence tissue levels of mood-regulating minerals, such as mag- and a multitude of chronic illnesses and neurological condi-
nesium and zinc [85, 86]. tions.
Since fatty acids seem to play an important role in shap-
ing the gut microbiota metabolism, it is unsurprising that »» No disease that can be treated by diet should be treated
with any other means. –Maimonides.
they have been considered as a dietary means to impede cog-
nitive decline in aging. Human and animal studies on
omega-3 polyunsaturated acids (n-3 PUFAs) have shed light
on their neuroprotective roles through pathways of synaptic
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98. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psy- stress, and inflammatory markers in patients with type 2 diabetes:
chotropic. Biol Psychiatry. 2013;74(10):720–6. a clinical trial. Iran J Med Sci. 2013;38:38–43.
99. Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics 110. Dwivedi Y.  Brain-derived neurotrophic factor: role in depression
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III – convergence toward clinical trials. Gut Pathog. 2013;5(1):4. 111. Brunoni AR, Lopes M, Fregni F.  A systematic review and meta-­
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755–64. ticity and disease. Ann N Y Acad Sci. 2008;1144:97–112. https://
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depression. Clin Psychopharmacol Neurosci. 2015;13(3):239–44. 113. Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki
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 407 26

The Role of Nutrition

in Integrative Oncology
Cynthia Henrich

26.1 Introduction – 409

26.1.1  hat Is Cancer? – 409
W
26.1.2 Types of Cancer – 409
26.1.3 Statistics of Cancer – 409

26.2 Mechanisms of Oncogenesis and Metastases – 411

26.3 The Hallmarks of Cancer – 411

26.4 Current Conventional Medical Treatment – 411

26.4.1  hemotherapy and Targeted Therapies – 411
C
26.4.2 Radiation – 413
26.4.3 Surgery – 414

26.5 Terrain Versus Cancer – 414

26.6 Optimization and Protection – 414

26.7 Synergistic Therapies – 414

26.8 Emotional Aspect of Cancer – 415

26.9 Lifestyle Detoxification – 416

26.9.1  void or Remove? – 416
A
26.9.2 Sepsis – 417
26.9.3 Integrative and Functional Nutrition – 417
26.9.4 Liquid Oral or Enteral Nutrition – 418
26.9.5 Tea Therapy – 418
26.9.6 Turmeric – 418
26.9.7 Ginger – 419
26.9.8 Dandelion – 420
26.9.9 Methyl-Rich Foods – 420
26.9.10 Melatonin-Rich Foods – 421
26.9.11 Honokiol – 421
26.9.12 Limonene – 421
26.9.13 Cruciferous Vegetables – 421

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_26
26.9.14 S eeds – 422
26.9.15 Medicinal Mushrooms – 423
26.9.16 Bee Products – 423
26.9.17 Iodine Sufficiency – 423
26.9.18 Seaweed and Algae – 423
26.9.19 Fiber, Prebiotics, and Short-Chain Fatty Acids – 424
26.9.20 Modified Citrus Pectin and Pectin – 424
26.9.21 Fermented Foods and Probiotics – 425
26.9.22 Artemisia – 425
26.9.23 Carotenoid- and Polyphenol-Rich Foods – 425
26.9.24 Essential Oils – 425

26.10 Dietary Interventions – 426

26.10.1 S easonal Eating and Living – 426
26.10.2 Autoimmune Paleo Diet – 426
26.10.3 Vegetarian Diet – 427
26.10.4 Ketogenic Diet – 427

26.11 Integrative Therapies Adjunctive to Nutrition Therapy – 429

26.11.1  yperthermia – 429
H
26.11.2 Mindfulness Practices or Meditation – 429
26.11.3 Movement and Exercise – 430
26.11.4 Massage or Touch Therapy – 430
26.11.5 Posttreatment: Creating an Empowerment Plan – 430

26.12 Conclusion – 431

References – 431
The Role of Nutrition in Integrative Oncology
409 26
Learning Objectives more than 4800 new cases daily, and approximately 606,880
55 Understand conventional cancer modeling and treat- cancer deaths [1] (7 Boxes 26.1 and 26.2).
 

ments and their limitations and failure points.

55 Create a repertoire of integrative therapies.
55 Recognize the complexity of creating an integrative
cancer protocol. Box 26.1  Statistics List
55 Three most common cancers diagnosed in men: prostate,
55 Fit together the puzzle pieces of human metabolism, lung, and colorectal
cancer cell metabolism, tumor microenvironment, and 55 Three most common cancers diagnosed in women: breast,
integrative therapies. lung, and colorectal
55 Learn to use nutritional therapies to complement 55 Second most common cause of death among children
aged 1–14 years in the US is cancer
conventional cancer care.
55 Lifetime probability of being diagnosed with cancer: 39.3%
for men and 37.7% for women
55 Based on data from Ref. [1]
26.1  Introduction

26.1.1  What Is Cancer?

Cancer is not a singular disease but a group of highly com- Box 26.2  5-Year Relative Survival Rate
plex diseases characterized by unregulated cell proliferation 55 Highest:
that share pathways and molecular and metabolic mecha- 55 Prostate 98%
55 Melanoma of the skin 92%
nisms for oncogenesis, invasive growth, and metastases.
55 Female breast cancer 90%
55 Lowest:
55 Pancreas 9%
26.1.2  Types of Cancer 55 Liver 18%
55 Esophagus 19%
55 Lung 19%
Cancer can be grouped into two main categories: solid
55 Based on data from Ref. [1]
tumors and blood cancers. Within those two groups, there is
differentiation based on the type of cell in which the cancer
originates.
Solid Tumors: Abnormal Mass of Tissue  – Benign or One out of every two males and one out of every three
Malignant females can expect to be diagnosed with cancer within their
55 Carcinomas originate in the epithelial tissues, including lifetimes. Certain cancers have seen significant improvement
the skin and tissues that line and cover the internal in relative survival and cure rates, such as childhood leuke-
organs and body cavities. mia, while the incidence of other cancers and their mortality
55 Sarcomas develop in connective tissues, including the rates are increasing. The American Association for Cancer
bones, cartilage, tendons, muscle, and other fibrous Research released some unexpected projections for a shift in
tissues. cancer statistics:
55 Central nervous system cancers develop in the brain and “Cancer incidence and deaths in the United States were
spinal cord. projected for the most common cancer types for the years
55 Lymphomas begin in the lymphatic system, including the 2020 and 2030 based on changing demographics and the
lymphatic glands and vessels, the spleen, and the bone average annual percentage changes in incidence and death
marrow. rates. Breast, prostate, and lung cancers will remain the top
cancer diagnoses throughout this time, but thyroid cancer
Hematological Cancers: Blood-Forming Tissue Cancers will replace colorectal cancer as the fourth-leading cancer
55 Leukemias originate in the blood and bone marrow. diagnosis by 2030, and melanoma and uterine cancer will
55 Multiple myeloma become the fifth and sixth most common cancers, respec-
55 Lymphoma tively. Lung cancer is projected to remain the top cancer
killer throughout this time period. However, pancreas and
liver cancers are projected to surpass breast, prostate, and
26.1.3  Statistics of Cancer colorectal cancers to become the second and third leading
causes of cancer-related deaths by 2030, respectively” [2].
Despite medical science shining  a tremendous amount of These statistical analyses are done to determine the allo-
light on the growth mechanisms of these cancers, we have cation of research funding as well as the relative effectiveness
not yet made significant strides in conquering this disease. of the conventional routes of cancer treatment: chemother-
According to the American Cancer Society, in 2019, there apy, radiation, surgery, hormone therapy, immunotherapy,
will be an estimated 1,762,450 new cancer cases diagnosed, and targeted therapies.
 410 C. Henrich

26.1.3.1   he Functional, Integrative, Holistic,

T eggs, lectins, nightshades, or other common allergens
and Nutritional Perspective and inflammatory triggers, based on the needs of the
A deeper holistic look at these statistics can illustrate shifts in individual.
26 causality, such as toxic exposures, infection [3], and dietary 55 Targeted supplementation based on a nutritional and
deficiencies [4]. This perspective is an opportunity to create clinical assessment of any nutrient deficits (e.g., vitamin
change. D, zinc, methyl nutrients, minerals) is important to
The statistics do not tell the story of the bio-individual optimize immune function until goal test markers are
aspects of the whole person. Lifestyle, exposure to toxins and reached and maintained.
pathogens, diet, emotional wellness, use of supplements, 55 Herbal therapies: Certain herbs and roots have gained a
physical activity, exposure to EMF radiation, preconception reputation as cancer fighters but should be examined in
history, all of these affect the molecular and epigenetic the setting of any underlying disease as well as drug
changes that can initiate or prevent the growth of cancer in regimens. For instance, turmeric/curcumin [6] being
the body. contraindicated when used in combination with certain
On his deathbed, Louis Pasteur famously recanted his chemotherapy drugs such as camptothecin, mechlor-
germ theory and said, “Bernard is correct. I was wrong. The ethamine, doxorubicin, or cyclophosphamide in the
germ is nothing. The terrain is everything.” Claude Bernard’s treatment of breast cancer [7–10].
work aligned with that of Antoine Bechamp who originated 55 Detoxification support: Cytochrome pathways (dis-
the terrain theory [5]. Bechamp felt that disease resulted cussed below) should be checked for inhibition or
when microbes “changed form, function and toxicity” based induction potential of food, herb, and drug combina-
on the terrain of the host. tions. Some of these situations are synergistic, while
others are potentially harmful.
»» The constancy of the internal environment is the
condition for a free and independent life. –Claude
Moving forward, our goal should be to utilize the ability of
Bernard [5]
certain foods and herbs to positively impact quality of life,
Cancer is the same. Conventional treatment focuses on the sensitize cancer cells, protect healthy cells, and manipulate
“germ or microbe” (tumor). Integrative care focuses on both the tumor microenvironment to the benefit of the patient. If
the germ and the terrain (the health of the person). a substance can increase the amount of time that a chemo-
Conventional therapy is effective at surgical debulking therapeutic agent is held in the body, while positively affect-
cytoreduction (surgically reducing tumor bulk), with or ing disease markers, it may be possible that the drug dose can
without chemotherapy and/or radiation. It does not address be reduced while simultaneously creating a positive patient
protecting healthy cells during treatment. Unfortunately, outcome due to reduced side effects of the drug. This
many therapies leave the patient with the risk of secondary approach may make dose reductions of both chemo and
cancers due to the toxicity of treatment, depression of the radiation possible without a loss of efficacy, consequently
immune system causing a host of issues, the most dangerous allowing for potentially fewer side effects, better quality of
of which is sepsis, as well as the risk of recurrence or metas- life, and extension of treatment potential by resolving dose-­
tasis of the original cancer in an enriched state. Enriched limiting toxicities and time to resistance.
cancer cells arise when tumor bulk is reduced, but the stem Phytonutrition is the therapeutic potential of the col-
cells are not eradicated. These remaining “enriched” stem orful pigments in plants to act as modifiers of physiologi-
cells then become resistant to future treatment, akin to cal function with growing evidence related to modulation
MRSA in the bacterial world. of carcinogenesis [10]. For the nutritionist, understanding
The ability of the body to prevent the growth of cancer the functional parameters that impact the absorption and
and the potential of the immune system to conquer it are our utilization of these compounds will allow for their use to
most overlooked weapon in the war on cancer. Factors that be optimized in specific interventions. Although most
can be optimized to create a body that can effectively engage plants contain significant amounts of phytochemicals,
in this battle include lifestyle, diet, honoring bio-individual certain groups are higher in lycopenes, such as red and
needs, consuming anti-inflammatory foods that nourish the pink fruits and vegetables, or the isothiocyanates found in
tissues and cells, reducing the toxic burden of the body, and cruciferous vegetables. An awareness of the evidence-
attending to emotional and energetic imbalances [4, 6]. This based research specific to the impact of specific phytonu-
improves clinical outcome and quality of life and aids in the trients on certain cancers can create a significant impact
management of conventional treatment. These are exactly on dietary recommendations for patients. This can enable
the efficacy endpoints of any cancer treatment. the creation of integrative food- and botanical-based
When considering how to utilize nutrition and supple- nutrition protocols for prevention and adjunctive thera-
mentation in complementary and adjunctive cancer therapy, pies. The same theory can be applied to the metabolic
several things should be considered: function of fats and proteins and their physiological
55 Anti-inflammatory diet: Any biologically contraindi- effects. Whole food and herbs can truly perform as com-
cated foods should be avoided, such as gluten, dairy, plementary medicine [10].
The Role of Nutrition in Integrative Oncology
411 26

reprogramming genome
energy Instability and
metabolism mutation
enabling
evading growth
replicative
suppressors
immortality
activating
invasion and
metastasis

tumor evading
promoting immune
inflammation destruction
sustaining
evading cell
proliferative
death
signaling

Inducing
angiogenesis

..      Fig. 26.1  Graphic Hallmarks of Cancer (Courtesy of Cynthia Henrich)

26.2  Mechanisms of Oncogenesis complexity in that they contain a repertoire of recruited,

and Metastases apparently normal cells that contribute to creating the tumor
microenvironment (. Fig. 26.1) [11].
 

The wealth of research on the mechanisms of cancer can be

used to reverse engineer similar effects utilizing diet, lifestyle,
and natural therapies either alone or integrated with conven- 26.4   urrent Conventional Medical
C
tional therapies. This integration can improve quality and Treatment
length of life for patients while simultaneously contributing
to their whole-body wellness. First, we must examine the Chemotherapy, radiation, surgery, immunotherapy, hor-
underlying framework of mechanisms that enable the trans- mone therapy, and targeted therapies have been designed to
formation of a healthy cell into a malignant cell capable of interrupt some point in the process of transformation of the
metastasizing to distant sites. According to the conventional cell into malignancy or to prevent that event from recur-
model, the mechanisms are as follows and should each be ring. To offer individualized treatment options, histological
viewed as an opportunity to affect the outcome with integra- compatibility and oncotyping tests have been developed to
tive strategies: examine the genetics of a patient’s tumor and their best
response to treatment options. This can help to identify
growth mechanisms and potentially chart a course for drug
26.3  The Hallmarks of Cancer therapy.

Although cancer is a collection of highly complex diseases,

cancer cells demonstrate a set of distinct traits across tumor 26.4.1  Chemotherapy and Targeted
types that enable them to reproduce and metastasize, accord- Therapies
ing to conventional theories. Drs. Hanahan and Weinberg
began to elucidate and expand on these traits [11]. Research According the SEER∗Rx Interactive Antineoplastic Drugs
has emerged of late that cancer cell metabolism and stem Database on the National Cancer Institute website, there are
cells are not following the previous dictums and challenging currently 1867 drugs that can be combined into 510 potential
these hallmark traits. Tumors exhibit another dimension of regimens for conventional cancer treatment [12].
 412 C. Henrich

Gaining an understanding of the classes of chemothera- 26.4.1.2  Plant Alkaloids

peutic agents and their typical side effects, such as impact on Plant alkaloids are chemotherapy treatments derived from
platelets and cytochrome pathways, can make it easier to certain types of plants. The vinca alkaloids are made from the
26 determine functional and genomic interactions with supple- periwinkle plant (Catharanthus roseus). The taxanes are
ments and food. This will enable the practitioner to more made from the bark of the Pacific Yew tree (taxus). The vinca
carefully construct a dietary and botanical protocol that is alkaloids and taxanes are also known as antimicrotubule
most useful to the patient. There are several types of chemo- agents. The podophyllotoxins are derived from the mayapple
therapy, each of which can be administered via oral, intrave- plant. Camptothecin analogs are derived from the Asian
nous, intraperitoneal, transdermal, or implantable routes “Happy Tree” (Camptotheca acuminata). Podophyllotoxins
depending on the drug and cancer: and camptothecin analogs are also known as topoisomerase
inhibitors, which are used in certain types of chemotherapy.
26.4.1.1  Alkylating Agents The plant alkaloids are cell-cycle specific. This means they
Alkylating agents were one of the earliest classes of drugs attack the cells during various phases of division.
developed to treat cancer. They work by chemically altering 55 Vinca alkaloids: Vincristine, vinblastine, and vinorelbine
the DNA of a cancer cell by adding an alkyl group to directly 55 Taxanes: Paclitaxel and docetaxel
modify DNA bases or form cross-links to prevent replication 55 Podophyllotoxins: Etoposide and teniposide
and/or induce apoptosis. These drugs are particularly devas- 55 Camptothecin analogs: Irinotecan and topotecan
tating to the rapidly dividing cells that line the gut.
Tremendous damage to the mucosal barrier impacts diges-
tion and absorption, as well as frequently inducing side 26.4.1.3  Antitumor Antibiotics
effects such as diarrhea and dehydration that can limit or end Antitumor antibiotics are chemotherapeutic treatments
a course of chemotherapy [13]. made from natural products produced by species of the soil
Alkylating agents are most active in the resting phase of fungus, Streptomyces. These drugs act during multiple phases
the cell. These types of drugs are cell-cycle nonspecific. There of the cell cycle and are considered cell-cycle specific. This
are several types of alkylating agents used in chemotherapy class of drugs will have a significant impact on the diversity of
treatments: the microbiome that must be addressed during and post-
55 Mustard gas derivatives: Mechlorethamine, cyclo- treatment. There are several types of antitumor antibiotics:
phosphamide, chlorambucil, melphalan, and ifos- 55 Anthracyclines: Doxorubicin, daunorubicin, epirubicin,
famide mitoxantrone, and idarubicin
55 Ethylenimines: Thiotepa and hexamethylmelamine 55 Chromomycins: Dactinomycin and plicamycin
55 Alkyl sulfonates: Busulfan 55 Miscellaneous: Mitomycin and bleomycin
55 Hydrazines and triazines: Altretamine, procarbazine,
dacarbazine, and temozolomide 26.4.1.4  Antimetabolites
55 Nitrosoureas: Carmustine, lomustine, and streptozo-
Antimetabolites are types of chemotherapy treatments that
cin. Nitrosoureas are unique because, unlike most
are very similar to normal substances within the cell. When
types of chemo treatments, they can cross the blood–
the cells incorporate these substances into the cellular metab-
brain barrier. They can be useful in treating brain
olism, they are unable to divide. Antimetabolites are cell-­
tumors.
cycle specific. They attack cells at very specific phases in the
55 Metal salts: Carboplatin, cisplatin, and oxaliplatin
cycle. Antimetabolites are classified according to the sub-
(7 Box 26.3).
stances with which they interfere.
 

55 Folic acid antagonist: Methotrexate

55 Pyrimidine antagonist: 5-fluorouracil, floxuridine,
Box 26.3  Nutritional Therapies That Can Be Used cytarabine, capecitabine, and gemcitabine
to Preserve the Mucosal Barrier Function During 55 Purine antagonist: 6-mercaptopurine and 6-thioguanine
Treatment 55 Adenosine deaminase inhibitor: Cladribine, fludarabine,
55 Glutamine (cabbage is rich in the amino acid L-glutamine)
55 Zinc carnosine
nelarabine, and pentostatin
55 Mastica
55 Butyrate (ghee is rich in butyric acid)
55 Immunoglobulin-rich colostrum
26.4.1.5  Topoisomerase Inhibitors
55 Probiotic and prebiotic foods Topoisomerase inhibitors are types of chemotherapy drugs
55 Mushrooms such as Cordyceps and Ganoderma that interfere with the action of topoisomerase enzymes
55 Plant-based protein powders (topoisomerase I and II). During the process of chemother-
55 Elemental diet therapy
55 Turmeric
apy treatments, topoisomerase enzymes control the manipu-
55 Ginger lation of the structure of DNA necessary for replication.
55 Herbs such as slippery elm, licorice root, aloe, marshmal- 55 Topoisomerase I inhibitors: Irinotecan and topotecan
low root and chamomile 55 Topoisomerase II inhibitors: Amsacrine, etoposide,
etoposide phosphate, and teniposide
The Role of Nutrition in Integrative Oncology
413 26
26.4.1.6  Miscellaneous Antineoplastics 55Human epidermal receptor type 2 (HER2) tyrosine
Several useful types of chemotherapy drugs are unique: kinase inhibitor
55 Ribonucleotide reductase inhibitor: Hydroxyurea ȤȤ Anti-EGFR therapies can inhibit the activation of
55 Adrenocortical steroid inhibitor: Mitotane the EGFR signaling pathway in cancer cells which
55 Enzymes: Asparaginase and pegaspargase has been linked to increased cell proliferation,
55 Antimicrotubule agent: Estramustine angiogenesis, metastasis, and decreased apoptosis.
55 Retinoids: Bexarotene, isotretinoin, tretinoin (ATRA) 55 Biologic response modifier agent: Denileukin diftitox
55 Proteasome inhibitor: Bortezomib [17]
Targeted therapies have been designed to target pathways
outside of the common feature of cancer cells to be able to
divide rapidly. Because many normal cells in the human body 26.4.2  Radiation
also divide rapidly, multiple side effects may unfortunately
occur that can limit treatment and cause significant damage Radiation therapy uses high-energy X-rays, gamma rays,
or morbidity to the person [14, 15]. electron beams, or protons to make small breaks in the DNA
The different types of targeted therapies are defined in of cells or to create free radicals within the cells that will pre-
three broad categories. Some targeted therapies focus on the vent replication and cause cancer cell death. The radiation
internal components and function of the cancer cell. The tar- may be delivered as external beam radiation therapy or as
geted therapies use small molecules that can get into the cell internal radiation therapy, also known as brachytherapy, via
and disrupt cellular function, resulting in apoptosis. There radioactive material placed in the body near the tumor.
are several types of targeted therapy that focus on the inner Systemic radiation therapy uses radioactive substances, such
parts of the cells, while other targeted therapies focus on as radioactive iodine, to travel throughout the body to kill
receptors that are on the outside of the cell known as mono- cancer cells. Approximately half of all cancer patients receive
clonal antibodies. some type of radiation therapy sometime during the course
Antiangiogenesis drugs target the blood vessels that sup- of their treatment.
ply oxygen to the cells, ultimately causing the cells to starve. Radiation use is generally limited by late-onset adverse
Specifically, this class of drugs is designed to stop the forma- events that can occur during treatment or even months or
tion of new blood vessels. There is some research indicating years later. Secondary cancers, inflammatory conditions
that this particular hallmark of cancer may need to be revis- such as pneumonitis and proctitis, and radiation fibrosis, an
ited because certain tumors seem to have the capability to irreversible condition characterized by increased connec-
co-opt existing blood vasculature. This can account for resis- tive tissue stiffness and loss of tissue function at the irradi-
tance to antiangiogenic drugs and may distinguish which ated site, are a few of the typical outcomes of radiation
tumors may be susceptible to therapy [16]. therapy.
Monoclonal antibodies are a targeted cancer therapy that It may be possible to predict who may be at risk of
use an antibody to specifically target an antigen on the sur- radiation-­induced fibrosis via genetic markers and methyla-
face of a cancer cell. This lock-and-key function causes less tion status. The application of this research may include
toxicity to healthy cells but is limited to the cancers in which dietary modification and supplement use to optimize meth-
antigens and their respective antibodies have been identified. ylation status, restore nutritional insufficiencies, monitor
One way the immune system attacks foreign substances in hypercoagulation (fibrinogen, platelets, and d-dimer mark-
the body is by making large numbers of antibodies. An anti- ers), and mitochondrial protection [18].
body is a protein that sticks to a specific protein called an Radiation has been found to create more cancer stem
antigen. Antibodies circulate throughout the body until they cells (CSC) that are resistant to treatment. Recent evidence
find and attach to the antigen. Once attached, they can recruit indicates that radiation converts non-stem cancer cells into
other parts of the immune system to destroy the cells con- cancer stem cells, which exhibit similar radioresistance to
taining the antigen. The following are monoclonal antibod- intrinsic CSCs (cancer stem cells which are resistant to
ies: alemtuzumab, gemtuzumab ozogamicin, rituximab, treatment and cause relapse and metastasis) [19]. A possible
trastuzumab, and ibritumomab tiuxetan. mechanism of cancer resistance to radiation may be through
Other targeted therapies include the following: CSCs that should be killed by radiotherapy but are able to
55 Signal transduction inhibitors: survive radiotherapy. After radiation-induced stresses dis-
55Imatinib mesylate (protein-tyrosine kinase inhibitor) appear, these newly generated CSCs, together with the
55Gefitinib (epidermal growth factor receptor tyrosine intrinsic CSCs, contribute to the relapse and metastasis of
kinase inhibitor, EGFR-TK) cancer [19].
ȤȤ Tyrosine kinases are a family of enzymes which An alternative to conventional radiation therapy is pro-
catalyze phosphorylation and regulate biological ton therapy. Proton therapy is an advanced form of radiation
processes like growth, differentiation, metabolism, therapy that uses protons—positively charged atomic parti-
and apoptosis of cells. cles—instead of the photons used in standard X-ray radiation
55Cetuximab (epidermal growth factor receptor) therapy. With proton therapy, doctors can precisely target the
55Lapatinib (epidermal growth factor receptor (EGFR)) tumor while minimizing damage to the surrounding healthy
 414 C. Henrich

tissue. Unlike X-ray radiation, such as intensity-modulated optimize the human terrain will shift the entire way that we
radiation therapy [IMRT], protons deposit much of their approach cancer prevention, treatment, and survival. These
radiation directly in the tumor and then stop. For example, in methods will enable practitioners to optimize the wellness of
26 prostate cancer, proton therapy eliminates about 60% of the patient, thereby creating a strong foundation for the body
excess radiation delivered to healthy tissues surrounding the to withstand treatment, balance immune function, and tailor
prostate compared to IMRT. Proton therapy can treat recur- a dietary strategy that is ideal for the patient throughout dif-
rent tumors in patients who have already received traditional ferent stages of treatment and recovery.
forms of radiation, reduce the incidence of short- and long-­
term side effects, and incur a lower incidence of secondary
tumors. This may potentially allow the use of higher, more 26.6  Optimization and Protection
effective doses of radiation.
The inclusion of the appropriate balance of macronutrients,
saturation of micronutrients, and exclusion of harmful and
26.4.3  Surgery toxic anti-nutrients is the core of cellular optimization. This
allows the enzyme-driven processes of methylation, acetyla-
Surgical resection of a tumor with clear margins and negative tion, phosphorylation, ubiquitination, and sumoylation to
lymph findings is the single best predictor of survival. Many appropriately regulate cellular function and epigenetic
conventional therapies are aimed at reducing tumor bulk in expression, thereby enabling optimal mitochondrial metabo-
order to perform surgery. If tumor debulking surgery is not lism.
optimal, vascular endothelial growth factor (VEGF) may Mitochondria are the primary source of energy for the
increase, which could increase angiogenesis. body and dealing with mitochondrial metabolism can be
thought of as two sides of a coin: optimize function and pre-
vent dysfunction. The approach to this is multifaceted: pro-
26.5  Terrain Versus Cancer vide the necessary nutrients, precursors, and cofactors;
optimize liver function and detoxification; and determine
Perhaps the most overlooked aspect in standard cancer care bio-individual requirements for certain vitamins, condition-
is the biological and emotional condition of the person. ally essential nutrients, amino acids, and fatty acids to ensure
Science is doing an excellent job at uncovering pathways, optimal enzymatic function and genetic expression.
genetics, and mechanisms of the genesis and growth of can- The importance of optimal mitochondrial function can-
cer, but because the focus is on drug development, the epi- not be overstated. It is implicated in stem cell self-renewal,
genetic impact of nutrition and lifestyle on these processes cardiomyocyte regeneration, neural stem cell survival [20],
is largely ignored. The research, however, is extremely use- skeletal and heart muscle function and repair, neurological
ful in terms of reverse-engineered nutrition and lifestyle inflammation [21], cellular senescence [22], telomere short-
solutions. ening [23], oncogene initiation, and more.
Consider the old argument of germ versus terrain refer-
ring to pathogenic infectious organisms and apply the con-
cept to oncology. Enormous potential exists in the unexplored 26.7  Synergistic Therapies
realm of cancer versus terrain. Use the information gleaned
from the laser-focused study of cancer cells and tumors to Synergistic therapy in integrative oncology means that a par-
reduce the manifestation of cancer by optimizing the cellular ticular substance or action will protect healthy cells while
processes of the body through intensive bio-individually enabling another therapy to work more effectively. This can
appropriate nourishment and detoxification. Imagine potentially enable the reduction of a chemotherapy drug
accounting for this within the framework of cancer statistics. dose through enhanced chemosensitivity, thereby reducing
We account for age, but none of the other driving factors that toxicity and side effects, or even dramatically shift an out-
enable cancer to develop; or in the survivors, where radical come by tapping into the power of diet on biology.
lifestyle changes may dramatically shift where they fit in (or Synergistic therapies [24, 25] can be administered or
now defy) the survival statistics. performed concurrently with standard therapies, or they
It is the epitome of the poem, “The Road Not Taken,” by can be cycled throughout the regimen based on drug
Robert Frost: metabolism, pharmacokinetics, and pharmacogenetics.
Each individual therapy, food, herb, vitamin or mineral,
»» Two roads diverged in a wood, and I— exercise, or mindfulness practice needs to be assessed on an
I took the one less traveled by,
individual basis, taking into consideration the regimen
And that has made all the difference.
being administered as well as the bio-individual nature of
Dietary epigenetics, medical nutrition therapy, lifestyle med- the person. For instance, certain genetic markers or liver
icine, circadian medicine, and detoxification protocols to metabolism factors can create a need for optimization of
The Role of Nutrition in Integrative Oncology
415 26
methylation or adjustment for more rapid clearance of a Melatonin is also involved in genetic expression, pri-
substance through the cytochrome pathways. There is more marily with the genes controlling the cell cycle, adhesion,
and more information correlating phytonutrients and sup- and transport. It specifically impacts mitochondrial gene
plements with these metabolic pathways. It is helpful to expression. Melatonin increases the production of cyto-
check which pathway may be affected and cross-check that kines IL-2, IL-6, IL-12, and IFN-gamma from lymphocytes
with the regimen and the patient. and monocytes, which then increases the amount of natural
Cytochrome P450 enzymes are essential for the metabo- killer cells.
lism of many medications [26]. Although this class has more The waterfall effect of stress reaches well past melatonin.
than 50 enzymes, six of them metabolize 90% of drugs, with As cortisol levels remain inappropriately elevated over time,
the two most significant enzymes being CYP3A4 and stress is placed on the adrenal glands and adrenaline produc-
CYP2D6. Genetic variability (polymorphism) in these tion. Adrenaline is required to stimulate the G-protein for
enzymes may influence a patient’s response to commonly the oxidative phosphorylation cycle of mitochondria, pro-
prescribed drug classes, including beta-blockers and antide- ducing ATP by converting glucose in the Krebs citric acid
pressants. Cytochrome P450 enzymes can be inhibited or cycle. As adrenaline production is depleted, the conversion
induced by drugs, resulting in clinically significant drug-­ of glucose to ATP is inhibited, and instead the glucose fer-
drug interactions that can cause unanticipated adverse reac- ments and creates lactic acid as a by-product inducing cellu-
tions or therapeutic failures [26]. lar DNA and mitochondrial mutations.
Drug metabolism is not limited to liver biotransforma- Circadian rhythms and traditional Chinese medicine
tion but also occurs through the kidney, intestinal cells, (TCM) both correlate time with physical balance and energy
lungs, central nervous system, gastric mucosa, prostate, and, [29]. As described, in TCM, there are 14 major meridians
in some cases, even the skin. that conduct the flow of Qi throughout the body. Twelve of
Because many regimens include premedication to allevi- these meridians make up the 24-hour clock, representing 2
ate side effects or to act as adjuvant therapy, the metabolism/ hours each. The energy is constantly flowing through all of
drug interactions can become even more complicated. these meridians throughout the 24 hours, with each merid-
Referring to a clinical pharmacology P450 drug interaction ian having a 2-hour period of time as the primary meridian.
table such as the one from the Indiana University School of The meridian reflects the energy of its associated organ, but
Medicine can be helpful, but the complex nature of multi- also it reflects other processes in us: thoughts, emotions, col-
drug metabolism can make the use of therapeutic doses of ors, sounds, seasons, and even spiritual aspects [29]. The
food or supplements an incredibly complex situation [27]. meridians are coupled in pairs of Yin (receiving energy) and
Yang (expressing energy) of one of the five elements—earth,
metal, water, wood, and fire [29].
26.8  Emotional Aspect of Cancer So, for instance, recurring insomnia at the same time
each night, or a physical complaint at the same time each day,
Psycho-oncology explores how trauma and prolonged may correlate to an emotion or issue that is causing a disrup-
chronic stress can play a part in oncogenesis. It is extremely tion or stagnation in the life force energy or chi. Examples
common when working with cancer patients for them to include the following:
share that an emotional conflict or trauma occurred 55 Liver-gallbladder: anger, resentment, and frustration
approximately 18–24 months prior to their diagnosis. The 55 Heart-small intestine: emotional instability, discontent,
processing of a trauma of this nature can impact deep lack of focus, and heartbreak
sleep patterns and the production of melatonin. Melatonin 55 Spleen-stomach: worry and lack of empathy
is primarily synthesized by the pineal gland and is a natu- 55 Lung-large intestine: sadness and unresolved grief
ral antioxidant with immune-enhancing properties. 55 Kidney-urinary bladder: fear, abandonment, and anxiety
Melatonin production declines with age and may be one of
the major contributors to immunosenescence and cancer Often, the emotion of the initiating trauma will line up with an
genesis [28]. illness manifesting in the corresponding organ pair. This type
Among the various functions attributed to melatonin in of work is a beautiful opportunity to walk the border between
the control of the immune system, antitumor defense physiology and emotion, navigating the Rivers of Qi.
assumes a primary role [28]. The nighttime physiological If you can recall the moments of childhood where hours
surge of melatonin in the blood or extracellular fluid has were spent so busy, happy, and content that one might forget
been suggested to serve as a natural restraint for tumor initia- to eat unless called, you can see that emotional balance and
tion, promotion, and/or progression. Melatonin was demon- joy are sustenance in their own right. Addressing these emo-
strated to be oncostatic for a variety of tumor cells like breast tional needs or imbalances by simply acknowledging their
carcinoma, ovarian carcinoma, endometrial carcinoma, existence is often enough to create awareness and initiate the
human uveal melanoma cells, prostate tumor cells, and GI healing process. Nourishing the spirit can further that heal-
tumors [28]. ing (7 Box 26.4).
 
 416 C. Henrich

Chemicals  Scented products, such as air fresheners and

Box 26.4  Nutritional and Lifestyle Strategies dryer sheets, cleaning products, beauty and personal prod-
for Emotional Support ucts, detergents, and soaps that are commonly found in most
26 55 Optimize sleep
55 Melatonin and foods rich in melatonin
households should be avoided. Styrofoam in packaging,
drinking cups, and food containers should be avoided.
55 Theanine (found in green tea)
55 Magnesium Pesticides, fertilizers, and herbicides are commonly applied
55 Apply a blue light filter on devices to mimic sundown. to crops, and patients undergoing treatment should be
55 Sleep in a completely dark room. encouraged to purchase organic, if possible. Check labels of
55 No caffeine packaged food and personal products to eliminate chemical
55 Mindfulness and meditation
exposures, preservatives, and artificial ingredients and sweet-
55 Yoga
55 Deep breathing eners. Perfluorinated alkylated substances (PFAS) such as in
55 Acupuncture Teflon-coated clothing or cookware, fire retardant-coated
55 Exercise clothing, furniture, and carpeting should be avoided.
55 Spiritual practices
55 Clean diet free of chemicals
EMF exposure  Be conscious of the use of electronic devices
in the evening as it will impact melatonin production. Leave
your phone outside of your bedroom or set to airplane mode
26.9  Lifestyle Detoxification overnight. Do not carry the device close to your body and use
air tube headsets to reduce EMF exposure to the head and
From a holistic perspective, what you avoid and the relation- neck area.
ships that influence you are as important as what you include
in your life. Every action, product, food, movement, emo- Microbiome disruptors  Meat, fish, or animal products that
tion, and breath is an opportunity to positively impact your are laden with hormones, antibiotics, and chemically altered
wellness. Sharing this concept with patients will empower feed have the potential to disrupt not only the animal micro-
them to gain a sense of control and to participate in their biome but also the consumers. Fat stores from the animals
healing process. contain even higher concentrations as these chemicals are
Detoxification is such an important aspect of wellness, lipophilic and of great concern.
both in the material and emotional world. Removing existing
toxins and avoiding potential toxins reduce the environmen- High-glycemic foods  Fast food, processed food, foods high
tal burden, making it easier for the body to focus on healing. in sugar, alcohol, and high-fructose corn syrup are not nutri-
Cleaning up the diet, personal and household products, and tious options for patients undergoing cancer treatment.
the emotional realm are the first steps toward wellness (see Processed foods of low-nutrient density, such as high calorie,
7 Chap. 13).
  low nutrient density liquid enteral food and other chemically
laden foods, sugar, undesirable fats, synthetic vitamins, and
casein-filled anti-nutritive beverages, should be avoided and
26.9.1  Avoid or Remove? alternate recommendations made.

Antigenic triggers  Based on the bio-individual needs of a IV nutrition  Intravenous nutrition is the fastest, most
patient, eliminate any potential allergens that might not have assured way of reaching clinically effective levels of the
been previously considered: gluten, dairy, corn, eggs, soy, and administered substances in the body. Deficiencies of stom-
nightshades. ach acid and enzymes or inflammatory gut conditions may
inhibit the absorption of a variety of nutrients. IV nutrition
Mold  Any mold exposure should be remediated or avoided. bypasses the digestive tract and delivers the nutrients directly
This is extremely toxic and immunosuppressive. into the bloodstream for more direct access to the organs and
tissues in need. It can also work to increase energy levels and
Amalgam fillings  Although controversial and especially reduce side effects and is excellent for recovery posttreat-
when considered during cancer treatment, amalgam fillings ment. Careful follow-­up of vitamin and mineral levels are
may be removed by a biological dentist who uses the right needed to ensure safety.
precautions and detoxification procedures. The decision may Linus Pauling, one of the fathers of orthomolecular
depend on the degree of deterioration of the fillings. medicine and the Linus Pauling Institute of Oregon State
University [30], have laid the foundation for evidence-
Plastics as endocrine disruptor compounds (EDCs)  Plastic based research on micronutrients. Several physicians and
wrap, plastic water bottles, and even the bisphenol-­free plas- clinics have contributed vast stores of knowledge to this
tics have been found to leach EDCs. Patients should be story, including Jeanne Drisko, MD [31], Dwight McKee,
advised to never heat food in those containers but rather MD [32], Paul Anderson, ND and Mark Stengler, ND [33],
transfer it to a safe container for heating. and Keith Block, MD [34].
The Role of Nutrition in Integrative Oncology
417 26
The NIH National Cancer Institute, Office of Cancer Inspired by that experience, they went on to enroll and
Complementary and Alternative Medicine (OCCAM) has treat 47 septic patients with a cocktail of 1.5 g vitamin C IV
references for clinical trials as well as specific drug integra- every 6 hours, hydrocortisone 50 mg IV every 6 hours, and
tion [35]. They report that laboratory studies of high-dose thiamine 200 mg IV every 12 hours (thiamine inhibits oxalate
vitamin C have shown decreased cell proliferation in pros- production and has potential benefits in septic shock).
tate, pancreatic, hepatocellular, colon, mesothelioma, and Controls were 47 patients matched in baseline characteristics.
neuroblastoma cell lines and that patients report improved Hospital mortality was 4 of 47 (8.5%) in those treated with the
quality of life and decreased cancer-related side effects. Refer cocktail, compared to 19 of 47 (40%) in those not. Vasopressors
to the Human Clinical Studies page for more examples and were weaned off in all cocktail-treated patients, usually in <24
ongoing clinical trials [36]. hours (vs. 4 days for the controls). Renal function reportedly
Intravenous therapies may include: improved in all patients with acute kidney injury [41].
55 Ascorbic acid (a G6PD test should be run prior to Intravenous nutrition therapy should be a first-line as
administration as fatal hemolysis can occur if a patient well as an integrative therapy consideration for every patient.
has glucose-6-phosphate dehydrogenase deficiency; also Riordan Clinic has developed a compendium of evidence-­
contraindicated is renal insufficiency) [37] based research when deciding on treatment [42].
55 Glutathione
55 B vitamins
55 Magnesium 26.9.3  Integrative and Functional Nutrition
55 Potassium
55 Lipoic acid The impact of good nutrition in cancer prevention or as part
55 L-carnitine of an integrative treatment program is well established. Food-­
55 Minerals based nutrients are capable of preventing cellular DNA dam-
age from carcinogenic environmental factors. The correct
Mixtures of various ingredients known as cocktails are also dietary choices can ensure proper detoxification, immune
created to specifically target particular issues. system function, and metabolic function, reduce inflamma-
One combination of alpha lipoic acid (ALA), low-dose nal- tion, increase longevity and quality of life, and minimize side
trexone (LDN), and vitamin D has been shown in case reports effects of conventional treatment. The challenge lies more in
to have potential promise in the treatment of stage 4 adenocar- breaking down the information so as not to fall into the trap
cinoma of the pancreas [38, 39]. The authors described the of a one-target, one-compound solution mind-set.
long-term survival of a man with pancreatic cancer with The tapestry of synergistic nutrient and herbal benefits
metastases to the liver, treated with intravenous ALA and oral contained in food is woven from:
LDN without any adverse effects, and was alive and well 78 55 Essential vitamins and minerals
months after initial presentation. Three additional pancreatic 55 Fatty acids
cancer case reports were presented. At the time of the report, 55 Fiber
the first patient was alive and well 39 months after presenting 55 Thousands of phytochemicals including:
with adenocarcinoma of the pancreas with metastases to the 55Terpenes
liver. The second patient who presented with the same diagno- 55Polyphenols
sis was treated with the ALA/LDN protocol, and after 5 months 55Carotenoids
of therapy, PET scan demonstrated no evidence of disease. The 55Isoflavones
third patient, in addition to his metastatic pancreatic cancer, 55Flavonoids
had a past medical history of B-cell lymphoma and prostate 55Chlorophylls
adenocarcinoma. After 4 months of the ALA/LDN protocol, 55Alkaloids
the CT/PET scan demonstrated no evidence of disease [38]. 55Lignans
55Phytosterols
55Sulforaphanes
26.9.2  Sepsis 55Stilbenes
55Catechins
Sepsis is a common end-of-life occurrence in oncology [40]. 55Tannins
Marik et al. will soon publish in Chest their own small before-­ 55 Folate
and-­after unblinded cohort study, born of an anecdote that 55 Inositol
should intrigue any intensivist: Three patients with “fulmi- 55 Sulfides
nant sepsis ... almost certainly destined to die” from shock
and organ failure, were infused with vitamin C and moderate-­ Each food and nutrient, as well as bio-individual physical suf-
dose hydrocortisone out of desperation. All three patients ficiency of nutrients, either influences or is metabolized
recovered quickly and left the ICU in days “with no residual through detoxification pathways, including phase I CYP P450
organ dysfunction.” isoenzymes, phase II conjugation enzymes, Nrf2 signaling,
 418 C. Henrich

and metallothionein [43]. CYP450 enzymes are essential for choose high-quality teas that are not contaminated with
the production of cholesterol, steroids, prostacyclins, and heavy metals, fluoride, or pesticides. Tea contains polyphe-
thromboxane A2. Within the population, there is genetic vari- nols that include the catechins, alkaloids (caffeine, theophyl-
26 ability or polymorphisms of CYP450 enzymes, with about line, and theobromine), amino acids, chlorophyll, and
50% of the population having normal function and the rest minerals.
having altered rapid to very low function. So ultimately, we From the NIH National Cancer Institute [47], among
need to consider the patient’s particular metabolism, often their many biological activities, the predominant polyphe-
referred to as normal, rapid, or slow metabolizers, layered with nols in green tea—EGCG, EGC, ECG, and EC—and the
the effect of nutrients, and then the effect of drug regimens. theaflavins and thearubigins in black teas have antioxidant
Viewed this way, it is an extremely complex undertaking [43]. activity. These chemicals, especially EGCG and ECG, have
Super doses or consumption of certain nutrients, either substantial free radical scavenging activity and may protect
via food or food-based supplements, will influence specific cells from DNA damage caused by reactive oxygen species.
enzymes in a dose-dependent manner. They may increase or Tea polyphenols have also been shown to inhibit tumor
decrease the function of a pathway or act as adaptogens, bal- cell proliferation and induce apoptosis in laboratory and ani-
ancing the function of an enzyme. Consumption of bioactive mal studies [47]. In other laboratory and animal studies, tea
supplements in this manner may or may not be therapeutic, catechins have been shown to inhibit angiogenesis and tumor
while food forms are often better tolerated and less poten- cell invasiveness. In addition, tea polyphenols may protect
tially problematic. A whole foods-intensive diet is the safest against damage caused by ultraviolet (UV) B radiation, and
and most important way to optimize biofunction [44, 45]. they may modulate immune system function. Furthermore,
green teas have been shown to activate detoxification
enzymes, such as glutathione S-transferase and quinone
26.9.4  Liquid Oral or Enteral Nutrition reductase, that may help protect against tumor development.
Although many of the potential beneficial effects of tea have
A simple glance at the label of any commercial oral or enteral been attributed to the strong antioxidant activity of tea poly-
feeding product will explain why they should be avoided: phenols, the precise mechanism by which tea might help
Sugar, corn syrup, sodium caseinate, corn maltodextrin, soy prevent cancer has not been established.
protein isolate, corn oil, and canola oil form a who’s-who list of Chamomile tea is a potent source of apigenin [48].
what not to consume. These ingredients are generally geneti- Apigenins appear to play a role in gene regulation, essentially
cally modified and contribute to the toxic burden of the body. reprogramming cancer cells so they act more like normal
Sugar and corn syrup are two of the preferred energy sources cells and die on schedule. One of the most striking discover-
for cancer and contribute to obesity, one of the leading causes ies in this body of research is that apigenins could potentially
of cancer, as well as nonalcoholic fatty liver disease. Although stop the spread of breast cancer. The latest research suggests
high in calories, the only vaguely nutritive value is added syn- apigenin binds to one of three types of proteins, each with a
thetic vitamins. The added inflammatory and endocrine-dis- specific function. One of those proteins is called hnRNPA2.
rupting potential of filler ingredients is in direct opposition to In a healthy hnRNPA2 protein, only one type of splicing
the needs of the cancer patient. There are far healthier prod- takes place [48].
ucts on the market made of real organic high-quality ingredi- However, in cancer cells, two types of splicing take place.
ents. The Oley Foundation is a fantastic resource for real food This abnormal splicing is a factor in about 80% of all cancers.
options for blenderized or tube feeding needs [46]. Splicing is important because it prompts the production of
Batch cooking and preparation are extremely helpful since mRNA, or messenger RNA, which then carries out instruc-
patients are generally exhausted during times that require the tions regarding gene activation. When apigenin connects
greater food absorption and digestive rest that liquid nutri- with the hnRNPA2 protein in breast cancer cells, it changes
tion provides. True nourishing support can be found with the the protein from two splices back to a single-splice setup.
following: freshly made vegetable and fruit juice blends (low And with splicing back to normal, cells are able to die on
sugar), smoothies (made with low-sugar ingredients and schedule—or, at the very least, they become more vulnerable
greens), blended soups, protein powders (pea, hemp, grass- to the effects of chemotherapy drugs [48].
fed beef protein, grass-fed whey, nutritional yeast, egg white Herbal tea blends are available to gently cleanse the liver,
powder as tolerated), organic whole fruit and vegetable and support the mucosal health of the digestive system, support
grass powders, and bone broths and collagen support sourced throat and esophageal health, relieve nausea, and more.
from grass-fed, free-range, organic animals.

26.9.6  Turmeric
26.9.5  Tea Therapy
Turmeric is a member of the ginger family, and the rhizome
Tea is a simple, yet powerful, way to provide daily support for has been used for thousands of years for its healing proper-
detoxification, reduction of inflammation, and overall cancer ties. Although the active constituent, curcumin, is the focus
care. Tea is a gentle way to enter the herbal realm. As always, of much research, there are a multitude of compounds
The Role of Nutrition in Integrative Oncology
419 26
identified in the rhizome, and some research on curcumin- tumor stability for 18 months, and reduce clinically relevant
free turmeric indicates that these non-curcumin com- biomarkers, all without toxicity [55]. It was found to be safe
pounds, as well as the whole plant synergy, may hold for use in gemcitabine-resistant patients with pancreatic can-
equivalent efficacy [49]. cer [56]. Curcumin reduced the number and size of polyps
Turmeric compounds include the yellow-colored poly- found in the precancerous condition familial adenomatous
phenols curcumin (diferuloylmethane), demethoxycur- polyposis (FAP). Curcumin reduces clinically relevant bio-
cumin (curcumin II), and bisdemethoxycurcumin (curcumin markers in colorectal cancer that is refractory to chemother-
III), as well as turmerin, turmerone, elemene, furanodiene, apy. Pretreatment with curcumin considerably reduced the
curdione, bisacurone, cyclocurcumin, calebin A, and ger- dose of cisplatin and radiation required to inhibit the growth
macrone [49]. Studies have indicated that turmeric oil, pres- of cisplatin-resistant ovarian cancer cells [57]. Curcumin
ent in turmeric, can enhance the bioavailability of curcumin. combined with oxaliplatin may enhance efficacy of the latter
Dietary turmeric is especially important because consistent in both p53wt and p53 mutant colorectal tumors [58].
consumption in food overcomes some of the bioavailability Curcumin has been tested for safety and potential effect
issues of turmeric due to its hydrophobic nature, poor with the maximum tolerable dose range between 4 and 8 g
absorption, and metabolism. Different methods of delivery per day. Bear in mind that combining curcumin with piper-
of curcumin have been studied, including using in combina- ine will dramatically alter its bioavailability, thus changing
tion with heat, fat, and the piperine compound from pepper. that limit. All concurrent drug therapies should be checked
Much of these challenges are overcome naturally when tur- for cytochrome isoenzyme activity to prevent toxicity and
meric is incorporated consistently in the diet [50]. Turmeric ensure efficacy [59].
milk (turmeric mixed in warm milk) has been used for thou-
sands of years as a tonic in India.
Evidence-based research indicates that turmeric pos- 26.9.7  Ginger
sesses anti-inflammatory, hypoglycemic, antioxidant,
wound-healing, antimicrobial, anticancer, and immune-­ One of the ancient remedies for ailments ranging from stom-
supportive properties that support overall wellness [49, 50]. ach upset to aches and pains, the ginger rhizome now has a
The polyphenol curcumin exhibits anticancer effects through growing body of evidence of efficacy in cancer. There are
a multitude of pathways, including the modulation of the cell many active compounds in this root, some of which are in
cycle, by binding directly and indirectly to molecular targets the layer just under the peel, so when using the young root, it
including transcription factors (NF-kB, STAT3, β-catenin, is best to scrub it, as opposed to peeling it, if making a tea,
and AP-1), growth factors (EGF, PDGF, and VEGF), enzymes smoothie, or juice. If the root is harvested later, past the
(COX-2, iNOS, and MMPs), kinases (cyclin D1, CDKs, Akt, 9-month mark, the skin will be tougher and may need to be
PKC, and AMPK), and inflammatory cytokines (TNF, MCP, removed. The older roots yield higher amounts of ginger oil
IL-1, and IL-6). [60, 61].
There is upregulation of proapoptotic (Bax, Bad, and Bak) The anticancer activity of ginger has many mechanisms
and downregulation of antiapoptotic proteins (Bcl(2) and including reducing inflammation, upregulating tumor-­
Bcl-xL) [51]. Additionally, curcumin can suppress the activa- suppressor genes, cell-cycle arrest, inducing apoptosis via the
tion of dendritic cells (DCs) by modulating the JAK/STAT/ mitochondrial pathway and production of ROS, inactivation
SOCS signaling pathway to restore immunologic balance in of VEGF pathways, and modulation of signaling molecules
an experimental colitis model, colitis being a risk factor for such as NF-kB, STAT3, MAPK, PI3K, ERK1/2, Akt, TNF-α,
colon cancer [52]. Because curcumin exhibits numerous COX-2, cyclin D1, cdk, MMP-9, survivin, cIAP-1, XIAP, Bcl-­
mechanisms of cell death, it is possible that cells may not 2, caspases, and other cell growth regulatory proteins [61] all
develop resistance [53]. essentially affecting a multitude of targets in the various
Most critically of all, turmeric is proving to be an effective stages of oncogenesis, angiogenesis, and metastasis.
weapon against cancer stem cells in many types of cancer. Additionally, ginger has been found to be neuroprotective,
Cancer stem cells (CSCs), as discussed above, are a subpopu- antiemetic, antimicrobial, antifungal, and protective of the
lation of tumor cells that possess the stem cell properties of liver, gastrointestinal system, and lungs [61, 62]. The main
self-renewal and differentiation. These cells have been identi- compounds of interest in ginger are terpenes, including
fied in many solid tumors including breast, brain, lung, pros- zingiberene, β-bisabolene, α-farnesene, β-sesquiphellandrene,
tate, testis, ovary, colon, skin, and liver and also in acute α-curcumene, zerumbone, and phenols including gingerol,
myeloid leukemia. The CSC theory clarifies not only the issue paradol, and shogaol.
of tumor initiation, development, metastasis, and relapse but Ginger can be taken internally in the following forms:
also the ineffectiveness of conventional cancer therapies. powdered spice, tea, pickled ginger, candied ginger, pre-
Treatments directed against the bulk of the cancer cells may served ginger, ginger oil, or raw root, and it has been used
produce striking responses, but they are unlikely to result in in skin cancer research as a topical preparation. Ginger can
long-term remissions if the rare CSCs are not targeted [54]. stimulate appetite and enhance digestion. Caution is
Curcumin was tested in a group of 25 advanced pancreatic advised in patients on anticoagulants or with bleeding dis-
cancer patients and found to induce tumor regression, induce orders [62].
 420 C. Henrich

Ginger has shown efficacy in the following cancers: skin, Dandelion flowers have antibacterial properties in their pol-
breast, lung, gastrointestinal, bile duct, pancreatic, ovarian, len; contain a terpene known as helenin, which is a powerful
cervical, renal, prostate, liver, and brain. Ginger has been antifungal agent [68]; and are rich in vitamins A and B12.
26 found helpful in ameliorating side effects of conventional Dandelion leaves and flowers were found to be protective
treatment with radiation, doxorubicin, and cisplatin, as well against UVB exposure and cellular senescence, suggesting
as working synergistically with gemcitabine in pancreatic potential use for UV sun protection and antiaging applica-
cancer by sensitizing tumor cells and suppressing tumor tions [69]. Perhaps the most powerful part of the dandelion is
growth. the root. The German Commission E has approved dande-
Interestingly, ginger combined with Gelam honey was lion root for the treatment of disturbances in bile flow, stimu-
found to produce more tumor cellular apoptosis than the use lation of diuresis, loss of appetite, and dyspepsia.
of 5-fluorouracil alone in the treatment of colorectal cancer The University of Windsor in Ontario is currently
cells [63]. The component zerumbone has been found to ­running the Dandelion Project, a clinical trial using dande-
enhance the radiosensitivity of colon cancer cells. Beyond lion root extract (DRE) for terminal cancer cases. Two refrac-
inducing apoptosis, autophagy, and modulating angiogenesis tory hematological malignancies experienced unusual
in ovarian cancer, ginger compounds may help to overcome responses to DRE [70]. DRE was shown to have the potential
chemotherapeutic drug resistance [64]. Perhaps the most to induce apoptosis and autophagy in human pancreatic can-
encouraging research on ginger comes in the form of its abil- cer cells with no significant effect on noncancerous cells [71].
ity to address stem and dendritic cells [65]. The ginger com- Dandelion extracts have been used in traditional Native
pound 6-shogaol was found to inhibit both breast cancer American medicine and traditional Chinese medicine to
monolayer cells and stem cell spheroids at doses that are not manage gastrointestinal and liver disorders. Upon study,
toxic to normal cells [65, 66]. DRE was found to be selectively cytotoxic to cultured leuke-
Also significant is the potential of 6-shogaol to decrease mia cells [72].
cancer development, progression, and metastasis by inhibit- Chronic myelomonocytic leukemia (CMML) is aggres-
ing the production of tumor-associated dendritic cells. The sive and highly resistant to treatment. DRE holds promise as
study reported tumor-associated dendritic cells (TADCs) a potential treatment [73]. DRE was shown to have selective
facilitate lung and breast cancer metastasis in vitro and in vivo efficacy in inducing two forms of programmed cell death in
by secreting inflammatory mediator CC-chemokine ligand 2 highly aggressive and resistant CMML cell lines. Rapid acti-
(CCL2), but it is also the first to reveal that 6-shogaol can vation of caspase-8 not only activated the extrinsic pathway
decrease cancer development and progression by inhibiting of apoptosis but also triggered pro-death autophagy selec-
the production of TADC-derived CCL2. Human lung cancer tively in these cells, suggesting that this extract has compo-
A549 and breast cancer MDA-MB-231 cells increase TADCs nents that enhance its selective efficacy in targeting CMML
to express high levels of CCL2, which increase cancer stem cells. These results indicate that within the vast array of avail-
cell features, migration, and invasion, as well as immunosup- able natural products and compounds, there are nontoxic
pressive tumor-associated macrophage infiltration [66]. alternatives to conventional chemotherapy that are safe and
6-shogaol decreases cancer-induced upregulation of effective [73].
CCL2 in TADCs, preventing the enhancing effects of TADCs And one of the most common cancers, colon, may also
on tumorigenesis and metastatic properties in A549 and benefit from DRE treatment [74]. Phytochemical analyses of
MDA-MB-231 cells. A549 and MDA-MB-231 cells enhance the extract showed complex multicomponent composition of
CCL2 expression by increasing the phosphorylation of signal the DRE, including some known bioactive phytochemicals
transducer and activator of transcription 3 (STAT3), and the such as α-amyrin, β-amyrin, lupeol, and taraxasterol. This
activation of STAT3 induced by A549 and MDA-MB-231 is suggested that this natural extract could engage and effec-
completely inhibited by 6-shogaol. 6-shogaol also decreases tively target multiple vulnerabilities of cancer cells. Therefore,
the metastasis of lung and breast cancers in mice. 6-shogaol DRE could be a nontoxic and effective anticancer alternative,
exerts significant anticancer effects on lung and breast cells instrumental for reducing the occurrence of cancer cells drug
in vitro and in vivo by targeting the CCL2 secreted by TADCs. resistance [74].
Thus, 6-shogaol may have the potential of being an effica- Dandelion root tea and extract are readily available and
cious immunotherapeutic agent for cancers [66]. should be considered in all stages of treatment.
Ginger in all of its forms deserves a place of honor in our
herbal healing arsenals for virtually all aspects of wellness,
but specifically for cancer prevention and treatment. 26.9.9  Methyl-Rich Foods

Methyl-rich foods are epigenetically powerful and include

26.9.8  Dandelion those that are high in folate, methionine, and choline, such as
meat, fish, eggs, dairy, citrus, leafy greens, strawberries, and
Bitter greens, especially dandelion greens, are plentiful in the mushrooms [75].
spring and have been used traditionally for centuries to stim- Chemicals that enter our bodies can also affect the epig-
ulate bile and aid in phase 2 liver detoxification [67]. enome. One example, bisphenol A (BPA), is a compound
The Role of Nutrition in Integrative Oncology
421 26
used to make polycarbonate plastic. It is in many consumer appreciable toxicity. Honokiol affects multiple signaling
products, including water bottles and linings of tin cans. pathways in molecular and cellular targets, including nuclear
Controversial reports questioning the safety of BPA have factor-κB (NF-κB), STAT3, epidermal growth factor receptor
prompted some manufacturers to stop using the chemical. In (EGFR), cell survival signaling, cell cycle, cyclooxygenase,
the laboratory, BPA appears to reduce methylation of the and other inflammatory mediators [85].
agouti gene in mice. Agouti mice studied show yellow moth- Honokiol can be used in combination with oxaliplatin in
ers give birth to pups with a range of coat colors from yellow the chemotherapy of colon cancer. This combination allows a
to brown. When mothers were fed BPA, their babies were reduction in oxaliplatin dose, thereby reducing its adverse
more likely to be yellow and obese. However, when mothers effects. It may also enhance the chemotherapeutic effect of
were fed BPA along with methyl-rich foods, the offspring oxaliplatin for this disease [86]. Honokiol inhibits migration
were more likely to be brown and healthy. The maternal of non-small cell lung cancer cells [87].
nutrient supplementation had counteracted the negative Molecular docking analysis of honokiol in EGFR binding
effects of exposure [76]. site indicated that the chemotherapeutic effect of honokiol
From there, it is easy to see the cascade effect of how against head and neck squamous cell carcinoma (HNSCC) is
attention to methylation and epigenetic programming can mediated through its firm binding with EGFR, which is bet-
mitigate daily exposure to toxins, thereby reducing cancer ter than that of gefitinib, a commonly used drug for HNSCC
risk. treatment [88]. Furthermore, honokiol shows effectiveness
against several multidrug-resistant tumor cells [89].

26.9.10  Melatonin-Rich Foods

26.9.12  Limonene
We have previously discussed the critical role of melatonin
on the immune system. The decline in the production of Limonene is a bioactive monoterpene found in the peel of
melatonin with age has been suggested as one of the major citrus fruit. Even though it was proven to completely regress
contributors to immunosenescence and the possible devel- mammary tumors in rats over 25 years ago [90], human
opment of neoplastic diseases [77]. To further complicate clinical trials are lacking. However, a recent study on the
matters, melatonin metabolism from dietary sources can metabolomics of limonene is very promising and suggests
compete in the liver with other compounds, can be that limonene’s activity is likely through a general systemic
impacted by hormones, is affected by cytochrome enzymes, effect rather than through a specific target [91].
and is subject to other clinical deficiencies, such as pyrol- Limonene is distributed extensively to human breast tis-
uria [78]. Pyrrole disorder, sometimes referred to as the sue when eaten and results in reduced breast tumor cyclin D1
mauve factor, is consistently associated with higher inci- expression that may lead to cell-cycle arrest and reduced cell
dence of mental health issues, such as ADHD, bipolar dis- proliferation. Overexpression of cyclin D1 promotes the
order, and schizophrenia, all of which can be mediated with transition of cells out of the G1 and into the cell cycle and is
vitamin and mineral therapy, thus impacting endogenous commonly overexpressed and deregulated early in breast
melatonin production. There can also be a focus on foods tumorigenesis in humans [92]. This is notable because cyclin
that contain the necessary B6 and zinc and cofactors such D1 is a key regulator of cell proliferation. It also controls
as folate, B12, and manganese [79]. Also, as with any phyto- other aspects of the cell fate, such as cellular senescence,
chemical, plant levels are dependent on growing conditions apoptosis, and tumorigenesis [93].
and harvesting [80]. D-limonene enhanced the antitumor effect of docetaxel
Some excellent dietary choices for melatonin are tart against prostate cancer cells without being toxic to normal
cherry juice, tart cherries, walnuts, mustard seed, toma- prostate epithelial cells. This combined beneficial effect
toes, chilies, almonds, pineapple, bananas, oranges, fenu- could be through the modulation of proteins involved in
greek seeds, sunflower seeds, corn, rice, ginger root, the mitochondrial pathway of apoptosis. D-limonene could
peanuts, grains, corn, asparagus, mint, black and green tea, be used as a potent nontoxic agent to improve the treatment
broccoli, pomegranate, olives, Brussel sprouts, and cucum- outcome of hormone-refractory prostate cancer with
bers [81–84]. docetaxel [94].

26.9.11  Honokiol 26.9.13  Cruciferous Vegetables

Honokiol is a phytochemical isolated from the bark and Broccoli, broccoli sprouts, cabbage, watercress, kale, and all
leaves of the magnolia tree [85]. Honokiol has been demon- cruciferous vegetables are high in isothiocyanates, such as
strated to possess anticarcinogenic, anti-inflammatory, anti- sulforaphane, which have been found to not only prevent
oxidative, and antiangiogenic properties, as well as an cancer but to reduce and slow the growth of existing tumors
inhibitory effect on malignant transformation of papillomas in bladder, breast, colorectal, endometrial, gastric, lung,
to carcinomas in vitro and in vivo animal models without any ovarian, pancreatic, prostate, and renal cancers [95].
 422 C. Henrich

Sulforaphane induces apoptosis in human prostate cancer foraphane) are promptly conjugated to glutathione by a class
by initiating ROS generation [95]. Although sulforaphane of phase II detoxification enzymes known as glutathione
garners much of the anticancer attention, there are other S-transferases (GSTs). This mechanism is meant to increase
26 compounds working synergistically to power this potential, the solubility of isothiocyanates, thereby promoting a rapid
such as benzyl isothiocyanate (BITC). The three processes excretion in the urine. Isothiocyanates are thought to play a
that are impacted by BITC are ROS production, autophagy, prominent role in the potential anticancer and cardiovascu-
and apoptosis. When a cruciferous vegetable is chewed or lar benefits associated with cruciferous vegetable consump-
macerated, the enzyme myrosinase is released from a cellular tion. Genetic variations in the sequence of genes coding for
compartment to hydrolyze the glucosinolates, producing GSTs may affect the activity of these enzymes. Such varia-
ITCs and other products. There are nearly 120 identified tions have been identified in humans. It has been proposed
ITCs, with sulforaphane and BITC simply being very well that a reduced GST activity in these individuals would slow
studied [96]. the rate of excretion of isothiocyanates, thereby increasing
The referenced studies explore direct anticancer proper- tissue exposure to isothiocyanates after cruciferous vegetable
ties, but there are other factors to be considered. Cabbage, for consumption. GSTs are involved in “detoxifying” potentially
instance, contains a significant amount of the amino acid harmful substances like carcinogens, suggesting that indi-
L-glutamine, as well as vitamins C and K, folate, B6, calcium, viduals with reduced GST activity might also be more sus-
magnesium, manganese, selenium, chlorophyll, flavonoids, ceptible to cancer [101].
fiber, carotenoids, indole-3-carbinol, lignans, phytosterols, Finally, induction of the expression and activity of GSTs
and sulfur bioactives (other than glucosinolates). and other phase II detoxification/antioxidant enzymes by
Glutamine is a rich component of cruciferous vegetables isothiocyanates is an important defense mechanism against
and is the most abundant amino acid in the body and condi- oxidative stress and damage associated with the development
tionally essential, meaning that normally the body produces of diseases like cancer and cardiovascular disease. The ability
enough but can utilize much more under conditions of stress. of sulforaphane to reduce oxidative stress in different settings
Adding glutamine to parenteral nutrition prevents deteriora- is linked to activation of the nuclear factor E2-related factor
tion of gut permeability and preserves mucosal structure 2 (Nrf2)-dependent pathway. Some, but not all, observational
[97]. Glutamine has been shown to prevent muscle wasting, studies have found that GST genotypes could influence the
one of the confounding factors of cancer morbidity. associations between isothiocyanate intake from cruciferous
Adding glutamine to the nutrition of clinical patients, vegetables and risk of disease (see 7 Chap. 17).
 

enterally or parenterally, may reduce morbidity. Several

excellent clinical trials have been performed to prove efficacy
and feasibility of the use of glutamine supplementation in 26.9.14  Seeds
parenteral and enteral nutrition. The increased intake of glu-
tamine has resulted in lower septic morbidity in certain criti- Seeds such as sunflower, pumpkin, chia, hemp, flax, sacha
cally ill patient populations [98]. It has been found that the inchi, and sesame are very rich in essential fatty acids, vitamin
use of glutamine supplementation is safe and can diminish E, B vitamins, and minerals like selenium, phosphorus, iron,
risks of high-dose chemotherapy and radiation. There is copper, zinc, and potassium. Some seeds contain a significant
some evidence that adequate glutamine availability can ben- amount of protein. Hemp seeds in particular are a complete
eficially affect outcome, especially in patients undergoing source of all 20 known amino acids and are 25% protein,
bone marrow transplantation [99]. higher than many other seeds, including chia and flax.
Glutamine supplementation was found to protect against The benefits of lignans have been called into question for
radiation-induced mucositis, anthracycline-induced cardio- hormone-linked cancers due to their phytoestrogenic action.
toxicity, and paclitaxel-related myalgias/arthralgias. However, the Oncology Nutrition Practice Group of the
Glutamine may prevent neurotoxicity of paclitaxel, cisplatin, Academy of Nutrition and Dietetics shares that lignans are
oxaliplatin, bortezomib, and lenalidomide and is beneficial the type of phytoestrogens in flaxseeds, and they may change
in the reduction of the dose-limiting gastrointestinal toxic estrogen metabolism [102]. In postmenopausal women, lig-
effects of irinotecan and 5-FU-induced mucositis and stoma- nans may cause the body to produce less active forms of
titis. Dietary glutamine reduces the severity of the immuno- estrogen and is believed to potentially reduce breast cancer
suppressive effect induced by methotrexate and improves the risk. There is evidence that adding ground flaxseeds into the
immune status of rats recovering from chemotherapy. In diet decreases cell growth in breast tissue as well. Some cell
patients with acute myeloid leukemia requiring parenteral and animal studies have shown that two specific phytoestro-
nutrition, glycyl-glutamine supplementation could hasten gens found in lignans, enterolactone and enterodiol, may
neutrophil recovery after intensive myelosuppressive chemo- help suppress breast tumor growth. Researchers do not yet
therapy [100]. know if these results will apply to women with breast cancer,
There are individual genetic influences to be considered but this approach—adding flaxseed to the diet—looks prom-
that may affect the metabolism of isothiocyanates. The Linus ising. And several studies in women have shown that higher
Pauling Institute discusses this in detail [30, 101]. Once intake of lignans, the key phytoestrogen in flaxseeds, is asso-
absorbed, glucosinolate-derived isothiocyanates (such as sul- ciated with reduced risk of breast cancer [102].
The Role of Nutrition in Integrative Oncology
423 26
Further, lignans in the diet are associated with less aggres- effects [107]. In cisplatin-treated mice, AHCC increased its
sive tumor characteristics in women who have been diag- antitumor activity while reducing side effects and showed
nosed with breast cancer. In other words, women who have synergistic effects with gemcitabine in pancreatic cancer
already been eating lignans at the time of diagnosis seem to cells. A prospective study showed early evidence that AHCC
have tumors that are less aggressive [102]. improves prognosis after curative resection of hepatocellular
carcinoma. AHCC also reduced chemotherapy-associated
adverse effects in patients with advanced cancer, and in those
26.9.15  Medicinal Mushrooms with pancreatic ductal adenocarcinoma [107].

Mushrooms have been used medicinally since ancient times.

The chief medicinal uses of mushrooms to date are antioxi- 26.9.16  Bee Products
dant, antidiabetic, hypocholesterolemic, antitumor, antican-
cer, immunomodulatory, anti-allergic, nephroprotective, and Both integrative and conventional medicine support the use
antimicrobial [103]. The mushrooms known to have antican- of bee products as elixirs for virtually every health condition,
cer effects belong to the genus Phellinus, Pleurotus, Agaricus, including cancer [108–110]. Propolis, honey, royal jelly, pol-
Ganoderma, Clitocybe, Antrodia, Trametes, Cordyceps, len, and even venom have been found to be antimicrobial,
Xerocomus, Calvatia, Schizophyllum, Flammulina, Suillus, anti-inflammatory, antioxidant, immune supportive, anti-
Inonotus, Inocybe, Funlia, Lactarius, Albatrellus, Russula, and parasitic (parasites are an often-overlooked initiator of can-
Fomes. The anticancer compounds play crucial roles as reac- cer), antidepressant, capable of inducing apoptosis, helpful in
tive oxygen species promoters, mitotic kinase inhibitors, increasing energy levels, and wound healing.
antimitotic, angiogenesis inhibitors, and topoisomerase
inhibitors, leading to apoptosis and eventually halting cancer
proliferation [103]. 26.9.17  Iodine Sufficiency
A particular mushroom compound, Active Hexose
Correlated Compound (AHCC), acts as a biological response Although all parts of the body contain iodine, many tissues
modifier [104]. In vivo and human clinical trials have shown and organs in our body concentrate iodine [111]. Organs that
that AHCC modifies both the innate and adaptive immune have a concentration function include thyroid, stomach
responses by increasing the production of cytokines, increas- mucosa, salivary glands, breast tissue, thymus, skin, placenta,
ing the activity of NK cells by as much as 300–800%, increas- ovaries, uterus, prostate, pancreas, choroid plexus, and the cil-
ing populations of macrophages and in some cases doubling iary body of the eye. The role of iodine in these tissues is
it, increasing the number of dendritic cells, and increasing believed to include antioxidant, anti-inflammatory, antiprolif-
the number of T cells by as much as 200%. erative, antibacterial, proapoptotic, and pro-­ differentiating
Data from the treatment of more than 100,000 individu- effects [112].
als with various types of cancer have shown AHCC treatment Research suggests that the therapeutic form of iodine in
to be of benefit in 60% of cases. AHCC is particularly effec- breast cancer is molecular iodine (I2) and that I2 is capable of
tive for liver, lung, stomach, colon, breast, thyroid, ovarian, inducing apoptosis in human breast cancer cells through
testicular, tongue, kidney, and pancreatic cancers [105]. In mitochondrial-mediated pathways [112, 113]. Iodine may
addition to being able to fight cancer directly, AHCC also also affect the binding of estrogen receptors, thereby having
alleviates many of the side effects of chemotherapy [106]. an antiestrogenic effect on gene expression. Gastric cancers,
Chemotherapy is replete with side effects, which range from such as stomach cancer and Barrett’s esophagus, were found
psychologically distressing to life-threatening. Doctors to have decreased or absent iodine levels in gastric tissues
noticed that chemotherapy patients taking AHCC did not [113]. The subject of iodine and companion minerals, such as
lose hair. Subsequently, an in  vivo study found that mice selenium, for endocrine health and breast cancer prevention
treated with AHCC were protected from chemically induced and treatment has been a topic of popular publications [114,
hair loss. Clinical studies in Korea and Japan have indicated 115]. Iodine-rich foods include seaweeds, sea vegetables, spi-
that AHCC remarkably improves symptoms of nausea and rulina, and chlorella, with lesser amounts in cranberries,
vomiting in cancer patients. baked potatoes, pastured eggs, organic dairy, shrimp, wild
Chemotherapy inhibits bone marrow function, which caught fish, and navy beans [116, 117].
can be life-threatening. AHCC has been shown to raise the
white blood cell count of cancer patients by about 30% [106].
One of the major drawbacks of chemotherapy is the demise 26.9.18  Seaweed and Algae
of healthy cells in addition to cancer cells. An in vivo study
found that rats given chemotherapy without AHCC experi- Spirulina and chlorella are nutrient-dense chlorophyll-rich
enced large increases in liver enzymes while those given che- blue-green algae [118–121]. Part of their benefit is that there
motherapy plus AHCC had normal levels of liver enzymes. is a significant amount of nutrition available in powder or
Importantly, in vitro and animal studies show that AHCC tablet forms, which is perfect for when appetite is waning but
has anticancer effects, not just effects on chemotherapy side nutrient needs are high. Rich in phytonutrients, B-complex
 424 C. Henrich

vitamins, carotenoids, iron, zinc, magnesium and other min- Butyrate has direct and specific anticancer potential
erals, protein, amino acids, and fatty acids, they earn the rank [132–135], is known to induce autophagy and apoptosis of
of superfoods. Chlorella can increase excretion and decrease cancer cells, inhibits the growth of cancer cells in the bowel,
26 absorption of cadmium, lead, mercury, and other heavy met- supports the cancer-fighting effect of photodynamic therapy
als, as well as radioactive particles [118–121]. on astrocytoma cells, and increases the sensitivity of resistant
Chlorella supports several aspects of immune function, cancer cells to irinotecan in the treatment of colon cancer.
including enhancing NK cell activity [122]. One prelimi- Propionate is mainly taken up by the liver and has been found
nary study reported that patients taking chlorella suggested to reduce systemic inflammation and counteract malignant
that the cellular components and functions of the immune cell proliferation in liver tissue [136].
system remained at near-normal levels and were less
adversely affected when patients were undergoing chemo-
therapy and/or taking immunosuppressive medications 26.9.20  Modified Citrus Pectin and Pectin
such as steroids [122].
Fungal overgrowth is a common occurrence in oncology Modified citrus pectin (MCP) is a complex water-soluble
patients. The immunostimulatory effects of spirulina were indigestible polysaccharide obtained from the peel and pulp
reported to support clearance of systemic fungal conditions of citrus fruits and modified by means of high pH and tem-
in a mouse model by increasing levels of tumor necrosis fac- perature treatment. MCP has been found to sensitize prostate
tor alpha and interferon gamma [123]. Phycocyanin, a com- cancer cells to radiation therapy, overcome radioresistance,
ponent of spirulina, was found to induce apoptosis and and reduce clinical radiation dose [137]. In addition, MCP
autophagic cell death in pancreatic cancer cells [124]. One has antimetastatic properties for multiple malignancies,
report indicates that the phycocyanin compound was able to including melanomas, and inhibits tumor angiogenesis and
affect multiple targets of oncogenesis in a variety of cancer galectin-3, a regulator of cancer cell apoptosis which can
types [125]. increase the sensitivity of many cancer cell lines to various
Seaweed is another nutritional powerhouse [126]. As chemotherapies [138].
with the algae, seaweed should be sourced carefully to obtain Pectin is a complex polysaccharide found in plant cell
contamination-free products. Seaweed is a rich source of walls that acts as a natural gelling agent. When it interacts
vitamins and minerals and is naturally high in iodine. Sea with acid, it produces compounds including arabinogalac-
vegetables contain fucoidan, a polysaccharide studied for its tans and galactans, which can bind to and inhibit galectin-3
ability to inhibit tumor development, induce cancer cell as noted above. Pectin is also an excellent binding agent that
death, inhibit metastasis, protect against toxicity associated may remove heavy metals such as mercury, lead, and alumi-
with chemotherapy and radiation, and act synergistically num, as well as radioactive particles from the body. It has
with certain chemotherapy regimens [126]. been used in the Chernobyl region as recommended by the
BELRAD Institute as part of food rations for children to
effectively reduce the body burden of cesium [139].
26.9.19   iber, Prebiotics, and Short-Chain
F MCP is protective against radiation-induced mucositis and
Fatty Acids works synergistically with doxorubicin to significantly increase
the rate of apoptosis and limit the rate of cell-cycle division in
A high-fiber diet decreases the risk of metabolic syndrome, prostate cancer cells [140]. MCP was also reported to be
thereby addressing one of the major risk factors for cancer immune supportive and anti-inflammatory, protecting intesti-
[127]. The decreased transit time, dilution of fecal carcino- nal stem and epithelial cells against inflammation, especially
gens, and increased microbial diversity of a high-fiber diet following bacterial infection, by increasing tight-­junction pro-
contribute to a decrease in cancer rates, including proximal teins and thus preserving the mucosal barrier [140].
and distal colon cancer [128], colorectal adenoma [129], Low-molecular-weight citrus pectin (LCP) effectively
breast cancer [130], and renal cell carcinoma [131]. inhibits the growth and metastasis of gastrointestinal cancer
The short-chain fatty acids (SCFAs), butyrate, propionate, cells, while demonstrating synergistic tumor-suppressor
and acetate, are generated in the large intestine through bac- activity with 5-fluorouracil (5-FU) [141] against gastrointes-
terial fermentation of dietary fiber and resistant starches tinal cancer cells [142]. LCP can enhance the ability of oxali-
[132–135]. Additionally, a rich source of butyrate can be platin to inhibit cell proliferation and induce apoptosis,
found in bovine milk and milk-fat products such as butter which may be associated with the activation of mitochon-
and ghee. Insoluble fiber such as oat bran, wheat bran, and drial apoptosis pathways [143].
psyllium, as well as resistant starches found in cooked and MCP affects numerous rate-limiting steps in cancer
cooled potatoes or rice, legumes, green bananas and plan- metastasis and works synergistically with chemotherapy and
tains, or Jerusalem artichokes, supports the bacterial fermen- radiation treatment. It has been shown to be effective both
tation process. These foods act as prebiotics or nourishment in vitro and in vivo against prostate carcinoma, colon carci-
for the healthy bacterial species that generate the SCFAs and noma, breast carcinoma, melanoma, multiple myeloma, and
serve to increase bacterial diversity, increase insulin sensitiv- hemangiosarcoma. This is known as “one bullet with multiple
ity, reduce inflammation, and increase metabolism. targets” in oncology [144].
The Role of Nutrition in Integrative Oncology
425 26
26.9.21  Fermented Foods and Probiotics a point of entry to induce selective apoptosis in leukemia
cells by combining holotransferrin with Artemisia com-
Fermented probiotic-rich foods and supplements support pounds [154]. This was also reported in radiation-resistant
the health of the gastrointestinal system. The gut microbiome breast cancer cells [155], in drug-resistant small-cell-lung
affects metabolism, nutrient absorption, and immune func- cancer cells [156], as well as a therapeutic effect against glio-
tion. Certain strains can diminish the incidence of postop- blastoma [157].
erative inflammation in cancer patients and relieve diarrhea
resulting from radiation and chemotherapy. Some compo-
nents of the immune response, including phagocytosis, natu- 26.9.23  Carotenoid- and Polyphenol-Rich
ral killer cell activity, and mucosal immunoglobulin A
Foods
production, can be improved by some probiotic bacteria
[145]. Saccharomyces boulardii is an effective strain to pre-
Carotenoids are red, orange, yellow, and green pigments
vent and resolve Clostridium difficile infection, antibiotic-­
found in plants and algae and include carotenes, xanthins,
associated diarrhea, and enteral nutrition-related diarrhea,
lutein, and lycopene. Partially functioning as antioxidants,
all of which are concerns with immunocompromised oncol-
certain carotenoids convert to vitamin A in the body,
ogy patients [146].
although that conversion is dependent on digestive function
A review article on immunomodulation related to pro-
and absorption as well as thyroid function. Maceration or
biotics states the immune properties of the digestive mucosa
processing, cooking, and the presence of dietary fat increase
are assisted by the gut-associated lymphoid tissue (GALT)
the absorption of dietary carotenoids. Carotenoid-rich foods
[147]. The epithelial lining of the intestine comprises the
include carrots, sweet potatoes, peppers, dark leafy greens
primary physical barrier where immune responses are initi-
and lettuce, tomatoes, melons, cruciferous vegetables, squash,
ated. This intestinal barrier protects the host from the
pumpkin, and citrus [158].
ingested external environment with a protective mucous
Polyphenols are responsible for the vibrant colors of fruit,
layer, secretory IgA, and the tight junctions. Bacteria within
berries, vegetables, and spices and add to their bitterness,
the intestinal lumen interacts with intestinal epithelial and
astringency, flavor, and aroma. These phytochemicals are cre-
dendritic cells, macrophages, and lymphocytes. Probiotics
ated by the plant in response to stimuli such as UV radiation,
modulate the immune system through the induction of
pathogens, bugs, and harsh climate [159]. In the human
cytokines from epithelial cells, and this is reported to be
body, polyphenols help to reduce oxidative damage and
strain-specific [147].
inflammation, protect the skin from UV radiation, are neu-
There are high-quality nutraceutical probiotic blends tai-
roprotective, and help protect DNA from free radical damage
lored to specific needs that are strongly recommended for
and reverse epigenetic markers in the DNA, thereby prevent-
consideration for cancer prevention and during treatment.
ing the development of cancer and reducing the growth of
Good probiotic food choices include organic whole milk
tumors.
yogurt (if casein/animal milk is  tolerated), organic kefir (if
The European Journal of Clinical Nutrition created a list
casein/animal milk is tolerated), fermented foods such as
of the 100 richest dietary sources of polyphenols. The richest
kimchi, sauerkraut, miso, and kombucha. If the patient is
sources were various spices and dried herbs, tea, some juices,
severely immunocompromised, each probiotic strain and
whole grains, fruits, seeds and nuts, vegetables, cocoa prod-
food choice should be carefully researched to determine if it
ucts, and some darkly colored berries [160]. The bioavail-
is appropriate for use.
ability of polyphenols is increased when consumed with
dietary fat.
26.9.22  Artemisia Polyphenols found in pomegranate, green tea, broccoli,
and turmeric have demonstrated significant anticancer
Artemisia or wormwood plant contains powerful antipara- effects involving angiogenesis, apoptosis, and proliferation,
sitic, antimicrobial, antifungal, and anti-inflammatory specifically in prostate cancer [161]. They can inhibit cancer
compounds, particularly artemisinin [148]. It is another cell growth by interacting with multiple signaling pathways
multifaceted healer particularly in parasitic infections. in multiple cancers, including breast, gastrointestinal, pros-
Artemisinin has been found to reduce or prevent the for- tate, pancreatic, lung, and ovarian, as well as refractory can-
mation of breast tumors [148], rapidly induce apoptosis in cers and hormonally responsive cancers [162].
cancer cells [149], and recognized as an important world-
wide medicinal plant [150, 151]. The entire plant, with all of
its active compounds, is reported to be more effective than 26.9.24  Essential Oils
the artemisinin isolate [152]. Another study shows a syner-
gistic cytotoxicity when artemisinin was used with butyric Essential oils (EO) are aromatic volatile organic compounds
acid [153]. that are the very olfactory essence of a plant [163]. They are
Lai and Singh have shown that with high concentration of typically extracted through steam distillation or cold-­
iron in many types of cancer cells, it is possible to use this as pressing. Their chemistry is extremely complex, consisting of
 426 C. Henrich

hundreds of unique chemical compounds or constituents 26.10  Dietary Interventions

that depend on everything from climate to the soil the plant
is grown in to the sounds that the plant “hears” while grow- Dietary interventions for cancer treatment are abundant, but
26 ing. Drought will yield a plant that is higher in certain con- common sense should be the ruling factor. Low-­carbohydrate,
stituents that the plant expressed in order to survive those vegetable-fruit phytonutrient-rich and nutrient-dense whole
conditions. Ancient writings and traditions tell us that essen- foods are fundamentals for all oncology dietary recommen-
tial oils have been used for thousands of years and, alongside dations. Certain diets may be very beneficial for a period of
herbs, were perhaps man’s first medicine, both for physical time for detoxification or healing but may not be supportive
and spiritual purposes. Modern science seems to be on the for the long term. Think of it in the same terms that you
cusp of uncovering the biochemistry of what has been used would with conventional treatment: acute and maintenance
for millennia. interventions. Tailored targeted care should be prescribed
The last decade has brought scientific discoveries indi- depending on the patient’s current treatment. Remain flexi-
cating that odor receptors are not found solely in the nose ble and responsive to the whole person, and avoid being
but throughout the body—in the liver, heart, kidneys, locked into a doctrine or belief that does not serve the
muscle tissue, skin, even sperm—where they are responsi- patient’s needs.
ble for initiating important physiological functions [163].
When we inhale a fragrance, those molecules are recog-
nized first by the chemical receptors that line the olfactory 26.10.1  Seasonal Eating and Living
membranes in our nose. Olfactory receptors behave like a
lock-and-key system, with an odor molecule the key to the Humans are creatures of light and dark seasons and respond
receptor’s lock. When the right molecule lines up with the best when caring for themselves within the parameters of
right receptor, it sets in motion an elaborate choreography their location on the earth, with a nod to their heritage and
of biochemical reactions. These signals are transmitted to genetics. For instance, in Ayurveda, seasonally balanced eat-
the limbic system and the olfactory sensory nerves at the ing based on the seasons and a person’s individual balance of
base of the brain. From there, physiological functions can dosha is essential: bitter greens in the spring to cleanse and
be initiated. detoxify the liver, gallbladder, and pancreas; cooling fruit and
The constituents of EOs have been found to be antibacte- citrus in the summer to balance heat-induced lethargy; root
rial, antiviral, antifungal, anti-inflammatory, analgesic, anti- vegetables, nuts, fats, meat, and hibernation foods in the
emetic, anxiolytic, and antidepressive [164]. EOs and their autumn to conserve energy; and tonics in the winter to sup-
constituents act by multiple pathways and mechanisms port the kidney, bladder, and heart in the darker months of
involving apoptosis, cell-cycle arrest, antimetastatic and anti- contemplation and rest (see 7 Chap. 45). Despite modern-­
 

angiogenic, increased levels of reactive oxygen and nitrogen day conveniences and artificial light and stimulation, at our
species (ROS/RNS), and DNA repair modulation to show core, we are disrupted when we do not remain in sync with
their antiproliferative activity in the cancer cell. Reports also nature. Simply contemplate the effect of blue light at night on
discuss tumor-suppressor proteins (p53 and Akt), transcrip- our endocrine health or the stress of technology on our emo-
tion factors (NF-κB and AP-1), MAPK pathway, and detoxi- tional health (see 7 Chap. 34). Harmony with our natural
 

fication enzymes like SOD, catalase, glutathione peroxidase, surroundings and striving to balance what is lacking in our
and glutathione reductase [164]. environment if we are city dwellers, should be our goal. This
The use of essential oils is making great strides in oncol- theory is applicable at all times for all people.
ogy as aromatherapy, massage oils, and primary treatment.
This is supported by in  vitro and in  vivo clinical research
[165, 166]. Be cautious as cold-pressed citrus oils can cause a 26.10.2  Autoimmune Paleo Diet
photosensitive reaction [166]. Research also points to bene-
fits associated with components of the Boswellia species, or This approach is an effective strategy for reducing inflamma-
frankincense. The positive outcomes have been attributed to tion and promoting gut healing. The AIP diet removes most
boswellic acids, but this most recent case study of bladder potentially inflammatory and typically allergic foods and
cancer suggests that the hydrodistillates may also have sig- focuses on nutrient-dense foods: vegetables, limited fruit,
nificant effect [167]. proteins including organ meats, fermented foods, and bone
EOs are analyzed and categorized via gas chromatogra- broths. However, in an oncology setting, it is important to
phy. They consist of the hydrocarbons, including the ter- not be overly focused on proteins as too much protein stimu-
penes, such as pinene, beta-caryophyllene, myrcene, lates the mTOR pathway and contributes to the growth of
limonene, chamazulene, and farnesene, and the oxygen- cancer [168].
ated compounds, which are mainly esters, aldehydes, The mammalian target of rapamycin (mTOR) is an
ketones, alcohols, phenols, and oxides. Each plant’s essen- ancient molecular-signaling pathway that, when inhibited,
tial oil contains a unique profile of a combination of these will upregulate maintenance and repair, increase longevity,
constituents, and thus its own particular biochemical and impede the growth of cancer. When stimulated, it will
potential application. allocate nutrients for growth, replication, and reproduction.
The Role of Nutrition in Integrative Oncology
427 26

Stress

Amino acids Energy levels

Oxygen Growth factors

Rapamycin mTORC1 mTORC2

Macromolecule Metabolism Cell survival

biosynthesis
Autophagy Growth Cytoskeletal
Cell cycle organization
progression

..      Fig. 26.2  mTOR: master regulator of the nutrient-sensing hormones insulin, leptin, and insulin-like growth factor (IGF). (Adapted from
Laplante and Sabatini [168]. With permission from Elsevier)

The human biological imperative is geared toward reproduc- chemicals, it provides enough protein to satisfy biological
tion to keep the species alive, as opposed to longevity. mTOR requirements and, with attention to bio-individual needs,
is a master regulator of the nutrient-sensing hormones insu- can be essentially autoimmune in nature [172]. Vegetarianism
lin, leptin, and insulin-like growth factor (IGF), determining is really a spectrum of diets that is based on eating only
where and how nutrition will be used. Reducing protein plant-based foods but may include certain food groups such
intake reduces IGF, which in turn increases life span [169]. as dairy, eggs, and fish or may avoid cooked foods, as in the
Glucose and amino acids are nutrients and fuel necessary for raw diet.
replication and reproduction. If glucose, amino acids, insu-
lin, and growth factors like IGF are kept low, mTOR is sup-
pressed, thereby allowing the upregulation of the genetic 26.10.4  Ketogenic Diet
expression of maintenance and repair. mTOR also plays an
important role in autophagy. A similar process is known as The research around the ketogenic diet and cellular metabo-
mitophagy, where damaged mitochondria are removed and lism is compelling (see 7 Chap. 22). An ideal ketogenic diet is
 

replaced with new, healthy ones, and this process is also rich in healthy fats (70%), sufficient in clean proteins (25%),
largely regulated by mTOR (. Fig. 26.2).
  and low in carbohydrates (5%). This typically induces a state
There is new evidence that protein restriction may be of nutritional ketosis where the body burns fat as fuel instead
even more important than the restriction of net carbohy- of sugar-glucose-carbohydrates, generating fewer reactive
drates [170]. This theory has in fact been tested and found to oxygen species (ROS) and secondary antioxidants, thereby
hold true. One study reported that longevity and health were lowering inflammation [173]. The effect of a ketogenic diet
optimized when protein was replaced with carbohydrate. The on the mitochondrial energy metabolism of cells may indi-
authors reported that longevity may be extended in ad cate that an additional hallmark of altered metabolism should
libitum-­fed animals by manipulating the ratio of macronutri- be added as a hallmark of cancer as described by Ward and
ents to inhibit mTOR activation [170]. However, the conser- Thompson in 2012 as altering cell signaling and blocking cel-
vation of protein may be even more important than the lular differentiation. Altered metabolism is a direct response
manipulation of carbohydrates. There is general agreement to growth factor signaling [174]. Most cancer cells and prolif-
in oncology that the ideal amount of protein daily should not erating normal cells still derive a significant fraction of their
exceed 1 g per kilogram of lean body mass [171]. ATP through oxidative phosphorylation. Oxidative phos-
phorylation is the foundation of energy production within
the ketogenic diet [174].
26.10.3  Vegetarian Diet
»» Data now support the concepts that altered metabolism
results from active reprogramming by altered oncogenes
A vegetarian diet is a nourishing option as long as it involves
and tumor suppressors and that metabolic adaptations
consuming primarily vegetables and fruit, with a healthy
can be clonally selected during tumorigenesis. Altered
dose of healthy fats. Unfortunately, many times, a vegetarian
metabolism should now be considered a core hallmark
diet focuses on refined starches, like pasta, and other foods
of cancer [174].
devoid of nutritive value that impart no healthful benefits,
verging on a junk food diet at its most extreme. When a veg- In normal cellular metabolism, cells convert glucose or glyco-
etarian diet consists of organic vegetables and fruit with gen stored in the liver into pyruvate through glycolysis. In an
enough healthy fats to ensure the absorption of the phyto- aerobic environment, this will result in the production of ATP
 428 C. Henrich

via the Krebs citric acid cycle (CAC) or tricarboxylic acid never smoked. Some patients have deep emotional consider-
cycle (TCA) through the electron transport chain, known as ations to account for, others are well adjusted. Each of these
oxidative mitochondrial phosphorylation. Normal cells are nuances needs to be accounted for and addressed. It’s really a
26 able to adapt to utilize glutamine and ketones for energy pro- marriage of ancient medicine with today’s science.
duction in a reduced glucose or fasting environment. Many clinics and physicians around the country are
In the early twentieth century, German biochemist Otto embracing these integrative strategies with successful out-
Warburg noted that cancer cells produced lactate as a by-­ comes, including case studies of work originally from Dr.
product, essentially a fermentation process in which the William Kelley and subsequently from Drs. Nicholas
focus is on proliferation as opposed to energy production. Gonzalez and Linda Isaacs. Their approach is based on the
Cancer cells are found to behave this way whether in an aero- pancreatic proteolytic enzyme research of the Scottish
bic or anaerobic environment. Warburg believed this was due embryologist John Beard, who worked at the University of
to damaged mitochondria [175]. The Warburg effect is the Edinburgh at the turn of the twentieth century [181].
basis behind the PET scan, which delineates potentially can- This is an excellent summation of this concept, taken
cerous areas based on uptake of a glucose-based tracer. from an interview done by Dr. Conners with Dr. Gonzalez
Altered metabolism stems from damaged mitochondria, [182]:
results from reprogramming of signaling pathways to sustain
proliferation, and evades growth suppression and/or cell »» We divide patients into different metabolic categories,
depending on each patient’s particular genetic,
death [174].
biochemical and physiological make-up. In this model,
Revisiting this consideration of mitochondrial cellular
patients with solid epithelial tumors, such as tumors of
metabolism provides for a different potential application of
the lung, pancreas, colon, prostate, uterus, etc. do best
diet in oncology. Restricting glucose to induce ketosis can
on a largely plant-based diet. Such patients have a
theoretically optimize mitochondrial function, therefore
metabolism that functions most efficiently with a specific
directly impacting the malignancy and transformation of
combination of nutrients that are found in fruits,
cells. In contrast to the nuclear somatic mutation, research
vegetables, nuts, whole grains and seeds, and with
across a broad range of tumor types, animal species, and
minimal to no animal protein.
experimental techniques has shown that normal mitochon-
On the other hand, patients with the blood or
dria can suppress tumorigenicity. Nuclear transfer experi-
immune-­based malignancies such as leukemia,
ments suggest that tumorigenesis arises more from
myeloma and lymphoma do best on a high-animal
mitochondrial defects than from somatic mutations in the
protein, high-fat diet. Such patients do extremely well
nuclear genome [176].
with a diet based on animal products with minimal to
Ketogenic diets may act as an adjuvant cancer therapy by
moderate amounts of plant-based foods, the particular
increasing the oxidative stress inside cancer cells and may
design of the diet again depending on the individual
also potentiate radiation and chemotherapies. A small trial
patient’s metabolic make-up. We find patients with
of 10 patients with advanced cancer found that a ketogenic
pancreatic cancer always do best with a largely
diet was able to halt or regress disease based on the extent of
plant-­based diet that emphasizes fruits, vegetables and
ketosis [177].
vegetable juice, nuts, seeds and whole grains. Allowed
The combination of a ketogenic diet with hyperbaric oxy-
protein includes fish one to two times a week, one to
gen therapy (HBOT) was found to have a synergistic effect
two eggs daily and yogurt daily, but no other animal
and to inhibit tumor progression and prolong survival in
protein. In our therapy, we use diets specifically because
animal studies [178]. A paleo-ketogenic diet alone has been
of the effect of food on the autonomic nervous system.
shown to halt the progression of and partially regress a soft
This system consists of the sympathetic and
palate tumor in a patient over a 20-month period [179]. In
parasympathetic branches and ultimately controls all
many ways, a ketogenic diet mimics the effects of calorie
aspects of our physiology, including immune function,
restriction, such as reducing inflammation, decreasing side
cardiovascular activity, endocrine function and the
effects of treatment, potentiating standard therapies, and
entire action of our digestive system. The sympathetic
reducing cachexia [180].
and ­parasympathetic systems have opposing actions on
26.10.4.1  Bio-individual Diets and Protocols the target organs and so can adjust our physiology
depending on needs and demands, enabling our bodies
A bio-individual protocol entails assessing all aspects of the
to react to any situation, condition or stress. We believe
patient’s condition, as discussed within this section, and then
disease, whatever the form, occurs because there is an
crafting a program of diet, supplements, detoxification, exer-
imbalance in autonomic function. For example, we find
cise, and emotional support that will address both their ter-
solid tumors, such as tumors of the breast, lung,
rain and cancer. Some colon cancer patients have had colitis
pancreas, colon, uterus, ovaries and liver, occur only in
their whole lives, while others have been chronically consti-
patients who have an overly strong sympathetic
pated. Some lung cancer patients were heavy smokers, others
The Role of Nutrition in Integrative Oncology
429 26
nervous system and a correspondingly weak, ineffective challenge of cancer and enabling healing are being accom-
parasympathetic nervous system. We believe that plished on a field full of players who have opened their minds
blood-based cancers, such as leukemia, lymphoma and to the newer science of cancer as a metabolic disease rather
multiple myeloma, only occur in patients that have an than genetic in order to remain focused on the patient and
overly developed parasympathetic nervous system, and every potential avenue to serve that patient on their cancer
a correspondingly weak sympathetic nervous system. journey.
Previous research, such as Dr. Francis Pottenger’s
research during the 1920s and 1930s proposed that
much if not all disease has autonomic imbalance as at 26.11  Integrative Therapies Adjunctive
least one of the major causes.
to Nutrition Therapy
We have found that specific nutrients and foods
have specific, precise and predictable effects on the
26.11.1  Hyperthermia
autonomic nervous system. For example, a vegetarian
diet emphasizes fresh fruits and vegetables, particularly
Hyperthermia has been used with an intent to cure tumors
leafy greens, and contains large doses of minerals such
for at least 4000 years and as a tool for the destruction of
as magnesium and potassium. It has been shown in
tumor masses well before that [183]. Hyperthermia effec-
many studies that magnesium suppresses sympathetic
tively stimulates metabolic activity, triggering the release
function, while potassium stimulates parasympathetic
of stored toxins through detoxification pathways.
activity. Furthermore, a largely vegetarian diet tends to
Hyperthermia helps your body to mimic a fever response,
be very alkalinizing, and the neurophysiologic research
which is what it uses normally to fight infection and can-
documents that in an alkalinizing environment,
cer. Therapies include whole-body hyperthermia, hyper-
sympathetic activity is reduced, and parasympathetic
thermic intraperitoneal chemotherapy, radio-frequency
activity increased. So, whatever other effect a
ablation, regional hyperthermia, and the most recent
vegetarian diet has, in terms of autonomic nervous
advance, laser interstitial thermal therapy. Laser interstitial
system function, such a diet will reduce sympathetic
thermal therapy (LITT) is an emerging technique being
activity and stimulate the parasympathetic system.
used to treat primary and metastatic brain tumors by
A meat diet is loaded with minerals such as
implanting a laser catheter into the tumor and heating it to
phosphorus and zinc, which tend to have the opposite
temperatures high enough to kill the tumor [184].
effect. A high-meat diet stimulates the sympathetic
Hyperthermia or infrared therapy can extend to patients’
system and tones down parasympathetic activity.
homes. Excellent options exist to provide support on a
Furthermore, such a diet is loaded with sulfates and
daily basis and for the long term, such as home infrared
phosphates that in the body are quickly converted into
heating pad devices or an in-home infrared sauna.
free acid that in turn stimulates the sympathetic
nervous system while suppressing parasympathetic
activity.
26.11.2  Mindfulness Practices or Meditation
So, by the careful use of diet, we are able to effect
major changes in autonomic function and bring about
Mindfulness meditation is defined as the nonjudgmental
balance in a dysfunctional nervous system. We find,
awareness of experiences in the present moment [185]. The
further, as the autonomic system comes into greater
components through which mindfulness meditation exerts
harmony and balance, when the autonomic branches
its effects are regulation of attention, body awareness, self-­
are equally strong, all systems – from the immune
awareness, and regulation of emotion.
system to the cardiovascular system – work better
Emotions hold the power to manifest wellness or illness.
regardless of the underlying problem. In essence, we are
Ancient practices of medicine tell us that improperly pro-
using diet to bring about greater physiological efficiency.
cessed emotions create stagnation and block energy meridi-
For cancer patients, long experience has taught us that it
ans in our body. Because humans are electrical beings, these
is not enough to load patients with enzymes; the
blocked channels can result in physical illness. The hormonal
question of autonomic imbalance must also be
stress response to prolonged stress, anger, hopelessness, fear,
addressed. In terms of pancreatic patients specifically, a
and chronic fatigue can contribute to immune suppression.
plant-based diet provides all the nutrients to correct
Learning to live life as a meditation from moment to moment
autonomic dysfunction. –Dr. Nicholas Gonzalez
is one of the keys to a peaceful life.
Essentially, no one diet is perfect for everyone or all condi- Mindfulness meditation aids in lowering blood pressure,
tions; there are just far too many factors to take into consid- improves immune system and brain function, and minimizes
eration. But the prevailing concept of eating clean whole pain sensitivity [186]. It can improve mood and reduce dis-
foods in moderation will always be sensible. Conquering the tress and distractive thoughts and behaviors [187].
 430 C. Henrich

26.11.3  Movement and Exercise energy meridians of the body to facilitate healing. Back mas-
sage given during chemotherapy significantly reduces anxi-
The human body was created to be in motion. In ancient ety and acute fatigue [190]. Massage therapy can be
26 times, movement was essential for survival, but the conve- supportive in relieving lymphedema due to surgery or treat-
niences of modern life have drastically reduced that depen- ment. Gentle massage is used to help move lymph out of the
dence. Our lymph system, which is essentially our immune swollen area and into areas with working lymph vessels [191].
system, is dependent on our physical movement to stimulate Postsurgical scar formation can benefit from massage
flow. The value of motion is important to our very well-being. therapy in several ways. A valuable resource can be found to
The joy of moving our body, from a simple stretch or deep describe forms of massage therapy [192].
breath to a trail race, should be something that you enjoy as 55 Manual lymph drainage optimizes lymphatic circulation
opposed to a dreaded task. and drainage around the injured area.
This becomes more complicated when experiencing 55 Myofascial release helps ease constriction of the affected
treatment-induced fatigue or related to the cancer itself. At tissue.
that point, the goal is to incorporate even the simplest move- 55 Deep transverse friction can prevent adhesion formation
ments. The benefits of physical activity have been connected and rupture unwanted adhesions.
to every aspect of our health, from our brain to our bone 55 Lubrication of the scar helps soften and increase its
density. Exercise has been shown to reduce stress, improve pliability.
sleep, prevent cognitive decline, alleviate anxiety, boost 55 Stretching aids in increasing range of motion.
memory and ability to learn new things, enable neurogenesis 55 Heat application helps the pliability and flexibility of the
(the creation of new brain cells), improve productivity and scar.
creativity, increase strength and flexibility, increase bone
density, reduce the risk of cardiovascular disease, metabolic
syndrome, and type 2 diabetes, reduce the risk of cancer, and 26.11.5  Posttreatment: Creating
increase longevity [188]. an Empowerment Plan
During treatment, proceed with care. The NCCN Clinical
Practice Guidelines in Oncology (NCCN Guidelines®) for Cancer treatment is a tug of war between fear and empower-
Cancer-Related Fatigue advise starting slowly and progress- ment. Much of our power is handed over to physicians and
ing incrementally [189]. Depending on fitness and comfort the system during the duration of therapy, and when that
level, some people may want to start with a 10-minute walk time comes to a close, there is a big void in a patient’s life.
around the block; others may find they can exercise for 20 Oftentimes, fear and uncertainty fill this void, and several
minutes (or longer) initially, but the goal should be at least 30 outcomes are a result of this phase. Some patients will return
minutes of aerobic exercise 5 days a week or more if tolerated. to their old ways with a misguided sense of the threat being
Caution is advised to find the level that fits with the circum- over, some will remain stagnant in survivor groups reliving
stances. the trauma in a sense, some will throw caution to the wind
The guidelines give practical suggestions for planning and adopt habits that make them potentially more at risk for
exercise such as if the patient doesn’t have the energy to exer- recurrence, and some will want to know how to lock the door
cise a full half hour, break it up; try three 10-minute walks in all ways possible to their cancer returning. This is a tre-
during the day; make exercise enjoyable; recruit a walking mendous opportunity to positively impact and empower
partner or listen to music with headphones while on a recum- each and every one of these people and to arm them with
bent bike or treadmill; dress comfortably and drink plenty of holistic strategies to optimize their future. Giving patients
water; consider yoga and tai chi which, while not aerobic, strategies to keep themselves healthy, to rebuild their bodies,
integrate movement and meditation and enhance wellness; and to nourish and detoxify themselves can powerfully shift
and look for programs designed for cancer patients. Some both their physical and mental well-being. Creating a plan
health clubs and hospitals offer exercise classes that address for living should be the last step before releasing patients
the challenges and needs of people with cancer; avoid swim- from treatment. Here are some ideas that the author incorpo-
ming pools as they can expose the patient to bacteria that rates as a foundation for an empowerment plan and can be
may cause infections and the chlorine may irritate skin; and modified depending on the particular patient and their
don’t encourage exercise if the patient is not feeling well or mind-set and prognosis: Achieve and maintain optimal
running a fever [189]. weight and body mass, detoxify, restore and optimize micro-
nutrient levels in the body through food and supplements,
and employ mental well-being strategies to manage fear,
26.11.4  Massage or Touch Therapy stress, worry, and body image and function.
Nutrition ultimately is about nourishing the body and the
Touch therapy is one of the oldest therapies known to man. soul, and cancer treatment and posttreatment periods are
From the lightest touch to deep tissue massage, the benefits incredibly powerful times to positively impact a patient’s life.
range from relief of muscular pain to the opening of the Take full advantage of that potential on every level to affect
The Role of Nutrition in Integrative Oncology
431 26
the metabolism, immune system, and mindfulness of the
Box 26.5  Sample IFMNT Nutrition Care Process patient.
55 Stage 4 adenocarcinoma of the lung – non-smoker This illustration best summarizes the idea that we must
55 Assessment Data: 63 yo female, BMI 23.5, osteoporo-
focus on the terrain before the germ, the person before the
sis, mild central adiposity, hx constipation, cough,
mast cell allergy, with high-stress lifestyle for many cancer. It also brings to light the fear and disempowerment
years. Abnormal immunological findings in experienced by patients and the potential to radically improve
serum/+viral load/nutritional insufficiencies: vitamin the level of their care through education and the implemen-
A, zinc, vitamin D with genomic homozygous VDR, tation of an integrative plan.
high Cu:Zn Ratio 2.1 (goal 0.9–1.0), anemia,
The majority of cancers arise from lifestyle issues and
macrocytic RBC, low IgA, low NK cell count and
activity. Presented to ER with shortness of breath environment, which impact immune function, create inflam-
and X-ray revealed large masses in lung and liver, 4 mation, and/or initiate epigenetic triggers that allow cancer
liters fluid removed from pleural cavity. Diagnosis: to develop. It is critical to explore every avenue available that
Stage 4 adenocarcinoma of the lung cancer. Further can best optimize the response of the patient throughout
testing ROS1+ (rare genetic mutation statistically
treatment by bolstering their whole person and creating
does not respond to immunotherapy).
55 Nutrition Diagnosis: Multiple nutritional insufficien- evidence-­based synergies where available with conventional
cies/deficiencies with compromised immune system therapies.
secondary to poor diet history and confirmed Each person will present with a unique history, experi-
through laboratory testing. ence, mind-set, and disease progression that will help to
55 Interventions: Refer to integrative doctor for
define which options may support their best outcome. Each
assessment. IV Rx: Antiviral plan with oral artemis-
inin, Lauricidin, Vit D3, zinc, copper−/iron-free supportive strategy will provide results, but each patient may
multivitamin/mineral with bioactive forms of B respond better to a stronger focus on different options.
vitamins, vitamin C, quercetin, and sulforaphane Strategies discussed above should be employed in such a
(broccoli sprout) with ketogenic diet. Educated in manner that they will optimize and complement any conven-
application of ketogenic diet with monitoring and
tional treatment the patient is undergoing. Tremendous
logging to maintain nutritional ketosis with
intermittent fasting and use of exogenous ketones. clinical data supporting the effectiveness of each of the
Follow up regarding nutrition plan and ketogenic abovementioned therapies has been presented, dictating
diet weekly × 4 weeks and then monthly. their value in both stand-alone and integrative applications.
55 Monitoring and Evaluation: Weekly monitoring of diet The creation of a patient-centered team empowered with
history, lab findings, and urine ketone log. Goal to
holistic, restorative, functional integrated modalities will
maintain average of 1.5–3.0 ketones, healthy body
mass, and no muscle cramps. IVs: Weekly high-dose define the future of cancer treatment.
vitamin C, artesunate, and immune support
nutrients.
55 Follow-Up 1 Year: “I feel amazing, better than I have
in a long time.” Cancer markers normal, CT/PET no
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 437 27

The Microenvironment
of Chronic Disease
Steven Gomberg

27.1 Introduction – 438

27.2 The Microenvironment in Malignancies – 438

27.3 Components of Tumor Microenvironments – 438

27.4 Cellular Components – 438

27.5 Molecular Components – 439

27.6 Nutritional Influences on the Tumor Microenvironment – 439

27.6.1 I nfluences on the Extracellular Matrix – 439
27.6.2 Angiogenesis – 440

27.7 Inflammatory Influences – 440

27.8  he Microenvironment in Chronic Autoimmune

T
Disease and Similarities to Cancer – 440

27.9  utritional Influences on the Autoimmune

N
Microenvironment – 441

27.10 The Microenvironment of Arthritic Conditions – 441

27.11 N
 utritional Influences on the Microenvironment
in Arthritic Conditions – 442
27.12 The Blood as a Potential Reflective Microenvironment – 442

27.13 Conclusion – 443

References – 444

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_27
 438 S. Gomberg

27.1 Introduction environment, including angiogenesis, metastatic potential,

and the tumor load [9].
The term microenvironment related to disease states has
many possible meanings. Typically, conventional designa-
tions about biological microenvironments distinguish a 27.3 Components of Tumor
smaller part of the larger organism that is related to, yet Microenvironments
27 distinct from, the larger macro environment. In this con-
text, we will be referring to the milieu involving a neoplastic The tumor microenvironment (TME) in cancer is defined as
site, an inflammatory site such as a joint or organ system, or the various places a tumor can exist, including blood vessels,
even the blood. In the diseased state, various pathologies lymphocytes, immune cells, fibroblasts and signaling mole-
can alter localized physiological processes, creating unique cules, and the extracellular matrix [10, 11]. Tumors develop a
encapsulated microenvironments. These microenviron- milieu in which they can modulate pathological processes
ments nurture disease progression locally and have the contributing to their progression and metastasis, as well as
potential to affect other organ systems in the larger context the induction of peripheral immune intolerance [12]. This is
of the organism. This chapter will introduce several disease done largely through the process of cell signaling and gives
state microenvironments and the factors leading to the for- cancer cells the ability to express different morphology, met-
mation of these environments. Nutritional considerations abolic features, motility, gene expression, proliferation, meta-
will be addressed that may lead to the initiation or progres- static and angiogenic potential, and immune adaptivity.
sion of these disease states, as well as the nutritional inter- These processes stem from the phenomenon of tumor het-
ventions that may be appropriate for their reversal. The erogeneity [13, 14].
microenvironments of tumors, autoimmune-affected organ Although cancer cell antigens initially trigger a CD8+
systems, and arthritic conditions will be discussed. This T-cell response, there is good evidence that possible immu-
chapter will also include a discussion of the blood as a phys- noediting and TME immune suppression can lead to a failure
iological microenvironment that can be reflective of patho- of a systemic immune response aimed at controlling the
logical changes elsewhere in the body through the prevalence and growth of a tumor [15].
examination of live red and white blood cell morphology
and pathology.
27.4 Cellular Components
27.2 The Microenvironment in Malignancies The tumor connective tissue or stroma in carcinomas typi-
cally sits beneath the epithelial cells that it is derived from
Microenvironment alteration is an area of great interest in and contains the extracellular matrix, including fibroblasts
cancer disease progression. Microenvironmental changes and various immune cells. The cancer stroma is prone to
occur in a variety of malignancies and in specific stages of inflammatory response when challenged by intrusion of
disease progression [1]. Malignancies insidiously alter their other normal immune components, such as tumor-­
own environments through a variety of processes to increase infiltrating lymphocytes. This inflammation can encourage
the potential for proliferation and metastasis [2, 3]. In doing angiogenesis, increase cell cycling, and discourage apoptosis
so, malignancies contribute to relentless progression and and taken together may enhance tumor growth [16].
cause secondary pathologies in local environments [4]. The Normal cellular fibroblasts typically produce collagen and
alteration of malignant microenvironments relates not only other fibrotic components of connective tissue. However, in
to aberrantly mutated cells but also to other cellular tissues malignancies, cancer cells can pirate the function of normal
in the vicinity that have been negatively affected by the fibroblasts, directing their function toward carcinogenesis
inflammatory changes. There is collateral damage to the nor- [17]. These carcinogenesis-associated fibroblasts (CAFs) per-
mal cells in the local microenvironment. These include form a variety of different cancer-inducing functions, includ-
blood vessels and vascular cell precursors, stromal cells, and ing the secretion of such proangiogenic factors as
cellular components of the immune system, which form a platelet-derived growth factor (PDGF), basic fibroblast growth
heterogeneous matrix [5]. The tumor manipulates this factors (bFGFs), and vascular endothelial growth factor
matrix to avoid rejection by the immune system and increase (VEGF). CAFs can also shuttle lactate to cancer cells as they
its metastatic potential [6]. In addition, the largely anaerobic are capable of aerobic glycolysis [18]. CAFs are also associated
microenvironment of tumors increases the potential for with extracellular matrix (ECM) remodeling, a process by
localized infection [7]. Research has revealed a variety of which collagen fibers in the matrix are malformed and release
pathways related to the interactions between tumor cells and matrix metalloproteinases, enzymes involved in the degrada-
their localized environment, creating these pathological and tion of the extracellular matrix [19]. This ECM remodeling
physiological changes, and has identified ways in which diet allows for cancer cells to escape the local environment by
can affect this progression [8]. In addition, specific nutri- destabilizing the proteins in the TME.  CAFs inhibit T-cell
tional compounds, including phytochemicals and their penetration into the tumor microenvironment by increasing
derivatives, can alter the various aspects of the tumor micro- the density of the stromal matrix in the ­microenvironment.
The Microenvironment of Chronic Disease
439 27
Chemokine (C-X-C motif) ligand 2 (CXCL2) is a small cyto- alcohol consumption with the increased likelihood of p53
kine belonging to the CXC chemokine family that is also called mutations in breast cancer [33].
macrophage inflammatory protein 2-alpha (MIP2-alpha), p53 can bind with T-cell antigens, forming complexes
growth-regulated protein beta (Gro-beta), and Gro onco- that inactivate immune molecules, and mutated p53 can acti-
gene-2 [12]. Biosynthesis of CXC motif cytokines (CXCL12) vate tumor development through several different pathways
targets the most promising actionable treatments for antican- [31]. Overall, the cellular role of p53 is quite broad and
cer therapy [20]. CAFs such as pericytes also increase the includes involvement in energy metabolism, cell senescence,
potential for metastasis through angiogenesis promotion and immune response, cellular motility and migration potential,
in shielding tumors from anti-VEGF therapies [21]. cell signaling and communication, cell cycling regulation,
In the TME, other cellular components responsible for and apoptosis. In addition to its intracellular effects, there is
inflammatory immune response are upregulated. One group growing evidence that in its normal state, p53 can suppress
of cells that has a very strong correlation between the inflam- angiogenesis by increasing collagen-derived antiangiogenic
matory response and cancer are tumor-associated macro- molecules in the extracellular matrix by transcription sup-
phages (TAMs). TAMs are one of the myeloid-derived pression of VEGF and through the stimulation of hypoxia-­
suppressor (MDSC) cells, a variety of tumor-infiltrating inducible factor 1 alpha (Hif1ά) degradation [34].
immune cells, all of which have well-established roles in the NFκβ is another intracellular transcription factor that
progression of cancer. These cells have various attributes. binds specific DNA sequences involved in several intracel-
They can repress T-cell response in general, and they tend to lular processes, including regulating cellular growth and
gravitate toward the necrotic areas of a tumor where they development, subsequent apoptosis, and immune and
mask it from the immune system through the secretion of inflammatory responses. Dysregulation of NFκβ has been
interleukin 10 [3]. Activated TAMs can support tumor linked to a variety of diseases including cancer, viral infec-
growth by secreting various factors such as epidural growth tions, septic shock, and inflammatory and immune diseases
factor (EGF) [22]. TAMs also secrete a variety of angiogenesis-­ [35]. NFκβ is an important regulator of these processes as it
promoting factors such as VEGF [23], PDGF, and transform- is rapidly acting – no additional proteins need to be synthe-
ing growth factor beta (TGFβ) [24]. TAMs also slowly sized for it to become active. NFκβ typically resides in the
upregulate nuclear factor kappa beta (NFκβ) expression, cellular cytoplasm, but when activated, it moves to the cell
which leads to enduring inflammation [25]. Overall, many nucleus to initiate the expression of genes with specific
studies show that infiltrating TAMs are indicative of a poor binding sites. This can then lead to cellular proliferation, an
prognosis in malignancies, especially breast cancer and cer- inflammatory or immune response, or an antiapoptotic
tain lymphomas [26, 27]. response [36].
Typical initiators of NFκβ activity include reactive oxygen
species (ROS), tumor necrosis factor alpha (TNFα), interleu-
27.5 Molecular Components kin 1 beta (IL-1β), bacterial by-products, certain drugs, and
ionizing radiation [34]. As a potent upregulator of inflamma-
Dysregulation of molecular pathways is characteristic of can- tion, NFκβ has a direct effect on the TME. NFκβ is a known
cer in general, but it is also increased in the established can- inducer of such inflammatory tumor-promoting cytokines as
cer microenvironment due to chemical imbalances occurring interleukin 6 (IL-6), as well as progenitors for such inflamma-
secondary to overstimulation of cells by inflammatory che- tory cytokines as cyclooxygenase 2 (COX-2). It also leads to
mokines, cytokines, and other substances [28]. Several path- low-level prolonged smoldering inflammation that is charac-
ways that respond to nutritional interventions are involved in teristic of the TME [37]. NFκβ is also associated with another
this disrupted and divergent cell-signaling process. One such DNA transcription factor known as signal transducer and
substance is the tumor protein p53, which is a crucial compo- activator of transcription 3 (STAT3). STAT3 and NFκβ engage
nent of tumor suppression in multicellular organisms. p53 in a variety of crosstalk, mediating the release of inflamma-
has various cellular functions, such as activation of DNA tory cytokines in the TME.  STAT3-­ mediated acetylation
repair, restriction of cell cycling in cases where DNA is dam- causes NFκβ to remain active in the cell nucleus longer and
aged, and initiation of apoptosis if DNA damage is irrepara- prolongs inflammatory response, which results in increased
ble [29]. In normal tissues, p53 levels are difficult to detect, activity of TME inflammatory cytokines [38].
being present in actively proliferating cells but not in resting
cells [30]. In most human cancers, p53 is found in increased
amounts and generally found to be mutated with deranged 27.6  utritional Influences on the Tumor
N
function [31]. Of all the genes associated with cancer sup- Microenvironment
pression, p53 is the most commonly mutated. A 2002 study
showed various lifestyle and dietary components associated 27.6.1  Influences on the Extracellular Matrix
with p53 mutations [32]. A high glycemic load, consumption
of fast food, trans-fat consumption, and consumption of red Many nutritional compounds can have an impact on the
meats were associated with increased p53 mutation as various aspects of the destabilized TME. One compound that
opposed to control groups [32]. Other studies have linked helps to stabilize the extracellular matrix is epigallocatechin
 440 S. Gomberg

gallate (EGCG), derived from green tea. In vitro studies have acids and increasing omega-3 fatty acids may decrease
shown that EGCG can inhibit both matrix metalloprotein- activation of PKC and improve this aspect of angiogenesis
ases (MMP) 2 and 9 [39]. Vitamin D levels were inversely activation [55, 56].
associated with circulating MMP-2 and MMP-9  in several Both p53 and Nfκβ have been extensively researched as
studies and therefore may be of benefit as well [40]. players in the progression of carcinogenesis and angiogene-
Resveratrol may also be useful in downregulating both sis. Consequently, many nutritional substances have been
27 MMP-2 and MMP-9, as shown in studies on chondrosar- identified as modulators of these two upregulators of the
coma and fibrosarcoma cells [41]. Curcumin, one of the pig- TME. p53 functionality is closely related to redox status since
ment compounds of turmeric, has been shown to inhibit and the p53 protein contains numerous cysteine particles that are
regulate MMPs in a variety of diseases [42], as well as acting sensitive to antioxidants, so increased levels of antioxidants
with proanthocyanidins to downregulate collagenase, which can be important in the prevention of p53 dysregulation.
also degrades the ECM in the TME [43]. The anti-inflamma- Zinc deficiency also seems to be associated with increased
tory effects of omega-3 fatty acids also seem to decrease cir- oxidative damage to DNA and p53 upregulation and muta-
culating MMPs in studies in MS patients [44]. The botanical tions [57]. Other natural dietary compounds that influence
yarrow achilleifolia has also been shown to downregulate p53 mutations include vitamin E, retinoic acid, quercetin,
MMP-2 and MMP-9 in the inflammatory response [45]. and folate, which all may inhibit the expression of mutated
p53 [56].

27.6.2 Angiogenesis
27.7 Inflammatory Influences
The inhibition of the angiogenic cascade or signaling switch is
also a potential target of many nutritional compounds. As As previously mentioned, the transcription factor NFκβ ini-
previously discussed, TAMS promote a variety of angiogenesis-­ tiates a variety of cascades in the TME, notably those leading
promoting factors such as VEGF, PDGF, bFGF, TGFβ, and to inflammation. There are many nutritional supplements
EGR.  Nutritional inhibitors of VEGF include EGCG [46], that can inhibit the NFκβ activation process. Dietary compo-
resveratrol, curcumin, and proanthocyanidins. Other natural nents with anti-inflammatory and antioxidant properties
compounds isolated from botanicals having a direct effect on that inhibit NFκβ include curcumin, quercetin, EGCG, and
VEGF include artemisinin (extracted from Artemisia annua), 6-gingerol, extracted from ginger. Zinc, in addition to its
baicalin (extracted from Scutellaria baicalensis), silymarin effects on p53 mutations, influences NFκβ levels and associ-
(extracted from milk thistle), and honokiol (extracted from ated VEGF expression relative to its depletion [58] and thus
magnolia bark) [47]. Dietary flavonoids and Vitamin E have may play a role in regulating NFκβ and modulating copper
also shown to be effective modulators of VEGF [48]. PDGF levels resulting from an acute-phase reaction and low zinc
expression can be affected by ellagic acid, a polyphenol found status [59].
in fruit and nuts. Ellagic acid also simultaneously suppresses Normalization of the stromal density in a TME may be
VEGF expression [49]. EGCG influences PDGF receptors, facilitated by the inhibition of CXCL12. Diindolylmethane, a
modifying their propensity to be stimulated by PDGF and brassican compound isolated from cruciferous vegetables,
can consequently inhibit PDGF effects through cell signaling was shown to downregulate CXCL12 in breast cancer
[50]. bFGF can be affected by stabilizing the ECM overall, patients [60].
which reduces its availability through motility inhibition.
TNFα stimulates production of bFGF, so agents that inhibit
TNFα can also decrease bFGF.  Nettle leaf extract has been 27.8  he Microenvironment in Chronic
T
shown in studies to be a potent TNFα inhibitor [51]. TGFβ is Autoimmune Disease and Similarities
typically a tumor inhibitor initially, but in the hypoxic TME, to Cancer
tumor cells become resistant to it and proliferate due to its
presence. Inhibitors of TGFβ include curcumin, emodi (a The environments of cancer and autoimmune disease share
phytochemical found in rhubarb and Japanese knotweed) common characteristics. Specifically, both show hallmarks of
[52], and resveratrol [53]. TAMs also increase EGF, which an upregulated immune response, leading to inflammation
itself promotes tumor growth. Retinol has been shown in and subsequent tissue damage (see 7 Chap. 19). The ­divergent
 

studies to decrease secretion of EGF in endothelial cells [54]. point of the two disorders relates to how the pathology in the
As previously discussed, CAFs increase lactic acid microenvironment progresses. In malignancy, the tumor
shuttling and contribute to the hypoxic environment in the microenvironment induces immunosuppression where
TME, which can promote angiogenic signaling of VEGF tumor cells are unrecognized by the immune system. There is
via protein kinase C (PKC). This produces a high-insulin mixed immune response in malignancy. The tumor cells have
environment, stimulating hypoxic cells to produce more an increased anti-inflammatory response but are invisible to
lactic acid, which contributes to cell signaling. Improving specific antibodies, while the surrounding microenviron-
insulin metabolism and decreasing insulin resistance by ment is pro-inflammatory. Tumors in a sense are wounds
decreasing dietary omega-6 linoleic and arachidonic fatty that do not heal, as the tumor reorients the immune system’s
The Microenvironment of Chronic Disease
441 27
healing response and uses it to drive its own progression and ment, such as VEGF and Hif1a, can be important in terms
self-promotion. of destabilizing the autoimmune microenvironment (AIM).
In contrast, the microenvironment in autoimmune dis- Dietary modulators of VEGF have been previously dis-
ease shows an activated inflammatory response that escalates cussed in the section on cancer and include anti-inflamma-
in response to a lack of self-tolerance. The focus of the inflam- tory plant compounds that may also affect cytokine
matory response is the host tissue itself. There is expression expression in autoimmune disease, such as curcumin,
of antibodies that are misrecognized, leading to further EGCG, proanthocyanidins, and resveratrol [46, 47].
attack by the immune system. This self-perpetuating cycle Modulation of cytokine activity, both pro-inflammatory
results in permanent tissue damage over a long period. and anti-inflammatory, and transcription factors, such as
Typically in the microenvironment of autoimmune disease, NFκβ, are of interest in terms of the autoimmune microen-
the immune infiltrate is comprised primarily of either Th1 vironment (AIM). In some autoimmune diseases, macro-
cells, and their inflammatory cytokines such as interleukin 2 phages release TNFα, stimulating the migration of NFκβ
and 17, or Th2 cells, and their anti-inflammatory cytokines into the cell nucleus, which in turn will upregulate inflam-
such as interleukin 4 and 10. One interesting characteristic of mation and code for hyperproliferative cytokines such as
autoimmune diseases is the diminished presence or impair- interleukin 1, 6, and 8 [65]. Nutritional compounds that
ment of CD4+ and CD25+ T regulatory cells, which have regulate TNFα and NFκβ include curcumin, quercetin, B6,
come to be thought of as an essential component of immune and EGCG [66–69].
modulation and homeostasis [61]. One well-known factor in autoimmune disease is the
Another commonality between the microenvironments connection to pro-inflammatory “Western” diets high in fat,
of cancer and autoimmune disease is the propensity toward a sugar, processed food, protein, and salt and the effect on
hypoxic state. In autoimmune disease, the hypoxic environ- CD4+ T cells in autoimmune disease [70]. Obesity tends to
ment is established largely due to immune cell infiltration, impact immunity through Treg cells and can promote a pre-
which increases the demand for oxygen over the available dominantly Th17 environment with upregulated IL6, which
supply. In some autoimmune disorders, such as multiple scle- continues to signal immune response [70]. Consequently, the
rosis, the increased migration of lymphocytes and macro- management of obesity and abnormal insulin response can
phages also increases the secretion of proangiogenic factors be crucial in managing autoimmune disorders, especially of
such as VEGF and MMPs. Although autoimmunity and can- the inflammatory kind [71]. Vitamin D also seems to have a
cer represent opposing ways in which the immune system special role in the initiation and progression of autoimmune
can become dysfunctional, there is considerable overlap in diseases. Vitamin D has been shown to increase the release of
terms of the potential targets for nutritional intervention. anti-inflammatory IL4 from immune cells and stimulate the
Because of the propensity for inflammation, many of the production of Treg cells, which prevent the immune system
cancer microenvironment anti-inflammatory strategies that from initiating autoimmune response by inducing self-­
downregulate proangiogenic factors, such as VEGF, could be tolerance [71].
considered appropriate. There are some different factors to
consider, however. While there is good understanding of the
role of macrophages and other immune cells in the cancer 27.10 The Microenvironment of Arthritic
microenvironment, certain assumptions about the roles of spe- Conditions
cific immune cells in the microenvironment of autoimmune
disease have led to research with conflicting conclusions. For Arthritic conditions, both inflammatory and noninflam-
example, there is an assumption that m1 macrophages would matory, have an obvious inherent potential for microenvi-
be present in Th1-type autoimmune diseases such as rheuma- ronmental changes and pathology. The microenvironment
toid arthritis, Hashimoto’s thyroiditis, and multiple sclerosis, of the synovial capsule is an important target. It was previ-
but the research data is somewhat controversial [62, 63]. ously assumed that the tendency for inflammation in
Conversely, the role of autoantibodies in autoimmune disease arthritic conditions was isolated to those associated with
is well understood, but there is little understanding of their sig- autoimmune dysregulation, such as rheumatoid arthritis
nificance in cancer progression. Disease states such as hepato- and psoriatic arthritis. However, research has shown that
cellular carcinoma induced by hepatitis C or liver cirrhosis are even in osteoarthritis, inflammation is a subclinical event
proving to be helpful in delineating the role of the immune that can lead to degradation of the joint [72]. One study
system in cancer progression [64]. examined the activation and infiltration of CD5+ cells in
both rheumatoid and osteoarthritis and found them to be
comparable [72]. Chondrocytes in an inflammatory syno-
27.9  utritional Influences on the
N vial environment seem to be less susceptible to selective
Autoimmune Microenvironment cell death and apoptosis and increase the inflammatory
environment by secreting additional inflammatory cyto-
Hypoxia and proangiogenic factors are two components kines such as MCP-1 and MIF [73]. Once tissue in the
that cancer and autoimmune disease share. Consequently, superficial zone of articular cartilage is damaged by
suppressing factors that contribute to a hypoxic environ- inflammation, the mesenchymal stem cells present in it
 442 S. Gomberg

lose the ability to regenerate, and tissue damage becomes proangiogenic factors through the use of proanthocyanidins
permanent. Inflammatory cytokines such as IL2, which and curcumin could be useful [82].
upregulate Nfκβ, lead to low-level persistent inflammation Because of the role of the gut microbiome in inflamma-
[74]. Again, we see the prevalence of an inflammatory tion in arthritic conditions, optimizing the gut and
­cascade in a disease microenvironment becomes self-sus- decreasing the load of pathogenic bacteria could possibly
taining and difficult to reverse. Even in supposed nonin- have a significant effect, especially in RA. Increased levels
27 flammatory arthritic conditions, changes in the synovial of Prevotella copri have been observed in the gut microbi-
microenvironment affect the regeneration of the joint cap- ota of patients with RA, and it has been postulated that
sule. One study showed that changes in the synovial ME in lowering the levels of Prevotella and optimizing the diver-
osteoarthritis changed the RNA sequencing in joint chon- sity of the microbiota in RA patients could be of clinical
drocytes, resulting in downstream changes in the joint significance [83].
cartilage formation [75]. Another interesting aspect of
arthritic conditions and microenvironmental concerns is
the correlation between the gut microenvironment in 27.12 The Blood as a Potential Reflective
inflammatory bowel disease and the development of Microenvironment
enteropathic arthropathies. One etiological theory pro-
posed is that lymphocytes or macrophages from the gut One microsystem of the body that is relatively easy to explore
may migrate to the synovium and bind to the synovial tis- is that of the blood. The blood microenvironment can be
sue vessels, dependent on the development of adhesion observed through a microscope, most effectively in dark-­
molecules such as vascular adhesion protein 1 (VAP1). field and phase-contrast viewing. Due to the fluid nature of
This in turn leads to the development of inflammatory blood, one can experience the living dynamics of the blood
arthritis in the affected joint [76]. environment by observing it soon after obtaining a sample,
Another proposed mechanism relates to mesenchymal without having to stain the blood or through time elapse,
cells present in both the gut and joint being predisposed to which could cause the sample to degrade. Dark-field illumi-
stimulation with simultaneous overexpression of TNF nation, which condenses light by blocking light that passes
leading to TNF-mediated inflammation [77]. The develop- through the specimen and allowing only for oblique rays
ment of loss of tolerance of normal bacterial flora in inflam- from the circumference of a specially designed condenser,
matory bowel disease (IBD) seems to be the initiator of this allows for the viewing of objects that are unstained and
cascade of events leading to IBD-centered arthropathies absorb little or no light, such as bacteria and cell wall struc-
[78]. Also, activation of toll-like receptors on immune cells tures. Dark-field microscopy is less effective in determining
by certain bacteria in the intestinal environment, such as intracellular dynamics [84–86]. Phase-contrast illumination
overabundant Prevotella copri in RA, can lead to the upreg- allows light to be passed through the sample at a variety of
ulation of inflammatory cytokines in the joint, such as Nfκβ angles, offering an almost three-dimensional aspect to sam-
and IL1r [79]. ple viewing. In this way, the cellular structure and viability of
red blood cells and white blood cells can be evaluated, and
extrapolations can be made as to the nature of the blood
27.11 Nutritional Influences microenvironment, the plasma.
on the Microenvironment The test itself is controversial, and there is limited evi-
in Arthritic Conditions dence for the validity of the interpretations of dark-field and
phase-contrast live blood examinations. But it is important
Dietary factors that help mediate low-level inflammation are that practitioners are educated about the practice, in case
important in inflammatory response but also in mediating tis- patients ask about it or bring in results from a test.
sue damage in the joint capsule. Consequently, nutritional Practitioners of live blood cell analysis assert that the
supplements that downregulate inflammatory cytokines, TNF, evaluation can be seen as more qualitative rather than quan-
and Nfκβ – such as curcumin, quercetin, polyunsaturated fatty titative. Since the blood is observed immediately after the
acids (PUFA) like fish oil, and EGCG – are important. PUFAs, sample is obtained, the dynamics of both the cells themselves
such as those contained in krill oil, reduce cytokine infiltration and the plasma are visible. For example, in conventional
into the joint capsule [80]. Collagen, in addition to being an hematology, it is possible to quantify the numbers of various
important constituent of the joint capsule and being necessary types of white blood cells such as neutrophils, macrophages,
for its regeneration, also seems to assist in regulating T-cell and basophils, but it is difficult to determine the viability of
function so they do not become activated and attack the joint these cells. Observing them live in the blood can lead to pos-
cartilage [81]. Vascular remodeling has been shown to be an tulations about the actual nature of potential immune
important factor in the potential infiltration of macrophages response by assessing their viability. For example, although
and T cells into the joint capsule, so the downregulation of there may be many white cells present in a sample, they may
The Microenvironment of Chronic Disease
443 27
exhibit poor phagocytic activity when observed in a live the dynamics of the red blood cells. One such phenome-
microscopic evaluation. non is the observation of rouleaux or stacking of the red
There are crucial considerations for sample preparation blood cells. From a conventional perspective, rouleaux
so that the possibility of artifacts remains minimal. Most may be caused by acute-phase protein elevations in the
often, comparing two samples from a patient as well as vari- blood, leading to a change in the overall pH of the blood
ous views from a sample can reveal any inconsistencies aris- microenvironment. Many times, it can be associated with
ing from the sample preparation (e.g., abnormalities in slides increased fibrinogen or globulin levels, and often it is
or slide covers, air bubbles, or exogenous microorganisms). seen accompanied by spicules in the blood, also indica-
This section will briefly review some of the potential findings tive of elevated fibrinogen [92]. In any case, the shift in
in live blood and the potential reflective clues they may have valence of the serum pH can alter the potential of red
related to nutritional status. In terms of clinical relevance, blood cells to easily move through the peripheral vascula-
findings in the live blood should generally not be considered ture, causing problems with circulation [93]. Often,
diagnostic per se, but they may be useful in prioritizing other improving protein digestion or the administration of pro-
diagnostic testing or comparing to other diagnostic findings teolytic enzymes can reverse this condition in a short
when considering a potential diagnosis. period of time.
Live blood cell analysis is most useful in enhancing exist- Outside of conventional hematological findings that
ing findings arising from a conventional complete blood can be observed in the live blood, there are often observed
count (CBC) or, in some cases, findings in the metabolic panel findings that have a variety of potential interpretations.
(CMP). This relates to observing the morphology and activity These observations are more often than not viewed as arti-
of the blood cells within the microenvironment of the plasma. facts by conventional science. From the standpoint of cer-
Cell wall structure can be observed, and phase-­contrast view- tain schools of alternative medicine, these findings show
ing allows for some intracellular observations to be made. the propensity of the blood microenvironment to be more
One example relates to relative cell size. Variabilities in cell conducive to various pathological processes [87, 94].
size are easily visible in the live blood, and since anisocytosis Several microbiologists in the past, including Gunther
is almost always associated with the various mechanisms lead- Enderlein and Gaston Naessens, have embraced this the-
ing to anemias, it can validate inferences about iron status or ory and extrapolated on the potential meaning of these
B vitamin levels, specifically B12 and folate [87]. In addition, a findings in the live blood microenvironment [95, 96]. One
great variation in the sizes of RBCs can be interpreted as oxi- example is the formation of pteroharps, or platelets spread-
dative stress due to excessive homocysteine or, in cases of ele- ing like wings of butterflies, in the blood. Platelets are
vated oxidant catalysts such as mercury or excess iron, within observed to have spread out on the slide in a formation of
the RBCs themselves [88]. In this case, the majority of cells a shadowy background. This does not occur in all samples
tend toward macrocytosis. Another observation discernible and is variably interpreted to mean either a change in the
in the live blood relates to cell membrane structure and viabil- blood valence due to an abnormal blood pH, similar to the
ity. Many different abnormalities in the cell wall structure are rouleaux formation in the red blood cells, or it is inter-
visible under the microscope and include poikilocytosis, preted to be a manifestation of an L-form bacteria without
schistocytosis, and acanthocytosis. The blood cells appear a cell wall. This finding is often associated with leaky gut
with surface corrugations or spiculations. Two inferences can syndrome and intestinal flora imbalances. Another typical
be made: potential oxidative stress causing the cell membrane finding in live blood is the presence of thecits, which are
to rupture and poor formation of the cellular membrane due often thought to be corpuscles broken off other cells. An
to suboptimal essential fatty acid status subsequent to insuffi- alternative interpretation is that these are a cell wall-defi-
cient intake or metabolism. cient form of bacteria often correlated with intestinal dys-
White blood cell morphology is easily determined in either biosis.
phase-contrast or dark-field viewing and can often enhance an
understanding of the quantitative measurement available with
a blood draw. For example, a CBC may show adequate neutro- 27.13 Conclusion
phils but may be hyper-segmented under microscopic viewing
and therefore suggest B12 deficiency [89]. Reduced motility of The human body is complex and composed of a variety of
various leukocytes may result from immunodeficiency disease structures and systems that are potential arenas for
processes [90]. Another example is related to the status of baso- pathologies that can alter the local biological terrain and
phil activity. In conventional analysis, basophils may appear to then have the potential to affect the organism. The under-
quantitatively be within range, but microscopic evaluation may standing of disease microenvironments, therefore, is
show excessive degranulation of the basophils, which would important not only in uncovering the process of systemic
lead to an assumption of increased histamine activity [91]. pathology but also in targeting nutritional interventions
Viewing the live blood under either phase-contrast or that can undermine the root of pathological processes
dark-field illumination can also show abnormalities in before systemic disease occurs.
 444 S. Gomberg

Case Study: Cervical Cancer

A 42-year-old female patient was diagnosed with stage IVb inhibition of angiogenesis in addition to standard anti-­
cervical cancer 1 month prior to initial integrative medicine inflammatory and immune-modulating natural protocols. The
consult. The patient was diagnosed after an abnormal PAP patient was given an extract of curcumin, EGCG, and baicalin
smear and biopsy with follow-up radiologic evaluation for targeted to affect VEGF, PGGF, and p53 expression. In addition,

27 staging. Multiple metastatic lesions were identified including

the rectum and the supraclavicular lymph nodes. The patient
she received high-dose resveratrol, which has been shown to
inhibit STAT3 signaling. After the six cycles of treatment, the
otherwise was generally healthy, slightly obese, and only patient was sent for follow-up radiological exam and had
complained of chronic neck pain attributed to a previous motor negative CT/PET scan results. Conventional treatment was
vehicle accident. She elected to undergo conventional discontinued, but she remained on botanical and nutritional
chemotherapy consisting of combined paclitaxel and platin-­ protocols for several years afterward. No adverse events were
based therapy administered every 3 weeks for 6 cycles. The identified with this protocol. To date, 9 years after initial
patient sought additional supportive integrative approaches treatment, the patient remains disease-free. This case points to
throughout her therapy. Since antiangiogenic therapies such as potential benefits possible when conventional cancer therapies
bevacizumab were not used in the treatment of cervical cancer are combined with dietary and medicinal plant interventions.
at this time, integrative treatment interventions focused on

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65. Kinne R, et  al. Macrophages in rheumatoid arthritis. Arthritis Res. 81. Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Fafard RD, Pre-
2000;2(3):189–202. uss HG. Effects of orally administered undenatured type II collagen
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 447 28

Chronic Pain
Jena Savadsky Griffith

28.1 Introduction – 448

28.1.1  echanisms of Pain (See . Fig. 28.2) – 449
M  

28.1.2 Plant Compounds – 460

References – 465

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_28
 448 J. S. Griffith

28.1  Introduction induced neuropathy, obesity, rheumatoid arthritis (RA) or

post-traumatic stress disorder (PTSD). As a central product
Aristotle described pain as emotional, a passion of the soul, of inflammation, pain intersects most chronic diseases
and the heart as the center of sensation. Later, Descartes today. According to the 2011 Institute of Medicine Report,
asserted that pain was outside of the mind, a disturbance to there are more than 100 million people in the United States
the machine (body) that passed along nerve fibers through a living with chronic pain, which is more than those affected
pathway that led to the brain. The gate control theory intro- by diabetes, heart disease, and cancer combined [6]
duced the brain as deeply involved in pain processing and (. Fig. 28.1). It is the primary reason for visiting physicians
 

28 perception [1]. In 1974, the International Association for the and a leading cause of total disability, costing up to $635
Study of Pain (IASP) essentially married the mind, body, and million per year [7]. Affecting a total of 1.5 billion people
soul, weaving all theories into its current and finalized defini- worldwide, chronic pain is an increasing public health bur-
tion: “an unpleasant sensory and emotional experience asso- den in most developed countries and afflicts people
ciated with actual or potential tissue damage [2].” Although throughout the lifespan [8]. It is estimated that 25–46% of
our understanding of pain is still in evolution, this integrative children and young adults experience chronic pain, most
definition includes an emotional response, which, depending often in the form of headache or abdominal or musculo-
on the individual physiology, behavior and life experiences, skeletal pain [9]. Of those surveyed, more than half of older
will be perceived and then expressed differently for each per- adults, 53%, reported pain within the last month [10]. Pain
son [3]. Even though pain and emotion travel similar path- in the elderly is often undertreated. It significantly affects
ways, this aspect of pain as personal experience is often quality of life and frequently crosses over into insomnia,
ignored; it cannot convey what pain is or what it feels like to depression and anxiety. Chronic pain not only becomes the
each individual [4]. Importantly, it does recognize that pain central part of life for the sufferer, it impacts family, friends
can be felt without tissue damage, as is the case with many and the communities in which they live.
chronic pain sufferers. Most patients suffering with chronic pain are treated with
Thus, chronic pain is a complex multifactorial, biopsy- pharmacology, local injection or surgery. Although these
chosocial experience [5]. Chronic pain, as opposed to acute therapies play an important and necessary role, there is no
pain, exists for at least 3–6 months or beyond typical heal- epidemiological evidence that they have yet to alter the
ing allowance [2]. It is a disease in and of itself, as in mus- course or make a significant difference in patient outcomes,
culoskeletal pain or headaches, or it can be associated with disability or cost [11, 12]. With its bio-individual manifesta-
other chronic conditions, such as diabetic or chemotherapy-­ tions, pain is ideally suited for an integrative and functional

120

100

80
Millions

60

40

20

0
Chronic Diabetes Cardiovascular Cancer Stroke
Pain Disease

..      Fig. 28.1  Prevalence of Chronic Pain. (Courtesy of Jena Savadsky Griffith, RDN, IHC; Based on data from Pain [6], Diabetes [236], Heart Disease,
Stroke [237], Cancer [238])
Chronic Pain
449 28
approach. The patient often needs multidisciplinary medical multiple organ systems [5]. This hypersensitivity involves
support and expertise in all aspects of life that are physical, neuronal and microglial plasticity in response to activity,
emotional, and spiritual. A 2012 report on the practice of inflammation or neural injury [17]. The ensuing dysregula-
integrative medicine across America outlines significant tion produces allodynia (a greater-than-normal response to
strides being made in chronic pain, with nutrition at the non-painful stimuli), hyperalgesia (heightened response to
therapeutic forefront [13]. In the first Multidisciplinary Pain painful stimuli) and/or enables non-injured tissue to pro-
Research workshop in Rome, 2016, researchers stated that duce pain [18]. Localized pain can become generalized pain
patients with chronic pain should undergo nutritional assess- and manifest in joints or muscles. Pathophysiologically, sig-
ment and counseling at the onset of treatment and that naling persists past the point of tissue healing and creates a
including nutrition in personalizing pain medicine is formi- sensory illusion where pain may be experienced with low or
dable and will improve any analgesic therapy, patient compli- even absent sensory stimuli. These processes can either facil-
ance and quality of life [14]. itate or inhibit pain transmission. This abnormal connectiv-
ity is driven by imbalances in concentrations of CNS
neurotransmitters that control sensory processing, sleep,
28.1.1  Mechanisms of Pain (See . Fig. 28.2)   alertness, affect and memory [19]. Further, as a result of MR
morphometry, it is now known that the cerebral cortex is
28.1.1.1  Nociceptive Pain reorganized and gray matter is decreased, creating a common
Nociceptive, or acute, pain results when noxious stimuli acti- “brain signature” in chronic pain sufferers [20].
vate nociceptors in the peripheral nervous system (PNS) and Although an injury may be present with CS, it is not nec-
serves an important protective function. This activation essarily pathology of the tissue detected on a scan, but a func-
causes depolarization via first-, second- and third-order neu- tional pathology. Central sensitization is the underlying
rons in C fibers or A delta fibers that lead to the dorsal horn pathophysiology associated with fibromyalgia, irritable
of the spinal cord and then up through the brainstem [5]. The bowel syndrome (IBS), tension headaches, migraines, sleep
thalamus then relays this nociceptive information to the disturbances, restless leg syndrome, chronic back and neck
higher cortical regions that include the amygdala, hypothala- pain, osteoarthritis (OA), rheumatoid arthritis (RA), intersti-
mus, periaqueductal grey, basal ganglia and regions of the tial cystitis, and temporomandibular syndrome (TMJD).
cerebral cortex where the pain is processed, perceived and Importantly, CS is also implicated in anxiety, depression and
localized [15]. Pain is mediated via descending pathways by PTSD [5, 21–23]. Whether or not chronic pain begins with a
both excitatory (glutamate) and inhibitory (gamma-­ specific acute injury, as pain becomes chronic, multiple
aminobutyric acid  - GABA) neurotransmitters that either mechanisms overlap for many (. Fig. 28.3). That is, the pain
 

increase or decrease pain perception [5, 15]. Dysfunction can appears to be caused by a complex mixture of nociceptive,
occur at all levels of ascending and descending pathways, neuropathic and psychological factors with central sensitiza-
resulting in chronic pain. The sequence of events in pain sig- tion playing a dominant role [24].
naling involves four processes: transduction, transmission,
modulation and perception [16]. 28.1.1.4  Psychological Pain
Chronic pain often exists in the absence of any physiological
28.1.1.2  Neuropathic Pain cause or injury. Although patients should never be told that
Neuropathic pain is a complex multifactorial chronic pain the pain is “in their head,” a new paradigm concludes that
state caused by a lesion, injury or dysfunction of either the CNS processing may be altered by emotional states and trau-
peripheral or central nervous system (CNS). Accompanied matic events, in childhood or adulthood, much like a physi-
by tissue damage or injured nerve fibers, these fibers misfire cal injury, into what is called psychological pain [25]. A
and send incorrect signals to various pain centers. These history of trauma and adverse early adulthood experiences
changes may not quickly resolve, as in diabetic neuropathy or co-exists with many pain syndromes [26, 27]. Pain is experi-
postherpetic neuralgia. Thus, the impact of injury includes enced as more severe than expected, and emotional process-
both damage to the fiber itself and the areas surrounding the ing seems out of proportion to physical pathology, if any
injury. With neuropathic pain, neurons may continue to fire, exists. The nervous system is sensitized over weeks, months
leading to spontaneous pain and pain upon movement [5]. or years. More subtly, chronic pain may develop because of
There may be inhibition impairment and alterations in cen- unresolved emotional issues. Although those experiencing
tral pain processing, which is key in chronic pain. Neuropathic trauma have good psychosocial adjustment, experiencing
pain can manifest in patients as shooting, burning, tingling pressure or an unrelated stressful incident at a later time may
or numbness. recall the initial trauma.

28.1.1.3  Central Sensitization 28.1.1.5  Psychosocial Mediators

It is now known that most patients with chronic pain have Most of the study and treatment of pain has been based on
some degree of alteration in central nervous system process- the linear concepts of physical medicine. Pain was simply
ing called central sensitization (CS). CS is defined as a state in nociception. In the 1960s, pain was recognized as a multidi-
which the CNS is hyperactive or magnifies sensory input in mensional experience with sensory (location, quality and
 450 J. S. Griffith

Biological
nerve
injury/damage,
trauma, infection,
illness,
inflammation

28
Environmental
Psychosocial
Diet, lifestyle,
Mediators
activity,
sensory, cognitive- Chronic Pain employment,
evaluative, relationships,
affective spiritual practice,
sleep, stress

Genetic/Epigenetic
predisposition for
pain amplification

Medical Treatment IFMNT Complementary Therapies

• Pharmacotherapy-NSAIDS, • Correct nutritional deficiencies • Acupuncture

opioids, antidepressants, • Remove food allergens • Chiropractic
anticonvulsants,
• Detoxification • Dry needling
• Interventional procedures-
injections, ablations, • Individualized diet: Anti- • Yoga, Tai Chi, Qi Gong
implants inflammatory, AIP, vegan, etc. • Meditation
• Surgery • Nutrient supplementation- • Essential oils
omega-3's, magnesium,
• Physical therapy vitamin D • Biofeedback
• Exercise • Plant compounds-herbal • Hypnosis
• Heat/cold therapy supplementation: turmeric, • Electrotherapy
• Cognitive Behavioral Therapy boswelia, cannabinoids • Energy medicine
• Massage • TCM
• Homeopathy
• Emotional Freedom Tech.
• Brain Integration
• Guided imagery

..      Fig. 28.2  Chronic Pain Pathophysiology and Management Algorithm. (Courtesy of Jena Savadsky Griffith, RDN, IHC)

intensity), affective (degree of unpleasantness) and cognitive-­ for each person’s pain experience. The degree of pain felt
evaluative (attitude and beliefs about pain) components [28]. depends on disposition, mood, history of pain reactivity,
It integrated the common denominator of the individual and attention, motivations, cognition, social influences, commu-
the embodiment of a person’s history, energies and percep- nity, health and nutrition status and myriad other variables
tions. Significantly, biopsychosocial factors provide a context unique to that individual [12, 29].
Chronic Pain
451 28

Nociceptive Neuropathic Centralized Pain

(peripheral) (peripheral) (central sensitization)
· Inflammation or mechanical · Damage/dysfunction of peripheral · Central disturbance in pain
tissue damage nerves processing
· NSAID, opioid responsive · Responds to NSAIDs, opioids, (hyperalgesia/allodynia)
· Procedures TCAs, neuroactive compounds · Treated with neuroactive compounds
to affect neurotransmitters
Examples Examples Examples
Acute pain due to injury Diabetic neuropathic pain Fibromyalgia
Osteoarthritis Post herpetic neuralgia Irritable bowel syndrome
Rheumatoid Arthritis Trigeminal neuralgia TMJD
Cancer-related pain Phantom limb pain Tension headache
Post-operative pain Complex regional pain syndrome Low back pain

MIXED PAIN STATES

-Any combination may be present-

..      Fig 28.3  Mechanisms of pain. (Courtesy of Dr. Daniel Clauw, University of Michigan. NSAIDs nonsteroidal anti-inflammatory drugs, TMJD
temporomandibular joint disorder, TCAs tricyclic antidepressants)

28.1.1.6  Sleep, Depression and Chronic Pain ures estimate 30% of newly diagnosed cancer patients have
Pain can trigger a cascade of events and often has a cyclic pain, 30–50% of patients undergo active treatment ­experience
relationship with anxiety, depression, sleep disturbance, pain, and 70–90% of patients with advanced disease experi-
PTSD, obesity, and inactivity. Connections with pain, ence pain [34, 35]. Pain in cancer patients may be related to
depression and anxiety are expected as they share similar the cancer itself (metastatic bone disease or local tissue dam-
biological pathways and neurotransmitters with overlap- age), to procedures (post-surgery, injections) or it can be
ping pathophysiology in the central nervous system [19, related to treatment (radiation, chemotherapy) [12, 35, 36].
30]. Those in chronic pain are four times more likely to have In addition, patients may experience nociceptive, neuro-
comorbid anxiety or depression than pain-free primary care pathic pain or both. Pain is one of the most feared aspects of
patients [31], with studies assessing comorbidity from 30% cancer for both patients and their families; however, there are
to 60% [30]. Similarly, up to 75% of those with depression in many diet and lifestyle interventions that can relieve patients
primary care settings complain of chronic pain, including of anxiety and stress, increase nutritional status, and empower
headache, stomach pain, neck and back pain and idiopathic patients to play an active role in their own care.
pain [31].
Sleep complaints are present in 67–88% of chronic pain 28.1.1.8  Nutrition and Chronic Pain
conditions [32]. Most studies confirm its reciprocal relation- Eating is a daily practice that can contribute to or detract
ship, with pain causing sleep disturbances and insomnia from health. According to the Centers for Disease Control
causing increased pain sensitivity. Loss of sleep increases and Prevention, 70% of all deaths in the United States result
inflammation, alters metabolism, depresses immunity and from chronic preventable diseases that are attributed to diet
does not allow the body time to rest and replenish energy and lifestyle [37]. The current standard diet may be the most
stores. Released along with glutamate during pain signaling serious threat to public health [38]. Deficiencies, toxicities
is neurotransmitter substance P.  During deeper stages of and sensitivities within any one or multiple biochemical and
sleep, substance P is naturally decreased; therefore, inade- signaling processes can contribute to chronic pain condi-
quate sleep amplifies pain as more substance P remains [33]. tions. While research is just beginning to address diet and
Nutrition and lifestyle intervention should address inflam- pain, the connections are undeniable and individual dietary
matory aspects of diet, coffee intake (see hydration), poten- roadmaps can be created. There is evidence that specific
tial insulin resistance, supplementation, use of NSAIDs, foods, nutrients, diets and herbs can provide pain relief while
stabilization of the gut microbiome and exercise. other foods and dietary patterns contribute to increased
pain. Regardless of the chronic pain label, from diabetic neu-
28.1.1.7  Cancer-Related Pain ropathy to migraines to fibromyalgia, addressing food and its
Due to the breadth and depth of cancer-related pain as its ingestion, absorption, digestion and elimination is an
own entity, the chronic pain conditions discussed in this empowering and worthwhile first line of defense when a
chapter are non-cancer-related. Cancer is a leading cause of patient presents with chronic pain. Nutrition and diet may be
chronic pain and presents challenges to both patient and the most appropriate initial recommendation for pain suffer-
practitioner. The American Cancer Society’s most recent fig- ers to activate a healing response [12].
 452 J. S. Griffith

28.1.1.9  Obesity pain [64]. In the absence of injury, nerve inflammation

Chronic pain and nutrition status are linked in direct and causes neuropathic-like pain and induces spontaneous
indirect ways. Nutrition is clearly implicated in diabetes, activity away from the generation site [65].
obesity-related musculoskeletal pain, or where a food trigger Designed to protect, inflammation is the body’s immune
may be at play, such as in migraines or IBS. Obesity and pain response to pathogens, injury, or contaminants. As medicine
coexist and have negative reciprocal effects. As an epidemic looks less at symptoms of disease and more toward systems,
with 150 million people, the treatment of obesity and chronic inflammation gets more attention as a root cause and has
pain should be considered as synergistic [14]. As BMI become a common pathway for many of the chronic condi-
28 increases, so does pain. That includes less obvious conditions tions that exist today, including persistent pain. A specific
as neuropathic pain and headaches [39]. In a survey of one food can trigger an inflammatory response. Repeated con-
million Americans, chronic pain rates were 68–254% higher sumption of inflammatory foods or dietary pattern can keep
in obese individuals compared to those who were non-obese the body and immune system in a hyperactive inflammatory
[40]. Women who are overweight or obese have a 60–70% state. The current Western diet of highly processed, high-­
greater risk of developing fibromyalgia [41]. Extra weight can calorie foods, lower nutrient value, less fiber and suboptimal
compress and cause body malalignment that leads to pain in antioxidant power presents a heavy inflammatory load on all
the back, neck, knee, foot and hip [42]. Alternately, each systems of the body and is central to the pathogenesis of
pound of weight loss resulted in a four-pound reduction in chronic disease [38, 62]. The ideal balance of pro-­
stress on the knee per step, in a study of obese adults with OA inflammatory omega-6 essential fatty acids (EFAs) to anti-­
[43]. Further, in the Framingham study, an 11-pound weight inflammatory omega-3 EFAs is 3:1; however, our standard
loss was associated with a 50% reduction in the risk of symp- American diet (SAD) supplies 20:1 and, for some, up to as
tomatic knee arthritis [44]. Although most trials have been much as 50:1 [66]. This often leaves a person profoundly bur-
done with OA and knee pain, weight loss reduced pain and dened, malnourished, deficient and vulnerable to pain and
increased function in those with fibromyalgia and low back pathogens. A ratio of 2–3:1 of omega-6 to omega-3 sup-
pain as well [45, 46]. Importantly, obesity and metabolic pressed inflammation in patients with rheumatoid arthritis
imbalance can be a consequence of chronic pain. Its continu- [67]. In response to chronic pain, an anti-inflammatory diet
ance often leads to a decline in physical activity, trouble is a logical step. (see 7 Chap. 23 and below 7 Sect. 28.1.1.16)
   

sleeping and use of food as coping mechanism [47, 48].

Chronic pain patients may have reduced ability to experience 28.1.1.11  Gut Microbiome
pleasure from food and thereby increase consumption, espe- A normal inflammatory pain response requires a healthy gut
cially regarding “sugary and fatty foods [49].” Addressing and microbiome. Although in its infancy, research continues to
modifying the diet in the clinical setting is key in the man- confirm Hippocrates’ long-held edict that health begins and
agement of pain chronification and its further progression to ends in the gut. Home to 100 million microbial cells, the gut
metabolic dysfunction. microbiome not only facilitates nutrient absorption but has
come to be known as the intrinsic regulator of the immune
system, where 70–80% of it resides [68–70]. In a 2015 study,
28.1.1.10  Inflammation patients with RA had similarly altered gut and oral microbi-
Greater than a function of overload, however, obesity is omes that normalized after treatment [71]. A study of 42
more often related to pain as a product of systemic inflam- fibromyalgia patients found that 100% of them had small
mation. Increased pain in non-weight bearing regions intestinal bacterial overgrowth (SIBO—bacterial transloca-
include the spine, neck and upper extremities, as well as tion from the large to the small intestine) [72]. Additionally,
conditions including fibromyalgia, migraine and headaches IBS was present in 30–70% of fibromyalgia patients [73]. This
[42, 50–52]. Markers of inflammation, including C-reactive points to the disruption of a healthy microbiome and dysbio-
protein (CRP), tumor necrosis factor alpha (TNFα) and sis as an underlying feature for many with chronic pain and
various cytokines, are elevated in progression of OA and other inflammatory conditions.
low back pain, particularly in the obese population [39, With IBS, it is easier to make a direct food–gut connec-
52–54]. For almost every type of chronic pain, whether it is tion as the pain resides in the abdomen. Affecting almost
biochemical, structural or stress-induced, systemic, local 15% of the population, it is the primary reason for visits to a
tissue or neural inflammation is an underlying or contrib- gastroenterologist and second most common reason for
uting factor [55–62]. By definition, pain is one of the four work absence [74]. Etiology of IBS is, like chronic pain, as
manifestations of inflammation [63]. All pain states—noci- diverse as the people afflicted. While altered gut bacteria and
ceptive, neuropathic, and mixed pain related—are associ- infection are often causes, most attribute their condition to
ated with inflammation. Inflammatory mediators act to food sensitivities which are found in 50–84% of IBS patients
exacerbate or inhibit pain. An increase in proinflammatory [75]. The most common trigger foods are corn, wheat, coffee,
cytokines is linked to the maintenance and induction of eggs, tea, citrus and dairy foods. Followed by food sensitivity
neuropathic pain, and these cytokines and free radicals and lactose tolerance testing, and stool analysis, patients were
produced at the site of injury may be involved with nocicep- put on an elimination diet for 1 year. In addition to many
tor sensitization and maintenance of nerve-injury-induced other symptomatic improvements, pain was reduced by 90%
Chronic Pain
453 28
[76]. It is common, however, to overlook the gut-brain con- 53% of migraine patients resolving headaches after avoidance
nection that exists in IBS and chronic pain. As a regulator of of all allergenic foods with partial improvement shown in an
the digestive process, the enteric nervous system (ENS) has additional 38%. Further, most research indicates a wide range
its own pain receptors, nerves and neurotransmitters often of food as causation [95, 96]. Children with severe, frequent
identical to those in the CNS. Further, as the ENS has bidi- migraines were put on an elimination diet that consisted of
rectional communication with the brain, anxiety or stress one meat (lamb or chicken), one carbohydrate (rice or
can alter gut bacteria or altered bacteria can result in stress or potato), one fruit (banana or apple), one vegetable, water, and
anxiety. This confirms the central sensitization pathophysio- vitamin supplements for 3–4  weeks. Children who did not
logical framework of life experience + psychological response improve were given a second elimination diet. On both diets,
+ physiology that underlies the basis of chronic pain. Analysis 88.6% recovered completely. Fifty-five foods provoked
of the gut microbiome has identified patterns of altered gut migraines. The most common were milk, egg, chocolate,
flora in patients with chronic pain conditions that also orange and wheat. Other causes of migraines may be amines,
include complex regional pain syndrome, chronic fatigue nitrates, histamine, monosodium glutamate and artificial
syndrome, restless leg syndrome and comorbid conditions of sweeteners [96, 97].
anxiety, depression and obesity [77–79]. Trigger foods can only be identified if eliminated and
Diet can detract from or enrich the diversity of the then reintroduced. Although time consuming, individual-
microbiome. In general, a varied, fibrous whole-foods-rich ized approaches where patients keep meticulous food jour-
diet that includes fruits, vegetables, nuts, quality protein, nals (with symptoms) is an invaluable tool that helps patients
whole grains (if non-reactive), healthy fats that include understand the effect of food on their pain. Nutritional defi-
omega-3 fatty acids, fermented foods and sufficient hydra- ciencies linked with migraines and other forms of chronic
tion, and is tailored to the individual goes far in restoring pain include vitamin D, magnesium, vitamins B2, B6, B12,
and maintaining health. Additional nutritional tools that folic acid, COQ10 and alpha lipoic acid. (see Nutrients).
can therapeutically increase gut health are prebiotics and
probiotics [79, 80]. Detractors may be refined sugars, pro- 28.1.1.13  Oral Function
cessed foods and hydrogenated vegetable oils/transgut Affecting 7% of the population, oral facial pain (OFP) has a
microbiome fats, additives, preservatives, artificial sweeten- direct and reciprocal effect on nutritional status with risk for
ers and high fructose corn syrup, in addition to multitude of malnutrition. Due to decrease in function and chewing abil-
other lifestyle factors that include alcohol, smoking, NSAIDs, ity, common dietary advice suggests altered consistencies.
antibiotics, acid blockers, other pharmaceuticals, chronic However, simply recommending a soft diet may further con-
stress, cesarean sections and widespread use of antiseptics tribute to deficiencies and malnutrition [98]. Offering cus-
and sanitizers [80–85]. tomized dietary guidance based on an individual’s challenges
Thus, disruption of the gut microbiome does not only that may include protein (powders), antioxidant (fruit and
cause local distress but can affect other biological systems. vegetables), omega-3 and fiber rich (nuts, flax seeds) smooth-
Chronic pain patients may also present without traditional ies will potentially ensure maintenance of nutritional status,
symptoms of gastrointestinal (GI) distress, leading clinicians if not improvement in the pain condition.
to potentially miss an integral piece. For example, it is esti-
mated that 57% of those with neurological dysfunction of 28.1.1.14  Nutrition Assessment
unknown cause have gluten sensitivity [86]. In addition, 20 As the first step, a complete nutritional assessment and inter-
fibromyalgia patients, 17 of which had IBS and 8 with view of the chronic pain sufferer is crucial and improves out-
migraines, all testing negative for celiac disease, went on a comes and patient satisfaction [99]. All systems need to be
gluten-free diet for at least 6  months. All 20 participants reviewed and should include a comprehensive diet history,
reported dramatic improvement in widespread chronic pain, current intake, nutrition-focused physical findings and func-
with 15 indicating they were pain-free [87]. tional labs. An integrative assessment includes current and
past medical and social health history, current work, stress-
28.1.1.12  Food Sensitivities ors, role of exercise, sleep quality, relationships, current
Food sensitivities also play a direct role in migraine head- familial support and spiritual practice. It is a “how are you?”
aches, the second most common pain condition and one of as opposed to “where is your pain?” Many chronic pain
the most prevalent pain disorders in the world. Overlapping patients arrive angry, depressed, hopeless and have experi-
many other pain conditions, migraines have genetic, hor- enced losses in work and life that had previously given them
monal, immune, environmental and potentially mitochon- meaning and purpose. Because of chronic pain’s pervasive
drial influences and are usually activated in response to a effect on the psychological and social aspects of life, listening,
trigger [88, 89]. Overlooked causes include dehydration [90], understanding and giving attention to the pain patient’s story
altered oral and gut microbiome [91], celiac disease [92], glu- is the goal and builds trust [100]. Due to the multifactorial
ten sensitivity, hypothyroid [93] or hyperinsulinemia [94]. nature of pain, a thorough, thoughtful and compassionate
As the most well-known trigger, food’s association with patient-centered assessment cannot be understated. Patient
migraines has been studied for over a century. Much research participation, investment and co-creation of goals is an inte-
follows similar patterns to the 1930 study which resulted in gral part of the relationship and is also necessary for a p
­ ositive
 454 J. S. Griffith

outcome. Asking open-ended questions and motivational culture. The intervention may be as individual as the biology
interviewing is an optimal approach [101]. As caring for the and biography of the patient in which it resides.
chronic pain patient can be challenging, the health of the cli- The Elimination Diet is universally accepted as the stan-
nician must also be a priority. Introducing a more healthful dard for identifying and eliminating potential food intoler-
diet is easier and more acceptable if the clinician can speak to ances and is a frequent beginning diet. Although there are
its benefits from personal experience. There are myriad many versions, suspect foods are eliminated from the diet
assessment tools that measure pain intensity, its effect on for a certain period, usually 3–12 weeks, followed by a rein-
function, mood and specific types of sensation. As men- troduction and food challenge phase [104, 105]. After the
28 tioned, there are many secondary factors and pain comor- set period of elimination, foods are brought in one at a time,
bidities including mental health, which encourages an every 4 days, eating the food often. Accounting for 90% of
interdisciplinary team approach. Although reduction of pain all food reactions, the top eight allergens are milk, eggs, pea-
is clearly a goal, the overall objective is to increase wellbeing nuts, nuts, wheat/gluten, soy, fish and shellfish [106]. Foods
and function. that are eaten most often that patients “cannot live without”
are usually the most problematic. Many start out eliminat-
28.1.1.15   unctional Labs to Assess
F ing refined sugar, dairy, wheat and processed foods.
Nutritional Status Removing these foods potentially translates to less activa-
Deciding what testing is needed for a patient is an art, a skill tion of innate immune pathways, less inflammation and less
and different for each individual. Tests cannot reveal every- pain perception.
thing, and they should not be solely relied upon, but together Celiac disease testing is recommended for pain patients
with interviews and questionnaires, they can help uncover due to the many non GI manifestations of the disease, but
integral pieces of the puzzle to create a treatment plan to gluten-free diets have been used successfully without having
optimize health. As many chronic illnesses begin in the gut, a celiac diagnosis. Migraines, fibromyalgia, different forms of
GI tests are often used. Below is a suggested list representa- arthritis, IBS, chronic musculoskeletal pain and various
tive of baseline laboratory testing that is tailored to the indi- ­idiopathic and identified neuropathies have been substan-
vidual patient: tially improved on gluten-free diets [ 86, 87, 107]. There are
55 Organic acids test ongoing trials to study gluten’s effects on low back pain [108].
55 Comprehensive stool testing If the root cause of pain is chronic inflammation, the anti-­
55 Immunologic: Food allergy/sensitivity/intolerance inflammatory diet (AID) is a reasonable option. Considered
testing to be the hallmark of integrative pain management, the AID
55 Glucose tolerance tests is followed by many without chronic pain or illness, as it
55 Candida antibody tests complements a healthy lifestyle. There are several versions,
55 SIBO tests but the concepts are similar and strictness can be adjusted.
55 Methylation testing The AID emphasizes high amounts of fruits and vegetables,
55 Hormone testing whole grains, legumes, soy, fish, herbs and spices. Each
55 Vitamin D status dietary component addresses potential inflammatory mark-
55 Nutrient status testing ers that influence pain. High intake of antioxidants replete
55 Amino acid testing with vitamins and minerals modulate inflammatory cyto-
kines, C-reactive protein production and temper damaging
oxidative stress. In particular, evidence exists that removal of
28.1.1.16  Therapeutic Diets free radicals—nitric oxide, superoxide, and peroxynitrite—
As most pain patients view their situation as hopeless, diet can prevent and reverse inflammatory pain, neuropathic
can be a powerful and potentially transformative interven- pain, morphine-induced hyperalgesia, and tolerance [14]. In
tion [102]. Most research involving food and a certain dis- the British Cohort study, low intake of fruits and vegetables
ease state focuses on one isolated nutrient. The power of contributed to chronic widespread pain [109]. Soy foods may
food, however, comes from its synergistic effect: a naturally be beneficial in neuropathic pain and osteoarthritis [109,
coordinated and complex array of phytochemicals and nutri- 110]. Broccoli, grapes, fish oil, ginger, green tea and tomatoes
ents combined, not only with other foods of high biological were found to reduce inflammation and pain [111]. Inclusion
value, but how it interacts with the biology, genetics and of fish and fish oil supplementation maximizes the omega-3
biography of each individual. A shift in the patient’s dietary anti-inflammatory prostaglandins, while mitigating the com-
pattern brings the most lasting change. Although much of peting omega-6 arachidonic cascade that is highly influential
the research linking dietary patterns and chronic pain has in modulating pain. (see . Fig.  28.4). A personalized anti-­
 

focused on different forms of arthritis [103], as outlined inflammatory diet can reduce the prevalence of many of the
below, many diets have been successful in improving quality chronic conditions associated with pain including diabetes,
of life and ameliorating pain, at times, to resolution. Further, obesity and autoimmune disease.
as the etiology of pain is steeped in bio-individuality, the The Mediterranean diet, a mainstay in the nutrition world,
dietary intervention should follow suit, and be tailored to the is also recommended to pain patients and has been success-
individual, including personal preferences, traditions and ful in those with RA [110–112]. Similar to the anti-­
Chronic Pain
455 28

n-6 Fatty acids n-3 Fatty acids

(sunflower, safflower, corn, (flaxseed, walnut, hemp, chia seed)
soybean, cottonseed, canola)

Linoleic acid Alpha linolenic acid

(LA) (ALA)
----6-desaturase----

Gamma-Linoleic acid Stearidonic acid

(GLA)
----Elongase---

Dihomo-gamma-linoleic acid
(DGLA) Eicosatetraenoic acid
---5-desaturase--

Arachidonic acid COX Eicosapentaenoic acid

(AA) 5-LOX (EPA)

Pro-inflammatory Docosapentaenoic acid

Prostaglandins (PG2) Anti-inflammatory
Thromboxanes (LTB4) Prostaglandins(PG3)
Leukotrienes (TXA) Thromboxanes(TXA3)
Leukotrienes(LTB5) Docosahexaenoic acid DHA)
Fish oil, marine algae

..      Fig. 28.4  Inflammatory Pathways of Essential Fatty Acids. (Courtesy of Jena Savadsky Griffith, RDN, IHC)

inflammatory diet, it is plant-heavy and features fruits, has yet to catch up with all who have successfully adopted
vegetables, whole grains, fish, less meat, legumes, nuts, olive AIP. While the scientific literature analyzing the efficacy of a
oil, red wine and exercise. When more attention is given to a paleo diet is small, it is unanimous [114]. In a 2017 study of 70
healthful eating plan, general health will improve, pain not- postmenopausal women who submitted to a paleo versus a
withstanding. prudent diet (low-fat, low-­calorie, low-salt), both groups lost
Based on the principle of the evolution discordance the- weight, but those on the paleo diet had greater reduction in
ory, genetic adaptation has not been able to adjust to our diet inflammatory markers [115]. Type 2 diabetes patients follow-
since the appearance of agriculture 10,000  years ago, and, ing a paleo diet versus the diet suggested by the American
more importantly, since the industrial revolution. Accordingly, Diabetes foundation (low fat dairy, whole grains, legumes)
food processing has altered these dietary indicators: (1) glyce- showed significantly greater glucose control and lipid profile
mic load, (2) fatty acid composition, (3) macronutrient com- [116]. Diagnosed with MS and confined to a wheelchair, Dr.
position, (4) micronutrient density, (5) acid-base balance, Terry Wahls began researching brain and mitochondrial
(6)  sodium/potassium ratio, and (7) fiber content [38]. health, adopted a version of the AIP, added supplements, life-
Considering we remain similar to Paleolithic ancestors, the style changes and ended her chronic pain, fatigue and
principle of the Paleo Autoimmune Protocol (AIP) follows that migraines. Her continued clinical trials repeating her process
their dietary pattern should still be relevant. Based on the have been successful and have large implications for chronic
work of Boyd Eaton, the paleo diet includes vegetables, fruits, pain conditions [117]. Critics of the diet suggest it has inade-
nuts, roots, meat and organ meats and excludes dairy, grains, quate calcium supply and maintain that digestive abilities
sugar, processed oils, alcohol and coffee [113]. Although open today are different than Paleolithic humans [118].
to interpretation, the AIP is generally an austere version of the Vegan, vegetarian and FODMAP (fermentable oligo-,
diet, retaining only the most nutrient dense foods while di-, monosaccharides and polyols) diets have also shown
excluding anything potentially inflammatory to even the efficacy in chronic pain conditions [119, 120]. Fasting is
smallest subset of people. In the age of information, research practiced worldwide for cultural, religious and health
 456 J. S. Griffith

r­easons. There is ample empirical and observational evi- mum level may be on a continuum well above or even below
dence that medically supervised therapeutic fasting from 7 the RDA [129] (See . Table 28.1).
 

to 21  days confers benefits for rheumatic diseases and For their role in scavenging reactive oxidant species and
chronic pain syndrome [121]. After a 7-day juice fast in an suppressing inflammation, antioxidant power is the back-
integrative medicine clinic, 952 patients with various bone of a healthy diet, for those with pain and without.
chronic pain syndromes significantly decreased their pain Further, concentrated nutrients that complement a healthy
and improved quality of life [122]. Observational data and antioxidant, fiber-rich diet can increase efficacy of dietary
experimental research also support caloric restriction, nutrition intervention and further mitigate risks of medica-
28 intermittent fasting and a ketogenic diet [123]. Fasting tions. Due to the nature of scientific research and the study of
mechanisms include increased ­production of neurotrophic nutrients in isolation, several supplements have been found
factors, reduced oxidative mitochondrial stress, autophagy to dramatically decrease the intensity of pain and increase
and neuroendocrine activation [124]. function. With any neuropathy, it is recommended that clini-
The nightshade vegetables and oxalate-containing foods cians check for “nutritional neuropathies” or those due to
may also be implicated in chronic pain. From the Solanaceae deficiency of specific nutrients, including thiamine, vitamin
family, the nightshades include more than 2000 species, but B12, vitamin E, vitamin B6, niacin, and copper and following
most notably, tomatoes, potatoes, eggplant, peppers of all bariatric surgery [130].
kinds and tobacco. Mostly linked with arthritis, the night- Bio-individuality is foundational for supplementation.
shades contain specific alkaloids—solanine in potato and Sufficiency for one patient may be deficiency or toxicity for
eggplant, tomatine in tomato, nicotine in tobacco and capsa- another. Patient involvement, testing, tracking, individual
icin in garden peppers—that inhibits neurotransmitter preferences, current state of microbiota, absorption, excre-
enzyme, cholinesterase. When these alkaloids accumulate in tion, skin color, age, other medical conditions, and medica-
the body, with help from other cholinesterase inhibitors such tions all factor in to finding the optimal diet and nutrients in
as caffeine, the result may be a paralytic-like muscle spasm, order to move toward reducing pain and restoring function.
aches, pains, tenderness, inflammation and stiff body move-
ments. Two surveys of arthritis patients adhering strictly to 28.1.1.18   mega-3 Essential Fatty Acids
O
the “no nightshade” diet reported 72–94% had complete or (See . Fig. 28.4)
 

substantial relief from the diet [125]. Due to their established role in inflammatory pathways, and
Foods high in oxalate may also cause inflammation and therefore pain control, long chain omega-3 (n-3) polyunsat-
pain. Oxalate is found primarily in plant foods, with highest urated fatty acids (PUFAs) are popular in pain management
amounts in spinach, rhubarb, almonds and yams. Ordinarily, and one of the most effective natural anti-inflammatory
oxalate is routinely metabolized, minimally absorbed and agents available. Higher levels of n-3s that include DHA,
excreted. However, compromised gut health causes oxalates EPA, and vegetable-sourced ALA are associated with lower
to bind with calcium and form crystals that can lodge not levels of inflammatory mediators, anti-nociception, and
only in the kidneys, but within body tissues causing pain. greater emotional/cognitive functioning. Competing
Excess oxalate also leads to oxidative damage and depletion omega-6 (n-6) PUFAs are associated with inflammation,
of glutathione [126, 127]. The connection of pain and high nociception and greater psychological distress [131].
oxalates is the basis for the Pain Project where participants ­Additionally, when EPA and DHA are metabolized by cyclo-
have gotten relief from fibromyalgia, vulvodynia, interstitial oxygenase and lipoxygenase, they are converted into power-
cystitis and pelvic floor dysfunction after following a low ful resolvins and protectins that cause inflammatory recovery
oxalate diet [128]. While restoring gut health is of primary and suppression. Although both are essential, ratios of
concern, experimenting with the elimination of these foods n-6:n-3 have increased substantially over and above the rec-
may be a next step if other therapeutic diets are not yielding ommended 3:1 to about 20:1 or higher, causing greater
expected results. inflammation within cell membranes and a biochemical sus-
ceptibility to excitotoxicity, cell damage, central sensitivity
and chronic pain [132]. Omega-3s alleviated chronic non-­
28.1.1.17  Nutrients and Supplementation surgical back and neck pain after taking 1200–2400 mg for
in Pain Management 8  weeks, with 59% discontinuing their use of prescription
Correcting deficiencies and alleviating inflammation are at NSAIDs [133]. Similar results were found for RA with 2.7 g/
the core of most evidence-based supplementation for chronic day for 3 months [134], and after a dietary intervention of
pain. Supplementation of high doses is often used, but impor- high n- 3s and, importantly, a low intake of n- 6s, chronic
tantly, use of supplements has significant advantages and is headache sufferers reduced headache pain, altered antinoci-
universally preferred as the side effects are drastically reduced ceptive lipid mediators, and improved quality of life [135].
versus pain pharmacotherapy. Changing little over the last Although the mechanism is hypothesized, animal studies
40  years, micronutrient recommended dietary allowances have found n- 3s to be protective and alleviate neuropathic
(RDAs) are population statistics, represent rough estimates pain, post-traumatic brain injury, stroke, ALS, diabetes,
and are, to some extent, arbitrary figures. Therefore, the opti- lupus and other neuroinflammatory conditions [136]. Five
Chronic Pain
457 28

..      Table 28.1  Summary of dietary supplements used in the treatment of chronic pain

Nutrient/supple- Pain states Known action Suggested Considerations

ment/functional dosage
food

Omega-3 All Anti-inflammatory 2.7 g/day EPA Anticoagulant properties

and DHA

Omega-6, borage/ Anti-inflammatory, 500–1800 mg/

EPO anti-thrombotic day

Cod liver oil All Immunity, inflammation, 1 tsp/day

(A,D,omega-3) bone health

Vitamin D All Immunity, inflammation, Level dependent Personalization, with A, K2,

bone health 1000–2000 iu/ magnesium
day

Magnesium All Inflammatory mediator, 400 mg/day or Cofactors B6 and boron

muscle function, energy more
production, immunity

Vitamin B1/thiamine FM, alcoholic neuropathy Mitochondrial function 600–1800 mg/

day

Vitamin B2/riboflavin Headaches Mitochondrial function 400 mg/day

Vitamin B12 Back, neck, neuropathy, Neuroprotection, 1000 mcg/day Cofactor folate
neuralgia regeneration

Bee pollen Anti-inflammatory, ½–1 tsp. Begin slowly to ascertain

antioxidant, rich nutrient tolerance/allergy
profile including B
complex

Quercetin RA, inflammatory pain, Antioxidant, anti-­ 500–1000 mg/ Often formulated with
allergy headache, gout, inflammatory, analgesic, day Bromelain, Contraindicated for
spinal cord injury antihistamine kidney disease

Turmeric Arthritis, JP, FM, IBS, DN, Anti-oxidant, anti-­ Average of Anticoagulant properties
PMS, gout inflammatory, analgesic, 400–600 mg/3×/
anti-arthritic day

Ginger RA, OA, migraine, JP, Anti-inflammatory 200–500 mg/day

dysmenorrhea

Boswellia RA, OA, dysmenorrhea Anti-inflammatory, 300–500 mg/2–

analgesic 3×/day

Willowbark Headache, back, myalgia, Anti-inflammatory, 240 mg Not for use with children, peptic
RA, OA, dysmenorrhea, analgesic ulcers or any condition where
gout aspirin is contraindicated

Butterbur Migraine/headache Anti-inflammatory, 50–150 mg/day, Extracted to remove hepato-

antispasmodic age dependent toxic alkaloids

Feverfew Migraines, RA, dysmenor- Anti-inflammatory, inhibit 6.25 mg 3×/day. Not with anticoagulants or
rhea platelet aggregation (CO2 extracted) during pregnancy

FM Fibromyalgia, JP Joint pain, RA Rheumatoid Arthritis, OA Osteoarthritis

patients with chronic pain resulting from burns, spinal ste- lower need for omega-3s. Quality sourcing of all essential
nosis, carpal tunnel syndrome, fibromyalgia, and cervical fatty acids and understanding the potential for interaction
disc herniation were given 2400–7200 mg of EPA/DHA for with other anticoagulants (herbal and pharmaceutical) is
at least 7 months, with all reporting significant pain reduc- important in clinical application.
tion [137]. Fish oil also appears to attenuate the negative cel- Discovered in 2008, unsaturated fatty acid palmitoleic
lular and behavioral effects of opioids [138]. A lower dietary acid, or Omega-7, has also been found to have potential anti-­
intake of omega-6 fatty acids, however, will necessitate a inflammatory effects on metabolic diseases and muscle pain.
 458 J. S. Griffith

Potentially controlled by mTOR (mechanistic target of Testing should be done every 3 months. Vitamin D status
rapamycin) signaling, it is found in macadamia nuts, sea is most often measured by storage 25(OH)D in the blood.
buckthorn oil, olive oil and in certain fish, such as salmon The US lab reference is 30–74 ng/mL, while the Vitamin D
and anchovy [139]. Council recommends 40–80  ng/mL.  However, based on a
review of more than 1000 studies, the IOM recommends a
28.1.1.19  Omega 6 Fatty Acids more conservative range of 20–50 ng/mL, citing little to no
While omega-3s understandably receive all of the anti-­ benefit over 50 and increasing evidence that high levels cause
inflammatory notoriety, omega-6 fatty acids are in fact, essen- harm. According to these definitions, the entire population
28 tial and offer their own, often overshadowed, benefits for may be deficient, and in fact, low OH (25) levels are found in
chronic pain and inflammation. Gamma linolenic acid (GLA) both sick and healthy individuals. Therefore, a re-evaluation
specifically, has proven anti-inflammatory benefits. Found in of this method of measurement is needed, as it does not con-
plentiful amounts in our food supply, linoleic acid (LA) from sider the active form of vitamin D, the relationship between
seed oils (sunflower, soy, corn) is the starting point for the storage and active D, metabolic factors affecting its conver-
synthesis of omega 6, mirroring the processes of omega 3, sion (inflammation, infection, current mineral and nutri-
using the same or similar enzymes to form arachidonic acid: tional status), genetics and other matters of bio-individuality.
LA → (GLA) → dihomo-gamma-linolenic acid (DGLA) In order for a nutrient, vitamin or mineral to become
→ arachidonic acid (AA) (See . Fig. 28.4).
  metabolically active, it often needs cofactors [143]. The
DGLA is anti-inflammatory and anti-thrombotic and metabolism of storage or pre-formed D, 25(OH)D (calcidiol)
counteracts the inflammatory actions of AA.  However, at every stage—in the skin, liver and kidney—into its active
DGLA must be synthesized in the pathway from LA and form 1,25(OH)2 (calcitriol) requires sufficient magnesium.
GLA with all enzymes functioning, specifically, delta-6-­ In a state of hypomagnesemia, calcium is usually high. As
desaturase, which naturally decreases with aging. If the con- Vitamin D absorbs intestinal calcium for use, with ample cal-
version process is compromised, AA, in oversupply from the cium, vitamin D may remain low. While magnesium has its
diet, flourishes, creating greater inflammation. Regarding own cofactors, attention should also be given to sodium and
chronic pain states, this reduced capacity to create DGLA has potassium to balance electrolytes. Further, vitamin A is D’s
been associated with rheumatoid arthritis, diabetes and asso- biological antagonist. For vitamin D to be effective, sufficient,
ciated neuropathy, dermatitis/eczema, premenstrual syn- fat-soluble, vitamin A is needed; thus, vitamin A and vitamin
drome, obesity, cancer and cardiovascular disease. D protect against the other’s toxicity [144].
Recent studies also suggest that A and D also need vita-
28.1.1.20  Vitamin D/Vitamin A min K2, found in animal fats and fermented foods. Vitamin
Extensive research concludes a worldwide deficiency of vita- K2 ensures that calcium is appropriately transported to bones
min D, from 40% to 75% of the population, greater in the and teeth rather than to the soft tissues, contributing to dis-
northern hemisphere and in those with pain. Known for its ease. The many roles of vitamin D in the maintenance of
most direct role in osteomineral metabolism, vitamin D is health is a subject of continuing research. Whether low vita-
more recently known for its contribution to immunity min D is a physiological response or cause of disease has yet
strength, cell growth, neuromuscular function and inhibition to be absolutely confirmed. In an integrative and functional
of inflammation [140, 141]. With vitamin D receptors in vir- setting, it is important to investigate the potential root cause
tually every cell, it may be responsible for regulating more before artificially raising vitamin D levels with supplementa-
than 200 genes and has potential influence on multiple bio- tion.
logic systems of the body. It is also considered a neuroactive
steroid that may modulate neuronal excitability. Some 28.1.1.21  Magnesium
research shows indirect support for a role for vitamin D in Magnesium plays an essential role in hundreds of physiologi-
nonspecific musculoskeletal pain, central sensitization cal processes and is critical to the electrical stability of cells.
(migraines and fibromyalgia), abdominal pain, knee pain, As it relates to pain, magnesium is instrumental in blocking
back pain and various pain comorbidities [142]. Although the NMDA receptor, whose excessive stimulation is the pri-
several studies have shown vitamin D supplementation to mary mechanism of central sensitization. Low magnesium
improve sleep, mood, pain levels and well-being, there is also enables excess substance P response, which triggers the
inconclusive evidence to implicate vitamin D deficiency in entire inflammatory cascade [145]. Magnesium deficiency
the etiology or maintenance of chronic pain or that supple- should be considered a public health crisis with some experts
mentation alone will confer alleviation [142]. The most effi- estimating current magnesium deficiency of the population
cient source of vitamin D is the sun. Small amounts of as high as 80%. It quietly contributes to the process of inflam-
vitamin D are found in several foods, including fatty fish, egg mation and pain, therefore implicating all chronic disease
yolks, yogurt and mushrooms. The highest amount of food- and pain comorbidities including insulin resistance, obesity,
sourced vitamin D is in cod liver oil at 450 iu/tsp and is often depression, anxiety and insomnia. Magnesium is central in
used, as it has a complementary amount of vitamin energy production, bone health, and muscle relaxation with
A. Pastured butter or ghee are additional sources of K [143]. deficiencies leading to cramping, spasms, myofascial tight-
If supplementation is used, vitamin D3 is the preferred form. ness, and tightness in the smooth muscles of the GI tract.
Chronic Pain
459 28
Supplementation significantly alleviated pain in patients with should be assessed, as neuropathy can be the result of depleted
migraines, fibromyalgia, neuropathic pain, chronic low back thiamine. Riboflavin, vitamin B2, addresses the potential
pain, IBS, diabetic neuropathy and postherpetic neuralgia cause of migraines as aberrant mitochondrial metabolism.
[146–151]. Correcting magnesium deficiencies can poten- Daily use of 400  mg of B2 for 3  months resulted in a 50%
tially correct both the symptom and cause of chronic pain. reduction in headaches for the majority of patients [154].
With most magnesium stored in bone and soft tissue (99%) Due to its integral role in neurological function and
and the remaining under tight control, testing serum magne- myelin integrity, vitamin B12 (methylcobalamin or hydroxy-
sium is inefficient and deficiency often goes unnoticed. A cobalamin or adenosylcobalamin,) has been used for decades
preferred test would be a Mag RBC test (magnesium red to treat pain. In other countries it has been labeled as an anal-
blood cell). Although not without its limitations, assessing gesic drug. Through supposed neuroprotective and regenera-
RBC magnesium inside the cell as opposed to serum outside tive actions, B12 administered orally and via injection has
the cell will provide an earlier indicator of magnesium defi- been successfully used to decrease pain in chronic low back
ciency. An increase in refined foods, greater environmental pain, neck pain, diabetic or chemo-induced neuropathy and
and emotional stress, inflammation, infection, excess cal- various forms of neuralgia [155]. Pain may be alleviated even
cium, excess vitamin D, depleted soil mineralization, and with adequate levels of B12. Vitamin B12 supplementation of
drug interactions account for many of the contributing fac- 1000 mcg, combined with a plant- based diet, improved pain
tors for deficiency. Cofactors include vitamin B6 and boron in diabetic neuropathy patients compared to just supplemen-
for absorption and proper utilization. Magnesium needs and tation alone [156].
levels fluctuate, depending on absorption, stress levels and A deficiency of B12 is linked to inadequate folate. Proper
myriad other factors with many deficiency symptoms functioning of the folate cycle ensures formation of neu-
included in a pain sufferer’s profile: anxiety, insomnia, rotransmitters, the pain signal messengers. As a critical
depression, fatigue, constipation, hypertension, muscle cofactor for B12, inadequate folate can mask B12 deficiency;
cramping, headaches, etc. As magnesium is a critical, water-­ therefore, giving isolated folate without B12 is contraindi-
soluble electrolyte needed daily, attention should also be cated. A sublingual dose of B12 at 1000 mcg is helpful. B12
given to the balance of sodium, chloride and potassium. may improve pain, insomnia and fatigue [157]. Assuming no
Including mineral-rich sea salt and food sources of potas- genetic polymorphisms (MTHFR), taking a full range of B
sium (virtually all fruits and vegetables) is required to keep vitamins in combination may also be beneficial than one in
minerals regulated and/or from one mineral depleting the isolation. Vitamins B1, B6 and B12  in combination with
other. Dietary sources of magnesium include greens—one of other medical therapy alleviated pain and increased mobility
the most missing foods in the modern diet—as well as nuts, in those with back pain [158].
seeds, and whole grains. Supplementation in the form of gly- As the body does not store water-soluble B vitamins well,
cinate, malate, taurate, or threonate, 200–400 mg or higher, the need for them may be increased for the chronic pain
may be best for chronic pain sufferers; however, magnesium population. Liver, poultry, shellfish and eggs have high
form may need to be personalized and started slowly. No less amounts of B vitamins, especially B12. Plant sources include
important is magnesium in oil form applied topically and whole grains, potatoes, lentils and beans. Leafy greens are
Epsom salt baths. high in folate. An overlooked source of B-complex vitamins,
including B12, is bee pollen, one of the richest sources of
28.1.1.22  B Vitamins vitamins found in a single food in nature. If folate supple-
Essential for various metabolic processes, several B vitamin mentation is used, L-methylfolate or folinic acid is preferred.
deficiencies are implicated in chronic pain. Vitamin B6 is a Other nutrients studied for their effect in the manage-
cofactor for the enzyme reaction that converts excitatory ment of pain include coenzyme Q10, 5- HTP, glucosamine
neurotransmitter glutamate into inhibitory neurotransmit- and chondroitin, MSM, alpha lipoic acid, melatonin and res-
ter, GABA.  Without sufficient B6, there is more glutamate veratrol.
and less GABA, which fuels excitotoxicity in the CNS [145].
Without sufficient B6, blood homocysteine levels increase, 28.1.1.23  Essential Nutrients
contributing to inflammation and potential toxic effects on In a larger context, everything taken in, from food to oxygen
CNS neurons. Elevated homocysteine is one potential mech- to art, is essentially a nutrient, with its own specific energy.
anism for migraines [152]. Neuropathy due to B6 deficiency Experiences of life are absorbed in many ways that have
begins with numbness, paresthesias or burning pain in the physical, emotional and spiritual effects. Nutrients can be put
feet which then ascends to affect the legs and eventually the on a continuum from inflammatory to nourishment, depend-
hands. Although deficiencies are rare in the general popula- ing on individual, context and other known and unknown
tion, chronic pain patients with inflammation and higher variables. Other overlooked and underestimated nutrients
intake of NSAIDs will have disrupted B6 metabolism. Excess that increase pleasure, comfort, and joy while decreasing
B6 can also cause neuropathy [130]. pain that are evidence-based and empirically substantiated
Fibromyalgia may have symptoms in common with thia- include light, nature, music (“robustly relieves pain”), love,
mine deficiency; high doses of thiamine, 600–1800 mg/day, touch, community, dancing and laughter, hugging yourself
produced significant decreases in pain [153]. Alcohol intake and others, gratitude, and spiritual practice [159–167].
 460 J. S. Griffith

28.1.1.24  Hydration way [63, 174]. Turmeric contains at least six different
Thirst is our own odometer, a signal from the hypothalamus COX-2 inhibitors, the enzyme responsible for the inflam-
that our blood volume is too high. However, for many, the matory prostaglandin PG-E2, and may also deplete sub-
sense of thirst becomes dulled. It is especially an issue within stance P.  Studies indicate pain relief with turmeric in
the vulnerable pain populations of the elderly and children. arthritis, diabetic neuropathy, gout, joint pain, IBS, PMS
Among children and adolescents, water accounted for only and fibromyalgia, in addition to positive influences on
33% of fluid intake, with the remaining coming from high-­ obesity, diabetes and depression [175, 176]. Curcumin
calorie beverages [168]. As an underappreciated disease eti- was equal to and advantageous to ibuprofen in a 4 week
28 ology, dehydration causes decreases in cognition and GI study of OA of the knee [177]. The most comprehensive
function, headaches, muscle and joint pain. Recently, even summary of turmeric benefits concluded that it outper-
mild dehydration was found to increase pain sensitivity and forms many pharmaceuticals against chronic and debili-
pain perception [169]. Water provides lubrication for tissues, tating diseases with virtually no adverse side effects [178].
cartilage, discs and joints. Without water, there is slowed Results have been found with as little as 200 mg/day or up
nutrient transportation, a buildup of metabolic waste and to 8 g with an average dosage of 400–600 mg three times
increased inflammation. Increased water intake reduced gout per day. In addition to capsule form, it can be added to
attacks by almost 50% [170]. There are several recommenda- food, taken as tea, and heated and made into a turmeric
tions for water intake including the standard six to eight milk. Bioperine (black pepper) increases the bioavailabil-
glasses or half the individual body weight in ounces, with ity of curcumin by up to 2000% [179]. Turmeric’s antico-
needs fluctuating depending on activity, season, temperature, agulant properties should be considered.
and energy intake.
In addition, many of the fluids commonly consumed 28.1.2.2  Ginger (Zingiber officinale)
today are diuretics—soft drinks, alcohol, tea and coffee. The Ginger is one of the most consumed dietary condiments and
most widely consumed legal drug in the world, coffee, is a a member of the same plant family as turmeric
CNS stimulant that is more of a cultural habit, than a hot (Zingiberaceae). It has been used alone and in combination
beverage. Coffee as a recommendation for pain relief is con- with other herbs for thousands of years for its antioxidant
troversial. Although the mechanism is unknown, caffeine is anti-­inflammatory properties. Ginger is effective in treating
said to potentially reduce pain through its effect on adenos- pain of RA, OA, migraine (in combination with feverfew),
ine receptors [171]. Conversely, caffeine triggers a stress joint pain and dysmenorrhea. Historically used for OA and
response and causes various alterations in brain chemistry RA, ginger inhibits several inflammatory mediators, most
including neurotransmitter imbalances (serotonin, dopa- notably enzymes 5-lipoxygenase and COX-2. Dosages range
mine, GABA) that lead to irritability, mood issues, depres- from 200 to 500 mg daily [180, 181].
sion, headaches, insomnia and fatigue. It decreases melatonin
[172] and can affect nutritional status by increasing insulin 28.1.2.3  Boswellia
resistance, depleting vitamin B6 and inhibiting absorption of Considered one of the most ancient and valued herbs in
magnesium, B vitamins calcium, iron and vitamin D [173]. Ayurveda, gum resin is tapped from the boswellia tree then
Although it is considered an antioxidant, there are individual dried to extract the oil and solidify the resin. The resin has
sensitivities and varied genetic traits related to caffeine various terpenes and four major boswellic acids responsible
metabolism. Considering its range of parallel effects in the for the inhibition of pro-inflammatory enzymes. The most
chronic pain population (sleep, anxiety, glucose control, potent is acetyl-11-keto-β-boswellic acid (AKBA) that spe-
dehydration), assessing function and pain without coffee/caf- cifically inhibits leukotrienes via 5-Lipoxygenase (5-LOX), a
feine would be recommended. major inflammatory enzyme [182].
Boswellia has been used analgesically for RA, OA and
dysmenorrhea. Pain from knee OA was reduced notably
28.1.2  Plant Compounds within 7 days, and there were significant improvements seen
after 90 days of using boswellia standardized to contain 30%
28.1.2.1  Turmeric (Curcuma longa) AKBA. Beyond its analgesic effects, patients had unexpected
A long history of use in Ayurvedic medicine and extensive joint regeneration, assigning disease modification benefits
research over the past half century has confirmed that [183]. Often taken with other herbs, a combination of
turmeric, with active ingredient curcumin (77%), has anti- boswellia and curcumin proved superior in effectiveness and
oxidant, anti-plaque, anti-arthritic, anti-cancer and anti- tolerability compared to diclofenac for OA [63]. A later OA
inflammatory properties. In Sanskrit, turmeric is credited study proved similar results versus 200  mg celecoxib (cele-
with 53 names, most likely due to its various mechanisms; brex) with a combination capsule of 700 mg curcumin and
however, research indicates that blocking the activation of 300  mg boswellia extract. Boswellia products vary, but it is
NF-kB, the body’s central inflammatory switch, along typically given as an extract standardized to contain 30–40%
with other inflammatory mediators, may be its main path- boswellic acids, 300–500 mg two or three times/day [63].
Chronic Pain
461 28
28.1.2.4  Willowbark the topic [190]. Cannabis or medical marijuana is one of the
Dating back to the time of Hippocrates, patients were advised most pharmacologically active plants known, with more than
to chew on willow bark for pain and fever [184]. It is often 400 chemical compounds, 85 of which are cannabinoids. The
called “nature’s aspirin” because the active ingredient of wil- main cannabinoids by volume and notoriety are delta-9-tetra-
low bark is salicin, used to develop aspirin in the 1800s. Its hydrocannabinol (THC), its primary psychoactive compound
analgesic and anti-inflammatory properties, however, come and cannabidiol (CBD), the non-­psychoactive counterpoint
from salicin’s combination with flavonoids and polyphenols [191]. Among its many properties, THC is a potent antioxi-
within the bark. Although both are nonselective COX-1 and dant, neuroprotective, anti-inflammatory and painkiller.
COX-2 inhibitors, its multicomponent synergy gives willow Influencing many pathways, THC inhibits glutamate release, a
bark a broader mechanism of action than aspirin, without central mechanism in most chronic pain conditions. CBD
the GI damage. People have used the herb for headache, low dampens THC’s psychoactivity and elevates the plant’s potency
back pain, myalgia, OA, RA, dysmenorrhea and gout. Patients with its own complex anti-inflammatory and analgesic regu-
with low back pain receiving 240 mg of willow bark had more lating effects. Possessing 20 times the antioxidant power of
significant relief than those receiving 120  mg or placebo vitamin C and E, CBD notably inhibits TNFα. The study of
[185]. Willow bark should not be used in children, in those cannabinoids led to the discovery of the endocannabinoid sys-
with peptic ulcers or any other condition where aspirin is tem, a group of endogenous cannabinoid receptors, CB1 and
contraindicated [63]. CB2, throughout the CNS and PNS that regulate homeostasis
and have a significant role in the ­regulation of pain. Much like
28.1.2.5  Butterbur and Feverfew the bicarbonate buffer system regulates blood pH, the endo-
Headaches are one of the most common types of chronic cannabinoid system reacts to the environment and mediates
pain reported by Americans. After magnesium, both butter- response to mood, sleep, hormone regulation, pain and
bur and feverfew, respectively, are commonly used in head- immunity [191, 192]. Notably, dietary omega-3 fatty acids
ache treatment and prevention, separately and in reverse the dysregulation of the endocannabinoid system,
combination. Butterbur, Petasites hybridus root extract, is improve insulin sensitivity and control body fat [66].
thought to inhibit inflammatory leukotriene production and Current pain conditions may be a potential endocannabi-
have a potential antispasmodic effect on cerebral blood vessel noid deficiency. Although current research is hindered by its
walls [186]. Migraine frequency was reduced by 48% in those schedule one status by the US Drug Enforcement
who took 75 mg of petasites BID [187]. Almost 80% of chil- Administration, studies confirm that cannabis alleviates
dren and adolescents reported a reduction in migraine fre- chronic pain conditions, neuropathic pain, headache, and
quency of 50% by taking 50–150 mg/day, depending on age, untreatable pain, often with relief from stress/anxiety and
for 4  months [188]. Butterbur has hepatotoxic alkaloids so insomnia, with minimal, if any side effects [193, 194]. Adverse
the extract must be manufactured carefully to remove them. effects are more often reported with synthetic versions [195].
Called medieval aspirin, the parthenolides within the Further, in 2014, the American Academy of Neurology pro-
leaves of feverfew are thought to be its active ingredient and vided a level A effectiveness to oral cannabis extract for spas-
mechanistic driver. These compounds may relieve migraines, ticity related symptoms and pain [196]. Cannabinoids are
RA and menstrual pain by inhibiting inflammation and delivered via smoking, vaporizers, sprays, tinctures and edi-
platelet aggregation, which normalizes blood flow. Feverfew bles. Medical marijuana is currently legal in 33 states and
contains many medicinally active compounds including Washington, D.C., with only a few states approving treatment
melatonin and an essential oil, chrysanthenyl acetate. Some specifically for chronic, severe or intractable pain [197].
evidence shows lack of efficacy which is thought to be due to Interest in medicinal potential of CBD has catalyzed a
varying plants and bioavailability, extracts used and dosage rebirth of hemp in the USA and CBD hemp oil. Often con-
[186, 189]. Feverfew is not recommended during pregnancy fused, hemp and cannabis come from the same species,
or with anticoagulants. If taking for more than 1 week, stop- Cannabis sativa; however, hemp contains only trace amounts
ping abruptly could produce rebound headaches and/or joint of THC.  In order to be legal, it must have a THC content
pain. Studies have used 100–325 mg up to four times daily for below 0.03%. There are varying hemp laws by state and much
adults, standardized to contain 0.2–0.4% parthenolides. For is imported [192, 198]. Securing its non-psychotropic status,
feverfew supplements that are carbon dioxide extracted, it is considered a less controversial alternative while still
6.25  mg, 3 times daily, for up to 16  weeks was successfully maintaining the plant’s benefits. Animal studies show CBD-­
used [189]. induced suppression of chronic pain without tolerance.
Researchers suggest these non-psychoactive components of
28.1.2.6  Cannabinoids cannabis may represent a novel class of therapeutic agents for
Despite political, legal and social issues surrounding its use the treatment of chronic pain [199]. Usual methods of deliv-
and history, the addition of cannabinoids to the clinician’s ery for CBD hemp oil include tincture and capsule form.
toolbox offers another approach and is evidential in chronic Standards range; therefore attention must be given to a
pain. Further, surveys report that due to lack of education and ­product’s cultivation, harvest, extraction, exact constituents,
resources about cannabinoids, clinicians often do not bring up testing, and manufacturing.
 462 J. S. Griffith

28.1.2.7  Medical Treatment and Nutritional including gastritis, abdominal pain, ulceration, edema, hem-
Implications orrhage, renal impairment, hypertension and death. This was
A thorough physical, functional and psychological examina- the stimulus for the creation of such selective COX-2 NSAIDs
tion with detailed pain, medical and psychosocial history is as celecoxib (celebrex). However, more recently, all NSAIDs
vitally important to guide diagnosis and treatment. and in particular, COX-2, were found to increase risks for
Additional testing is usually done to categorize the pain, heart attack and stroke [204]. After 14 days, Ibuprofen was
determine its etiology and consider emotional and environ- found to reduce testosterone production in males with impli-
mental factors. There is not one diagnostic test for chronic cations for fertility, muscle mass and strength, fat distribu-
28 pain and, although helpful in certain cases, imaging does not tion and mental health. Recommendations are to prescribe
always reveal a specific pathology or problem. Despite pain lowest possible doses for shortest duration. To mitigate GI
as one of the most universal symptoms in medicine, the damage from NSAIDs, many patients are given proton pump
assessment of a pain patient is challenging and takes time not inhibitors (PPIs). Usually given for gastrointestinal reflux
often available. As pain is a subjective experience unable to (GERD), PPIs are among the top ten most widely used drugs
be viewed by others, the evaluation of pain characteristics in the world with many patients remaining on them for long
relies on self-­reporting. Its complexity has further led to periods of time, without evidence-based indication [205].
varying pain measurement scales and questionnaires that However, these medications do not offer protection to the
attempt to capture the patient, the pain and contributing and lower small intestine, but exacerbate NSAID-induced small
relieving factors. There are one-dimensional tools that that intestinal lesions and increase the presence of pathogenic
measure pain intensity, as in the Verbal Rating Scale (VRS), bacteria in the gut microbiome. The initial microbiotic insult
Numerical Rating Scale, Visual Analogue Scale (VAS) and from NSAID use decreases beneficial lactobacilli and impairs
Faces Pain Scale, which is helpful with children. More com- intestinal pH, permeability, mucosal production and immu-
plex tools, such as the McGill Pain Questionnaire, distinguish nity [206]. Following PPI treatment, there is an additional
nociceptive from neuropathic pain and attempt to decipher loss of beneficial and protective bacteria Bifidobacterium and
the pain dimension: sensory, affective and/or evaluative. Lactobacillus. Further, PPIs are associated with a deficiency
Additional tools exist to assess function, substance abuse, of vitamin B12, iron, vitamin C, calcium, and magnesium
opioid risk, emotional distress, potential for catastrophizing [14, 204–207].
and pain-­related fear and depression [200–203]. Due to the gastrotoxicity of NSAIDs, and PPIs when
As complete analgesia is rarely achievable, the goal of applicable, acetaminophen is recommended by the American
medical treatment is to improve pain, and more importantly College of Rheumatology for mild-to-moderate pain as first
to optimize physical function and coping. One in three line therapy for OA of the knee and hip and lower back pain
patients will get greater than 50% pain relief, which is [208]. For its safety profile over NSAIDs, acetaminophen is
regarded as an excellent result in chronic pain [200]. Pain also recommended for the elderly population [209].
medications fall into three general categories: Although too mild for most for most chronic pain patients
1. Non-opioids: aspirin, non-steroidal anti-­inflammatories and lacking in anti-inflammatory properties, it may have a
(NSAIDs), and acetaminophen (paracetamol). sparing effect when taken with NSAIDs and opioids. Care
2. Opioids: morphine, codeine, hydrocodone, oxycodone, should be taken regarding the potential hepatotoxicity of
methadone, fentanyl, etc. Although not true opioids acetaminophen and its interaction with high doses of vita-
biochemically, Tramadol and tapentadol are included as min C [210].
they work on the same receptors. Opiates are the mainstay of pain management for severe
3. Non-opioid or adjuvant analgesics: Medications that may chronic pain. While opiates stem specifically from the alka-
alleviate pain, although primary use is for another loids of the poppy plant (heroin, morphine, codeine), opioids
indication: antidepressants, anticonvulsants and are synthetic drugs that produce opiate-like effects and
antiarrhythmics, corticosteroids, muscle relaxants, local include oxycodone, Percocet, Demerol and methadone.
anesthetics, topical medications, adrenergic agonists, Clinically, the term “opioid” now encompasses all natural
sympatholytics, and neuroleptics. and synthetic versions that act upon opioid receptors in the
CNS, PNS, and immune system. The opioid system consists
The use of NSAIDs remains a first line of defense for most of three G-protein coupled receptors, Mu, Delta and Kappa,
classic physicians for mild to moderate joint, spine-related usually activated by endogenous opioid peptides like endor-
pain and headaches. Besides their well-known inhibition of phins. Individual drugs interact with each receptor, account-
prostaglandin synthesis via both COX-1 and COX-2 ing for the differences in analgesia and various side effects;
enzymes, their mechanism of action in producing analgesia however, the majority of activity occurs on the Mu receptor.
is multifactorial, exhibiting both central and peripheral Opioids are often called Mu agonists. The net effect of Mu
effects [63]. By blocking COX-1, which also normally acts to receptor activation is inhibition of pain signal transmission
protect the gastrointestinal mucosa, nonselective NSAIDs to the brain and a decrease in the perception and experience
and aspirin can cause significant GI and other tissue damage of pain [11, 211].
Chronic Pain
463 28
Opioid receptors are also involved in other functions of examining pain behavior in female twins, genetic factors
the body, including modulation of reinforcement and reward could account for 22–55% of the variance in chronic pain
mechanisms, which can sometimes drive the addictive pat- [218]. Although in early stages of research, various genes
tern of use. Results of activation also include the most com- encoding for receptors are now known to play a role in pain
mon side effects of constipation, respiratory depression, sensitivity, reporting and susceptibility. Overall, the genetic
itching, sedation and nausea. With rates ranging from 15% to contribution to chronic pain suggests small variations in a
90%, mitigating opioid-induced constipation is an important large number of single nucleotide polymorphisms (SNPs)
aspect of the management of a patient’s quality of life. that may represent different functional pathways [219, 220].
Increasing fiber, fluids, and activity is recommended, with One of the most extensively studied “pain genes” is catechol-­
fiber intake occurring several hours before or after taking the O-­methyltransferase (COMT), an enzyme involved in the
drug so as not to interfere with bioavailability [11]. inactivation of dopamine, epinephrine, and norepinephrine
Other side effects can be altered mood and cognitive (catecholamines) neurotransmission [221]. Sustained eleva-
function, dry mouth, urinary retention, sexual dysfunction, tion of catecholamines, released from the adrenal glands in
sleep disturbances, dizziness, hypotension and myoclonus response to stress or severe pain, is associated with chronic
(muscle twitching) [11]. Due to adverse side effects, approxi- pain conditions. Several single nucleotide polymorphisms
mately 20% discontinue therapy [212]. Often unrecognized, (SNPs) of the gene that encodes COMT have been found to
long-term opioid use also causes hormone suppression. lower its activity, thereby increasing pain sensitivity. SNPs in
Opioids action on receptor sites can lead to inhibitory or the Mu opioid receptor gene, OPRM1, may contribute to
stimulatory effects on hormone release. Testosterone appears individual differences in pain sensitivity. Further, mutations
to be most often affected, leading to decreased libido and in OPRM1 and COMT combined may modulate opioid
erectile dysfunction in men, oligomenorrhea or amenorrhea ­efficacy [222].
in women, and bone loss or infertility in both sexes [213]. There are several genes that affect neurotransmitters.
Frequently misunderstood, tolerance and dependence SNPs of the GCH1 gene (encoding GTP cyclohydrolase) has
are normal physiological responses to opioids. A more been shown to have a protective effect on lower back pain
recently recognized opioid toxicity is induced hyperalgesia after surgery, less sensitivity to heat, ischemic and pressure
(OIH), where increasing the dose of the opioid exacerbates pain and reduced incidence of low back pain. Polymorphisms
the pain [214]. of the serotonin transporter gene (SLC6A4), beta 2 adrener-
While accepted for cancer-related pain, the use of opioids gic receptor ADRB2, and serotonin receptor 2A HTR2A are
for chronic pain has been controversial due to concerns all associated with an increased risk for chronic widespread
about side effects, long-term efficacy, functional outcomes, pain. Alterations in pain-related genes associated with ion
and the potential for drug abuse and addiction. These con- channel function may also contribute to chronic pain suscep-
cerns have often led to the undertreatment of pain patients. tibility as found in sciatica, OA, phantom limb pain and dis-
Heeding criticism, physicians began prescribing more pain cogenic disease. Called the neuropathic pain susceptibility
medications in the 1990s with the support from many profes- gene, CACNG2, a protein involved in the transport of gluta-
sional pain societies. In response to the growing prevalence matergic AMPA receptors, significantly affects susceptibility
of chronic pain and its disabling effects, opioid prescriptions following nerve injury [221].
have increased to the point that they are the most commonly Although not related directly to pain signaling, genetic
prescribed class of medications in the USA, with pharmacies mutations in enzymes involved in the folate methylation
dispensing 245 million prescriptions in 2014. The rate of pathway may be a factor in the pain population. Two com-
death from opioid overdose has quadrupled in the past mon SNPs, C677T and A1298C have been identified in the
15  years and nonfatal overdoses needing hospital care MTHFR gene that codes for the methylenetetrahydrofolate
increased six times [215, 216]. While many opioids are reductase enzyme, also MTHFR.  Mutations in this gene
diverted and improperly used, at the core of what is now cause decreased activity of the enzyme, thereby disrupting
called an opioid crisis is an increasing cohort of those in methylation and blocking key detoxification pathways [220].
chronic pain, overreliance on a known analgesic, and limited
alternatives for prescribing physicians [11, 217]. 28.1.2.9  Epigenetics
When pain cannot be controlled with medications and In an experimental study of healthy adults, pain intensity rat-
central sensitization cannot be prevented, there are various ings ranged from 0 to 100 (bottom and top of the scale) for an
interventional pain procedures that can be used. These identical cold-water stimulus [222]. As experienced by each
include nerve blocks, injections, ablative procedures, individual differently, the concepts of environment and bio-­
implants and neuromodulation. individuality are embedded within the definition of pain.
Environmental toxins, medications, diet, and psychological
28.1.2.8  Genetics stresses can alter epigenetic processes such as DNA methyla-
Genetics also has a role in the biopsychosocial matrix of an tion, histone acetylation, and RNA interference [223].
individual’s perception and response to pain. Heritability can Epigenetic mechanisms modify DNA expression depending
be explored across pain disease states or by the pain signaling on information received from the environment. Early life
process, adding another layer of complexity to its study. By experiences can positively or negatively leave their biological
 464 J. S. Griffith

mark on the genome. Negative childhood experiences have ment and is the basis for its recent characterization as a
been linked to mental health, drug addiction and obesity, all lifestyle disease. A cycle of fear, avoidance and catastrophiz-
mediating factors in chronic pain and treatment [224]. There ing leads to inactivity and physical deconditioning. In addi-
are also learned coping strategies and behaviors, learned tion, study of the mesolimbic reward system reports that
reactions to pain and attention received as the result of pain voluntary—as opposed to forced—exercise shows even
at all ages. Familial patterns, lifestyle and diet are more of an greater analgesic effects [230].
epigenetic factor than genetic, and have a profound influence Although the majority of low back pain (90%) resolves on
on susceptibility to disease. After nerve injury, more than its own in 3  months, it is often difficult to treat due to the
28 1000 genes may be activated or turned on with significant psychosocial nature of its cause and is the most prevalent
evidence pointing to epigenetic control from, at minimum, chronic pain condition [231]. With medical treatment often
inflammation, immune response and opioid receptor func- focusing on pain control instead of restoring function, modi-
tion. What turns the acute pain into chronic is the biological fiable lifestyle factors appear to make a difference and are
terrain and environment it occurs within [225]. studied often with this condition. Tai chi is an effective inter-
As an active mediator of inflammation, immunity and the vention regarding movement and posture in OA, low back
microbiome, nutrition has significant epigenetic power. pain, and fibromyalgia [232]. In a review of low back pain
Nutrients can influence gene expression by directly inhibit- sufferers, yoga was found to have positive and significant
ing enzymes that catalyze DNA methylation or histone mod- effects on function and pain. Co-creating gradual exercise or
ifications or by altering the availability of substrates necessary movement intervention that is tailored to the interests, needs,
for those enzyme reactions. Many of the components of an abilities and fears of an individual will better prevent attrition
anti-inflammatory diet have positive epigenetic effects. and increase function, quality of life and recovery.
Sulforaphanes like broccoli, Brussels sprouts and cabbage are Contributing to its elusive treatment, low back pain is
known to increase histone acetylation. Butyrate, or butyric also linked to anxiety, depression, job dissatisfaction, poor
acid, is a short chain fatty acid found most prominently in body image and somatization. Lack of support, in relation-
butter, but also created by fermentation of dietary fiber in the ships, family or work environments can lead to a perception
intestines. It is a favored source of fuel for the colon, contrib- of greater individual burden that can manifest physically. In
utes to a healthy gut microbiome and increases histone acety- addition to the physical demands of work, perceived lack of
lation [226]. Methyl donor nutrients include folate, vitamin support from supervisors and lack of encouraging culture in
B12, methionine, choline and betaine. Foods rich in folate the work unit are associated with an increased risk of intense
include leafy green vegetables and citrus fruits. Sources of low back pain and low back pain-related sick leaves [233].
vitamin B12 are fish, meat and eggs. Choline is oxidized to Stress is linked to pain in multiple causative and conse-
form betaine, found in high concentration in beef liver, eggs quential ways. In most chronic pain conditions, there is an
and toasted wheat germ. The anti-inflammatory actions of ongoing reactivation of the stress response from pain or
vitamin D may be accredited to DNA methylation and his- other stressors, that exhausts cortisol and the HPA axis, con-
tone modifications. Plant compounds curcumin and resvera- tributing to and/or causing pain and inflammation. Adding
trol, with known analgesic effects, have been found to insult to the initial injury or event, the depletion of cortisol
positively alter epigenetic mechanisms [227]. increases inflammation and creates vulnerability to patho-
gens, greater psychological stress and pain. Mind-body
28.1.2.10  Lifestyle approaches that include progressive muscle relaxation, medi-
As discussed, psychological, social and environmental fac- tation, laughter, mindfulness-based approaches, hypnosis,
tors including activity, obesity, support, sleep and stress are guided imagery, yoga, biofeedback, and cognitive behavioral
foundational in the chronification of pain. Elevated BMI, therapy have all shown efficacy in chronic pain [234].
past and current smoking and higher unemployment rate The typical chronic pain patient has a heavy toxic burden
were associated with chronic pain in the 1958 British Cohort that may include medications, decreased absorption, dis-
study. The study further concluded that chronic pain is a turbed sleep and increased stress that compound and/or cre-
cause of unhealthy diet and lifestyles rather than a conse- ate conditions that take an acute injury and turn it into
quence [109]. Increased risk for chronic low back pain is also chronic pain. There are clear opportunities for clinicians to
linked to weight gain and increased alcohol intake [228]. The facilitate changes in lifestyle that have the potential to
musculoskeletal overload and systemic inflammation of obe- improve function, decrease inflammatory burden and create
sity are significant contributors to the prevalence and severity conditions for patients to flourish. As neuronal plasticity can
of chronic pain. Exercise confers far-reaching, well-known cause central sensitization and chronic pain, diet and lifestyle
beneficial effects including weight loss, lower inflammation changes can potentially decrease inflammation, desensitize
and free radical reduction. Further, in the pain population, the nervous system and reduce chronic pain.
movement increases mental health, normalizes dysfunc-
tional brain connectivity found in central sensitization, 28.1.2.11  Language of Pain
increases GABA production and reduces pain perception As mentioned, in the premiere definition of pain, it is
[229]. Fear of movement (FOM) has been increasingly recog- described as a “negative experience.” Further, all descriptive
nized as a significant explanation for chronic pain develop- language for pain is in the context of weaponry and damage
Chronic Pain
465 28
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a disability, a disorder and now a disease. If pain can only be apy with lifestyle: the role of personalized nutrition and nutritional
supplements according to the SIMPAR feed your destiny approach.
negative, it can produce only negative effects and nothing J Pain Res. 2016;9:1179–89. Available at: https://www.­ncbi.­nlm.­nih.­
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an inherent obstacle to recovery from pain conditions. As an 15. Garland EL. Pain processing in the human nervous system: a selec-
integrative and functional medicine approach shifted its tive review of nociceptive and biobehavioral pathways. Prim Care.
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16. Benzon HT, Raja SN, Spencer LS, et al. Essentials of pain medicine.
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change as well. If pain could be viewed as an invitation, a 17. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain
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 473 29

Nutrition and Behavioral
Health/Mental Health/
Neurological Health
Ruth Leyse Wallace

29.1 Introduction – 474

29.1.1 S pectrums of Psychiatric Disorders – 474
29.1.2 Serious Mental Illness and Genetics – 474
29.1.3 Depression – 475
29.1.4 Bipolar Disorder – 475
29.1.5 Schizophrenia – 476

29.2  ther Conditions: Conditions that May Be Accompanied

O
by Changes in Mental Status – 477
29.2.1  rain-Derived Neurotropic Factor (BDNF) – 477
B
29.2.2 Celiac Disease – 477
29.2.3 Metabolic Syndrome – 477
29.2.4 Hyponatremia/Water Intoxication – 477
29.2.5 Caffeine Intoxication – 477
29.2.6 Food Insecurity – 477

29.3  he Effect of Micro- and Macronutrients on Mental/

T
Behavioral/Neurological Health – 478
29.3.1 L ipids, Glucose, Amino Acids – 478
29.3.2 Vitamins and Minerals – 479
29.3.3 Minerals – 483
29.3.4 Potentially Toxic Minerals – 486

29.4 Drugs: Nutrition and Mental Status – 486

29.5 Summary Statement – 487

References – 488

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_29
 474 R. Leyse Wallace

29.1 Introduction
Mania
The brain, nerves, neurotransmitters, and genes are constantly
impacted by numerous micro- and macronutrients. Gene
activity may be turned off or on by a vitamin or mineral;
nerves and cell membranes are built of essential fatty acids;
amino acids are the building blocks of neurotransmitters.
Brain structure is 80% lipid, and current evidence and theory
indicate, in contrast to the traditional view, that ketones also
Uni-
play vital roles as metabolic and signaling mediators, even BDI BDII
polar
Cyclo-
thymia
Dys-
thymia
N

29 when glucose is abundant [1]. It is known that brain, blood, Depression

and cell content reflects the nutrient intake from the diet or
supplements. There are communication pathways from brain
to gut and gut to brain [2]. How could mental processes not be
affected by nutritional status? [3] The question asked by nutri- ..      Fig. 29.1  Mood disorder spectrum. (Adapted with permission from
tionists, molecular biologists, psychiatrists, geneticists, and Nemeroff [11]). BDI Bipolar Disorder I and II, N Normal
other scientists is: “How?” Exactly how do nutrients affect
these processes, individually or acting together? In the past, the Autism Spectrum encompassed the
The answers are not all in. Some studies focus on mood, diagnoses of autism, Asperger Syndrome, Pervasive
which does not necessarily translate into clinical outcomes; Developmental Disorder Not Otherwise Specified, and
epidemiological and tissue studies, meanwhile, struggle to Childhood Disintegrative Disorder. The DSM-5 combined
disentangle the respective roles of nutrients in the body or these into one category: “Autism Spectrum Disorder.”
brain [4]. Despite these challenges, we understand the con- Features of these disorders include social deficits and
nection between nutrition and mental health more now than communication difficulties, stereotyped or repetitive
in the past. The Nutrition Care Process, more than ever, behaviors and interests, sensory issues, and in some cases,
needs to include assessment of nutritional factors that are cognitive delays [12]. (See also 7 Chap. 30 for Intellectual
 

influencing mental status. and Developmental Disorders).

In 2006 a poll of 1000 Americans indicated that more The spectrum of psychotic disorders includes schizo-
Americans feared loss of their mental capacity (62%) than phrenia, schizoaffective disorder, delusional disorder, schizo-
feared loss of their physical capacity (29%) [5]. In 2014, there typal personality disorder, schizophreniform disorder, and
were an estimated 9.8 million adults aged 18 or older in the brief psychotic disorder, as well as psychosis associated with
United States with serious mental illness (SMI)—4.2% of all substance use or medical conditions [13].
US adults [6]. There were an estimated 43.6 million adults in This chapter will provide in-depth discussion of the
the United States with any mental illness (AMI) in the past effect of nutrients on mental status and the major psychiat-
year—18.1% of all US adults [7]. The Surgeon General’s ric diagnoses of depression, bipolar disorder, and schizo-
Report of 1999 states that mental illness is the second leading phrenia.
cause of disability and premature mortality, comparable to
heart disease and cancer [8–10].
29.1.2 Serious Mental Illness and Genetics

29.1.1 Spectrums of Psychiatric Disorders Schizophrenia, bipolar disorder, and severe depression have
been shown to be genetically linked. A recent study deter-
With respect to mental status and functioning, the human mined that one of two genes code for the cellular mechanism
condition is wide-ranging and variable through time for each for regulating the flow of calcium into neurons. Variation in
individual. If functioning varies in certain ways, or to such a one of these genes, CACNA1C, is known to impact brain
degree that it disproportionately affects function and rela- activity involved in emotion, thinking, attention, and mem-
tionships, it may be diagnosed and treated to improve the ory—functions disrupted in mental illnesses [14].
quality of life of the individual. The ranges and degrees of An earlier study found a gene common to all three; it
differentiation of conditions may be expressed in a spectrum appears to influence which symptoms occur [15]. This genetic
or continuum. abnormality results in removal of eicosapentaenoic acid (EPA),
Mood disorders are a group of conditions that vary in docosahexaenoic acid (DHA), arachadonic acid (AA), and
severity and direction of the emotional states (. Fig.  29.1).
  gamma linolenic acid (GLA) from phospholipid structure. An
Each disorder has certain criteria for diagnosis. This spec- intake ratio of 3 EPA:1 DHA is advantageous for treatment.
trum differs from the Spectrum for Psychotic Disorders and This decreases the overactivity of one of the phospholipase
the Autism Spectrum. enzymes that breaks down phospholipids’ structures.
Nutrition and Behavioral Health/Mental Health/Neurological Health
475 29

..      Table 29.1  Selected genes, interventions, and mental health

Gene Effect Potential nutrition intervention Link to mental health

ACE Produces an enzyme to help Assess and advise re recommended Individuals on lithium need to maintain
regulate the body’s response to sodium intake consistent Na intake.
sodium intake. People with certain Assess fluid intake and interaction Polydipsia, water intoxication, and/or
variants are at greater risk for high between excessive fluid intake and Na hyponatremia has been noted in
blood pressure when eating lots of intake psychiatric populations
salt. 7 in 10 people are at risk

GLUT2 Helps regulate glucose, or sugar. Assess and advise re keeping % of kcal Psychotropic drugs may increase craving
People with certain variants prefer from low-nutrient sources. for sweets
sweet foods and drinks. 1 in 5 Assure adequate intake of Cr, Mg, and
people is at risk B-1, needed for CHO metabolism

CYP1A2 Gene variants result in slow or fast Assess and advise re caffeine intake. Caffeine may increase stimulation of
metabolism of caffeine. High residual caffeine increases risk of individuals in manic phase of bipolar
Heavy coffee drinkers who are having a heart disease, developing disorder.
slow caffeine metabolizers retain diabetes, and hypertension, already Patients with eating disorder may use
more of the stimulant in the body increased in individuals with mental caffeine beverages to manage food
health disorders intake

TPH2 Regulates serotonin synthesis and Assess vit D level: Goal ≥30 ng/dl Support serotonin synthesis and release/
Tryptophan release activation
hydroxylase
(Patrick and EPA, DHA intake Supplement: 2 g EPA “
Ames [16]) and 1 g DHA from fish oil

Exercise Promote tryptophan entry into the brain

In July 2015, Jonathan Flint found two genetic markers day). Baseline-to-endpoint EPA and DHA levels increased,
reproducibly linked to depression. One was unknown; one and depression symptom severity scores decreased, in both
was located next to a gene linked to energy production in low-dose and high-dose groups [20].
mitochondria (. Table 29.1) [17].
  A study of nutritional status in a group of depressed indi-
viduals showed intakes of vitamins A, B1, B2, B6, folate, C,
sodium, potassium, Mg, Ca, P, Fe, and Zn and fiber (p < 0.05)
29.1.3 Depression were lower in the depression group. Fasting blood glucose
levels, serum vitamins B12, and folic acid (p < 0.05) in the
Depression may present with a variety of non-specific symp- depression group were lower than controls. Meanwhile,
toms during a nutritional assessment—change in weight or median levels of body weight, waist circumference, hip cir-
appetite, fatigue, indecisiveness, or impaired concentration, cumference, and waist-to-hip ratio (p  <  0.05) were signifi-
as well as gastrointestinal symptoms and abdominal pain. cantly higher in the depression group. Serum insulin and
Partial and acute vitamin deprivation studies suggest that the Homeostatic Model Assessment (HOMA) levels of the two
earliest impairments occur in measures of mood rather than groups were similar [21].
mental performance [18]. Some researchers report the pres- Following a systematic search of PubMed, CINAHL,
ence of inflammation underlying depression. Polyunsaturated Cochrane Library, and Web of Science for clinical trials
fatty acids (PUFAs), folic acid, and probiotics are three sup- using adjunctive nutrients for depression, researchers con-
plements that target inflammation [19]. Evidence suggests a cluded current evidence supports adjunctive use of
dysregulation in serotonin neurotransmission is central to S-adenosylmethionine (SAMe), methylfolate, omega-3,
the pathophysiology and treatment of Major Depressive and vitamin D with antidepressants to reduce depressive
Disorder (MDD). symptoms [22].
Adolescents with Selective Serotonin Reuptake Inhibitor-
(SSRI)-resistant depression exhibited deficits in red blood
cell DHA compared with healthy adolescent controls, and it 29.1.4 Bipolar Disorder
was shown that supplementation with fish oil was effective
and well-tolerated. Two dose levels were compared: dose one Bipolar disorder (BD) is 80% heritable [23]. Folate-sensitive
was 2.4 g/day (EPA 1.6 g + DHA 0.8 g; 4 capsules/day) and fragile genetic sites were found to be more frequent in
dose two was 16.2 g/day (EPA, 10.8 g + DHA 5.4 g; 2 tbsp/ patients with BD than in controls [24]. Patients and relatives
 476 R. Leyse Wallace

had specific alterations in methylene tetrahydrofolate reduc- including schizoaffective disorder, delusional disorder, bipo-
tase (MTHFR) and were shown to have elevated homocyste- lar disorder with psychotic features, and depression with psy-
ine and be low in folate and vitamin B12 [25]. Normalizing chotic features. The DSM-5 terminology is “schizophrenia
these levels may decrease the symptoms of bipolar disorder. spectrum and other psychotic disorders” [35].
Altered metabolic end-products suggest that individuals Folate concentrations have been inversely related to the
with BD have metabolic differences in the metabolism of Scale for Assessment of Negative Symptoms total score [36].
PUFA when compared to control subjects. Patients with Negative symptoms associated with schizophrenia are social
bipolar disorder have lower intake of Se, EPA, DHA, AA, and isolation, lack of initiative, socially awkward behavior, and
DPA as determined using fasted plasma samples & 7-day diet discomfort when interacting with people. Positive symptoms
records [26]. A review of small trials reported that fish oil are psychosis, hallucinations, delusions, secondary agitation,
29 can enhance the effects of standard treatments for bipolar
disorder and yield improvement in their bipolar depression
and thought disorder. Cognitive symptoms, which include
memory, decision making, and problem solving, are a third
symptoms [27]. type of impairment [37].
Nierenberg et al. comment that data implicate mitochon- Studies show that phospholipids and essential fatty acids
drial dysfunction as an important component of the patho- are depleted in red cell membranes of schizophrenic patients
physiology of bipolar disorder. Biological processes that may compared with control subjects, particularly arachidonic
be dysregulated in BD are monoamine activity, immune and acid (AA) and DHA [38]. A healthy ratio decreases the over-
inflammatory processes, and oxidative stress [28]. Several tol- activity of a phospholipase enzyme and normalizes the
erable and readily available mitochondrial modulators (MM) removal of EPA, DHA, AA, and GLA from phospholipid
may be potential treatments, including N-acetyl-cysteine structure. Studies on the effect of diet and membrane changes
(NAC), acetyl-L-carnitine (ALCAR), (SAMe), coenzyme on tardive dyskinesia have had mixed results.
Q(10) (CoQ10), alpha-lipoic acid (ALA), creatine monohy- Another 4-week, double-blind study of patients experi-
drate (CM), and melatonin. Targets of treatment include encing an acute episode of schizophrenia or schizoffective
mitochondrial dysfunction, oxidative stress, altered brain disorder found that baseline levels of PUFA affected the
energy metabolism, and the dysregulation of multiple mito- response to supplements of ethyl-EPA, vitamin E and/or vita-
chondrial genes in patients with bipolar disorder. They con- min C, given in divided doses. Symptoms became worse in
clude that clinical trials of individual MMs as well as individuals with a low baseline level of PUFA after taking a
combinations are warranted [29]. supplement of either ethyl-EPA (500  mg) OR vitamins
Lithium salts have been in use for the treatment of bipolar (364  mg/day vitamin E or 1000  mg/day slow-release
disorder for more than 50 years. There is a narrow therapeutic vitamin  C). Use of the vitamin supplement increased the
range between effectiveness and toxicity for lithium treat- dose of medication needed for alleviating symptoms.
ment. Target lithium blood levels are generally 0.8– Symptoms that worsened included positive symptoms of sus-
1.1  mmol/L.  Levels above 1.5  meq/L may result in marked piciousness/persecution, delusions, hallucinations, paranoia,
tremor, nausea, diarrhea, or blurred vision. Levels above and hostility. Giving all three supplements neutralized this
2.0  meq/L have been associated with life-threatening side effect. These effects were not present in patients with a high
effects, such as neurotoxicity, delirium, and encephalopathy baseline level of PUFA. Low serum ɑ-tocopherol was the best
[30]. Reported cellular targets for Li (+) action involve Mg predictor of low PUFA baseline levels. A possible explanation
(2+)-activated enzymes, which are inhibited by Li(+) [31]. for this outcome is that, at high doses, vitamin E acts as a
Sodium intake affects renal clearance by 30–50%. A consis- pro-oxidant in an environment of insufficient antioxidant
tent intake of Na supports a stable blood level of the drug [32]. capacity. At low baseline levels, and only when not combined
Self-reported data from 348 patients in the United States with vitamins E & C, EPA increases RBC arachidonic acid,
diagnosed with bipolar disorder indicated the group had which increases positive symptoms (hallucinations, para-
tried over 40 different supplements, and the long-term users noia, delusions). Knowledge of baseline PUFA needs to inform
took 19 different supplements. The most commonly taken ­recommendations for supplements of vitamin C and E during
supplements for both groups were fish oil, B vitamins, mela- acute episodes of schizophrenia [39].
tonin, and multivitamins [33]. A comparison of diet histories of patients with schizo-
phrenia and a matched group from the Health and Nutrition
Examination Survey (NHANES) population led investigators
29.1.5 Schizophrenia to suggest that the higher proportion of obesity in the schizo-
phrenic group was related to factors such as medication side
In 2015 a proposal was made to drop the term “schizophre- effects and reduced physical activity rather than diet [40].
nia,” with its connotation of hopeless chronic brain disease, Another study of the intake of fatty acids and antioxidants
and replace it with a term like “psychosis spectrum syn- suggested that membrane changes may be caused by abnor-
drome.” Japan and South Korea have already abandoned this mal membrane phospholipid metabolism rather than intake.
term [34]. Past classifications did not acknowledge the conti- One explanation for the increased risk of obesity, meta-
nuity between schizophrenia and other psychotic disorders, bolic syndrome, and diabetes is fat storage; computed tomog-
Nutrition and Behavioral Health/Mental Health/Neurological Health
477 29
raphy showed that with equal total body fat and equal Weight-loss programs designed for those with mental ill-
subcutaneous fat, there was three times the amount of vis- ness have been successful [48]. The behavior change process
ceral fat stored by schizophrenic patients. The results of is facilitated through the use of self-monitoring, goal setting,
patients who were taking antipsychotics were no different and problem solving. Studies suggest that behavioral treat-
than those who were not. ment produces weight loss of 8–10% during the first 6 months
of treatment [49].

29.2  ther Conditions: Conditions that

O
May Be Accompanied by Changes 29.2.4 Hyponatremia/Water Intoxication
in Mental Status Psychotropic medications often increase dry mouth and
thirst, which may increase fluid intake. Water intoxication
29.2.1  rain-Derived Neurotropic Factor
B may lead to hyponatremia. Symptoms of water intoxication
(BDNF) in the early stages include nausea and vomiting, headache, or
changes in mental state such as confusion or disorientation.
Peripheral BDNF has been positively correlated with lifetime Low serum sodium (hyponatremia)  <  136  mEq/L is an
depression episodes, psychiatric hospitalizations, and sui- osmotic shift of water into brain cells causing edema in the
cide attempts. Brain-derived neurotropic factor (BDNF) has brain, caused by an excess of water relative to sodium. Signs
been proposed as a biomarker for bipolar disorder, individu- and symptoms of acute hyponatremia include headache,
als with BD having lower levels of BDNF than controls. The confusion, and stupor. More severe symptoms can also occur:
BDNF gene provides instructions for making a protein found muscle weakness, spasms, or cramps; seizures; unconscious-
in the brain and spinal cord. This protein promotes the sur- ness; coma. To prevent hyponatremia, avoid drinking more
vival of neurons during growth, maturation, differentiation, than 1 L of fluid per hour [50].
and plasticity. The BDNF protein is found in regions of the
brain that control eating, drinking, and body weight; it likely
contributes to the management of these functions. The nega-
29.2.5 Caffeine Intoxication
tive correlation between BDNF and number of mood epi-
sodes was moderated by impaired glucose metabolism [41].
Assessment for caffeine intoxication needs to include a
variety of potential sources: prescription and over-the-
counter medications, coffee, tea, soft drinks, caffeine shots,
29.2.2 Celiac Disease or chocolate. Signs and symptoms may involve (1) the cen-
tral nervous system (CNS): headache, lightheadedness,
Neurologic and psychiatric complications seen in gluten-­ anxiety, agitation, tremulousness, perioral and extremity
sensitive patients may be the primary presentation in patients tingling, confusion, psychosis, or seizures; (2) the gastroin-
suffering from this disease. Data suggests that up to 22% of testinal (GI) system: nausea and vomiting, abdominal pain,
patients with celiac disease (CD) develop neurologic or psy- diarrhea, bowel incontinence, or anorexia; or (3) the car-
chiatric dysfunction and as many as 57% of people with neu- diovascular system: palpitations or racing heart rate, or
rological dysfunction of unknown origin test positive for chest pain [51].
anti-gliadin antibodies [42]. Wang, Woo and Bahk [52] and others [53] have discussed
the possibility that caffeine could induce de novo psychotic
and manic symptoms as well as aggravate previous disorders.
29.2.3 Metabolic Syndrome Single doses of caffeine up to 200 mg (about 3 mg/kg for a
70-kg adult) are not a safety concern [54, 55].
The rate of metabolic syndrome was found to be higher in
individuals with bipolar disorder (33%) and schizophrenia
(47%) compared to matched NHANES controls (17% and 29.2.6 Food Insecurity
11%, respectively) [43]. Risk of metabolic syndrome was also
associated with higher depression scores and abdominal obe- Food-insufficient adolescents were significantly more likely
sity [44]. Nutrition care includes monitoring for indications to have had dysthymia, thoughts of death, and a desire to die
of the development of metabolic syndrome, and intervening and to have attempted suicide. Data from the NHANES III
to prevent long-term consequences of the syndrome [45, 46]. survey found that 5% of 15- and 16-year-old adolescents
(See also 7 Chap. 46.)
  reported they had attempted suicide, and 38.8% reported at
The combined effect of depression and metabolic symp- least one suicidal symptom [56, 57]. “Of all the top ten causes
toms was greater than the sum of the individual effects: An of death in the United States, only suicide is on the rise,” said
individual with both depression and metabolic risk factors is Charles Nemeroff, MD, at the Congressional Neuroscience
more than six times more likely to develop diabetes [47]. Caucus briefing on June 29, 2016 [10].
 478 R. Leyse Wallace

29.3  he Effect of Micro- and Macronutrients

T Use of EFA as an adjunct has allowed reduced doses of
on Mental/Behavioral/Neurological other medications and has reduced the relapse rate in bipolar
Health disorder [59].
Total normal brain and hippocampus volumes have been
Assessment vitamin, mineral, essential fatty acid, or amino directly associated with levels of omega-3 fatty acids in a
acid status is not common, and methods are not universally study of more than 1000 postmenopausal women [64].
accepted. These assessments are also an expense insurance After a review of evidence, essential fatty acids were
companies are not willing to support. However, it is clear that accepted in 2006 by the American Psychiatric Association
a deficiency of many nutrients will effect mental status and Committee on Research on Psychiatric Treatments, the
that the majority of Americans do not meet the 2015–2020 Council on Research, and the Joint Reference Committee of
29 guidelines for a healthy diet [58]. Less than 25% of Americans the American
option for
Psychiatric
depression.
Association
They concluded
(APA) as a treatment
that evidence of epi-
eat the recommended amounts of fruits, vegetables, or dairy
foods. Who knows how many Americans experience fatigue, demiologic and tissue compositional studies support a pro-
irritability, difficulty concentrating, altered cognition, anxi- tective effect of n-3 EFA intake for unipolar and bipolar
ety, low-grade inflammation, or other effects of poor nutri- depression. Bipolar disorder and major depression were
tional status? more influenced by supplementation than mild-to-moderate
depression. They also felt use of EPA and DHA appear to
have negligible risk. They concluded that the evidence for n-3
29.3.1 Lipids, Glucose, Amino Acids fatty acid’s protective effect for schizophrenia was less con-
clusive [65, 66]. The APA adopted the consensus recommen-
29.3.1.1  Essential Fatty Acids dations of the American Heart Association for an EPA + DHA
Substantial evidence implicates a dietary deficiency in long-­ dose of total 1 g/day in patients with MDD.
chain omega-3 (LCn-3) fatty acids, EPA and DHA, in the Controlled intervention studies have in general found
pathophysiology of psychiatric disorders, including MDD, that daily doses in the range of 0.2–2  g/day of EPA + DHA
bipolar disorder, schizophrenia, and attention deficit hyper- may be effective for the treatment of mood symptoms.
activity disorder (ADHD). A deficiency may coincide with, Emerging evidence also suggests that a larger ratio of EPA to
and may precede, the initial onset. Case–control studies have DHA may be more effective for treating symptoms of depres-
consistently observed low erythrocyte eicosapentaenoic acid sion. Edward Kane recommends a ratio of 4:1 LA:ALA (4
EPA and/or DHA levels in patients with these disorders [59]. parts n-6 [linoleic acid, or LA] to 1 part n-3 [a-linolenic acid,
Deficiency of essential fatty acids (EFA) has been linked to or ALA] [67]. The US Food and Drug Administration (FDA)
violence, hostility and aggression, and suicide [60]. consider LCn-3 fatty acids doses up to 3 g/day to be generally
It is wise to remember that research in these areas is com- regarded as safe.
plex and fairly recent. A 2015 Cochran Review of research on Use of fish oil and krill oil products, when matched for
the use of fatty acids for depression reports the quality of the dose and EPA + DHA content, yielded similar plasma and
evidence for all outcomes as low to very low. The number of RBC levels of EPA + DHA, indicating comparable bioavail-
studies and number of participants were low, and the majority ability irrespective of formulation [68].
of studies were judged to be at high risk of bias and also sug- Reference values for serum essential fatty acids and oth-
gested a likely bias toward a positive finding for n-3 PUFAs [61]. ers may be found at Mayo Clinic Medical Laboratories in
If n-3 fatty acids are replaced in the diet by n-6 fatty acids Rochester at 7  http://www. ­mayomedicallaboratories.­com/
the ratios in cell and brain tissues also change. Changes in test-catalog/Clinical+and+ Interpretive/82426 . The American
fatty acid content of cell membranes may increase vulnerabil- Medical Association current procedural terminology (CPT)
ity to depression. codes for blood fatty acid analysis by Gas Liquid
Messamore and McNamara report results that indicate Chromatography are (GLC) (82725, 82544, 82492), and
the majority (75%) of psychiatric patients exhibit whole-­ those for GLC testing in general are (82541, 82542).
blood EPA + DHA levels at ≤4% of total fatty acid composi-
tion. Twenty-five percent of the general population has this 29.3.1.2  Cholesterol
level of total fatty acids. Corrective treatment with fish oil-­ Cholesterol-reducing diets often reduce the n-3 fatty acids in
based products has resulted in improvements in psychiatric the diet and lower DHA, which is an essential part of the neu-
symptoms without notable side effects. This provides a ratio- ronal cell membranes. The brain synthesizes its own choles-
nale for screening for and treating omega-3 fatty acid defi- terol, and there is little correlation between blood levels
ciency in patients with psychiatric illness [59, 62]. of cholesterol and neurotransmitter function [69, 70].
Even a short course (2 weeks) of a nutritional supplement Exploratory correlations (but not planned statistical compari-
containing EPA has reduced the rates of new-onset depres- sons) of clinical variables revealed that mania severity and
sion to 10% [63]. In addition, both EPA and DHA delayed suicidality were positively correlated with UE:E EPA ratio
the onset of depression, and both treatments were well toler- (unesterified: esterified EPA), and that several plasma levels
ated, with no serious side effects. and ratios correlated with panic disorder and psychosis [71].
Nutrition and Behavioral Health/Mental Health/Neurological Health
479 29
Although there is controversy about cholesterol becom- brain. If undiagnosed or inadequately treated, it is likely to
ing too low, total blood cholesterol levels below normal/ proceed to Korsakoff ’s Syndrome. Wernicke-Korsakoff
desired levels have been linked to depression and suicide encephalopathy (WKE) has historically been associated with
[72], especially in the young and the elderly. Multivariate Cox alcoholism [85]; but it has more recently been recognized in
regressions predicting suicide, homicides, and accidents sug- patients who have anorexia nervosa, a history of bariatric
gested that three predictor variables were significant: low surgery, cancer [86], or who consume a diet of “empty calo-
total cholesterol, morbid depression, and anti-social person- ries” which result in a high calorie/thiamin ratio [87].
ality disorder. The interaction between low cholesterol and Thiamin diphosphate acts as a rate-limiting co-factor for
morbid depression (p  <  0.005) indicated individuals with a number of thiamin-dependent enzymes involved in the
both at baseline were ∼7 times more likely to die from exter- degradation of branched chain amino acids. Deficiency can
nal mortality. Patients presenting with low cholesterol and lead to exaggeration of emotional and stress reflexes, altered
morbid depression in clinical practice may warrant clinical mitochondrial activity, impaired oxidative metabolism, and
attention and surveillance [73]. In older (80-year-old) males, eventually selective neuronal death [88, 89]. Thiamin and its
total cholesterol levels of <160 mg/dL have been associated phosphate esters may regulate gene expression by influencing
with depression [74]. Women with non-medicated LDL lev- mRNA structure and in DNA repair [90]. Chronic alcohol-
els <100 were at increased risk of depression [75]. ism can impair the functions of gene mutations. Excessive
alcohol intake keeps SCL19A2 and SCL19A3 turned off [91].
29.3.1.3  Amino Acids
Amino acids are precursors of neurotransmitters Vitamin B2 (Riboflavin)
(. Table 29.2). The nine essential amino acids are histidine,
  An autosomal recessive disorder, Brown–Vialetto–Van Laere
isoleucine, leucine, lysine, methionine, phenylalanine, threo- Syndrome 2 (BVVLS2) is a progressive neurodegenerative dis-
nine, tryptophan, and valine. A non-protein amino acid, ease that is a consequence of severe riboflavin deficiency, related
homocysteine, can be produced from methionine or con- to disruption of riboflavin transporters. Treatment of a
verted into cysteine. Hyperhomocysteinemia is a risk factor 20-month-old female with BVVLS2 was initiated with 10 mg/
for brain atrophy, cognitive impairment, and dementia. kg/day dose of riboflavin and titrated up to 70 mg/kg/day over
Plasma concentrations of homocysteine can be lowered by 2  months. The child tolerated the riboflavin therapy well.
dietary intake of B vitamins. Symptoms began improving in a week with widespread improve-
ment in 2–3 months. No new symptoms were observed [92].
29.3.1.4  Carbohydrates: Glucose
Possible mental symptoms of hypoglycemia (<70  mg/dL) Vitamin B3 (Niacin)
include: changes in behavior or personality, irritability or A niacin deficiency, or decreased tryptophan (Trp) availabil-
nervousness, argumentativeness, and trouble concentrating. ity to the brain, has been linked to depression and anxiety
Signs and symptoms of hyperglycemia include fatigue, head- through a decrease in serotonin. Pellagra, the niacin-­
aches, constipation, diarrhea, and nerve damage. Fasting deficiency disease, is known by the “four Ds”: dermatitis,
hyperglycemia is defined as blood glucose higher than diarrhea, dementia, and death. Possible symptoms include
130 mg/dL after not eating or drinking for at least 8 hours. depression, anxiety, vertigo, memory loss, paranoia, psy-
Postprandial hyperglycemia is defined as blood glucose over chotic symptoms, and aggression [93].
180 mg/dL 2 hours after you eat [82]. Pellagra was present in 27% of patients who died during
hospitalization for alcohol dependence. It has been suggested
that niacin deficiency be included in the differential diagno-
29.3.2 Vitamins and Minerals sis of alcoholic withdrawal syndrome [94].

29.3.2.1  Vitamins Vitamin B6 (Pyridoxine)

Vitamins affect energy metabolism in all cells, the synthesis High total intakes of vitamins B6 and B12 are reported as
of neurotransmitters, the activation or inhibition of genes, protective against depressive symptoms over time. For every
the repair of DNA, and the function and atrophy of the brain 10  mg increase in the intake of vitamin B6 and for every
[83]. Below is information regarding the effects on mental 10 μg increase in vitamin B12 the risk of developing symp-
status of selected essential vitamins. toms of depression were decreased by 2% per year [95]. Low
concentrations of vitamin B6, but not of folate or homocyste-
Vitamin B1 (Thiamin) ine, have been associated with lower mini-mental state exam-
Thiamin deficiency often presents as changes in mental status ination (MMSE) scores and lower attention and executive
(alertness, attention, memory) and gait/mobility. Failure to function scores in a multivariate analysis [96].
suspect a vitamin deficiency can lead to permanent cognitive Beyond its role as a necessary cofactor in the folate cycle,
and physical disabilities that may necessitate lifelong care the role of vitamin B6 in amino acid metabolism makes it a
[84]. Wernicke’s encephalopathy is an acute neuropsychiatric rate-limiting cofactor in the synthesis of neurotransmitters
condition caused by an insufficient supply of thiamin to the such as dopamine, serotonin, γ-aminobutyric acid (GABA),
 29
480

..      Table 29.2  Amino acids and neurotransmitters

Neu- Related nutrients Effect on the brain Effect on mood Tissue secreting Other Food sources of neu-
rotrans- rotransmitter precursors
mitter

Sero- Tryptophan, with B6, Serotonin levels: Increased serotonin 80–90% is secreted by the Other amino acids, especially 1. Foods high in trypto-
R. Leyse Wallace

tonin—A B12, and folic acid   1. increase with levels: gastrointestinal tract; branched-chain amino acids phan: meats, milk,
mono- dietary carbohy-   1. improve mood; serotonin is synthesized by (leucine, isoleu-cine, and valine) yogurt, and eggs
amine drate;   2. increase pain the brain and neurons and compete with tryptophan to cross 2. Foods high in carbohy-
  2. increase with tolerance and secreted into synapses the blood/brain barrier; serotonin drates: grains, potatoes,
omega-3 fatty acids; sleep; between neurons synthesis is sensitive to the fruit, and milk
  3. decrease with   3. decrease aggres- availability of tryptophan from
high-protein diet sion and cravings meals [76]

Dopa- Tyrosine and phenyl-­ Tyrosine blood levels 1. Sufficient dopamine Produced in the brain and Stress depletes tyrosine from the 1. Sources of L-phenylala-
mine—A alanine; along with rise with a high-protein increases tolerance, released by the hypothala- blood nine: beef, poultry, pork,
mono- B-12, folic acid, diet; dopamine mood, alertness, mus fish, dairy products,
amine magnesium synthesis is insensitive cognition, and eggs, and soy products
to the availability of problem solving such as soybean flour
tyrosine from meals due 2. Dopamine depletion and tofu and almond
to activity of tyrosine results in blunted 2. The artificial sweetener
hydroxylase pleasure response, aspartame is also high in
clouded thinking, phenylalanine
lowered motivation, 3. Sources of tyrosine
and lowered include the following:
vigilance in patients oatmeal, soybeans, skim
with schizophrenia milk, beef, chicken,
[77] brown rice, and almonds
Norepi- Tyrosine with B12, folic Norepinephrine Low nor-epinephrine Norepinephrine is 1. Too much results in fear, Sources of tyrosine include
neph- acid, magnesium increases with a levels associated with synthesized and released depression, compulsivity, mood the following:
rine—A high-protein diet irritability, depression, by neurons in the brain and swings, mania, and addiction oatmeal, soybeans, skim
mono- moodiness central nervous system and 2. Too little results in depression milk, beef, chicken, brown
amine also by the sympathetic and paranoia rice, and almonds
ganglia located near the
spinal cord or in the
abdomen and is released
directly into the blood-
stream by the adrenal
glands

Histamine Histidine, one of the Histamine modulates Promotes/controls H3 subtype, focused on as Serum: Sources of histidine
essential biogenic neurotransmitters in the feeding behavior, the therapeutic target for N = diamine oxidase activity ≥80 include the following:
amines; responses, such brain, stress-related wakefulness [79] cognitive dysfunctions; HDU/ml (HDU = high-­ beef, pork, chicken, turkey,
as inflammation, gastric release of hormones expressed preferentially in dependency unit) peanut butter, cheese,
acid secretion, from the pituitary and neurons and modulates neu- Symptoms of excess histamine eggs, sesame seeds, and
neurotransmission, and central aminergic rotransmitter release [80]. include migraine headaches, sunflower seeds
immune modulation neurotransmitters [78] Produced by the granules gastrointestinal disorders, chronic Diamine oxidase is
Diamine oxidase breaks in mast cells and basophils fatigue, and ADHD available on non-prescrip-
down histamine to as part of a local immune tion basis
prevent buildup in response. Found in Avoidance of alcohol
plasma; deficiency may connective tissue; also advised
Nutrition and Behavioral Health/Mental Health/Neurological Health

be genetic or acquired synthesized in the brain;

Alcohol attacks diamine acts as a neurotransmitter.
oxidase and histamine Stored and released in the
builds up entero-­chromaffin-­like
(ECL) cells of the stomach

Adapted with permission from Leyse-Wallace [81]

29 481
 482 R. Leyse Wallace

noradrenaline, and the hormone melatonin. Even mild defi- [105]. In 2010, based on data from 2003 to 2004, 7% of the
ciency results in down-regulation of GABA and serotonin US population was determined to be biochemically defi-
synthesis [93]. cient in ascorbic acid [106]. Tobacco smoking is frequent
A 2012 report from the CDC demonstrated that 10.5% of in mental health populations, which increases the need for
the entire US population were biochemically deficient in vita- vitamin C and also folic acid.
min B6 [97]. Groups most likely to be deficient in B6 are Short-term therapy for hospitalized patients with vitamin
women of reproductive age, especially current and former C raised plasma vitamin C levels, improved mood distur-
users of oral contraceptives; male smokers; non-Hispanic bance by 71%, and reduced psychological distress by 51%
African-American men; and men and women over age 65 [98]. [107]. A number of reports describe observing signs of vita-
Sensory neuropathy typically develops at doses of pyri- min C deficiency in patients being treated for anorexia ner-
29 doxine in excess of 1000 mg/day with pain and numbness of
the extremities and in severe cases, difficulty walking. Since
vosa [108–111]. Low intakes of vitamin C, as well as other
nutrients, are reported by people experiencing food insecu-
placebo-controlled studies have generally failed to show rity [112].
therapeutic benefits of high doses of pyridoxine, there is little Polymorphisms in the vitamin C transporter genes have
reason to exceed the UL of 100 mg/day [99]. been shown to compromise genes encoding sodium-­
dependent ascorbate transport proteins [113].
Vitamin B12
Mental signs of a B12 deficiency include agitation, apathy, Folate
emotional instability, psychosis, irritability, memory prob- Low folate has been associated with changes in cognition
lems, mood swings, sleep disturbance, personality changes, affecting memory, attention, and language. Three weeks of a
suspiciousness/paranoia, and trouble concentrating. folate-deficient diet (5  μg/day) was reported to produce a
Psychiatric symptoms of B12 deficiency may present before decrease of serum levels from 7  ngs/mL to below 3  ngs/
hematologic findings [100]. Seventy to ninety percent of per- mL. In the 18th week, mental changes including insomnia,
sons with a clinically relevant B12 deficiency have neurologi- irritability, fatigue, and forgetfulness occurred, as well as ane-
cal disorders such as numbness and tingling in the hands and mia and red cell macrocytosis. Oral folate replacement of
feet; in about 25% of cases these are the only clinical manifes- 250 μg caused remission of symptoms [114, 115].
tations of the B12 deficiency [101]. Damage to the CNS may There are contradictory opinions in the literature regard-
become irreversible. A review by the Cochrane Group con- ing interpretation of studies involving folic acid and depres-
firmed orally administered cyanocobalamin with initial sion [116, 117]. A group that received selective serotonin
doses of 1000–2000 μg daily, then weekly, is just as effective reuptake inhibitors and selective norepinephrine reuptake
as parenteral administration [101]. Oral supplements have inhibitors (SSRI/SNRI), combined with 7.5–15  mg/day of
been confirmed to be as effective as injections. L-methylfolate, was more effective than monotherapy with
Vitamin B12 functions as a cofactor for methionine only an SSRI/SNRI [118].
synthase and L-methylmalonyl-CoA mutase. Methionine Taking folic acid does not appear to improve the antide-
synthase catalyzes the conversion of homocysteine to methi- pressant effects of lithium in people with bipolar disorder.
onine. Methionine is required for the formation of SAMe, a However, taking folate with the medication valproate
universal methyl donor for almost 100 different substrates, improves the effects of valproate. There is conflicting evi-
including DNA, RNA, hormones, proteins, and lipids [102]. dence about the role of folic acid in age-related decline in
A deficiency in vitamin B12 causes an accumulation of memory and thinking skills. However, other research sug-
homocysteine in the blood and may decrease the ability to gests no benefit [119].
metabolize neurotransmitters. A 16-week study showed that 2  mg of folic acid plus
Elderly patients judged to have normal nutritional status 400  μg of vitamin B12 improved negative symptoms of
using the Mini Nutritional Assessment (MNA) were found to schizophrenia significantly. However, improvements were
be low in vitamin B12 [103]. B12 and folate have indepen- noted only when genotype was taken into account. Only
dently been shown to predict positive affect [104]. patients homozygous for the 484T allele of FOLH1(rs202676)
demonstrated significantly greater benefit with active treat-
Vitamin C ment [120].
Prior to the development of scurvy, vitamin C deficiency The tolerable upper intake of folic acid for healthy adults
is accompanied by symptoms of mood disturbance, per- is 1000 mcg/day. Folate interacts with a large number of com-
sonality changes, and changes in scores on the Minnesota mon and specialty drugs. Doses over 1000 mcg/day should
Multiphasic Personality Inventory (MMPI). Psychological be assessed for potential interactions. Excess folate may cause
symptoms occur earlier and with less severe depletion low blood pressure and may lower blood glucose. The Mayo
than physical signs and symptoms. Kinsman reports per- Clinic website lists many herbs, supplements, and prescrip-
sonality changes occurred at levels of whole blood of tion and over-the-counter drugs that may interact with folic
1.21–1.17 mg/100 mL. Physical signs/symptoms occurred acid. For the entire list, see: 7 http://www.­mayoclinic.­org/
 

at 0.67–0.14  mg/100  mL ascorbic acid in whole blood drugs-supplements/folate/safety/hrb-20059475.

Nutrition and Behavioral Health/Mental Health/Neurological Health
483 29
Vitamin A Vitamin K
The retinoids are a family of compounds derived from vita- The vitamin K-dependent protein GAS6 is involved in che-
min A or pro-vitamin A carotenoids. They are necessary for motaxis, mitogenesis, cell growth, and re-myelination of
the function of the brain and central nervous system, and nerves. Low levels of vitamin K have been associated with
new discoveries point to a central role ranging from neuro- dementia and alterations in cognition, although much of the
plasticity to neurogenesis. Retinoic acid is important for a research on vitamin K and the nervous system has been on
regular pattern of sleep [121]. animals. One area of future research is the relative deficiency
Isotretinoin is a vitamin A-derived medication that is state of vitamin K induced by use of the drug Warfarin and its
associated with significant adverse effects including arthral- potential effect on cognition.
gia myalgia, nosebleeds, headache, dyslipidemia, liver dys-
function, and depression. Case reports describe depression,
suicidality, psychosis, violence, and aggression developing in 29.3.3 Minerals
conjunction with isotretinoin treatment (13-cis retinoic acid/
Acutane) used in treating severe acne [122]. Evidence sug- Some minerals are essential for health and functioning. Some
gests probable clinical exacerbation of bipolar mood disorder are generally toxic to humans. (See also . Table 29.3) Some
 

and possible links to psychosis. Genetic polymorphisms in are essential, but may be toxic at extreme levels of intake.
the retinoic acid receptor alpha (RARA), one of the main tar- Either inadequate or toxic levels of minerals may affect men-
gets of isotretinoin, showed an association with the adverse tal functioning.
effects of oral isotretinoin therapy [123].
29.3.3.1  Nutrient Minerals
Vitamin D Copper
Low levels of vitamin D are found frequently in those with High concentrations of copper are found in the brain. Recent
mental illness, especially schizophrenia [124–127]. One studies have found that copper helps brain cells communi-
study showed that vitamin D status was associated with cate with each other by acting as a brake when it is time for
more negative symptoms in first-episode schizophrenia. neural signals to stop [133]. Some patients with Alzheimer’s
Mixed results are reported in the relationship between vita- Disease had normal serum copper, but higher levels were
min D levels and depression. One study observed a trend found in cerebrospinal fluid [134]. In cases of copper defi-
toward a greater decrease in the Beck Depression Inventory ciency, dopamine-hydroxylase (DBH) activity may decrease
in the vitamin D treatment group than in the placebo group and result in elevated ratios of dopamine to norepinephrine.
[128]. One study showed that 58% of individuals who The balance between copper and zinc is important in main-
attempted suicide were deficient in vitamin D [129]. taining neurotransmitter levels and function. Walsh has
Another found initially low vitamin D levels were associ- associated overload of copper and copper-zinc imbalance
ated with clinically significant depressive symptoms across with schizophrenia, bipolar disorder, ADHD, and postpar-
follow-up [130]. tum depression [135].
Vitamin D is now considered a potent neuroactive/ Wilson’s disease is an autosomal recessive disorder result-
neurosteroid hormone, critical to brain development and ing in copper accumulation in basal ganglia and neuronal
normal brain function, and valued for its anti-inflammatory loss. One third of patients present with psychiatric symptoms
property. A vitamin D ligand-receptor has been found such as depression, labile mood, impulsiveness, disinhibi-
throughout the body including the central nervous system tion, self-injurious behavior, or psychosis.
[131]. Free plasma copper (in contrast to bound plasma cop-
A proposal by Patrick and Ames [16] in 2015 describes per) shows a significant inverse relationship with mini-
evidence that insufficient levels of vitamin D and essential mental state examination (MMSE) and attention-related
fatty acids may explain an underlying mechanism contribut- neuropsychological test scores. About 95% of patients with
ing to psychiatric disorders and depression through a vita- the neurological presentation manifest the Kayser-
min D receptor and the enzyme tryptophan hydroxylase Fleischer ring—a primary site of copper deposition in
(TPH2). Optimal intake of these nutrients may prevent and Wilson’s disease.
modulate the severity of brain dysfunction and alter behav- A case of a male diagnosed with celiac disease and a
ior. Tryptophan depletion in the brain reduces serotonin lev- hemoglobin of 4.9  g/dL, which was non-responsive to a
els, which results in favoring short-term over long term gluten-­free diet or supplements of iron, folic acid, and B12,
rewards, impulsiveness, antisocial aggressive behavior, feel- was found to be low in copper. Two months of copper supple-
ings of anger, and incidence of self-injury. They comment mentation normalized his neutropenia [136].
that exercise is a helpful intervention because muscles prefer-
entially absorb branch-chain amino acids, which compete Lithium
with tryptophan for transporters across the blood-brain bar- Lithium inhibits the release of thyroid hormone (TH), and
rier. Exercise facilitates more tryptophan crossing the brain-­ lithium treatment has been associated with the development
blood barrier for serotonin synthesis. of goiter within weeks to months of initiating lithium ther-
 484 R. Leyse Wallace

..      Table 29.3  Potentially toxic doses of drug of minerals [132]

Mineral Blood reference level DRI: adults, M/F Potentially

toxic dose

Calcium Serum Ca 1000–1300 mg/day 12,000 mg

Hypocalcemia ≤8.0–8.5 mg/dL, Hypercalcemia: S/S > 11.5 mg/dL, Critical value:
>12.0 mg/dL, A Medical emergency >15.0 mg/dL

Phosphorous Serum phosphorous, hypophosphatemia 700 mg/day 12,000 mg

1.5–2.4 mg/dL moderately low; not usually associated with clinical signs and
symptoms
29 <1.5 mg/dL may result in muscle weakness, hemolysis of red cells, coma, bone
deformity, and impaired bone growth
<1.0 mg/dL are potentially life-threatening
Values are lowest in the morning, peak first in the late afternoon, and peak
again in the late evening

Magnesium S/S  Mg deficiency ≤1.0 mg/dL. Levels ≥9.0 mg/dL may be life-threatening 320–420 mg/day 6000 mg

Iron Serum ferritin 8–18 mg/day 100 mg

Males, 24–336 mcg/L
Females, 11–307 mcg/L
May be elevated inflammation, liver disease, chronic infection, autoimmune
disorders, and malignancy
May be elevated in iron storage disorders such as hemochromatosis, hemolytic
anemia, and sideroblastic anemia and in those who have had multiple blood
transfusions
Native Africans, African Americans, and Asians may have higher mean
concentrations of serum ferritin

Zinc Normal urinary excretion of zinc—300 to 600 mcg/g creatinine/day 8–11 mg/day 500 mg
Serum zinc—0.66 to 1.10 mcg/mL
High urine/low serum zinc may be caused by hepatic cirrhosis, neoplastic
disease, or increased catabolism
High urine/normal or elevated serum zinc indicates a large dietary source,
usually in the form of high-dose vitamins
Low urine/low serum zinc may be caused by dietary deficiency or loss through
exudation or gastrointestinal losses

Copper 16 years ± Urine 15–60 mcg/L 900 μg/day 100 mg

Low urine copper levels: malnutrition, hypoproteinemias, malabsorption, and
nephrotic syndrome
Low serum copper associated with Wilson disease
Excess use of denture cream containing zinc can cause hypocupremia
Increased zinc consumption interferes with normal copper absorption

Fluoride Plasma N = 0.0–4.0 mcmol/L 3–4 mg/day 4–20 mg

Plasma fluoride >4 mcmol/L = excessive exposure
Plasma fluoride >4 mcmol/L = adverse effects
W/ fluoride-treated water-plasma fluoride 1–4 mmol/L
W/O fluoride-treated water-plasma fluoride <1 mcmol/L

Iodine Serum N = 40–92 ng/mL 120–150 μg/day 2 mg

80–250 ng/mL may indicate hyperthyroidism
I ≥ 250 ng/mL may indicate iodine overload

Selenium Serum N adult = 70–150 ng/mL (0.15 parts per million) 55 μg/day 1 mg

Children require less circulating selenium than adults
Se deficiency serum <40 ng/mL; associated with loss of glutathione peroxidase
activity
Usual treatment—Selenium supplementation to raise serum concentra-
tion > 70 ng/mL
Nutrition and Behavioral Health/Mental Health/Neurological Health
485 29
apy. Goiter in patients receiving lithium therapy ranges from Selenium
20% of patients in iodine-replete areas to 87% in patients Small amounts of selenium (Se) are essential; excess amounts
residing in iodine-deficient areas. Up to a third of patients on of selenium are toxic. There is greater uptake of selenium in
lithium therapy who develop goiter also may develop hypo- the brain than in other tissues. At times of deficiency, the
thyroidism, which usually remains subclinical, although it brain retains selenium to a greater extent than other areas of
could conceivably affect weight status [137]. the body.
The function of selenium in the brain is related to func-
Magnesium tions of selenium-dependent enzymes in the oxidative
Possible causes of hypermagnesemia include laxative abuse, damage-­ protective system: polyunsaturated fatty acids
diuretics, lithium intoxication, and hypothyroidism; causes (PUFA) are protected from peroxidation by selenium-­
of hypomagnesemia, meanwhile, can include gastrointestinal dependent glutathione peroxidase (Se-GPX). Se-GPX activ-
diseases (Crohn’s, ulcerative colitis, etc.), renal disease, vom- ity occurs in myelin tissue.
iting, laxative abuse, and alcohol abuse [138]. Energy-adjusted intakes of selenium have been found to be
Chronic magnesium deficiency may be related to numer- a predictor of high scores for depression on the Beck Depression
ous physical and mental disorders, including chronic fatigue, Inventory in Iran [141]. An analysis for 35 serum trace ele-
depression, irritability, disorientation, depression, and psy- ments showed a different profile in schizophrenic patients and
chosis. Magnesium ions may block synaptic transmission by controls in China. Concentrations of selenium, zinc, and
interfering with the release of acetylcholine. Consumption of cesium were significantly lower in schizophrenia [142].
alcohol, even in modest amounts, can double or even qua- Serum selenium concentrations decline with age.
druple the excretion of magnesium. Some over-the-counter Marginal or deficient selenium concentrations might be
and prescription drugs, such as proton pump inhibitors, can associated with age-related declines in brain function, possi-
lower body magnesium levels. bly due to decreases in selenium’s antioxidant activity [143].
Mg is essential for the proper activity of DNA poly- Supplementation with a selenium-rich Brazil nut has
merase I, RNA polymerase, and DNA helicase. Its deficiency shown potential in reducing cognitive decline in patients
results in errors during DNA replication, transcription, and with mild cognitive impairment (MCI) patients, and could
translation. prove to be an effective nutritional approach early in the dis-
Supplements in the form of magnesium oxide, chloride, ease process to slow decline. Response to intake of Brazil nut
or lactate provide 60–84 mg magnesium per tablet. Sustained-­ intake by mRNA appears to be influenced by a number of
release forms may reduce the potential diarrhea from mag- SNPs and genotypes [144, 145]. Brazil nuts contain very high
nesium supplementation. amounts of selenium (68–91 mcg per nut) and could possibly
cause selenium toxicity if consumed regularly.
Manganese A strong garlic-like odor is usually present in acute, sub-­
A U-shaped curve describes the need and effect of manga- toxic, and chronic selenium poisoning, attributed to dimeth-
nese in humans. Manganese (Mn) toxicity is a greater con- ylselenide. Neurologic symptoms of acute toxicity may
cern than deficiency. Manganese toxicity can result in a include tremor, peripheral neuropathy, muscle spasms, rest-
permanent neurological disorder such as tremors, difficulty lessness, confusion, delirium, and coma. The most common
walking, and facial muscle spasms. The toxicity syndrome, sign of chronic selenium poisoning are nail changes: Nails
manganism, may be preceded by psychiatric symptoms, such become brittle, with white spots and longitudinal streaks.
as irritability, aggressiveness, and even hallucinations [139]. Other signs include nausea, vomiting, diarrhea, fatigue, and
Iron deficiency has been known to increase manganese accu- skin lesions. As selenosis progresses, decreased cognitive
mulation in the brain. function, weakness, paralysis, and death occur [146]. The
In the brain, the manganese-activated enzyme glutamine upper limit for a maximum safe daily dietary intake, based
synthetase converts the amino acid glutamate to glutamine. on the amounts of selenium that are associated with hair loss
Glutamate, an excitotoxic neurotransmitter, is a precursor to and nail brittleness, has been estimated at 400  μg for sele-
an inhibitory neurotransmitter, γ-aminobutyric acid nium from food and supplements combined [143].
(GABA). Expression of genes implicated in manganese, iron,
and zinc homeostasis has been shown to increase with vita- Zinc
min D3 treatment. It is possible that the control of systemic Zinc deficiency has been shown to induce depression-like and
levels of zinc and manganese is regulated by vitamin D3 in anxiety-like behaviors, and zinc supplementation has improved
the intestine [140]. With vitamin D treatment, the gene the efficacy of antidepressant drugs in depressed patients. Zinc
encoding the zinc and manganese transporter, ZnT10, had deficiency may cause decreased appetite, change in the sense
about a 15-fold increase in expression. Vitamin D3 also of taste, and weight loss. Data may indicate a role for zinc defi-
increases expression of the SLC30A10 gene. Mutations of ciency in the development of mood disorders, but also show
SLC30A10 can cause manganese intoxication. that zinc may also be important in their treatment [147].
 486 R. Leyse Wallace

Zinc is found in in many body systems, participating in Since fish consumption is promoted for a healthy diet and
the activity of over 200 enzymes. Zinc functions in the incor- excess fish intake may carry contaminants such as mercury, fish
poration of thymine into DNA, one of the four bases forming consumption should be part of diet histories and comprehen-
the structure of DNA. Zinc deficiency leads to both primary sive health screenings to identify those at risk for mercury accu-
and secondary alterations in brain development and growth mulation. The symptoms of excess methyl mercury include
and is one of the causes of primary neural tube defect. Indirect fatigue, headache, decreased memory, decreased concentration,
effects of zinc deficiency occur in the lipid content of the muscle or joint pain, prickly sensations, and problems with fine
developing brain. motor coordination, speech, sleep, and walking. Although fish
Changes in brain zinc concentration are observed in is the main source of mercury, additional routes of exposure to
Alzheimer’s disease, Down syndrome, epilepsy, multiple scle- mercury are mercury vapor in certain occupations and some
29 rosis, retinal dystrophy, and schizophrenia. Recent investiga-
tions into molecular mechanisms suggest a role for zinc in the
medications, herbs, remedies, and vaccines [153].
A general medical practice in Seattle reported out of 700
regulation of neurotransmitter systems, antioxidant mecha- individuals who were screened, 123 needed laboratory evalu-
nisms, neurotrophic factors, and neuronal precursor cells. ation. One hundred three (89%) of these had had mercury
levels ≥5.0 μg/L; 63 (54%) had levels ≥10 μg/L; 19 (16%) had
levels ≥20 μg/L, and four had levels >50 μg/L. After patients
29.3.4 Potentially Toxic Minerals were advised to omit mercury sources or fish, follow-up
found mercury levels declined rapidly in the first 3  weeks,
29.3.4.1  Cadmium followed by a slower reduction over time. All but two patients
In a review of heavy metals, Wu et al. explained Cadmium reduced their level to <5.0 μg/L by 41 weeks [154].
(Cd) toxicities are expressed through depletion of glutathi-
one and bonding to sulfhydryl groups of proteins. Cadmium Mercury Reference Dose (RfD): no more than 0.1 μg
indirectly generates reactive oxygen species (ROS) by its abil- Hg/kg body weight/day.
ity to replace iron and copper. Lead becomes toxic to organ- Acceptable levels:
isms through the depletion of antioxidants [148]. Whole blood mercury level < 5.0 μg/L.
The most significant exposure to cadmium comes from cig- Hair level < 1.0 μg/g.
arette smoke. Occupational exposure to cadmium has led to (a)
slowing of visuomotor functioning on neurobehavioural testing;
(b) increase in complaints of peripheral neuropathy; (c) altered Consumer Reports lists these types of seafood as containing
equilibrium; and (d) lowered ability to concentrate, which were the lowest mercury content: shrimp, scallops, sardines, oysters,
dose-dependent with cadmium exposure. Environmental expo- squid, tilapia, and wild and Alaskan salmon. The publication
sure to cadmium has been shown marginally significant in rela- estimates that an adult could safely eat 36 ounces per week and
tion to the development of Alzheimer’s [149]. children could eat 18 ounces per week of these fish [155].
Sources of cadmium for non-smokers are terrestrial
foods (98%), aquatic foods (1%), and water (1%). The con-
tent of terrestrial foods varies significantly related to the type 29.4 Drugs: Nutrition and Mental Status
of food crop grown, agricultural practices, and the atmo-
spheric deposition of cadmium onto exposed plant parts. Weight gain is one effect of a number of psychotropic
With an absorption rate of 5% from ingestion, the average drugs. (see . Table  29.4) This, in turn, is a frequent cause
 

person is believed to retain about 0.5–1.0 μg of cadmium per of patients discontinuing medication. Nutrition counseling
day from food. The World Health Organization (WHO) ­incorporating diet and exercise principles has been success-
established a provisional tolerable weekly intake (PTWI) for ful with psychiatric patients, who have shown interest and
cadmium at 7 μg/kg of body weight. For a 150-pound (68 kg) motivation with multidisciplinary approaches [158].
person, this amounts to 477 μg/week, or 68 μg/day [150]. 55 Drug: Nutrient Interactions include:
55 Protein pump inhibitors (Prilosec, Prevacid), H2
29.3.4.2  Mercury receptor antagonists (Tagamet, Pepcid, Zantac), and
Methyl mercury is more than 95% absorbed and can accumu- metformin reduce absorption of vitamin B12 and
late if rates of consumption exceed rates of excretion. It has a may induce a deficiency.
strong affinity for sulfhydryl groups in tissues and accumu- 55 Antidepressant medications:
lates to a greater concentration in brain, muscle, and kidney. ȤȤ Taking vitamin B6 supplements may improve the
Methyl mercury easily crosses the blood-brain barrier, where effectiveness of some tricyclic antidepressants,
it is biotransformed into inorganic mercury. The brain: blood such as nortriptyline (Pamelor), amitriptyline
concentration ratio after the initial distribution is between (Elavil), desipramine (Norpramin), and imipra-
10:1 and 5:1. Once in the central nervous system, methyl mer- mine (Tofranil).
cury can be demethylated to inorganic mercury. Inorganic ȤȤ Monoamine oxidase inhibitors (MAOIs) may
mercury has a half-life of years in brain tissue [151, 152]. reduce blood levels of vitamin B6. Examples of
Nutrition and Behavioral Health/Mental Health/Neurological Health
487 29

..      Table 29.4  Nutrition and psychotropic medications [156, 157]

Medication type Generic Name (trade/brand name) Side effects

Antidepressants: Fluoxetine (Prozac) Weight gain

Selective serotonin reuptake inhibitors Sertraline (Zoloft) Gastrointestinal symptoms
(SSRIs) are often prescribed for depression, Paroxetine (Paxil) Avoid tryptophan supplements
obsessive compulsive disorder, social anxiety Fluvoxamine (Luvox) St. John’s wort
disorder, and occasionally eating disorders Citalopram (Celexa)

Antidepressants: Amitriptyline (Elavil) Carbohydrate cravings, slowing of metabolism,

Tricyclic Amoxapine (Asendin) and appetite stimulation
Nortriptyline (Aventyl, Pamelor) Weight gain may be dose-dependent and
Doxepin (Adapin, Sinequan) related to duration of therapy
Imipramine (Janimine, Tofranil) The greatest weight gain is from imipramine and
Desipramine (Norpramin) amitriptyline. Minimal weight gain occurs with
Clomipramine (Anafranil) protriptyline and desipramine
Protriptyline (Vivactil)

Antipsychotic Thioridazine (Mellaril) Appetite changes, elevated cholesterol, glucose

Novo-Ridazine up or down, weight increase
Haloperidol (Haldol, Peridol) Take Mg, Ca, and iron supplement separately by
Molindone (Moban) 4 hours
Chlorpromazine (Thorazine) May increase riboflavin need

Atypical antipsychotics Clozapine (Clozaril) Greatest association with weight gain with
Olanzapine (Zyprexa) clozapine and olanzapine
Sertindole (Serlect)
Risperidone (Risperdal)
Quetiapine (Seroquel)
Ziprasidone (Zeldox)

Antiseizure/anticonvulsants Divalproex (Depakote) Initial weight gain, esp if patient at or below

Phenytoin, Depakote anticonvulsants/ Carbamazepine (Tegretol) normal BMI
putative mood stabilizers Lamotrigine (Lamictal) May cause hyperinsulinemia; increased appetite
May be prescribed for seizure disorders, Gabapentin (Neurontin) May need Ca, Vit D, B-1, carnitine supplement;
bipolar disorder, and selected forms of Topiramate (Topamax) folate suppl frequently Rx; folic acid is an antago-
depression nist of phenytoin (dilantin), phenobarbitol,
methotrexate, and other medications, appetite
change

Lithium Requires consistent fluid and sodium intake;

moderate caffeine intake

Monoamine oxidase inhibitors Isocarboxazid (Marplan), Phenelzine Limit foods w/ tyramine with nonselective MAOI:
  Nonselective irreversible type (Nardil), Tranylcypromine (Parnate) chocolate, aged and mature cheeses, smoked
  Reversible (RIMA) types Moclobemide (Manerix) and and aged/fermented meats, hot dogs, some
Toloxatone (Humoryl) processed lunch meats, fermented soy products,
and draft beers

MAOIs include phenelzine (Nardil) and tranylcy- 29.5 Summary Statement

promine (Parnate).
55 Phenytoin (Dilantin used to treat seizures): Vitamin Nutritional status and deficient or excess nutrients have
B6 makes phenytoin less effective [159]. meaningful effects on mental status, through enzymes,
55 Riboflavin intake/status: Some drugs may lower neurotransmitters, and metabolism; they interact with
riboflavin levels, but riboflavin may improve the many drugs; and they influence genetic transcription.
effects of antidepressants: imipramine (Tofranil), Thorough nutritional assessment and targeted interven-
desimpramine (Norpramin), amitriptyline (Elavil); tions have the potential to improve the course of treatment
nortriptyline (Pamelor), phenothiazines (Thorazine), and quality of life for individuals suffering from altered
phenytoin (Dilantin). mental status.
 488 R. Leyse Wallace

References 18. Haller J. Biokinetic parameters of vitamins a, B-1, B-2, B-6, E, K and
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zure disorder medications. SCAN’s Pulse. 2003;22(2):7–12. SCAN is ment/vitamin-b6-pyridoxine.
a Practice Group of The Academy of Nutrition and Dietetics.

29
 493 30

Neurodevelopmental Disorders
in Children
Mary Anne Morelli Haskell

30.1 Introduction – 495

30.2 Children Are Not Little Adults – 495

30.3 Toxins and Toxicants – 495

30.4 Family History and Genetics – 497

30.5 Lifestyle Factors – 497

30.6 Autism Spectrum Disorders (ASD) – 498

30.7 History – 499

30.8 Gastrointestinal Symptoms – 499

30.9 Mitochondrial Issues in Autism – 500

30.10 Biomedical Assessment for Autism – 500

30.11 Functional Lab Assessment for Autism – 500

30.12 Family History and Autism – 501

30.13 Polymorphisms in Autism – 501

30.14 Genes Affecting GI Health – 502

30.15 Folate and Methylation Genes – 502

30.16 Transsulfuration Pathway Genes – 502

30.17 Neurotransmitter Genes – 502

30.18 Genes Affecting Detoxification – 502

30.19 Nutritional Support – 502

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_30
30.20 ADHD – 505
30.20.1 Lifestyle and Environmental Factors – 505

30.21 Dr. Amen’s Seven Types of ADHD [87] – 505

30.21.1 General Dietary and Lifestyle Strategies for ADHD – 506

30.22 Seizure Disorders – 508

30.22.1 C ontraindications to the Ketogenic Diet – 509
30.22.2 Ketogenic Diet Labs – 509
30.22.3 Supplements for the Ketogenic Diet – 509

30.23 PANDAS and PANS – 510

30.23.1 N IMH Guidelines for Diagnosing PANDAS – 510
30.23.2 NIMH Guideline for Diagnosing PANS [108] – 511

30.24 Conclusion – 513

References – 513
Neurodevelopmental Disorders in Children
495 30
Learning Objectives The developing immune system is influenced before birth
55 To support children with neurodevelopmental and neuro-­ by the fetal-maternal interface via the placenta and by the
immune disorders in reaching their optimal potential type of delivery. It turns out that there are more immune com-
through lifestyle teaching, individualized diet, targeted munications between mom and fetus than previously thought
supplements, and other modalities based on symptoms and [3]. With a vaginal delivery, the infant is colonized by mom’s
biomedical testing. vaginal and intestinal flora. However, during a C-section, this
55 To understand the use of biomarkers and genetic individual- contact with vaginal microflora is absent and environmental
ity to support vulnerable areas of their biochemistry as flora plays a more important role in colonizing the infants’
evidenced by related dysfunctions in multiple systems to microbiome. The circumstances of the C-­section also have an
help these children thrive. influence; a planned C-section, with no labor or rupture of
membranes, has less microbial exposure, while an emergent
C-section after a long labor with rupture of the membranes
30.1 Introduction will introduce more maternal flora [4].
Atopic disease tends to be more common in children with
The number of children with neurodevelopmental and C-section births than vaginal births, especially if there is a
neuro-immune issues is increasing at an alarming rate. family history of allergy. The lack of exposure to maternal
Changes in obstetrics, farming, food production, health care, vaginal and intestinal flora is associated with alterations in
and the sheer number of chemicals, pesticides, and toxins in the neonatal gut flora and cytokine responses which can lead
our daily life contribute to the rapid growth in neurologic, to changes in the Th1/Th2 helper cells that favor atopy [5].
developmental, and autoimmune issues our children face. You may notice immune differences in siblings related to
The importance of understanding these changes helps us their type of delivery and exposures prenatally and postna-
support the healing of the gut, the immune system, and the tally. The composition of the early microbiota is an important
neurologic system, including the brain, with therapeutic factor in the health of the immune system [6]. The initial
nutrition. Many factors need to be assessed to help these chil- colonization of the infant gut is affected by genetics, prenatal
dren to reach their optimal potential. The aim of this chapter exposures, antibiotics, type of delivery, and diet composition
is to highlight some of the current research relevant to help- of breast milk or formula (. Fig. 30.1).
 

ing children with neurodevelopmental disorders using Malamitsi-Puchner et al. found vaginal delivery promoted
autism spectrum disorder, ADHD, PANDAS, and seizure cytokines important to neonatal immune health. Exclusive
disorders as prototypes. breastfeeding, when possible, supports a healthy microbiota
in infants by seeding and selecting for specific populations of
bacteria. C-sections, antibiotics, and formula feeding may
30.2 Children Are Not Little Adults alter the development of the microbiome and have been
linked to increased metabolic and immune issues [7].
Understanding nutrition for growth and development, in
addition to harnessing nutrition to mitigate toxic exposures
prenatally and postnatally, is essential in caring for our chil- 30.3 Toxins and Toxicants
dren. Children are not “little adults.” They differ from adults in
their anatomy, physiology, musculoskeletal system, and organ Children and fetuses are more vulnerable to toxins and toxi-
systems as they are in the process of maturing. Children have cants. There is no known safe level of neurotoxins for an
a higher metabolic rate with an increased oxygen and caloric embryo and developing fetus. Due to trans-placental expo-
need. Newborns have a higher fluid-to-solid ratio: 75–80% sures and communication, the fetus is exposed to everything
water versus 60% in adults. Control of electrolyte status is less the mother takes in [8]. Of the 287 chemicals the
effective until 12–18  months of age, and children are more Environmental Working Group detected in umbilical cord
susceptible to malnutrition and electrolyte imbalance beyond blood in 2004 [9]:
18 months. The daily water exchange rate is higher in children. 55 180 cause cancer in humans or animals.
Small children are more susceptible to head injury [1] due to 55 217 are toxic to the brain and nervous system.
thinner cranial vault bones and a large head-to-torso ratio and 55 208 cause birth defects or abnormal development in
the length of time air-filled sinuses take to develop. At birth animal tests.
much of the skeleton is cartilage, while the flat bones of the
skull, face, and jaw are composed of membranous bone for After birth, infants and children experience greater exposure
safe passage of the baby. Until puberty, bones are softer and to chemicals pound-for-pound than do adults. They also have
more easily bent and fractured. The brain is immature at birth an immature and porous blood-brain barrier, which allows
and completes about 60% of its development in the first 2 years greater chemical/toxic exposures to reach their developing
of life. Because the brain is growing so rapidly during this brain. In addition, their neurological, immunological, and
time, adequate healthy fats, protein, energy, iron, zinc, copper, detoxification organs are not yet mature. The liver, the main
iodine, selenium, choline, folate, and vitamin A are important detoxifying organ, is more efficient by age 7, but it continues
for development of the brain and the nervous system [2]. to mature until late adolescence and beyond. Children are
 496 M. A. M. Haskell

..      Fig. 30.1  Colonization of

infant microbiome effected by Initial exposures Ongoing and interdependent
initial and ongoing issues.
(Reprinted from Houghteling and
Walker [6]. With permission from Gene
Wolters Kluwer Health, Inc.) Genetics expression

Mucus and
Prenatal barrier function
maternal
exposures Infant
microbiome Immunity

30 Delivery
mode
Metabolism

Breast
Nutrition
feeding

exposed to more pesticides and toxins because they spend because the skull and ears are thinner, allowing more radiation
more time at ground level and through their exploratory and to reach critical structures. Their brains contain more fluid and
hand-to-mouth behaviors. Pregnant and breastfeeding moth- therefore absorb more microwave radiation [16]. As body
ers would be wise to avoid toxic exposures in food and the organs and systems are developing, there is increasing risk aug-
environment. The father’s exposure history is also important menting damage from previous EMF exposure in utero.
to know. Has dad been exposed to work-related toxins, medi- There is evidence that these frequencies have many effects
cations, alcohol, recreational drugs, or infectious agents? down to the cellular level, adversely affecting mitochondria,
There is an increasing epidemic of learning difficulties, as causing oxidative damage from reactive oxygen species, and
well as ASD and ADHD, because of the ever-increasing impact affecting cell membrane permeability [17]. Oxidative stress has
of environmental toxins on the development of children. Heavy been demonstrated in the brains and livers of developing rats
metals can have a direct toxic effect reducing the ability to exposed to EMF related to decreased glutathione peroxidase
absorb essential nutrients. Mercury is considered the most and antioxidant concentrations. Negative effects have been
toxic heavy metal. It affects the nervous system and alters brain noted in rat testes and human reproduction. EMF exposure
function, leading to tremors, memory issues, irritability, and a affects a wide range of human body systems with symptoms
host of other issues [10]. Mercury (Hg) blocks the absorption of including headache, sleep issues, fatigue, skin problems, atten-
iron, zinc, and selenium; however rat studies suggest adequate tion, and memory issues, as well as neuropsychiatric effects
zinc can help decrease the toxicity of Hg exposure [11]. Zinc including depression and presumably autism [18]. The neuro-
supports homeostasis, immune function, and apoptosis and psychiatric effects appear to be from activation of voltage-­gated
reduces oxidative stress [12]. Aluminum displaces magnesium, Ca2+ channels (VGCCs) in the outer membrane of cells in the
calcium, and iron which can affect intercellular communica- brain, allowing excessive neurotransmitter and neuroendocrine
tion, cell growth, and secretory functions. Aluminum overload release [19]. Excess calcium in the cells increases oxidative
leads to inflammation and neurotoxicity [13]. Heavy metals stress and ultimately affects mitochondrial function and DNA.
and pesticides have a synergistic effect in humans and animals
[14]. Likewise, an abundance of nutrient minerals can help to
protect the body from absorbing as many toxic elements [15]. Because the World Health Organization considers
The enormous increase in electromagnetic frequency wireless radiation a possible human carcinogen,
(EMF) waves, such as radio, television, cell phones, and Wi-Fi, wireless radiation does not belong in schools with
is a vital concern for health. Radiofrequency radiation covers a young children.
wide range of frequencies from 900  MHz (megahertz) to – Anthony B. Miller, MD, PhD
greater than 15 GHz (gigahertz) for current 5G (5th-genera- expert advisor to WHO, Professor Emeritus, University
tion mobile networks). Children are disproportionately of Toronto
affected by cell phone radiation and EMF, and it is of greater The C4ST Women’s College Hospital Symposium
concern for the developing fetus, infants, and children whose 9/12/14
brains are thought to be more vulnerable because of smaller 7 http://c4st.­org/dr-anthony-miller/
 

head size. THe distance to the center of the brain is shorter

Neurodevelopmental Disorders in Children
497 30
30.4 Family History and Genetics 30.5 Lifestyle Factors

The field of genetics is changing daily. Going beyond genetic The basics of health are the same for all children:
determinism, epigenetics has shown us that factors such as 55 Remove foods containing additives and food triggers
diet, nutritional status, lifestyle, environmental toxicants and from the diet: processed foods, artificial colors, flavors,
toxins, including air and water pollution, food processing, preservatives, GMO foods, pesticides, nitrites, artificial
agricultural practices, and extremes of stress can affect an sweeteners, corn syrup, high fructose corn syrup, trans
individual as well as future generations [20, 21]. Epigenetic fats, MSG (monosodium glutamate), etc.
marks can change for the better in response to a positive atti- 55 Remove sources of environmental toxicants from the
tude, healthy diet and lifestyle, and limiting exposure to the home: pesticides, chemical cleaners, air fresheners,
increasing number of environmental toxins and toxicants. fabric softeners, plastics, outgassing furniture and
“Epi” means “above.” Epigenetics is “control above the carpets, as well as any sources of mold. Don’t forget EMF
genes.” It denotes a change in gene expression (phenotype) pollution and the effects of “smart meters.” [22]
caused by an external modification to DNA by the environ- Interestingly, many parents find their children sleep
ment that turns genes on and off without a change to the better when Wi-Fi is turned off at night. Avoid
DNA sequence (genotype). These changes are potentially ­electronics in the bedroom.
reversible and preventable. The cell membrane picks up envi- 55 Pure water is essential. Additives to municipal systems
ronmental signs that control the reading and expression of can also be absorbed through bathing. Use multi-stage or
genes. The embryo stage of development lays down the whole-house filters to remove species such as asbestos,
genetic code, and from the fetal stage on, there is epigenetic fluoride, arsenic, and other well-known biotoxins
modification. including drug residues. Because water is a source of
Our genes work in concert with biochemical chain reac- minerals in its natural state, insure adequate minerals in
tions. Nutrition and tailored supplementation are profound pure spring water or the diet.
shapers of epigenetic changes and the subsequent effect on 55 Basic healthy, whole-foods diet: fats, protein, carbohy-
metabolic processes. A gene with a single nucleotide poly- drates, fruits, and vegetables.
morphism (SNP) variation may mean the gene efficiency is 55 Basic dietary supplements as needed: fatty acids, enzymes,
altered; it could be working at a decreased or increased effi- probiotics, and appropriate multivitamin/mineral.
ciency or may have lost regulatory controls. Related to how an 55 Determine any special diet or dietary needs, including
enzyme functions, upregulation or downregulation can have any food sensitivities or allergies.
far-reaching effects. Metabolic pathways require nutrient 55 Increase nutrient-dense foods: eggs; meat from well-­
cofactors, which are vitamins and minerals required for raised, pastured chickens and animals; organic liver [23];
enzyme function. If there is an adverse effect related to a SNP, sweet potatoes; leafy greens; beans; legumes; nuts; seeds;
supplementation may help mitigate the effect by stimulating some grains; seaweed; blackstrap molasses; organic bone
the metabolic pathway affected. A deficiency in cofactors may or vegetable broth; balanced smoothies or fresh juices;
limit the efficiency of a metabolic pathway. Supplying cofac- and fermented foods as tolerated [24].
tors (vitamins and minerals) through supplementation may 55 Repair the gut: leaky gut, yeast overgrowth, parasites,
support gene function through epigenetic changes and/or dysbiosis, and balance intestinal flora (see 7 Chaps. 23
 

metabolic pathways; SNPs may be indirectly supported by and 24).

nutrients that modulate pathways through other mechanisms. 55 Targeted supplements: as indicated for immune support,
The tricky part is that the genes work in conjunction with reducing inflammation, healing the gut, and genetic
one another, so the knowledge of a single SNP does not give support.
a complete roadmap as effects vary for each person depend- 55 Support detox pathways: optimize elimination through
ing on their individual genetic makeup. For instance, if a healthy bowel function and liver function and consider
methylation pathway is affected by a methylenetetrahydrofo- mild chelators and binders.
late reductase (MTHFR) SNP, it may be under- or over-­
methylated and interact with other genes in this important Sleep is crucial for children [25]. Babies sleep 20 hours a day
pathway. (See 7 Chap. 18 on Methylation.) Biomarkers, such
  to support the metabolic demands of their rapidly growing
as homocysteine levels or actual genetic testing if available, brain. Most toddlers and preschoolers need 11–14 hours of
are useful to determine exposure, effect of exposure, disease sleep. Insufficient sleep can add stress to an already chal-
progression, and susceptibility factors, as well as which SNPs lenged nervous system and can affect the neuroendocrine
may need support. Genetic SNPs need only be addressed if system by elevating stress hormones. In fact, a study of ado-
they need support, based on symptoms and biomarkers. lescents has found that sleep deprivation can mimic ADHD,
Always treat the patient, not a lab test or SNPs. To under- including hyperactivity, impulsivity, poor attention, and
stand the workings of the genes and their integration with other behavior problems [26]. Parents can visibly recognize
biomarkers, it will take continued research and the help of the behavioral effects of sleep deprivation in young children,
artificial intelligence tools, since there are more than 20,000 which have been evidenced in studies as affecting cognitive
genes, of which only a fraction are well-understood. function as well as behavior [27].
 498 M. A. M. Haskell

sensitivity to developing ASD.  It has been aptly said that

The 6-A Epidemics genetic vulnerability loads the gun and environmental toxins
pull the trigger. This is an epidemic with high levels of special
needs, devastating families and taxing school systems.
Early signs that parents notice are the absence of big
smiles or warm joyful expressions by 6 months. No sharing
Alzheimers of sounds, smiles, and facial expressions by 9  months. No
Autism
babbling, pointing, or waving by 12  months. No words by
16 months. No two-word sentences by 24 months. Frequently
early development appears on track and parents later notice a
Allergy ADHD regression such as blank stares or loss of eye contact or words
which can occur over weeks or months. Persistent regression
is never normal in childhood development.
30 Autoimmune DSM-V criteria for autistic disorder describes a b
­ ehavioral
PANS Asthma
disorder with:
PANDAS
55 Impaired social interaction
55 Impaired social communication
55 Restricted repertoire of activities and interests

..      Fig. 30.2  Epidemics of developmental disabilities related to Assessment of severity is based on social communication
oxidative stress and inflammation impairments and restricted repetitive patterns of behavior.
This disorder affects the essence of a child’s ability to com-
The 6-A Epidemics are rising at an alarming rate and have municate, rephrase, and use language, as well as their sense of
oxidative stress mechanisms and inflammation in common. self. Recovery rates are estimated to be 3–25% with tradi-
They are influenced by environmental toxins, heavy metals, tional treatment. The earlier interventions are begun, the bet-
chemicals, infection, and damaged food. According to the ter the outcome, preferably before the age of 3. Changes are
Centers for Disease Control and Prevention report in 2008, slower after the age of 8. However, with proper biomedical
one in six children in the United States has a developmental care, continued improvements are possible into adulthood,
disability. At the same time, Alzheimer’s disease is also though they are more modest. Some children will be able to
increasing at an alarming rate. It is the sixth leading cause of lose the diagnosis of autism and be mainstreamed in school.
death in the United States, having increased 55% between Autism, once thought to be a behavioral disorder, is
1999 and 2014. What in our environment, lifestyle, and diet a ­ biological/neurological disorder involving systemic
are causing these dramatic increases in neurologic diseases in ­inflammation and changes in the brain [29]. Oxidative stress,
children and adults? (. Fig. 30.2).
 
mitochondrial dysfunction, and immune dysregulation/in-
flammation have been recognized using peripheral ­biomarkers
from blood and urine tests. Recent studies also report these
30.6 Autism Spectrum Disorders (ASD) abnormalities in brain tissue in individuals with ASD.
Associated conditions include:
Autism spectrum disorder (ASD) is one of the most con- 55 Seizures (30% +)
founding neurodevelopmental disorders in children. The 55 Cognitive deficits or intellectual disabilities
CDC data from November 2015 shows that 1 in 45 children 55 Savant skills
is now diagnosed with autism. 2.2% of children between ages 55 Sensory dysfunction and/or impaired sensory-motor
3 and 17 are currently affected by ASD. In the 1980s, the rate integration
was 1 in 10,000. Prior to 1960, most cases of autism showed 55 Motor dysfunction, including motor planning, delayed
signs at birth. However regressive autism now represents motor milestones, toe walking, etc.
80% of the cases where children appear to be developing nor-
mally and begin losing developmental skills, most often Autism is not one disease but is different in each child. Many
between 15 and 24 months [28]. The incidence is four to five different systems can be affected. Kenneth A. Bock, MD [30],
times higher in males, and families with one child with ASD suggests there are subgroups of autism. One or more areas
have a 2–18% chance of having a second affected child. may be affected. Looking at symptoms and biomarkers can
Although diagnosis and awareness have improved, teachers, lead to effective interventions:
grandparents, and pediatricians will tell you these children 55 Gastrointestinal: 50–70% have indigestion, constipation,
are truly different and each child is unique in their individual loose stools, or abdominal pain
presentation. ASD is a heterogeneous condition with many 55 Allergies/sensitivities (50% +)
variations in presentation. Genetic factors are involved, as 55 Immune deficiency/autoimmune/dysregulation
well as environmental and other epigenetics factors, but 55 Infections: viral, bacterial, fungal, and parasitic
genes do not create epidemics, though they may increase 55 Metabolic: enzyme, mitochondrial dysfunction
Neurodevelopmental Disorders in Children
499 30
55 Nutritional imbalances vaginal birth or C-section? How long was labor? A C-section
55 Hormonal imbalances after 36  hours of labor is a different stress than a planned
55 Toxic injury C-section. How was the birth? Was there birth trauma? Were
antibiotics given to mom during labor or baby? How did baby
Our food supply is compromised by the overuse of herbicides look at birth? Potential risk factors for birth trauma include an
and pesticides [31]. The toxicity of commonly used glypho- uncommon fetal presentation, umbilical cord issues, fetal dis-
sate, originally patented as an antibiotic is compounded by tress, birth injury, maternal hemorrhage, low birth weight, mul-
the adjuvants in the herbicide that enhance bioaccumulation. tiples and small size for gestational age [37]. Was medical
This affects plants grown for human consumption as well as intervention needed? Was the child taken to the neonatal inten-
meat, eggs, dairy and farmed fish and our entire food chain, sive care unit (NICU)? Did the infant need more than 3 days in
as animals and farmed fish are fed GMO feed. Many environ- a NICU? Were there issues with colic, sleep, feeding, or gastro-
mental factors come into play and affect homeostasis in mul- esophageal reflux? Was the sequential progression of develop-
tiple body systems. This creates physiological stresses that ment timely? Did any significant events happen around the
can include increased oxidative stress, heightened inflamma- time regression or developmental issues were first noticed?
tory responses, gut dysfunction, neurologic damage, and Finding the multiple risk factors and events that led to this child
immune dysregulation. to develop autism can help us unravel the puzzle that leads to
The interaction of genes and environmental toxins and improvement in their lives and the lives of their families.
toxicants in the prenatal, perinatal, and postnatal period are These are all very important questions to help in charting
contributing to the rise in ASD. Maternal immune activation a course of treatment and unraveling contributing factors.
can alter brain development and has also been linked to ASD Parents can do a timeline listing developmental events, vac-
[32, 33]. Neuro-inflammation is involved in autistic behavior. cines (note that reactions may not be severe or immediate),
Findings suggest microglia activation or dysfunction can affect illnesses, medications, stressful events, and toxic exposures
neurodevelopment [34]. Increased levels of inflammatory such as black mold or pesticides, to aid in pinpointing where
cytokines in patients with ASD have been reported, as well as insults may have occurred.
the presence of serum antibodies against the central nervous Prenatal factors associated with ASD are under study.
system and maternal IgG reactive to fetal brain ­tissue [35]. Several factors that are suspected to be contributors are ges-
tational or pre-gestational diabetes mellitus, some maternal
infections and other causes of maternal immune activation,
30.7 History valproic acid, SSRIs, organophosphates, pesticides, air pollut-
ants, alcohol, and heavy metals. Diabetes mellitus affects fetal
A thorough history and timeline are essential. Was pregnancy growth, which can increase complications during pregnancy
easily achieved or was intervention needed? Were the parents and delivery. Diabetes can also affect fine and gross motor
excited about the pregnancy? Was the mother in a supportive development and increase the rate of ASD, ADHD, and
relationship? What was her stress level? Were there drug or learning difficulties. It is thought maternal diabetes may
alcohol issues with either parent? What was the geographic cause increased fetal oxidative stress or epigenetic changes.
location? Were there environmental exposures? Were mom Tight control lessens the effects of diabetes on the fetus, but
or dad exposed to toxins at home or on the job? Were trans- does not eliminate risk [38].
generational epigenetic factors present, such as parental During pregnancy, the demands for folate increase to
exposure to diethylstilbestrol, war related issues, etc? support the growth and development of the fetus. Mothers
Were both parents in good health? Any illnesses or auto- with MTHFR and dihydrofolate reductase (DHFR) polymor-
immune conditions? Was mom adrenally depleted or diag- phisms do not process folic acid well and are better supported
nosed with low thyroid? Thyroid hormones are critical to with foods high in folate and vitamins that contain 5-MTHF
fetal development. Fetal thyroid function does not begin (methylated folate) [39]. Both of these polymorphisms are
until 14  weeks of gestation. Iodine deficiency can lead to common in parents and patients with ASD.
mental retardation. Inadequate thyroid hormone disrupts
neuronal migration into the cortical layers of the brain in the
fetus. Children with ASD can have defects of neurogenesis 30.8 Gastrointestinal Symptoms
and neuronal migration. Maternal hypothyroidism can
increase the risk of placental abruption, preterm labor, and Children with ASD have a greater risk of gastrointestinal
postpartum hemorrhage. Evidence suggests that low mater- issues, especially constipation, chronically loose stools, diar-
nal T4 levels can affect cortical development of the fetus [36]. rhea, gas, bloating, and abdominal pain [40]. Children with
Screening for congenital hypothyroidism between days 2 and intestinal inflammation may also have sleep disturbances,
4 is critical as specimens prior to 48  hours may be falsely behavioral issues, or unusual posturing [41]. Many adopt a
elevated. posture that puts pressure on the lower abdomen to lessen
What medications, vaccines, Rhogam (a necessary medica- pain. Those who are unable to effectively defecate on the toi-
tion but potential risk factor as it can contain a mercury preser- let may use a squatting posture to produce a Valsalva maneu-
vative), epidurals, Pitocin, etc., did mom receive? Was birth by ver. GI dysfunction can worsen symptoms through pain,
 500 M. A. M. Haskell

stress, and discomfort, resulting in such issues as agitation, Until we find more specific ways to support ­mitochondria,
anxiety, aggression, self-injury, brain fog and sleep issues. lifestyle, nutrition, and supplementation are helpful.
GI symptoms can occur via different mechanisms. Nutrients supportive of mitochondrial function are
Pathways affecting the gut-brain axis can affect behavior and L-­carnitine, coenzyme Q10, and vitamins C, D, E, and B5
cognition. Studies have shown in children and mice that hav- [53]. CoQ10 is needed to produce ATP, B1, B2, B3, B5, and
ing a gluten-free diet lessens GI symptoms and improves antioxidants [54].
behavior [42–44]. Gluten, a protein in some grains, can cause
inflammation by multiple means including allergy, intoler-
ance, gluteomorphin, celiac, non-celiac gluten intolerance, or 30.10 Biomedical Assessment for Autism
contaminants in the grain. Multiple mechanisms by which
gluten may cause issues can make definitive testing challeng- There is currently a search underway for nutritional and bio-
ing. Modern wheat has been hybridized to produce a higher markers in ASD [55]. Many tests are useful in teasing out
gluten content and is often desiccated with glyphosate. Some metabolic and nutritional issues in autism. Alterations in
30 children with GI symptoms have a lymphocytic enterocolitis metabolic pathways vary according to exposures and genetic
with dysregulated intestinal mucosal immunity and increased individuality.
cytokines. Therapeutic diets can decrease inflammation [45]. However, collecting blood and other bodily fluids can be
Pathophysiological mechanisms that may link ASD and quite traumatic for these children. An organic acid and urine
GI symptoms include [30]: peptide test is a good place to start as urine is usually the least
55 Intestinal inflammation (with or without autoimmunity) traumatic body fluid to collect.
55 Gluten-related issues, such as celiac, wheat allergy, William Walsh, PhD, of the Walsh Research Institute,
non-celiac gluten sensitivity, and gluteomorphin found 85% of children on the autistic spectrum were zinc-­
metabolites deficient and many had an increased copper-to-zinc ratio
55 Functional abdominal pain (should be 1:1). Another study indicated children with ASD
55 GI dysmotility with dysautonomia and GI disease showed less stimming and hyperactivity with
55 Gastroesophageal reflux zinc supplementation [56]. Optimizing zinc can improve
55 Gut microbiota dysregulation affecting gastrointestinal appetite, as taste buds are more efficient with adequate zinc.
permeability, mucosal immune function, intestinal Zinc can also lessen anxiety. Improving the zinc/copper bal-
motility, and sensitivity [46] ance can take 2 months to show improvement. There may be a
brief period of worsening symptoms as the copper is detoxed.

30.9 Mitochondrial Issues in Autism 30.11 Functional Lab Assessment for Autism

Studies have shown children with autism to have mitochon- 1. Urine for organic acid testing: to evaluate for mitochon-
drial issues including mitochondrial dysfunction, mtDNA drial function via Krebs cycle and amino acid metabo-
(mitochondrial DNA) over-replication, and deletions more lites, neurotransmitter metabolites, and microbial
often than neurotypical children [47]. Children with mito- overgrowth – yeast, bacteria, clostridia markers,
chondrial dysfunction can show nonspecific symptoms such nutritional and antioxidant issues, fatty acid metabolism
as anxiety and GI abnormalities as abdominal pain, constipa- and oxalates as well as detox indicators related to
tion, reflux, nausea, and vomiting; dizziness, headache and glutathione, ammonia, and GI bacteria.
fatigue. They may have a family history of mitochondrial 2. Urine peptide testing: gluteomorphin and casomor-
disease; neurodevelopmental regression (which should be a phin – neuropeptides can affect cognitive function,
very rare event in children); seizures; fatigue/lethargy; ataxia; speech, and auditory integration.
motor delay; or cardiomyopathy. Oxidative stress and inflam- 3. Blood chemistry: metabolic panel, CBC, magnesium and
mation adversely affect mitochondria [48–50]. Robert selenium, vitamin D, vitamin C, fat-soluble vitamins,
Naviaux, MD, a mitochondrial researcher at UCSD, has pro- ferritin, total iron-binding capacity (TIBC), serum lead,
posed the cell danger response (CDR) hypothesis that could cholesterol, RBC folate, RBC zinc, copper, and cerulo-
prove to be the root cause of autism, ADHD, asthma, atopy, plasmin.
allergies, epilepsy, Alzheimer’s disease, bipolar disorder, and 4. Markers of immune function and inflammation:
other chronic issues [51]. He describes it as universal meta- Activated T- and B-cell subsets, immunoglobulins,
bolic response to stress or injury and suggests that these cytokines, ANA, ESR, C-reactive protein, anti-casein,
issues trace back to an abnormal persistence of a normal, anti-­gluten, and anti-soy IgG. Viral/bacterial markers if
alternative functional state of the extracellular ATP signaling, indicated.
causing a loss of ATP.  The CDR is protective until these 5. Genetic screening: Genetic sequencing can be done by
changes become sustained. When they occur during preg- saliva or blood, which is still very expensive. It is difficult
nancy or the first 3 years of life, they can alter the trajectory to test the entire genome through saliva unless it is
of normal development [52]. possible to collect several milliliters; however several
Neurodevelopmental Disorders in Children
501 30
companies can test a limited number of genes from a mood swings, social anxiety, infections, sleep issues,
paper dot saturated with saliva. Some polymorphisms can absence of dreams, and light, sound, and tactile sensitivities.
be supported with supplementation. CGH (comparative Greater than 10 mcg/dl may indicate borderline pyroluria,
genomic hybridization) array identifies small deletions and greater than 20 mcg/dl is positive for pyroluria. In
and duplications to check for genetic anomalies. Note that pyrrole disorder, B6 and zinc are rendered inactive by the
FMR1 gene, which codes for fragile X mental retardation build-up of HPL (hydroxyhemopyrrolin-2-one) involved in
protein, has symptoms that can overlap with autism. the synthesis of heme. The result is a major deficiency of B6
6. Hormones: thyroid function – FT3, FT4, and TSH. Low and zinc. Individualized doses of B6, P5P, zinc, and possibly
thyroid can cause fatigue and brain fog. AM cortisol or manganese and evening Gamma linolenic acid may be
salivary cortisol. Low cortisol can be related to transition helpful. This condition should be treated prior to detox. If
difficulties, tantrums, and anxiety. pyrroles are an issue, results with supplementation can
7. Allergy: IgE, IgG – food sensitivity and delayed reactions usually be seen in 4 weeks.
can contribute to behavior issues. A large number of IgG
food allergies indicate a leaky gut. How a child acts after
eating a food should be noted. This information and 30.12 Family History and Autism
appropriate laboratory findings will help to decide which
foods are most important to eliminate. Diet should be as Neurologic and autoimmune issues commonly run in fami-
varied as possible. In some children, removing allergenic lies [62]. Neurologic disorders found in families with autism
foods may cause withdrawal and worsening behavior for include Asperger’s, Tourette’s, ADHD, depression, schizo-
up to 2 or 3 weeks. phrenia, and bipolar disorder. Autoimmune conditions in
8. Oxidative stress: can be evaluated by urine for lipid families with autism include lupus, Hashimoto’s thyroiditis,
peroxides indicating oxidative damage to cell mem- type 1 diabetes, chronic fatigue, rheumatoid arthritis, fibro-
branes and 8-OHdG-oxidative damage to DNA. Blood myalgia, and Crohn’s disease [63]. A common factor linking
markers: lipid peroxides, nitrotyrosine, transferrin, these issues may include impaired transsulfuration and
8-OHdG, glutathione, cysteine/cystine ratio, and the methylation pathways.
enzymes glutathione peroxidase and superoxide
dismutase. Oxidative stress is common in neuropsychi-
atric disorders [57]. 30.13 Polymorphisms in Autism
9. Mitochondrial dysfunction (MD): fasting morning
labs – lactate, pyruvate, free and total carnitine, acylcar- Autism has a strong genetic component. ASD is a heteroge-
nitine panel, ubiquinone, ammonia, CK, AST/ALT, CO2, neous disorder with marked genotypic and phenotypic vari-
glucose, and mitochondrial DNA sequencing. ASD has ability and complexity [64]. However, genes do not cause
been associated with elevations in lactate-to-pyruvate disease or epidemics. A gene codes for how to make a protein.
ratio, CK, ammonia, AST, and decreased carnitine. Some The protein and RNA molecules interact with one another in
of the newer biomarkers include buccal cell enzymology dance of dizzying complexity. The genome can provide many
and mitochondrial antibodies [58]. answers, as we learn its language and complex interactions.
10. Autoimmune testing: myelin basic protein autoantibod- Many genes have been associated with autism, but it is
ies indicate inflammatory demyelination, cerebellar genetically heterogeneous and has interactions with environ-
antibodies. Anti-neuronal antibodies have implicated in mental factors [64]. Monozygotic twin discordance studies
severe autism [59]. where only one twin is affected suggest a role for non-genetic
11. Toxins: urine porphyrins – an oxidized metabolite of factors [65].
heme biosynthesis associated with genetic disorders, The CHD8 gene is one of the few genes consistently
metabolic issues, oxidative stress, and toxic exposures to related to a small subtype of autism that occurs early in
metals like mercury, lead, and arsenic or chemicals. development consisting of ASD, macrocephaly with a promi-
Because porphyrins are assembled in the mitochondria, nent forehead, wide-set eyes and a pointed chin, GI com-
this gives information on the health of the mitochondria. plaints, and marked sleep dysfunction [66]. This disruption is
Patterns of porphyrin elevations can indicate clues to interesting because of the comorbidities between brain
specific toxicities. For example, coproporphyrin or development and enteric innervation.
precoproporhyrins can be associated with mercury It is thought that common gene variants contribute to the
exposure. Several labs have toxic panels that test for risk of developing autism. Many of these polymorphisms can
alkylphenols, organochlorines, organophosphates, be positively influenced by nutritional interventions [67] and
plasticizers, PCBs, and volatile organic compounds [60]. supporting biochemical pathways, such as methylation, sul-
12. Kryptopyrrole quantitative urine: tests for pyroluria, an fation, and neurotransmitter synthesis metabolism. Genes
inherited disorder that robs the body of zinc and B6. This considered clinically useful by integrative practitioners
condition may be found in ASD, ADHD, and behavior include those related to gut health, cellular energy, folate
disorders, including obsessive-compulsive disorder, anxiety metabolism, methylation detox, detoxification and the
and depression [61]. Symptoms include poor anger control, methionine cycle.
 502 M. A. M. Haskell

30.14 Genes Affecting GI Health TCN2: transcobalamin II gene encodes a protein that
transports vitamin B12 from blood into cells. One variant is
HLA (human leukocyte antigen) genes may increase the associated with low serum B12 and high homocysteine.
risk of gluten intolerance, peanut allergy, and celiac dis- Decreased brain levels of B12 can be found in autism.
ease.
MCM6 (minichromosome maintenance complex 6) con-
trols the activity of LCT gene, which codes for lactase. 30.16 Transsulfuration Pathway Genes
Variants in the MCM6 gene improve lactose tolerance and
lack of variants increase the risk of lactose intolerance. CBS: cystathionine beta synthase regulates homocysteine to
FUT2 (fucosyltransferase 2), involved in methylation cystathionine to the transsulfuration pathway. CBS muta-
pathway, can lead to lower levels of bifidobacteria and prebi- tions that upregulate this enzyme can cause excess ammo-
otics [68]. Disruptions in these genes can affect intestinal nia, taurine, and sulfur. A diet high in sulfur and related
health and contribute to GI comorbidity, as well as affect the supplements may have a negative effect with these SNPs.
30 strength of the immune system. The active form of B6, pyridoxal-5-phosphate can work bet-
ter for those with genetic variations that slow CBS activity.

30.15 Folate and Methylation Genes

30.17 Neurotransmitter Genes
MTHFR (methylenetetrahydrofolate reductase) is the
enzyme that activates folates to 5-MTHF needed for the COMT: catechol-O-methyltransferase helps break down cate-
re-­methylation of homocysteine to methionine. In studies cholamines, and the neurotransmitters dopamine, norepineph-
of Caucasian and Hispanic populations, it is estimated rine, and epinephrine, as well as some chemicals, toxins, and
that 40–50% of the population has at least MTHFR SNP estrogen. COMT affects parts of the prefrontal cortex which is
[69], but it is estimated 90% of children with autism have involved with personality, controlling behaviors, short-term
a SNP in one of the MTHFR genes and tend to under- memory, planning, abstract thinking, and emotion. COMT++
methylate. The incidence of MTHFR and MTRR SNPs individuals may have difficulty breaking down the above chem-
vary regionally and among different ethnic groups [70]. icals and may have difficulty with methyl donors, leading to
These SNPs affect detoxification, immune function, arte- hyperactivity, behavior issues, anxiety, and irritability.
rial health, vascular function, and neurocognitive and GABRB3: affects the GABA receptor and has been noted
mental health. in some cases of autism [72].
Physical signs associated with folate SNPs include mid-
line defects such as tongue, lip ties, spina bifida [71], hypo-
spadias, cleft palate, Mongolian spots, sacral dimples, 30.18 Genes Affecting Detoxification
umbilical hernia, and impaired detoxification. This author
has found many babies with tongue or lip ties have at least GST: glutathione S-transferase detoxifies some products of
one MTHFR gene SNP and some babies show multiple oxidative stress and toxins [73].
midline issues such as tongue tie, hypospadias, sacral GSTM1: (liver) and GSTP1 (lungs and brain) – responsi-
­dimple and midline birth marks. ble for making the master antioxidant glutathione [73].
MTHFR, FOLR (folate receptor), and DHFR (dihydro- PON1: Paraoxonase aids in clearing pesticides and other
folate reductase) gene variants may require more folate-rich toxins [73].
food or folate supplements. However, in people who over-­ SOD: Superoxide dismutase is an antioxidant enzyme
methylate, there can be difficulty with methyl donors which involved in Phase 2 liver detox that converts reactive oxygen
can manifest as irritability, behavioral issues, and/or hyper- species to hydrogen peroxide to quell free radical damage [74].
activity. Methylation is affected by numerous genes, nutri- CYP2C9: There are 60 CYP (cytochrome P450) genes
tion, and environment. With these SNPs, avoid folic acid in that aid the liver in clearing toxic substances in Phase 1 liver
enriched processed foods and supplements as unmetabo- detox [74].
lized folic acid can lead to immune dysfunction. The Variants in CYP, Pon1, SOD, GSTM1, and glutathione
MTHFR polymorphism calls for methylfolate instead of can decrease the effectiveness of detoxification and lead to
folic acid and methylcobalamin rather than cyanocobala- environmental and chemical sensitivities. SNPs are common
min. Adeno sylcobalamin or hydroxycobalamin may work in these genes with autism [74].
better depending on MTR (methionine synthase) and
MTRR (methionine synthase reductase) methionine cycle
genes. 30.19 Nutritional Support
RFC: reduced folate carrier polymorphisms in the mother
can affect embryogenesis and organogenesis by compromis- In Changing the Course of Autism, author Bryan Jepson
ing intrauterine availability of folate products and can dis- states, “Diet changes often result in rapid improvements in
rupt normal neurodevelopment. both neurological and GI function, leading to better
Neurodevelopmental Disorders in Children
503 30
absorption of nutrients, decreased GI inflammation and
decreased immune system activation: subsequent improve- Box 30.1  Signs of Phenol Sensitivity
ment in sleep, bowel function, mood and immunity 55 Sulfate in blood and urine
55 Reactions to phenol/salicylates/Tylenol
­follow” [75].
55 Cravings for phenolic foods—dark fruits, apples, onions,
A gluten-free/casein-free diet is a common starting point. potatoes, curly kale, cabbage
If a GF/CF diet seems like it would be difficult for the family, 55 Family history of autoimmune/neurologic issues
a urine peptide test for casomorphin and gluteomorphin is 55 Phase 2 liver detox test for sulfation
helpful to convince the family if a GF/CF diet is worth the
effort. If one or both tests are positive and the family is will-
ing to implement the diet, improved behavior is often seen excess masturbation, and bowel issues. Oxalates cause gut
[76]. Studies on GF/CF diets are inconclusive but parents inflammation and often show up high on urine organic acid
often report improvements in learning and language. A tests. Calcium citrate can be used to lower oxalates with
gluten-­free diet could foster inadequate B vitamins, iron, and meals. Many healthy foods contain oxalates such as spinach,
zinc as well as lower fiber intake; however, these deficiencies beets, berries, beans, nuts, and chocolate so just high oxalate
are easily overcome with a whole-foods diet and supplemen- foods are limited. Oxalates can be removed by soaking grains,
tation when needed. nuts, and beans [79].
A recent study showed improvement in 67 children and Many whole foods have a high phenolic content with
adults on a healthy gluten-free, casein-free, soy-free (HGSCF) many protective properties and antioxidants. However,
diet with sequentially added nutritional supplements. The ­children with autism tend to have low sulfate levels and
results suggest that dietary and nutritional intervention can phenol sulfotransferase (PST), leading to a decreased
improve nutritional status, non-verbal IQ, and other symp- capacity to detoxify phenols [80]. Dysbiosis and heavy
toms of autism [77]. metals can also adversely affect sulfation leading to phenol
In susceptible children, dietary intervention is to sensitivity. Common symptoms of phenol intolerance
reduce gut inflammation so the gut can heal. For instance, include dark circles under the eyes, red face/ears, head
a gluten-­free/casein-free diet is worth trying for at least banging, self-injurious behavior, behavior issues, hives,
3 months [78]. Though studies are not clear that this is a inappropriate laughter, diarrhea, and stomach aches [79]
helpful intervention, parents often report improvement. (7 Box 30.1).
 

Signs that a GF/CF diet could be helpful include a distant, Finding the best foods and diet takes patience. Whenever
“spaced out” effect, picky eater, diarrhea/constipation, possible, expand healthy food choices and rotate foods to
abdominal distention, and speech and auditory issues. lessen food reactions. Textures are often an issue. How food
Gluten and casein contain high levels of glutamate and is prepared can alter textures to be more acceptable.
aspartate, both excitatory neurotransmitters. Glutamate is Nutrient support: Children with autism have brain dys-
involved in memory and learning. Glutamate converts to function. These children operate in narrow range. Add
GABA, which is calming and helps with speech. However supplements very slowly and monitor the results. A vita-
too much glutamate inhibits GABA conversion and cre- min/mineral supplement designed for sensitive children
ates neurological inflammation [79]. A healthy gut with a can be added. Balanced essential fatty acid supplementa-
flourishing microbiome and good nutrition are key for a tion and healthy fats in the diet support brain health.
healthy brain. Digestive enzymes can be helpful. For children with phenol
Addressing biochemical individuality in diet is key. Clues sensitivity, No-Fenol and molybdenum can help process
can be assessed using food cravings, diet diary, food fre- phenols [79].
quency, reactions to food, symptoms, biomarkers and lab Carnitine helps transport fatty acids in cells, needed for
results, and genetics. After several months on a GF/CF diet, fatty acid metabolism and energy production in the heart
the diet can be fine-tuned, changed, or layered with other and muscle. Probiotics support gut health and Saccharomyces
diets. The Specific Carbohydrate Diet (SCD) is helpful for helps reduce clostridia overgrowth [81]. Vitamin D can have
bowel inflammation, continued diarrhea, and gut dysbiosis. an immunomodulatory on T helper cells and T regulatory
The Gut and Psychology Syndrome (GAPS) diet was derived cells [82].
from the SCD. It eliminates grains, dairy, sugars, and starchy Epsom salt baths or foot soaks work for some children.
carbs. It uses fresh meat and fish and bone broths to help heal Epsom salt is magnesium sulfate, which can be absorbed
the gut. The Body Ecology Diet is helpful for yeast over- through the skin. Start with 1 teaspoon for sensitive children
growth, digestive discomfort, excess gas, and yeast symp- and work up to ½ to 2 cups per bath for 20 minutes depend-
toms. A Low Oxalate Diet can be helpful for discomfort in ing on the size of the child. Some parents report their chil-
the urinary or GI tract, body pain, continued stimming, dren sleep better and are more relaxed with Epsom salt baths.
 504 M. A. M. Haskell

Case Study: ASD

Jack is a 2-year-old boy with developmental and speech Physical Exam Positives: well-developed child with pale skin,
delay and recently diagnosed with autism. He has decreased dark circles under his eyes, aphthous ulcers, distended
eye contact, aggressive behavior, and difficulty with abdomen, + gas, bloating, mild perioral rash, poor balance,
transitions and engages in solitary play. lumbosacral area is compressed, walks with his left leg
Prenatal History: Second pregnancy, which was a pleasant externally rotated, occipital and frontal bones show molding
surprise. Mom was in good health but suffered severe nausea from birth, and head feels compressed, particularly in the
for the first month. At 26 weeks of gestation, Mom had a TDaP occipital area. Restrictions in the occipital area can reflect on the
vaccine and the baby stopped moving for several weeks. health of the cerebellum, which is involved with motor skills,
Mom had severe redness and swelling at the injection site balance, and muscle memory. Poor motor skills affect social
and had difficulty lifting her arm for months. In the third skills and communication skills.
trimester, she developed severe depression, which persisted Labs: Gluten/Casein Peptides Test – positive for both
postpartum. indicating a GF/CF diet should be very helpful.
Birth History: Labor began spontaneously at 41 weeks and In this case, both gluten and casein are being metabolized
30 lasted 21 hours. No medications were used, but mom pushed in gluteomorphin and casomorphin peptides, having opiate-like
for 2 hours. Birth weight was 7.5 pounds and Apgar scores were effects causing behavioral issues, brain fog, and addictive
8 and 9. Baby’s head shape was crooked. Baby was alert and symptoms to these foods. Organic acid test showed high
nursed immediately but ineffectively. furancarbonylglycine, the only yeast and fungal marker that was
Milk supply was low, possibly due to a history of breast high. Several mitochondrial markers were high, including
reduction surgery. He initially lost 20 ounces in the first week. succinic acid which may relate to a relative deficiency of
He breastfed for 2 months. He preferred to bottle feed and was riboflavin and/or CoQ10 which are cofactors for succinic
intolerant to cow dairy and soy formula, so he was given a dehydrogenase in the Krebs cycle.
hypoallergenic formula and then a non-GMO sensitive formula. High malic acid supports the use of niacin and CoQ10 and
He spit up after every feeding. Spitting up is most often high aconitic acid requires glutathione to support the enzyme
irritation of the vagus nerve (CNX) from birth trauma but can aconitase. High quinolinic acid/5-HIAA ratio suggests neural
also be in response to a food that mom is eating or formula, excitotoxicity, common in autism. Inflammation from infection
most often cow dairy. Rarely it can be due to a congenitally lax or immune overstimulation, increased cortisol, or exposure to
sphincter. Difficulty latching is also a structural issue as birth phthalates all can increase this ratio. Carnitine, which mediates
trauma can cause compression of the hypoglossal nerve (CN the transfer of fatty acids across the membrane of the
XII), which does not have a canal yet, but traverses through a slit ­mitochondria, melatonin, turmeric, and garlic, may reduce
in the occipital condyles. He did not have a tongue tie, which is injury to the brain by quinolinic acid.
sometimes related to a MTHFR SNP. MAO B + (an X-linked gene): associated with aggression,
Past Medical History: At 2 months, he had DTaP vaccine. At poor breakdown of serotonin, COMT ++ affecting methylation,
3 months, he had a fever of 103 and was hospitalized for neurotransmitter degradation, MTHFR C677T +-, VDR + -.
late-onset Group B strep. At 8 months, he had a second DTaP MAO-B interacts with COMT and VDR. MAO-B may present
and became lethargic and miserable and lost his appetite. At clinically with anxiety, allergy, OCD (obsessive-compulsive
9 months, he developed repetitive play, spinning wheels of disorder), and tics. MAO-B++ tends to have high amines,
trucks, and stopped interacting in play. dopamine, and PEA (phenylethylamine), whereas MAO-B -tends
Diet History: Jack has a poor appetite and is a picky eater. to have low dopamine and MAO-B + - can have up-and-­down
His diet consists of oatmeal bars, crackers, yogurt, meat, dopamine.
chicken, nuts, a few fruits and veggies, as well as two bottles Treatment: Parents began a GF/CF diet and he continued his
daily of a pediatric meal replacement beverage. The meal basic supplements. He began a program of osteopathic manipu-
replacement contains water, sugar, corn maltodextrin, milk lative treatment aimed at releasing restricted areas of the body
protein concentrate, high oleic, safflower oil, canola oil, and soy and improving blood flow and glymphatic drainage in the brain.
protein isolate. Less than 0.5% of the following: short-chain (Glymphatics are essentially the lymphatics of the brain.) Within
fructooligosaccharides, natural and artificial flavor, cellulose gel, 3 weeks he began saying more words, developed better eye
potassium chloride, magnesium, phosphate, potassium citrate, contact, and began interacting with his siblings more (although
calcium phosphate, tuna oil, calcium carbonate, potassium, salt, not always peacefully). GSH cream and ascorbyl palmitate
cellulose gum, choline chloride, ascorbic acid, soy lecithin, vitamin C were added to support detoxification. Glutathione is a
monoglycerides, potassium hydroxide, m-inositol, carrageenan, major antioxidant and reduces oxidative stress from free
taurine, ferrous sulfate, dl-alpha-tocopheryl, acetate, L-carnitine, radicals, lipid peroxides, and heavy metals. Ascorbyl palmitate
zinc sulfate, calcium pantothenate, niacinamide, manganese vitamin C is lipid-soluble and thought to be most helpful for the
sulfate, thiamine chloride hydrochloride, pyridoxine hydrochlo- brain [83].
ride, riboflavin, lutein, cupric sulfate, vitamin A palmitate, folic Parents were instructed to do a 20-minute Epsom salt baths
acid, chromium chloride, biotin, potassium iodide, sodium twice a week and “clay play” with bentonite clay. Clay play is
selenate, sodium molybdate, phylloquinone, vitamin D3, and best done outside because plants love it but plumbing pipes do
cyanocobalamin. Corn maltodextrin, soy, safflower, and canola not. He continued progressive therapeutic measures with
oil are commonly from GMO crops. He prefers sweet and salty nutrient support, speech therapy, and occupational therapy
foods. (OT) and applied behavioral analysis (ABA) and continues to
Family History: postpartum depression, depression, and make progress.
anxiety.
Neurodevelopmental Disorders in Children
505 30
30.20 ADHD 55 Comprehensive Fatty Acids Test
55 Comprehensive stool analysis
ADHD is defined as inattention, hyperactivity, forgetfulness, 55 Gluten/Casein Peptides Test – urine
distractibility, and impulsive behavior, although symptoms 55 IgE/IgG food allergy/sensitivity testing including candida
and causes vary for each individual child. ADHD can trigger 55 Metals hair test or toxin testing histamine levels normal
intense emotions that overwhelm the brain. These children range: 40–70 ng/ml. Histamine is broken down by
tend to have low frustration tolerance, hot tempers, excitabil- methyl groups, so high histamine can relate to low
ity, social anxiety, and difficulty with relationships. According neurotransmitters and under-methylation, depression,
to CDC reports in 2016, one in nine children age 2–17 in the allergies, OCD, and hyperactivity. Low histamine can
United States has been diagnosed with ADHD. It is explod- relate to high neurotransmitters and over-methylation,
ing in incidence and there is no good answer for how to treat frustration, cries easily.
it or prevent it. A thorough assessment by a team is needed. 55 Gene testing: MTHFR SNPs are common. Dopamine D4
Treatment should include diet modification, biomedical receptor gene (DRD4), dopamine D5 receptor gene,
treatment, and nutritional supplementation as indicated, COMT, dopamine transporter gene (SLC6A3 or DAT1),
along with behavior modification, lifestyle change, and coun- and MAO genes are some genes thought to be involved.
seling. Medication can be helpful for some children, but Dopamine is often low.
should never be the only treatment as it has not been shown
to necessarily have long-term benefits.
Shaw found that children with ADHD are behind their 30.21 Dr. Amen’s Seven Types of ADHD [87]
classmates by about 3 years in brain development, although
they had precocious motor cortex development [84]. On the Dr. Amen’s clinical experience and SPECT brain scan imag-
positive side, these children can be fun, smart, creative, and ing led him to delineate seven types of ADHD.
driven and, as adults, often run large companies. 1. Classic ADHD: Inattentive, distractible, hyperactive,
One study shows the brain maturation delay theory to disorganized, and impulsive. Energetic, fun, loves to
include subcortical structures such as the nucleus accumbens play, often walked early. Difficulty with time, getting
(motivation, reward circuit, involves dopamine and sero- homework done efficiently.
tonin), amygdala (processing of memory, emotional reac-
tions, decision-making), caudate (procedural and associative Cause: Brain activity is normal at rest but decreases d ­ uring
learning and inhibitory control of action), hippocampus concentration. There is decreased blood flow to the prefron-
(short-term to long-term memory), and putamen (influences tal cortex, cerebellum, and basal ganglia. Dopamine supports
learning, uses GABA and acetylcholine) [85]. attention span, focus, and motivation and is likely deficient.
ADD/ADHD is not a single issue and it is difficult to Treatment: Stimulating supplements such as rhodiola,
define pathology. It tends to run in families and several genes green tea, L-tyrosine, and high EPA fish oil. Physical activity
are often involved. Environmental issues are an increased especially before school and homework. Stimulant medica-
issue. Similar symptoms can also be seen with other issues tions are sometimes used.
such as thyroid issues, lead toxicity, head injury, divorce, 2. Inattentive ADD: Short attention span, distractible,
environmental toxins, food additives, fetal alcohol syndrome, disorganized, procrastinates, and daydreams.
fragile X, mitochondrial issues, developmental delays, anxi-
ety, and food allergies. Cause: Dopamine is deficient.
Treatment: High-protein, lower-carb diets are helpful as
is regular exercise. For types 1 and 2, L-tyrosine can help
30.20.1 Lifestyle and Environmental Factors build dopamine. It is best taken on an empty stomach. It can
increase the brain level of phenylethylamine (PEA), a mild
ADHD may be caused by or made worse by toxic exposure, stimulant that can increase motivation. PEA is byproduct of
trauma, food allergies/sensitivities, yeast overgrowth, and the amino acid phenylalanine. (Chocolate contains PEA,
nutritional deficiencies. explaining its longtime popularity.)
Biomedical testing: 3. Over-focused ADD: Classic ADD with signs of having
55 Organic acid testing: difficulty shifting attention and negative thought
1. Evaluates biomarkers for Candida overgrowth, which patterns or behaviors.
can affect brain function and sensory issues and
contribute to self-stimulatory behavior, bacterial Cause: Dopamine and serotonin deficiencies, over-­activity in
overgrowth, and neurotransmitter metabolites the anterior cingulate gyrus, reducing flexibility.
2. Clostridia toxic metabolite markers Treatment: L-tryptophan, 5-HTP (can reduce depres-
55 Lab tests: cholesterol panel, copper/zinc ratio, ferritin, sion), saffron, and inositol (helps boost alertness, focus,
vitamin D, thyroid testing, and streptococcus antibodies. mood, and mental clarity). Avoid a high-protein diet if it
Copper/zinc ratio: Elevated copper with depressed zinc can triggers mean behavior. Neurofeedback can be helpful to
contribute to ADHD, hyperactivity, and rage behavior [86]. train the brain to recruit focus brain waves.
 506 M. A. M. Haskell

4. Temporal lobe ADD: Classic ADD as well as learning, ances, or chronic infections that can be improved with nutri-
memory, and behavioral problems such as quick anger, tion. Diet alone will not treat attention deficit issues.
aggression, anxiety, and mild paranoia. 55 A clean whole-foods diet is essential and can reduce
pesticide accumulation [89]. This is important for all
Cause: Changes in the temporal lobe, decreased activity in children. Encourage parents to purchase the best food
the prefrontal cortex. they can afford.
Treatment: Amino acid GABA is used to calm neural activ- 55 Avoid processed foods as much as possible. Help
ity and inhibit nerve cells from over-firing or erratic firing, children recognize the effects of what they eat and the
magnesium for anxiety and irritability, and gingko or vinpo- possible consequences.
cetine for learning and memory problems. Sometimes anti- 55 Reduce high-sugar foods and starchy carbohydrates.
convulsant medications are used to help with mood stability. These foods increase insulin levels triggering hypoglyce-
5. Limbic ADD: This type of ADD can include depression, mia. This can lead to the brain secreting increased
moodiness, negativity, irritability, social isolation, and glutamate, a chemical messenger which becomes an
30 low self-esteem. Depression tends to be cyclical, whereas excitotoxin in excess. Too much glutamate affects mood
ADD symptoms tend to be more constant. by causing agitation, anger, anxiety, depression, and
panic attacks.
Cause: Decreased prefrontal cortex activity, hyperactivity in 55 Free glutamate is a component of many food additives
the deep limbic (emotional center) center of the brain. Painful such as MSG, yeast extract, calcium caseinate, etc.
emotions can occur when the deep limbic system is inflamed. High-sugar diets also increase chronic inflammation.
The deep limbic system also processes the sense of smell and MSG and hydrolyzed vegetable protein can decrease
affects sleep, appetite, social awareness, motivation, and drive. dopamine levels.
Treatment: Diet and aerobic exercise. Amino acid supple- 55 High glycemic diets impair delta 5 and delta 6 dehydro-
ments, DL-phenylalanine and L-tyrosine. DL-phenylalanine genase, enzymes involved in EPA and DHA production
may cause anxiety, jitteriness, and hyperactivity in children. needed for brain health. Hydrogenated oils impair cell
6. Ring of fire ADD: Includes ADD symptoms with membrane and brain function.
sensitivity to noise, light, clothes, touch, rigid thinking, 55 Avoid allergens. The top seven are soy, wheat, cow dairy
grandiose thoughts, and unpredictable behavior. (goat milk does not contain A1 casein, which can
Symptoms tend to be consistent, as opposed to bipolar cross-react with gluten and may be better tolerated),
disorder where symptoms cycle. peanuts, tree nuts, eggs, and shellfish. Watch for food
family allergies. For instance, those with latex allergies
Cause: Hyperactive brain especially the cingulate gyrus, pari- might need to avoid avocados, bananas, kiwis, and
etal lobes, temporal lobes, and prefrontal cortex. papayas.
Treatment: Calming supplements GABA, 5HTP, and 55 Gluten sensitivity can affect the nervous system and the
L-tyrosine can be helpful. Stimulant medication may worsen brain. For children with a gluten intolerance, a GF diet
symptoms, if used alone. Diet to reduce allergies and inflam- can improve behavior and attention. Many patients with
mation and exercise are helpful. celiac disease have ADHD symptoms that improve with
7. Anxious ADD: Includes ADD symptoms with signs of a GF diet.
anxiety, headaches from stress, difficulty with social 55 Avoid food additives and genetically modified ingredi-
interactions, insecurity, and self-consciousness. ents. Blue #1 and #2, Green #3, Orange B, Red #3 and
#40, Yellow #5 and #6, and sodium benzoate are among
Cause: Over-activity in the basal ganglia affecting dopamine. the many food additives that can affect focus and
Treatment: Inositol, L-theanine, Holy Basil, and magne- behavior [90]. Artificial coloring can be found in sports
sium promote relaxation and focus. A combination of drinks, candy, cake, chewable vitamins, and toothpaste.
Magnolia officinalis and Phellodendron amurense has anti- Glyphosate, the active ingredient in Monsanto’s
stress benefits and reduces cortisol [88]. Physical exercise Roundup herbicide, was originally licensed as an
and reducing electronic overstimulation have calming effects. antibiotic. It destroys the microbiome of the soil and
Stimulant medications can increase anxiety and sleep issues the human gut. In addition, it limits the body’s ability
as well as cause these kids to become more mechanical. If to detoxify and blocks vitamin D. GMO foods have
stimulant medication is needed, try the lowest dose possible. been modified to survive direct application of herbi-
cides; hence eating GMO foods means ingesting
glyphosate and other toxic components of the herbi-
30.21.1  eneral Dietary and Lifestyle
G cide.
Strategies for ADHD 55 Nitrites used in some cured meats such as lunchmeat,
bacon, ham, sausages, and hotdogs can cause restlessness
Many children with ADHD have nutritional or metabolic and rapid heart rate as well as increased risk of type 1
imbalances, dietary issues, food allergies or sensitivities, diabetes, IBS, and cancer. Artificial sweeteners can affect
toxic exposures, yeast overgrowth, gastrointestinal imbal- cognitive function and emotional balance.
Neurodevelopmental Disorders in Children
507 30
55 Omega-3 fatty acids can be helpful in reducing hyperac- breaking down dopamine which helps regulate sleep.
tivity, behavioral issues, and learning problems. They Children with COMT gene snips may have more
support the executive function centers of the brain. difficulty with sleep. Medication and caffeine can also
DHA and EPA from clean fish or fish oil are most helpful affect sleep. A regular bedtime every day, a comfortable
as not all people can convert ALA from vegetarian bed, and a good sleep environment facilitate restful sleep.
sources. Wild-caught salmon also contains B6. Avoid 55 Melatonin can help with a faulty circadian clock when
damaged fats in refined processed foods. taken an hour before bedtime. Children’s dosages are
55 Support healthy bowel flora and healthy, daily bowel based on body weight and metabolism. GABA works for
movements. A toxic gut can increase behavior symp- some, and sleep tea or essential oils like lavender and
toms, ADHD, depression, and autism. rosemary can be helpful. Benadryl (diphenhydramine)
55 B-6 at 15–30 mg/kg may be helpful for focus with a B causes drowsiness but has been recently implicated in
complex, EPA/DHA, multi-mineral, and probiotics. dementia when used regularly so it’s not a good idea in
55 Vitamin D supplementation may improve cognitive children with brain challenges.
function and attention and lessen hyperactivity and 55 No computers, phones, or TV in the bedroom. Turn off
impulsivity in children with ADHD who are vitamin D Wi-Fi, which is low-level microwave radiation, at night
deficient [91]. (or better yet, use wired computers). Radiation from
55 Inositol, Bacopa, and theanine can be relaxing. wireless devices can delay deep non-REM sleep, which
55 Rhodiola rosea can improve focus. There are several good can impact learning and memory, as well as increase
supplement formulas for improving focus; however not oxidative stress. Electromagnetic frequencies (EMF)/
all are user-friendly for the pediatric population as they radiofrequency radiation (RFR) can also adversely affect
require cooperation and being able to swallow capsules. immune and metabolic function. Avoid placing beds
55 Sensory integration issues can compound ADHD and near walls that have smart meters outside.
interfere with learning. Sensory integration refers to how 55 Avoid blue light from computers, TV, iPads, and iPhones
our senses work together to process and organize incom- for 1–2 hours before bed. Blue light signals the pineal
ing information. gland to shut off melatonin production.
55 Exercise can enhance dopamine and norepinephrine 55 Digesting snacks too close to bedtime can keep children
production, which can help improve attention and focus. awake. Warm milk, turkey, or an apple contains trypto-
Regular exercise can help relieve stress, regulate hyperactiv- phan, which can facilitate sleep. Avoid GMO Arctic
ity, and improve concentration. Outdoor activity is apples.
important, including exposure to natural light. Avoid 55 Parenting is a tough job. This is particularly true for
“nature-deficit disorder,” a term coined by author Richard parents with ADHD parenting children with
Louv [92]. Exercise before school or on the way to school as ADHD. They can thrive on turmoil in relationships
well as before and during homework is helpful. Incorporate unconsciously because it stimulates their brain and
cross-body exercises such as running, skipping, marching, makes them more alert. Retraining patterns of behavior
or Simon Says using cross-lateral motions. or behavior modification can be a big help for families.
55 Downtime is important too: allow time for free play, 55 Some teens with ADHD self-medicate with marijuana,
building with Legos or blocks, drawing, playing in the often to reduce anxiety. Marijuana has negative effects
dirt, petting the cat, etc. on attention, memory, and learning that can last for days
55 Neurofeedback can help the frontal lobes learn to stay in to weeks. The hippocampus region of the brain is
a focused beta state. Studies show that the results can important for memory, learning, and the integration of
have lasting effects. Cognitive behavioral therapy can sensory experience with emotions and motivations as
improve skills and habits for executive function and may well as converting information into short-term memory.
improve emotional and social self-regulation. THC (delta-9-tetrahydrocannabinol) suppresses the way
55 Essential oils: vetiver and cedarwood can calm and the information processing system of the hippocampus
improve focus. Rosemary and peppermint can improve works [93].
alertness and enhance memory. Frankincense brings 55 Executive function support is helpful. Watches and
clarity and higher cognitive function. Ylang ylang and timers help with time periods needed for tasks. Break up
lavender are calming. lengthy tasks into small steps. Support emotional
55 Sleep issues are quite common in children with regulation and provide positive motivation.
ADHD. They may have difficulty falling asleep, restless 55 Finding the best teacher/school is essential. These
sleep, or difficulty waking. Areas of the brain that children need strategies for emotional regulation,
regulate attention also regulate sleep. Dysregulation of support planning for the future, externalized motivation,
the serotonin system can affect both these areas. Their and encouragement.
internal circadian clock may be off, not releasing
melatonin at the best time in the evening. This faulty Biomedical treatments, nutritional supplementation, and diet
signaling can contribute to difficulty with schedules and are an important adjunct to behavior modification, lifestyle
keeping track of time. The COMT gene is responsible for changes, executive function tutoring, occupational therapy,
 508 M. A. M. Haskell

Rare inherited metabolic disorders such as pyridoxine-­

Glyphosate dependent seizures, biotinidase deficiency, and folinic
GMO foods
used as desiccant acid-­responsive seizures respond to supplying the missing
Corn Wheat nutrient. Pyridoxine-dependent epilepsy is not responsive
Soy Barley to antiepileptic medication, but responds clinically and
Cotton Rice with improvements on EEG to large daily supplementation
Canola Sugar cane
Alfalfa Sugar beets of B6. The folate receptor 1 (FOLR1) gene may also be
Wheat-soon Canola involved.
Sugar beet Cotton A SNP in this gene can lead to cerebral folate deficiency
Squash Beans, peas, lentils
Sweet potato that may affect social interactions, developmental delay, and
Rye, buckwheat seizure control.
Millet Biotinidase deficiency can be profound or partial,
depending on how severe the enzymatic defect is [95].
30 Symptoms most often occur between 3 and 6  months with
..      Fig. 30.3  Recommended foods to avoid to lessen oxidative stress
seizures, hypotonia, developmental delay, skin issues, and
and inflammation
respiratory problems. There are four biotin-dependent car-
boxylases that can be treated with biotin. This issue may be
neurofeedback, and, if needed, medication. Underlying issues picked up on the newborn screening exam.
need to be addressed and medications should never be the The ketogenic diet, developed by Russell Wilder at the
only intervention because it does not provide long-term Mayo Clinic in 1921, is now considered an important thera-
improvements in attention and learning (. Fig. 30.3).
  peutic option for epilepsy as well as infantile spasms [96] and
is being investigated for children with autism and Rett syn-
drome. Despite the success in resolving or lessening seizures
30.22 Seizure Disorders it provided for many children, it remained little used until it
became popular in the 1990s, with the Charlie Foundation
Seizures have many different causes and can occur at any age. for Ketogenic Therapies. The ketogenic diet involves chang-
The term epilepsy encompasses various types of seizure disor- ing the body’s primary energy source from glucose to ketones.
ders thought to be caused by abnormal electrical signals in the The breakdown products of ketones, beta-hydroxybutyric
brain. Seizures in newborns can be triggered by anoxia, infec- acid, cross the blood-brain barrier and are used by the brain
tion, bleeding, metabolic imbalances and drug withdrawal. for energy. The ketogenic diet helps reduce microglial activa-
Structural damage to the brain can occur in the perinatal period tion, brain inflammation, and excitotoxicity. Studies have
and during birth from vascular or cerebral trauma; later from shown that half of children will have a 50% improvement in
head injury, sports injuries, bike or motor vehicle accidents, seizures and about one third show a 90% improvement. A
cerebrovascular accidents, as well as from intracranial tumors, small percentile of children become seizure-free [97]. This
metabolic diseases, toxins, vaccines, and drugs. This damage diet is sometimes initiated under hospital conditions. “The
may be visible or more often invisible and most often is not seen diet is difficult,” according to one mother, “but not nearly as
on CT or MRI studies. Electroencephalogram (EEG) is used to difficult as watching your child have a seizure.” It requires a
look for seizure activity in the brain, but in patients with lot of prep work, counting carbs, weighing food, and making
observed seizures, it is sometimes difficult to capture the activ- substitutions that suit a child’s taste, but the result can be
ity on EEG. For seizures resulting from a traumatic cause, cra- eventual resolution of seizures in some cases or a reduction
nial osteopathy or cranial sacral therapy may be helpful. in seizures.
Seizures impacting the life of a child are most commonly treated If the diet is successful, there are fewer emergency room
with anticonvulsant medications. Surgery is used only if there is visits and doctor visits and less medication which often
a specific identifiable focus. Seizures are driven by inflamma- translates to improved development. Some children with sei-
tion and excitotoxicity. Supportive care for children with sei- zures prefer high-fat foods, and one study from 2015 suggests
zure disorders includes diet, vitamins, supplements, herbs, this may be helpful in predicting which children will have
homeopathy, mind-body techniques, and manual medicine. success with the ketogenic diet. The ketogenic diet should be
A vitamin B6 (pyridoxine) deficiency can cause or worsen managed by a neurologist and dietitian. This is a medical diet
seizures, especially in infants and newborns [94]. B6 can some- and needs supervision for side effects, efficacy, medication
times help older children also. Sodium, calcium, and magne- adjustment, and weight gain. It is initiated by fasting during a
sium are necessary for stable electrical activity of the brain. brief hospital stay.
Low magnesium levels can trigger seizures and may lead to low Several other versions of the ketogenic diet that are used
calcium levels. Low blood sugar can trigger seizures and is for seizures include the modified Atkins diet (MAD), the
most common in children with type 1 diabetes taking insulin. medium-chain triglyceride (MCT) diet, and the low glyce-
Low sodium can be caused by diuretics, anti-seizure mic index treatment (LGIT) [98]. The efficacy of the MAD
medications such as carbamazepine and oxcarbazepine, or diet is good and it is easier to manage, although stricter keto-
excessive water intake. sis works better for some children. The modified Atkins diet
Neurodevelopmental Disorders in Children
509 30
One challenge of the ketogenic diet has been that the rec-
Box 30.2  Conditions Likely to Respond ommended fat sources were not always the healthiest and
to Ketogenic Diet contained damaged fats. By using healthy fat sources such as
55 GLUT-1 deficiency syndrome (SLC2A1 gene) grass-fed butter, organic ghee, nut butters, coconut and MCT
55 Mitochondrial disease
oil, olive oil, flaxseed, omega-3 fatty acids, and homemade
55 Children receiving tube feeding or mostly formula
55 Pyruvate dehydrogenase deficiency mayonnaise or mayonnaise made from healthier fat sources,
55 Myoclonic-astatic epilepsy (Doose syndrome) often the chances for brain healing on a cellular level are improved.
presents ages 3–5 years with head drop seizures Food additives such as colorings, preservatives, monoso-
55 Dravet syndrome (severe myoclonic epilepsy of infancy dium glutamate (MSG), and artificial sweeteners including
(SCN1A gene)
aspartame, saccharin, and phenylalanine can trigger seizures
55 Infantile spasms (West syndrome)-1 study showed 2/3
have greater than 90% reduction in spasms in some people. Some ketogenic formulas contain aspartame
55 Tuberous sclerosis complex—-may be more long-term or other artificial sweeteners. Substitute healthier sweeteners
treatment such as stevia for the artificial sweeteners often recommended.
55 Rett syndrome MCT is found in coconuts, in coconut and palm kernel
oil, and in smaller amounts in butter and high-fat dairy prod-
ucts from grass-fed cows and goats. There are four types of
MCTs. Coconut oil contains all types.
(MAD) can be started outside the hospital and does not 55 6 carbons (C6), caproic acid
require fasting to initiate. It should be under the supervision 55 8 carbons (C8), caprylic acid
of the neurologist. 55 10 carbons (C10), capric acid
The advantages of the modified Atkins diet (MAD) are: 55 12 carbons (C12), lauric acid – known for antibacterial,
55 No fluid or calorie restrictions or limitations. antimicrobial, and antiviral properties
55 There are no restrictions on proteins as fats do not have
to be weighed or measured. Typically 35% of calories for Fractionated coconut oil contains primarily C8 and C10,
a patient on the MAD come from protein. which support brain health and curb appetite.
55 Foods do not have to be weighed and measured, but MCTs have antioxidant and anti-inflammatory properties
carbohydrate counts are limited to 15–20 g a day. as they produce fewer oxygen species when metabolized to
55 The MAD is easier to manage outside the home and in ATP.  Most MCT oil products contain C8 and C10 fats. C8
restaurants and is easier for the family. (caprylic acid) converts to ketones more efficiently than C10.
55 Family members can eat the same way. Ketones make great fuel for mitochondria and support their
functioning. Some companies make MCT oil with a higher C8
MAD has a similar efficacy as the ketogenic diet (40–50% content, which may be better tolerated. High C8 MCT oil is best
with greater than 50% seizure reduction, including approxi- given in the morning as it wakes the brain up. Dose is important
mately 15% seizure-free). It works for men and women as too much MCT oil can cause diarrhea in some children.
equally and is being used in children, adolescents, and adults.
Like the ketogenic diet, it is most commonly used for patients
with daily seizures who have not fully responded to medica- 30.22.2 Ketogenic Diet Labs
tions. It is under study for regions of the world with limited
resources for which the classic ketogenic diet would be too Check labs prior to starting the diet and at 3 and 6 months
difficult and/or time-consuming. and then every 6 months thereafter.
The ketogenic diet is worth trying for all seizure types and Urinalysis
severities, in all ages and sizes (7 Box 30.2).
  After an 8-hour fast:
55 CBC with differential
55 Complete metabolic profile (SMA-20)
30.22.1 Contraindications to the  55 Complete lipid profile (fasting)
Ketogenic Diet 55 Selenium level
55 Carnitine profile (total and free)
55 Carnitine deficiency (primary) 55 1,25-OH-vitamin D level
55 Carnitine palmitoyltransferase (CPT) I or II deficiency 55 A red cell fatty acid profile can help guide choices of fats
55 Carnitine translocase deficiency
55 B-oxidative defects
55 Pyruvate carboxylase deficiency
55 Porphyria 30.22.3 Supplements for the Ketogenic Diet

Ketogenic diets do not work as well if there are issues main- 55 Multivitamins: Because the ketogenic diet eliminates
taining adequate nutrition, a surgical focus for the seizures, grains and limits fruits and vegetables, it is essential that
or parental or caregiver noncompliance. children take a complete, low-carb multivitamin.
 510 M. A. M. Haskell

55 Calcium and vitamin D: Many epilepsy medications

affect nutritional status including calcium metabolism Box 30.3  Medications That May Increase Seizure
and subsequent bone loss. In addition, the diet is low in Frequency
calcium sources. Heavy cream, often used in the 55 Antihistamines
55 Insulin and diabetes medications
ketogenic diet, is low in calcium. Consider the need for
55 Oxytocin
calcium supplements and vitamin D. 55 Antidepressants
55 Oral citrates can help prevent kidney stones by alkalin- 55 Clomipramine
izing the urine and solubilizing urine calcium. 55 Clozapine
55 Constipation is a common side effect of the ketogenic 55 Lithium
55 Fluoroquinolone antibiotics
diet. Food choices such as MCT oil, avocados, and
55 Methylphenidate
high-fiber vegetables like cucumbers, asparagus, and 55 Metronidazole or Tinidazole
zucchini are helpful, as well as sufficient fluids, and
exercise. Magnesium citrate is used to relieve constipa-
30 tion but check for drug interactions.
55 Check nutrient depletions related to anticonvulsants and There are herbal combinations and supplements in various
other medications for all patients. For instance, phe- cultures that have anticonvulsant properties. Also, there are
nytoin (Dilantin), carbamazepine (Tegretol), valproic herbal remedies and supplements that can have proconvul-
acid (Depakote), topiramate (Topamax), and gabapentin sant effects or interact with antiepileptic medications [104].
(Neurontin) can deplete B6, folate, and B12. General diet guidelines include avoiding artificial sweet-
55 Carnitine is needed for fatty acid to be transported into eners and food additives, excitotoxic food additives such as
the mitochondria during the breakdown of fats. Fatigue MSG, aspartame, l-cysteine, carrageenan, hydrolyzed pro-
and lethargy can be symptoms of carnitine deficiency. teins, soy proteins and isolates, soy sauce, autolyzed yeast,
Supplement if deficiency or symptoms occur. and caseinates. These foods can contribute to already over-
55 Selenium: an antioxidant nutrient involved in reducing stimulated glutamate receptors, which can trigger seizures.
oxidative stress and preventing cardiomyopathy. Food Cheese, milk concentrates, and mushrooms are high in gluta-
sources include Brazil nuts, tuna, beef, chicken, turkey, mate.
and grains. Check the multivitamin for adequate amounts.

Supplements to improve seizure threshold: 30.23 PANDAS and PANS

55 Curcumin, quercetin, carnosine, acetyl L-carnitine,
resveratrol, and bioflavonoids are anti-inflammatory, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders
potentially reducing microglial activation and excitotox- Associated with Streptococcal Infections) and PANS (Pediatric
icity. Autoimmune Acute-Onset Neuropsychiatric Syndrome) strike
55 DHA, omega-3 oils play a role in brain function, growth, fear in the heart of parents who have seen their children change
and development and are anti-inflammatory and reduce overnight, despite the hot debates about the existence of
excitotoxicity. Studies show a decrease in seizures in PANDAS for years.
children taking omega-3s (EPA-DHA) [99]. Some PANDAS was described in the 1990s at the National
children are low in arachidonic, an omega-6. Best to test Institute of Mental Health (NIMH) by Drs. Susan Swedo,
with a red blood cell fatty acid test. Henrietta Leonard, et al., who observed cases of OCD that
55 Magnesium citrate is anti-inflammatory and blocks one began abruptly, with dramatic symptoms rather than com-
of the main glutamate receptors in seizures. Magnesium ing on gradually over weeks or months which is typical of
has been shown to raise seizure threshold levels. Some OCD [105].
forms of magnesium may be more beneficial [100]. PANDAS began as a clinical diagnosis made when chil-
Magnesium L-threonate crosses the blood-brain barrier dren and adolescents develop an abrupt obsessive-­compulsive
and magnesium glycinate is well absorbed and less likely disorder and/or tic disorders following a strep infections.
to cause diarrhea. However, magnesium levels are More comprehensive tests to aid diagnosis are now available.
difficult to assess. An RBC magnesium test is more
accurate than serum.
55 Melatonin supports healthy sleep cycles and has anti-­ 30.23.1  IMH Guidelines for Diagnosing
N
inflammatory and antioxidant properties. PANDAS
55 One pilot study showed that correcting vitamin D
deficiency improved seizure control in drug-resistant 55 Presence of clinically significant obsessions, compul-
epilepsy [101, 102]. sions, and/or tics.
55 Grape seed extract contains oligomeric proanthocyani- 55 Unusually abrupt onset of symptoms or a relapsing-­
dins, which help protect the hippocampus. It reduces remitting course of symptom severity.
stress and supports mitochondrial function [103] 55 Pre-pubertal onset. Symptoms of the disorder first
(7 Box 30.3).
  become evident between 3 years of age and puberty.
Neurodevelopmental Disorders in Children
511 30
55 Association with Group A streptococcal (GAS)
..      Table 30.1  Factors contributing to exacerbations of
infection, repeat strep, rheumatic, or scarlet fever. PANDAS/PANS
55 Note: In PANDAS, GAS infections may be present
without apparent pharyngitis (i.e., no complaints of a Infectious Other
sore throat).
55 Association with other neuropsychiatric symptoms. Group A beta hemolytic strep Psychosocial stress

Colds, Coxsackie A and B Nutrition

Other common symptoms listed by NIMH include:
Sinusitis, EBV Medication
55 Parents can usually remember the day their child’s
behavior changed. PANS and PANDAS is characterized Mycoplasma pneumonia Genetics
by an abrupt onset of obsessive-compulsive disorders Influenza, CMV Allergies
and/or tics.
Varicella zoster Chlorine
55 Severe separation anxiety.
55 Generalized anxiety. Herpes simplex
55 Motoric hyperactivity, abnormal movements, and a Lyme, Babesia, Bartonella
sense of restlessness.
55 Sensory abnormalities (sensitivity to light or sounds), HPA axis dysfunction
distortions of visual perceptions, and, occasionally, PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome) may
visual or auditory hallucinations. begin with an infection other than strep, environmental toxins,
55 Difficulties concentrating and loss of academic abilities, or immune dysfunction
particularly in math and handwriting.
55 Increased urinary frequency or sense of urgency and/or
a new onset of bedwetting. sensitivity and cross-reactivity, organic acid testing,
55 Irritability (sometimes with aggression) and emotional genetic testing, and stool testing.
lability. Abrupt onset of depression can also occur, with 55 When Group A streptococcal infection is not found, test
thoughts about suicide. for other infections.
55 Developmental regression, including temper tantrums
and “baby talk.” Note: Titers from prior strep infection may remain elevated
for months. Exacerbations of PANDAS after an initial strep
It is hypothesized that PANDAS is related to immune dys- infection may be caused by non-strep triggers.
function at one or more levels [106]: Other support for PANDAS includes a positive family
55 Cross-reactive “anti-brain” antibodies trigger OCD, tics, history of OCD, tic disorders, and autoimmunity as well as a
and neuropsychiatric symptoms [106]. response to antibiotics or immunomodulatory therapy such
55 Inflammation of the basal ganglia which are involved as IVIG and plasmapheresis to remove autoantibodies
with movement and behavior. (. Table 30.1).
 

55 Disruption of chemokines or cytokines altering central

nervous system function.
30.23.2  IMH Guideline for Diagnosing
N
This emphasizes the link between autoimmunity and inflam- PANS [108]
mation with neuropsychiatric disease.
1. Abrupt, dramatic onset of obsessive-­compulsive disorder
30.23.1.1  Laboratory Testing for PANDAS 2. At least two additional neuropsychiatric symptoms:
55 Throat culture GABHS positive. 55 Anxiety, separation anxiety
55 Elevated antistreptolysin titers (ASO): two–four-fold rise 55 Emotional liability: extreme mood swings, depres-
in titer from initial infection in 1–4 weeks. sion
55 Elevated anti-DNase B: increases from initial infection 55 Irritability, aggression, or severe oppositional
in 6–8 weeks 2- to four-fold. behaviors
55 Cunningham panel: Elevated anti-neuronal antibodies 55 Behavioral (developmental) regression
such as dopamine D1 receptor, dopamine D2L receptor, 55 Deterioration in school performance
lysoganglioside, tubulin, and elevated CaM kinase II – 55 Sensory or motor abnormalities
results in neuronal excitation and increased dopamine 55 Sleep disturbances, bedwetting, or urinary frequency
transmission [107].
55 Increased basal ganglia volume on volumetric MRI. Treatment for PANDAS and PANS: Depends on the severity
55 Elevated B-cell antigen D8/17, a possible marker of of the illness and may include cognitive behavioral therapy
rheumatic fever, OCD, or Sydenham’s chorea. (CBT) and antibiotics. In severe cases, IV immunoglobulin
55 CMP, ANA, CRP, thyroid panel and antibodies, sed rate, (IV IG) and plasmapheresis are used for immunomodulation
ferritin, immunoglobulins, vitamin D, B12, folate, gluten to reduce offending antibodies. Address all basic nutrition,
 512 M. A. M. Haskell

immune, and genetic issues. Remove excitotoxins, sugar, toms, but are often not be well tolerated. Occasionally a
processed foods, junk food, hydrogenated, and trans fats and tonsillectomy is helpful if the tonsils are large, which can
allergic foods. cause sleep apnea, and become a reservoir for strep. In sus-
Support fatty acids and consider a red cell fatty acid test. ceptible children, aggressively treating infection may be
Steroids can reduce symptoms, but they tend to return after helpful. Antibiotic prophylaxis has pros and cons as gut
stopping the drug. Streptococcus salivarius probiotics are immunity is severely affected. Maintain serum
helpful for some children. Selective serotonin reuptake 25-hydroxyvitamin D above 30  ng/mL.  VDR polymor-
inhibitor medications are sometimes used for OCD symp- phism may need higher levels.

Case Study: PANDAS

Joe is an 11-year-old male who activity. Helpful nutrients include herbs were added and nutrients
30 developed a severe sore throat and N-acetyl L-carnitine, B6, phosphatidyl- increased. Intestinal dysbiosis was
flu-like symptoms. Several days into the choline, and phosphatidylserine. treated. He received cognitive
illness, he became severely agitated MAO-A (monoamine oxidase A) is behavioral therapy. As he began to
with aggressive and obsessive-compul- an enzyme that breaks down improve slowly, his appetite improved
sive behaviors. His mother and neurotransmitters such as noradrena- and he returned to school on a
grandmother have a history of anxiety line, adrenaline, serotonin, and modified schedule. The Cunningham
and OCD behavior. dopamine. It is located on the X panel had returned to normal when
Birth and previous medical history: chromosome, so men only carry one re-­checked a year later.
Term birth via C-section for breech copy. It is important in regulating As we learn to deal with the
position and early preeclampsia. Apgar mood and can be linked to anxiety, increase in neuropsychiatric
score was 9 and 10; he was nursed OCD, and an increased risk of autoimmune disorders, all the basics
immediately and received hepatitis B aggression and violence; hence it is of a functional medicine approach
vaccine on the first day of life. At referred to as the “warrior gene.” This need to be addressed. For autoim-
4 months of age, he received vaccines enzyme needs B2 (riboflavin). It may mune disease to be present, there
for seven diseases. He cried inconsol- cause an intolerance of methylfolate. need to be a genetic predisposition,
ably with a high-pitched cry for 6 In addition, adequate B12 is an environmental or infectious
hours, was limp with no eye contact, needed before supporting folate. With trigger, and intestinal permeability.
and was taken to the emergency room issues in CBS, homocysteine may We must have an appreciation of
for evaluation. create excess glutamate increasing these interactions between the
At age 3, he began stuttering and anxiety. behavioral, neural, endocrine, and
received speech therapy. At age 5, he COMT genes break down immune processes. The brain and the
had severe flu-like illness with sore neurotransmitters and catecholamines immune system are linked by the
throat, fever, and extreme fatigue with including dopamine and norepineph- autonomic nervous system and the
a negative throat culture. rine. neuroendocrine system.
He developed fear of germs, COMT is involved in the prefrontal Neurotransmitters and cytokines
repeatedly washed his hands, and cortex, which is involved with “talk” [109].
refused to come out of his room. personality, planning, emotion,
Gradually he improved, but never to behavior control, and abstract Factors include:
his previous baseline. He would thinking. With a double COMT SNP, 55 Infections: bacterial, viral, and
intermittently have vocal tics. enzyme activity to break down fungal
Labs: Cunningham panel showed dopamine can be reduced three–four- 55 Toxins, heavy metals, and
elevated dopamine D1 titers which fold. Methylation SNPs can further alter environmental allergies and
can be associated with aggression. the function of COMT genes. sensitivities
Tubulin and lysoganglioside titers Supportive nutrients include low-dose 55 GI issues: dysbiosis, intestinal
were mildly elevated CaM kinase lithium, magnesium, and B12. SAMe is hyperpermeability, food allergies,
II. Vitamin D level was 29. Gene sometimes helpful for some children and sensitivities
polymorphisms related to methyla- but may increase dopamine for others. 55 Nutritional issues
tion which affect mood and can cause MTHFD1 is an enzyme involved in 55 Hormonal and immunological
anxiety include CBS++, COMT++, the conversion of dietary folate. imbalances
MAO-A+, and MTHFD ++. Treatment in brief: He was treated 55 Stress, emotions, sleep, and
CBS genes convert homocysteine with azithromycin and his behavior lifestyle issues
to cystathionine and are involved in symptoms dramatically improved for a 55 Neurotransmitter imbalances
transsulfuration and glutathione time. Then he refused to go out of the
synthesis, ridding the body of excess house again for fear of germs. A course T he number of children suffering from
sulfur amino acids as well as part of of augmentin was given. His appetite developmental and mental illness,
the methylation cycle. Ammonia can was poor. He was started on a small depression, anxiety, OCD, oppositional
be a byproduct of sulfur metabolism, dose of a multivitamin with hydroxoco- defiant disorder (ODD), ASD, ADHD,
which can adversely affect brain balamin as well as lithium orotate 5 mg and PANS and PANDAS is increasing. It
function. to support B12 and folate uptake into is imperative that we look beyond
His SNP is related to high cells. Anti-inflammatory supplements, diagnosis and medication to address
homocysteine and reduced CBS colostrum, healthy fats, and antiviral the underlying causes of these issues.
Neurodevelopmental Disorders in Children
513 30
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2012;9(3):599–609. 2015;25:76–85.
91. Elshorbagy H, et al. The impact of vitamin D supplementation on 108. Chang K, et al. Clinical evaluation of youth with pediatrics acute-
attention-deficit hyperactivity disorder in children. Ann Pharma- onset neuropsychiatric syndrome (PANS): recommendations from
cother. 2018;52(7):623–31. online ISSN: 1542-6270. the 2013 PANS Consensus Conference. J Child Adolesc Psycho-
92. Louv R. Last child in the words: saving our children from nature- pharmacol. 2015;25(1):3–13.
deficit disorder. In: Algonquin Books. Chapel Hill; 2005. 109. Alder R, Cohen N, Felten D. Psychoneuroimmunology: interactions
93. Medina KL, Schweinsburg AD, Cohen-Zion M, Nagel BJ, Tapert between the nervous system and the immune system. Lancet.
SF.  Effects of alcohol and combined marijuana and alcohol use 1995;345:99–103.
 517 31

Nutritional Influences
on Hormonal Health
Filomena Trindade

31.1 Introduction to Hormonal Health – 518

31.2 Insulin – 518

31.2.1 I nsulin Resistance – 518
31.2.2 Impaired Glucose Tolerance – 518
31.2.3 Prediabetes – 519
31.2.4 Diabetes Mellitus Type 2 – 519
31.2.5 Metabolic Syndrome Vs. Insulin Resistance – 519
31.2.6 Identifying Patients at Risk for Insulin Resistance – 519
31.2.7 Protocol – 519
31.2.8 Staging the Patient – 520
31.2.9 Laboratory Evaluation – 520
31.2.10 Treatment – 521
31.2.11 A Final Word on Insulin Resistance – 523

31.3 Adrenal Dysfunction – 524

31.3.1  hat Is Adrenal Dysfunction? – 524
W
31.3.2 What Causes Adrenal Dysfunction? – 525
31.3.3 Assessment and Treatment of Adrenal Dysfunction – 525
31.3.4 A Final Word on Adrenal Dysfunction – 526

31.4 Thyroid – 526

31.4.1  ssessment – 527
A
31.4.2 Treatment – 527

31.5 Sex Steroid Hormones – 528

31.6 Conclusion – 529

References – 529

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_31
 518 F. Trindade

31.1  Introduction to Hormonal Health ago, only 3 percent of all diabetes cases in children were of the
type 2 variety; now that number has climbed to 50 percent.
An integrative or functional medicine approach to illness Furthermore, what is shocking is that 40 percent of children
involves identifying the root cause(s) and personalizing treat- are now overweight and two million are morbidly obese
ment plans to address those underlying causes. In this way, the (exceeding the 99th percentile for weight) [4].
approach helps patients avoid and reverse illness as they move It is known that people with diabetes suffer vascular dis-
toward optimal health. This is a giant leap forward from con- ease at much higher rates [5]. It is estimated that diabetics are
ventional drug-based symptom suppression and disease man- four times more likely to die of heart disease than their non-­
agement approaches. Fortunately, combining integrative/ diabetic counterparts. Furthermore, the rate of cerebrovas-
functional and conventional approaches to medicine is not cular accidents (CVAs) is three to four times higher in
entirely incompatible. It is wise to integrate the best of conven- diabetics. Unfortunately, these risks do not only apply to the
tional laboratory analysis, diagnostic imaging methods, and fully diabetic patient. Of concern, women are at an ever-­
appropriate treatments, along with cutting-­edge nutritional, increasing risk for cardiovascular disease, especially when
lifestyle, biochemical, and genetically driven interventions to insulin resistance is present, and women in perimenopause
create the best outcomes possible for patients. This approach of or menopause who suffer more hot flashes and night sweats
31 integrating the best of both paradigms has been useful in devel- are more likely to have undiagnosed insulin resistance [6].
oping and personalizing treatment of hormonal imbalance. The risk for cardiovascular disease also encompasses
A recent report highlighted the fact that endocrine active those who are considered prediabetic. Patients with predia-
chemicals (EACs) or endocrine disruptors may cause a varia- betes are four times more likely to die of heart disease and
tion in normal hormone function [1]. It has been found that have a 21 percent higher risk of stroke [7]. Therefore, the pre-
even small alterations in hormone concentrations, especially fix “pre” in prediabetes is arguably not really “pre”-disease.
during embryonic development, can have significant and People with prediabetes are diseased secondary to the ele-
lasting effects. Further, some EACs have the potential to vated degree of insulin resistance. Therefore, it is not the
impact human health at lower doses than those proposed in diagnosis of diabetes alone that renders the patient at high
traditional toxicity testing by regulatory agencies, which risk for major life-threatening disease but, rather, the state of
means that some effects may be overlooked [1]. insulin resistance. There is a critical need for clinicians to rec-
A protocol has been developed to address hormonal ognize and address insulin resistance and understand the
imbalances in a systematic way and includes nutritional influ- continuum of insulin resistance. The continuum refers to the
ences in hormone metabolism. To be effective, an ordered progression from insulin resistance to impaired glucose tol-
evaluation followed by systematic balancing is key, as will be erance to prediabetes to diabetes. Treatment of this contin-
detailed below. Achieving optimal hormonal health happens uum begins with detection of early insulin resistance and
as hormones are balanced individually and then as they begin of learning the tools to apply to reverse this state in order to
to work in concert with each other. Hormones are like a sym- avoid the consequences and progression to diabetes.
phony in that each hormone must not only be balanced or
fine-tuned but also working optimally with other hormones
to make beautiful music. In the author’s experience, the 31.2.1  Insulin Resistance
orderly approach in hormone balancing begins with insulin,
followed by the hypothalamic pituitary adrenal axis (herein- Simply put, insulin resistance is a condition where insulin
after referred to as Adrenals), thyroid, and sex steroid hor- becomes less effective at lowering blood sugar [5–8]. It is the
mones (estrogens, progesterone, and testosterone) with a final inability of insulin to facilitate glucose uptake from the blood
step optimizing estrogen metabolism in both men and women. into the cell because of poor insulin binding at the cells’
receptors. The body responds to this by stimulating the pan-
creas to produce more insulin to ensure that glucose can
31.2  Insulin leave the bloodstream and enter the cells. Initially, the body’s
response is effective in that the excess insulin is able to keep
Insulin is a major hormone and one of critical importance. It blood sugar in the normal range. The first sign of imbalance
not only affects all other hormones, but if there is decreased lies in the increased levels of insulin production.
insulin sensitivity or insulin resistance, it is postulated to con-
tribute to cardiovascular disease, premature death, cancer,
and dementia, to name a few [2]. Moreover, insulin resistance 31.2.2  Impaired Glucose Tolerance
is a major cause of premature aging and death in both the
developed and developing worlds. It is arguably our biggest Impaired glucose tolerance occurs when glucose rises above
global health epidemic. Human history has never before seen the normal range, despite the pancreas continuing to overpro-
as many new cases of type 2 diabetes diagnosed, particularly duce insulin [5–9]. The rise can be seen after meals (postpran-
in children [3]. The diagnosis of adult-onset or type 2 diabe- dial) or at in the fasting state. In many patients at this stage
tes in children has climbed astronomically, increasing more along the continuum, fasting glucose may be normal, but you
than 1000 percent over the past two decades. A mere 15 years will see an elevated glucose level after a meal or after a high
Nutritional Influences on Hormonal Health
519 31
glycemic load. Levels are elevated but not enough to qualify In the United States, we have seen a rise of obesity in epi-
the patient as prediabetic. These are the patients in which demic proportions over the past 20 years [2, 3, 5, 8, 10].
there is an elevated hemoglobin A1c (HgbA1c) despite a nor- Among the American adults who are simply overweight,
mal fasting glucose. Simply put, impaired glucose tolerance is more than 70 percent already have prediabetes because of
when the pancreas and its insulin production are no longer undiagnosed and untreated insulin resistance, with signifi-
able to keep blood sugar normal after a glucose challenge. cant increased risk of cardiovascular disease and death. The
unfortunate fact is that most are unaware of their condition
and its risks. The awareness problem is further aggravated by
31.2.3  Prediabetes the fact that there are no current national screening guide-
lines or reimbursement for healthcare providers to diagnose
As the pancreas continues to overproduce insulin, its ability and treat insulin resistance. Guidelines and reimbursement
to keep fasting blood sugar in the normal range is impaired are only available once diabetes develops. In addition, health-
as evidenced by a fasting blood sugar over 100 mg/dL to 125 care practitioners are not properly trained to diagnose or
mg/dL [5, 8, 9]. This should be considered an advanced state treat the largest epidemic in the United States. In sum, it is
of disease because close behind prediabetes is the end of the well-known that obesity increases insulin resistance and
continuum with type 2 DM. Therefore, prediabetes is clearly leads to diabetes. Conversely, the most important cause of
a state of major dysfunction and it is not “pre”-disease. It is a obesity is insulin resistance that often goes undiagnosed.
disease in and of itself.

31.2.6  Identifying Patients at Risk for Insulin

31.2.4  Diabetes Mellitus Type 2 Resistance

Diabetes mellitus type 2 is defined as fasting blood sugar of To determine if patients have insulin resistance, it is not as
126 mg/dL or higher or a random blood sugar of over 200 simple as looking at body habitus. According to the National
mg/dL on more than one occasion [5, 8, 9]. Health and Nutrition Evaluation Survey (NHANES) correla-
tion study from 1999 to 2004, up to 25 percent of normal
weight patients (BMI less than 25) may be insulin-resistant
31.2.5  Metabolic Syndrome Vs. Insulin [11]. Further, some patients may be insulin-resistant and still
Resistance have normal fasting insulin levels, normal HgbA1c, and nor-
mal fasting glucose but are on the continuum to develop type
The synergistic and aggregate effects of insulin resistance, 2 diabetes and metabolic syndrome. Important for clinicians,
obesity, hypertension (HTN), and dyslipidemia all form a the underlying causes of type 2 diabetes, metabolic syndrome,
construct called the metabolic syndrome [7]. Metabolic syn- and insulin resistance are reversible and preventable [5, 7] by
drome was initially coined “Syndrome X” by Gerald using nutritional and lifestyle interventions. The question
M. Reaven as “a constellation of lipid and non-lipid risk fac- becomes how do we identify the patients at risk? This is best
tors of metabolic origin.” Metabolic syndrome was formally addressed by looking at the confluence of genes and metabo-
recognized by the Adult Treatment Panel III (ATP III) of the lism, both of which underlie the abnormal patterns of func-
National Cholesterol Education Program (NCEP) 2004 tion seen in hyperinsulinemia. Clinicians need to determine
update and identifies the significance of cardiovascular dis- why and how a patient became insulin-­resistant. How and
ease (CVD) risk factors [8]. Risk factors for metabolic syn- where do we start? What is the root cause? How do we iden-
drome include visceral adiposity, high body mass index tify and treat insulin resistance?
(BMI), insulin resistance, and high insulin. In order to have
metabolic syndrome, a patient must have three out of the fol-
lowing five characteristics present: increased waist circum- 31.2.7  Protocol
ference (greater than 40 inches for men and 35 inches for
women), hypertension (blood pressure greater than 130/85 The author has developed a treatment protocol for insulin
mmHg), elevated triglycerides (greater than 150 mg/dL), resistance that incorporates integrative and functional
elevated fasting blood sugar (greater than 100 mg/dL), and medicine principles. This starts with collecting a thorough
decreased HDL (40 mg/dL in men and 50 mg/dL in women). and detailed history and conducting a complete physical
Focus has recently shifted to insulin resistance as the examination. In the process of data gathering, it is impera-
dominant and independent predictor of age-related diseases tive to look for basic imbalances in digestion/absorption/
[10, 11]. A normal blood sugar level is less than 100 mg/dL; barrier integrity, detoxification pathways, hormone/
however, we know that risks extend below that threshold. neurotransmitter health, immune/inflammatory process,
Studies have shown that a blood sugar greater than 87 mg/dL and mind/spirit equilibrium imbalance. The goal is to get to
equals a progressive increase of type 2 diabetes. Further, the the underlying cause of illness. This allows the practitioner
lowest risk of progression from insulin resistance to type 2 to connect the dots between the history and the physical
diabetes is a fasting blood sugar less than 75 mg/dL. exam to find clues leading to the root cause or foundation of
 520 F. Trindade

the dysfunction. Once the investigation into development 31.2.8  Staging the Patient
of insulin resistance has proceeded and potential underly-
ing cause(s) are identified, laboratory testing can be ordered Staging facilitates understanding of where the patient falls
and evaluated. Patients are staged along the continuum of along the continuum of insulin resistance. It is the stage that
insulin resistance at this juncture. Individualized treatment determines the treatment and predicts how likely they are to
protocols are prescribed that incorporate certain basic stan- progress to type 2 diabetes. In the continuum of insulin resis-
dards (see . Table 31.1).
 
tance, with wellness on one end and illness on the other, the
patient progresses from insulin-sensitive, to insulin-resistant,
to impaired glucose tolerance, followed by prediabetes, and
..      Table 31.1  Insulin resistance assessment protocol then to type 2 diabetes.
The three stages and their components are described in
Poor-quality diet Processed foods
detail below in the “Laboratory Evaluation” section. Stage 1 is
High in sugar and high fructose corn syrup
Trans, hydrogenated, and saturated fats when adiponectin (an adipose-derived protein) starts to
Polyunsaturated omega-6 oils (except decrease [11]. In stage 2, insulin is already starting to increase,
gamma linoleic acid, GLA) and in stage 3, proinsulin (the prohormone precursor to
31 Low in vegetables, fruits, and antioxidants insulin) increases [11]. Not everyone moves through these
Low in fiber
stages smoothly, as there may be variations in timing and
Hydration Assess hydration status and source/ presentation. We also know that there may be some patients
content of water and liquids who fall between type 1 and type 2 diabetes, related to an
Can be cause of insulin resistance, i.e., look
underlying autoimmune disease [12, 13]. Overall, these
for sugar and high fructose corn syrup drinks
stages are valuable as each stage will direct proper treatment.
Food allergies/ Modify and personalize elimination diet/ For instance, if a patient is found to have insulin resistance
sensitivities ketogenic diet and/or functional testing and hyperlipidemia, it is the insulin resistance that is driving
for allergies and sensitivities
the hyperlipidemia and the  progression to glucose intoler-
Oxidative stress Assess clinically and with laboratory evalu- ance and prediabetes. Consequently, we treat insulin resis-
and/or mitochon- ation tance first.
drial dysfunction

Stress and adrenal Lack of exercise

dysfunction Poor sleep 31.2.9  Laboratory Evaluation
Hormone Use history and physical exam, as well as
imbalance laboratory evaluation Laboratory evaluation is an important tool to help guide
Toxins Heavy metals, persistent organic
assessment of the patient’s stage along the continuum of insu-
pollutants, endocrine disruptors volatile lin resistance. Although not all insulin-resistant patients
solvents, dirty electricity, electromagnetic develop diabetes, it is insulin resistance that is the underlying
radiation, suboptimal estrogen metabo- problem driving metabolic syndrome and chronic disease,
lism, etc. such as cardiovascular risk. Consequently, it is very impor-
Dysbiosis Assess with comprehensive stool analysis tant to identify those with insulin resistance early and
promptly treat them to halt and/or reverse disease progres-
Infections Occult esp. dental
Gastrointestinal sion. Laboratory assessment is critical.
Viral, bacterial, parasitic, and fungal Most test result ranges in conventional laboratory
­analysis are very broad. This occurs because the lab is aggre-
Nutrient Including vitamins, minerals, antioxidants,
deficiencies amino acids, methylating factors, and gating multiple patients’ ranges who are considered normal
essential fatty acids although disease may be present at an early stage; these
Assess clinically with history and physical ranges are not functional ranges. A general guideline to
and with functional and/or conventional determine abnormality is to look at the upper third and
testing
fourth quartile when assessing conventional lab values for
Prescription drugs Prior or current use of statins or other glucose and insulin while looking at the first and second
cholesterol-lowering drug use, proton quartiles when assessing micronutrient levels. This gives a
pump inhibitors, or beta blockers more functional/integrative medicine reference range that
Hyperinsulinemia Review all above to look for root cause may guide intervention. It is important to understand that
causing insulin although the value may be in a normal range according to
resistance; beta the conventional lab, early disease and dysfunction may be
cell dysfunction
present. This helps when analyzing results for patients who
© Copyright 2013 Filomena Trindade MD, MPH. All rights can only afford to undergo conventional insurance-covered
reserved. Reprinted with permission of the author laboratory evaluations and do not have access to more exten-
sive laboratory testing.
Nutritional Influences on Hormonal Health
521 31
31.2.9.1  Hemoglobin A1c In stage 1 insulin resistance, adiponectin is declining while
Hemoglobin A1c (HbA1c) was originally developed to deter- fasting insulin remains normal [11, 17]. Postprandial insulin
mine if diabetic patients were being compliant with their might be elevated, but the primary determining factor of
glucose-lowering medication [8, 14]. Put simply, it measures stage 1 is a normal fasting insulin. Proinsulin, glucose read-
the amount of glucose bound to the hemoglobin molecule ings, HOMA-IR, and HbA1c are all usually normal, although
and reflects levels of glucose for the previous 90 to 120 days. HOMA-IR could be slightly elevated. Adiponectin is the key
It was not developed as a screening tool, although it is cur- factor that needs to be restored. Low adiponectin is a marker
rently being used as one. for insulin resistance, making the patient more at risk for dys-
With this in mind, what does it mean if a HbA1c is ele- lipidemia. Decreasing adiponectin also tends to be associated
vated? Where does the elevated HbA1c place the patient on with increasing inflammatory markers. With that, there is
the continuum? HgbA1c is an independent risk factor for increased risk for vascular injury and increased risk of pro-
cardiovascular mortality: “The predictive value of HgbA1c gression along the continuum toward type 2 diabetes [11, 17].
for total mortality was stronger than that documented for Treatment includes diet and lifestyle changes. Focus is on
cholesterol concentration, body mass index and blood pres- body composition and making sure patients are eating a
sure.” [14]. If HbA1c is 5.4 percent or higher, the patient has healthful diet. Experts recommend a Mediterranean-type,
impaired glucose tolerance and increased risk. If the HbA1c low glycemic load diet, but the diet needs to be personalized
is increased, the patient is having episodes of hyperglycemia. to the individual [18].
However, it might only be elevated postprandially and not in In stage 2 insulin resistance, adiponectin levels are
the fasting state. Consequently, patients must check the post- decreasing, insulin is starting to increase, while proinsulin
prandial blood sugars both in the laboratory and at home. remains normal [11, 17]. There may be early beta cell impair-
With insulin resistance it is imperative to preserve pancreatic ment. In stage 2, HOMA-IR is higher than normal and may
beta cell function and aggressively address the underlying be associated with a high postprandial glucose. At this stage,
cause of the dysfunction. fasting glucose may be borderline elevated while random and
postprandial sampling of glucose may be mildly elevated but
31.2.9.2  HOMA-IR at times be normal. Stage 2 treatment usually consists of diet
The homeostatic model assessment for insulin resistance and lifestyle changes and supplementation. Pharmacotherapy
(HOMA-IR) is a calculation based on plasma levels of fast- should not be started at this stage, but rather in early stage 3
ing glucose and insulin [15, 16]. It is used to assess insulin and even then, there is the potential for reversal with diet,
sensitivity. There may be better ways of assessing insulin nutrition, lifestyle modification and nutraceutical support.
resistance. Again, this is case dependent.
In stage 3 insulin resistance, proinsulin is increasing,
indicating the pancreas is struggling to keep glucose normal.
31.2.9.3  Adiponectin, Insulin, and Proinsulin:
The pancreas is attempting to excrete insulin as fast as it is
Staging the Progression of Insulin manufactured and before the final cleavage has happened. In
Resistance to Prediabetes and Type 2 stage 3 there is low adiponectin, high HOMA-IR, high insu-
Diabetes lin, elevated proinsulin, possibly high glucose, and high
Adiponectin is a protein hormone that is produced in fat cells HbA1c [11, 17]. There are some patients who can maintain
and helps regulate glucose levels and fatty acid breakdown normal or close to normal fasting glucose even in the face of
[17]. Adiponectin is protective against atherosclerosis, mod- these abnormalities. However, with glucose challenge testing,
ulates fat tissue production and breakdown, promotes insulin the post-challenge glucose level will be high. In most cases,
sensitivity, and decreases hepatic glucose and lipid produc- the postprandial glucose will elevate with a high glycemic
tion. Biologic adiponectin levels decrease prior to increases load meal. Despite these findings, the patient may not be
in insulin levels; therefore it can be considered a marker of classified diabetic. This group might not even fulfill the estab-
insulin sensitivity. Other markers assessed by laboratory lished criteria for prediabetes, as the American Diabetes
evaluation for insulin sensitivity include insulin, proinsulin, Association definition for prediabetes is a fasting glucose
HbA1c, fasting, 30 minute, 1 hour and 2 hour glucose levels, level of 100–125 mg/dl [8]. The overarching treatment aim in
a 30 minute, 1 hour and a  two-hour insulin level after a stage 3 is to preserve beta cell function. Having patients
75 gram glucose load. Both conventional and specialty labo- check postprandial glucose levels also helps the patient learn
ratories can provide these tests. While a specialty lab plots what foods increase their glucose level.
the results in graphical form with functional ranges, conven-
tional labs give numerical values that can be plotted in graph-
ical form by the practitioner. With optimal control and 31.2.10  Treatment
regulation of glucose, adiponectin will be normal, fasting
insulin will be 5–7 mIU/L, HbA1c will be 5.3 percent or less, 7 Box 31.1 presents the approach for the treatment of insulin
 

and fasting glucose will be less than 75 mg/dL.  The risk of resistance. It will be necessary to address and re-address
diabetes significantly increases when the fasting blood glu- these factors both at baseline and throughout the course of
cose is greater than 87 mg/dL [6]. treatment.
 522 F. Trindade

31.2.10.2  Exploring Detoxification

Box 31.1  Insulin Resistance Treatment Protocol Body burden of environmental toxins is known to be another
55 Foundation is nutritional support: Wholesome food that is underlying problem triggering insulin resistance [36–39].
fresh, whole, unprocessed, organic, colorful, fermented,
high in omega-3 fatty acids
Toxic endocrine disruptors affect estrogen and estrogen
55 Identify the underlying functional imbalances, prioritize, metabolism and are known to result in the etiology of type 2
and address diabetes mellitus [36–38]. Low-dose organochlorine pesti-
55 Personalize an elimination diet or modified ketogenic diet cides and polychlorinated biphenyls predict obesity, dyslipid-
according to individual patient needs emia, and insulin resistance among people free of diabetes
55 Lifestyle modification: Individualized stress reduction,
alcohol consumption, smoking cessation, sleep
[36–38]. Heavy metals may also be a problem and can con-
55 Exercise: Tailor to individual patient needs tribute to insulin resistance [39]. The liver enzyme, GGTP, in
55 Nutritional supplementation: Personalized based on the high normal range is associated with insulin resistance. It
clinical exam and laboratory testing may be helpful to monitor GGTP and consider it a predictor
55 Mind-body-spirit connection: Find and foster purpose and if it is 30 IU/L or higher. If it is over 40 IU/, then glutathione
meaning in life as well as gratitude, and explore history of
trauma that may be preventing compliance and develop-
production needs to be improved.
ment of treatment protocol
31 55 Assess possible need for pharmacological treatment based 31.2.10.3  Exercise
on functional testing, patient needs, and response to As exercise is an important tool for intervention in insulin
above approach resistance, it is critical to assess how much a patient is mov-
ing. It is imperative to design an appropriate exercise regimen
© Copyright 2012 Filomena Trindade MD, MPH. All rights
for each patient that incorporates aerobic exercise and weight
reserved. Reprinted with permission of the author
training and re-evaluate adherence to the program at regular
intervals with change as needed. It is wise to review the pub-
lished studies with patients and give them the choice between
31.2.10.1  Dietary Management diet, lifestyle, and physical activity versus medications with
Dietary management with healthful whole foods for patients their potential side effects. Typically, in the author’s practice,
with insulin resistance results in decreasing insulin stimula- patients choose diet and lifestyle changes for management.
tion and increasing insulin sensitivity [19–26]. Dietary modi- Patients need to be informed that if they do not change their
fications to decrease insulin release always begin with an diet and lifestyle, the outcome will likely be increased cardio-
initial assessment to explore the patient’s intake of fiber, good vascular disease and progression to type 2 diabetes. Are they
and bad fats, types and quantity of protein, and simple and willing to take those risks? When explaining how diet, nutri-
complex carbohydrates, as noted above. Education of patients tion, exercise, and lifestyle modifications have been proven
about the quality of dietary components and helping them superior to prescription medications [40], patients express
understand glycemic load is imperative at this early stage. amazement and choose to succeed with this approach.
Crucial is the fact that food components are important signal- According to the World Health Organization, adults 18–64
ing molecules that are not often found in processed foods should do at least 150 minutes of moderate-intensity aerobic
[27]. Many phytochemicals work as tissue-specific kinase physical activity throughout the week or at least 75 minutes
response modulators (SKRMs). Kinases are a group of of vigorous-intensity aerobic physical activity throughout the
enzymes with multiple functions that include facilitating week or an equivalent combination of moderate- and vigor-
insulin function. SKRMs are going to affect cellular commu- ous-intensity activity [41]. Aerobic activity should be per-
nication and cellular signaling. Some dietary phytochemicals formed in episodes of at least 10 minutes’ duration. For
that modulate these pathways include berberine, cinnamon, additional health benefits, adults should increase their mod-
ginseng, quercetin, resveratrol, green tea extract, and hops erate-intensity aerobic physical activity to 300 minutes per
extract. week or engage in 150 minutes of vigorous-intensity aerobic
Components of this type of diet include organic, fresh, physical activity per week or an equivalent combination.
whole, unprocessed, colorful food. It is important to make Muscle-strengthening activities should be done involving
sure patients have protein at every meal and snack. Emphasize major muscle groups on 2 or more days a week. Exercise
elimination of sugar, trans fats, some saturated fats, and food alters skeletal muscle metabolism and improves glucose
allergens. Patients need education regarding inflammatory uptake, reduces low-density lipoprotein, raises HDL, lowers
foods, including gluten, dairy, soy, corn, and nightshades. An blood pressure, and reduces inflammation and oxidative
elimination diet may be helpful to identify and remove any stress [42]. In a Diabetes Prevention Program Research
dietary source of inflammation. Also address the areas of Group 2002 study, 3234 people with prediabetes were ran-
dysfunction or imbalance in laboratory assessment and pri- domized to placebo, metformin, or lifestyle modification
oritize. Depending where the patient is on the continuum, it (≥7% weight loss and ≥ 150 min/week of physical activity)
may be necessary to start nutraceuticals that increase cellular for 2.8 years [40]. Compared to the placebo group, lifestyle
responsiveness to insulin, including chromium, alpha-lipoic intervention decreased incidence of type 2 DM by 58 per-
acid, magnesium, CoQ10, and protein kinase modulators, to cent. Metformin (850  mg BID) decreased type 2 diabetes
name a few [27–35]. See . Table 31.2.
  mellitus by only 31 percent.
Nutritional Influences on Hormonal Health
523 31

..      Table 31.2  Micronutrient recommendations for insulin resistance

Chromium [35] Generally, give 400 mcg/daily if insulin-resistant

Likely most effective if deficient but difficult to test

Vitamin D [32] Test 25(OH)D and supplement as appropriate (or supplement 2000–5000) IU/daily
Vitamin D levels should be 50–80 ng/ml, depending on whether other medical conditions are present
A study showed a positive correlation of 25(OH)D concentration with insulin sensitivity and a negative effect of
hypovitaminosis D on beta cell function
Subjects with hypovitaminosis D are at higher risk of insulin resistance and the metabolic syndrome
Increasing 25(OH)D from 10–30 ng/mL can improve insulin sensitivity by 60%

CoQ10 [28, 29] Supplement in patients with metabolic syndrome, insulin resistance, hypertension, or mitochondrial dysfunction
Dose depends on functional levels: Optimize to >2 mcg/mL (plasma)
In a patient with high oxidative stress or mitochondrial dysfunction, may need to supplement at a much higher dose
120 mg/day of coenzyme Q10 improves glycemic control and blood pressure in NIDDM
200 mg of CoQ10 daily improved HgA1C and blood pressure in NIDDM patients

Alpha-­lipoic acid Doses of 600 to 1800 mg/day may improve insulin sensitivity
[30, 31] 600–1200 mg/day of ALA may improve microcirculation and diabetic polyneuropathy

Magnesium Epidemiological studies show that high daily mg intake is predictive of a lower incidence of NIDDM
[33, 34] Poor intracellular mg concentration is found in NIDDM and in hypertensive patients
Daily mg administration in NIDDM patients and in insulin-resistant patients restores intracellular mg concentration
and contributes to improve insulin sensitivity and glucose uptake
Magnesium supplementation has been shown to improve insulin sensitivity
Patients have a hard time absorbing magnesium intracellularly
Buccal swab is the best way to assess intracellular magnesium
Patients with low magnesium are at a slightly higher risk for atrial fibrillation and arrhythmias
Many of these patients may also need potassium. Magnesium glycinate may have less effect on the gut causing loose
bowels, and it is generally well absorbed
Starting dose 200–400 mg of a chelated magnesium and increase to bowel tolerance if normal kidney function is
established

31.2.10.4  Stress and Autonomic Dysfunction 9 hours per night and ideally should be 8 hours [46]. It is also
Stress and autonomic dysfunction have a powerful impact on critical to ask patients about the quality of their sleep. Are
progression of insulin resistance and contribute to cardiovas- they waking up multiple times? Are they feeling rested when
cular disease. To assess autonomic dysfunction, an important they wake up? Is there snoring? Obstructive sleep apnea can
tool to incorporate is heart rate variability [43, 44]. As heart affect insulin resistance and metabolic syndrome through
rate variability lowers, there is progression from insulin resis- poor oxygenation. In addition, many patients with obstruc-
tance to impaired glucose tolerance to diabetes. Of interest in tive sleep apnea have undiagnosed insulin resistance.
patients with coronary artery disease, lower heart rate vari-
ability has also been correlated with impaired pancreatic
function. Visceral fat (not subcutaneous fat) has also been 31.2.11  A Final Word on Insulin Resistance
associated with lower heart rate variability as well. In patients
with either diabetes or a family history of diabetes, those We have established that insulin resistance is a disease con-
genetically predisposed to NIDDM have more visceral fat tributing to numerous chronic and life-threatening condi-
and lower insulin sensitivity compared with those unaffected tions and affects countless patients, many of whom go
individuals [45]. Knowing these connections, the dysregula- undiagnosed. The good news is that insulin resistance, as well
tion of the autonomic nervous system can now be linked to as the progression to diabetes, can not only be prevented but
visceral adiposity and insulin resistance. can be treated and reversed. Therefore, it is our responsibility
as clinicians to track down early cases of insulin resistance
31.2.10.5  Sleep before they advance into later stages along the continuum and
Sleep is another important factor in the management of insu- to reverse whatever damage may have occurred. Likewise, it is
lin resistance. Lack of sleep can affect insulin resistance in our duty to offer an effective protocol to those who already
several different ways as it can cause inflammatory-related suffer from a clinical diagnosis of prediabetes or diabetes.
insulin resistance, changes in glucose metabolism, altered Integrative and functional medicine tools help identify
appetite, and hypothalamic-pituitary-adrenal axis dysfunc- the underlying dysfunctions and the root causes in a person-
tion [46]. Sleep deprivation may lead to insulin resistance and alized manner. Using clinical evaluation, as well as laboratory
subsequently to diabetes mellitus. For those with metabolic measurements including adiponectin, fasting insulin, proin-
syndrome, recommended average sleep times range from 7 to sulin, HgbA1c, postprandial insulin, and glucose, the clini-
 524 F. Trindade

cian can assess where the patient lies along the continuum of are naturally higher. As we grow older, however, it behooves us
insulin resistance. Once the stage of insulin resistance has to pay more attention to the adrenal savings account and work
been identified, a personally tailored treatment plan is pre- to replenish any debt or accumulated depletion. No matter
scribed to reverse beta cell dysfunction and prevent further what age, we must learn to manage our adrenal bank account
progression to diabetes. As needed, treatment options may and live within our means. That means choosing diet, lifestyle,
address any of the following areas of a patient’s life: diet, hobbies, and sleep patterns that work to regenerate what has
sleep, stress, exposure to toxins and ability to detoxify, exer- been lost. If we do not do this, there are consequences.
cise, and/or micronutrient consumption. In conclusion, by There is a threshold of stress that our adrenals can handle
way of acknowledging the role of insulin resistance in the within a healthy range. Beyond that threshold, however,
bigger picture of obesity, diabetes, and cardiovascular dis- damage is done. This threshold setpoint differs for each of us
ease, we are able to recognize how vitally important it is to and is very much like the stress on a violin string. Insufficient
incorporate the effective diagnosis and treatment of insulin tension produces a dull, raspy sound. Too much tension
resistance into clinical practice. makes a shrill, annoying noise or snaps the string. However,
just the right degree of pressure can create a magnificent
tone. Similarly, we all need to find the proper level of stress
31 31.3  Adrenal Dysfunction that allows us to perform optimally and make melodious
music as we go through life.
We live in a world that is increasingly stressful and often A problem arises for many when they overspend their
coupled with sedentary lifestyle practices. Many people eat adrenal reserves and find themselves broke. In other words,
processed foods lacking in nutritive quality at most meals. we reach a level at which we can no longer adapt to further
Each day we are exposed to a skyrocketing number of syn- stress and have lost adrenal resilience. When this occurs, the
thetic chemicals in our personal care products, the food we body can no longer cope with stress as it once had and the
eat, the water we drink, and the air we breathe. Our minds effects are deleterious. Under normal circumstances, once an
are constantly distracted by relentless electronic stimulation. acute threat has passed, the stress response becomes inacti-
Societies have collectively induced self-psychological and vated and levels of stress hormones return to baseline levels
economic slavery. This is our world. The shocking part is this [47]. This translates into resilience (see . Table 31.3). In this
 

way of life is accepted and considered normal and the dys- case, we are using the normal relaxation response to recover
function may be difficult to perceive, much less find success- from stress. However, if  there is unremitting stress, we can
ful life balance. In this environment, feeling anxious and/or then reach a point where adaptation can no longer occur and
depressed is an understandable reaction to the overwhelm- adrenal dysfunction ensues. The hypothalamic-pituitary-­
ing stimuli of a typical modern lifestyle. adrenal axis responds to the unremitting stress by downregu-
lation at the level of the adrenal glands, and that is what we
are calling Adrenal dysfunction. The actual mechanisms
31.3.1  What Is Adrenal Dysfunction? involved are not yet fully understood. Adrenal dysfunction is
composed of three stages which were described by Hans
The adrenal glands are bean-shaped organs situated above Selye in the 1930s, although some controversy surrounds this
the kidneys with secretions that are required for maintenance classification [48]. Selye called the series of stages “the gen-
of life [47]. They are made up of an outer region or cortex and eral adaptation syndrome,” described in . Table 31.3.  

an inner region or medulla. The hormones of the  adrenal

cortex are steroids and act at the level of the genome to regu-
late expression of genes for operation of important processes. ..      Table 31.3  Stages of adrenal response
There are three major categories of adrenal steroid hormones,
Stages of
mineralocorticoids, glucocorticoids, and androgens, and all adrenal response
are essential for maintaining internal equilibrium [47]. The
adrenal medulla produces two important hormones, epi- Stage 1: Arousal Both cortisol and DHEA increase with epi-
nephrine and norepinephrine, that play a critical role in the sodic stress, but recovery returns to baseline
This may or may not be asymptomatic
response to stress. The catecholamines affect the cardiovas-
cular, respiratory, excretory, and skeletal systems and equip Stage 2: Cortisol is chronically elevated and DHEA
the body for fright, fight, or flight. An important function of Adaptation declines
Symptoms of stress arise such as anxiety
the adrenal glands is to provide dynamic balance or homeo-
attacks, mood swings, depression
stasis of the hormonal systems whether in rest or stress.
The job of the adrenals when it comes to homeostasis dur- Stage 3: Adrenal insufficiency yields low cortisol
ing stressful events is to handle the disruption in hormones. Exhaustion and DHEA levels
Patients present with depression and
Their handling of stress is akin to managing a bank account – severe fatigue
it’s your adrenal bank account. If you have a lot of adrenal
reserve, it means you can spend on the account. Thus, many Based on data from Ref. [48]
people choose to spend frivolously early in life when reserves
Nutritional Influences on Hormonal Health
525 31
Modern life poses ongoing stressful events that are not Awakening Response (CAR).  Salivary cortisol concentra-
short-lived. When we lose our resilience, we progress to stage tions reflect the free, biologically active fraction of cortisol in
2 adrenal dysfunction or “the adaptation phase.” If we con- the plasma, and tests of it provide results that are of greater
tinue to borrow from our account as our savings dwindle, diagnostic significance than plasma total concentrations
then we progress further to stage 3 (. Table  31.3). At this
  alone [52, 53].
point, stress becomes chronic. This continual exposure to The author has developed a three-legged stool approach
stress puts us at risk for many other health problems. Patients with an optional fourth leg, if needed, to treat adrenal dys-
at this stage often struggle with severe fatigue or chronic function. At the most basic level, the first leg of the approach
fatigue syndrome, fibromyalgia, hair loss, premature hor- covers modifications in nutrition and lifestyle. Eating organi-
mone loss or hormone imbalance, weight gain, autoimmune cally grown, phytochemically dense foods that are devoid of
disorders, suppression of the immune system, arthritis, anxi- fillers and preservatives is the foundation for recovery. Meals
ety, and depression [49–51]. need to have a low glycemic load and good sources of clean
Adrenal dysfunction, when at the severe maladaptation protein. The majority of the plate, about two-thirds, must be
stage, is generally referred to as adrenal fatigue. The term adre- composed of vegetables and a few servings of low-glycemic-­
nal fatigue has been inaccurately used to refer to any of the load fruits. Chewing food appropriately must be emphasized
stages of adrenal dysfunction. Correctly, it should strictly refer and hydrating well with clean water is critical. The first leg
only to the third stage of adrenal dysfunction. Patients may also includes the lifestyle component that incorporates exer-
present with a variety of symptoms of adrenal gland dysfunc- cise and dealing with trauma. Exercise recommendations
tion that include fatigue, low energy, weakness, moodiness, should be appropriate for the stage of adrenal dysfunction. A
anxiety or depression, muscle and bone loss, hormonal imbal- person in stage 1 adrenal dysfunction with high cortisol lev-
ance, insomnia, and skin problems, among others. Also com- els would need more of an aerobic program, whereas some-
mon is an overreaction to stress in which a minor event causes one in stage 3 needs more gentle movement that will not
a disproportionate reaction of anger, irritation, or sadness. cause further stress to the system. It is important to address
the level of stress and discuss how to best modify it. It is cru-
cial to emphasize hobbies that are enjoyable and a relaxation
31.3.2  What Causes Adrenal Dysfunction? protocol that works for the individual patient.  Further,
trauma or history of abuse must be explored. According to
Chronic unremitting stress is the leading cause of adrenal Bethel Van der Kolk in his book: The Body Keeps the Score
dysfunction and the term stress can refer to physical or psy- (brain, mind, and body in the healing of trauma) we must
chological stress [49–51]. For example, physical stress could address and heal trauma in order to restore health. This book
include environmental toxin exposure, infections, nutrient reviews  the scientifically proven ways to heal trauma by
deficiencies, hormone imbalances, allergies, and certain pre- rewiring the  brain  including eye movement desinsitization
scription medications. A nutrient-poor diet high in sugar, and reprogramming (EMDR), neurofeedback, emotional
simple carbohydrates, food preservatives, alcohol, or stimu- freedom technique (EFT) among others. It  is an essential
lants such as caffeine leads to adrenal dysfunction. These read inorder  to help patients fully recover from adrenal or
foods can cause the blood sugar to spike, and in response, the HPA axis dysfunction.   
adrenal cortex may produce excess cortisol, which over time The second leg involves tailored nutraceuticals that help
can  lead to  hypothalamic pituitary adrenal  dysfunction. heal and reverse the adrenal dysfunction. This includes
Psychological stress could be related to events such as divorce, nutraceuticals such as B-complex with B6 in the activated or
an unhappy marriage, a stressful job, difficult family life, lack P-5-P form, 5-MTHF, biotin, B5 or pantothenic acid,
of social or familial support  or history of past or current omega-3 fatty acids, vitamin C, magnesium, and zinc [54–
abuse (physical, sexual or psychological). It could also come 68]. Pantothenic acid has the added benefit that it can enter
in the form of perceived stress. For instance, reliving past the steroidogenic pathway early at the level of pregnenolone.
trauma or worrying about what people may be thinking takes This is particularly important for those patients who don’t
the same physiologic toll as an immediate stressful event. The want to use hormonal replacement as higher doses of panto-
body doesn’t know the difference between psychological thenic acid, up to 1500 mg per day, may be used. Zinc is an
stress – real or perceived – and a physical emergency. To the important mineral that helps with healing. See . Table 31.4.
 

body, stress is stress, whether physical or psychological or The third leg of the three-legged stool consists of adapto-
both, and both are equally detrimental. gens. Adaptogens are herbs and botanicals that help the body
adapt to the stressors and may facilitate communication
between the adrenals and the higher centers of the brain [69,
31.3.3  Assessment and Treatment of Adrenal 70]. Examples include Rhodiola rosea (tyrosol, salidroside,
Dysfunction rosiridin), Eleutherococcus senticosus (eyringin, eleuthero-
side E), Schisandra chinensis (schizandrin), Panax ginseng
One useful laboratory evaluation for adrenal dysfunction is a (ginsenosides), and Withania somnifera (sitoindosides). For
four-point or 6-point salivary cortisol test. The latter is the 4 the reader interested in greater detail, please explore the ref-
point salivary cortisol throughout the day with the Cortisol erences provided.
 526 F. Trindade

ized approach utilizing functional and integrative medicine

..      Table 31.4  Nutraceuticals for adrenal dysfunction
tools be tailored to the individual needs of each patient. With
Panto- Stimulates ability of adrenal cells to secrete
focus and attention to the nutritional content of the diet, life-
thenic acid progesterone and corticosterone style modification, and supplementation with vitamins, min-
(B5) 500–1500 mg/day erals, adaptogens, and possibly hormones, the good news is
Enters early in steroidogenic pathway that it is possible to achieve a complete recovery from adrenal
Can lead to increase in downstream adrenal dysfunction.
hormones. Induces adrenal hyperresponsiveness
to ACTH stimulation

B6 (ideally 50–100 mg/day 31.4  Thyroid

P5P) Higher need due to stress. A co-factor in energy
production
A brief review of the physiology of thyroid function is essen-
Folate 400–800 mcg/day tial here. The hypothalamus produces thyroid-releasing hor-
(5MTHF) Co-factor in energy production
mone (TRH), which signals the pituitary to release
Magnesium 400–600 mg/day of chelated form thyroid-stimulating hormone (TSH), which then acts on the
31 Co-factor in many reactions of the Krebs cycle.
Low magnesium increases the release of stress
thyroid gland to make 95 percent thyroxine (T4) and 5 per-
cent triiodothyronine (T3) [74]. The liver and kidneys are
hormones. Magnesium decreases nocturnal
ACTH secretion
responsible for converting T4 to T3. Free T3 is the active
form of the hormone. When properly functioning, thyroid
Zinc The glucocorticoid receptor, like all steroid hormone keeps metabolism in control.
receptors, is a zinc-finger transcription factor
>300 human enzymes require zinc
The thyroid is an endocrine organ that is susceptible to
30–50 mg/day balance with copper (10–20:1 nutritional and environmental challenges [36, 37]. There are
ratio) many disruptors of thyroid hormone function, including
food sensitivities and/or food allergies, toxins, infections,
Vitamin C Preferentially concentrated in adrenal glands
and lost in times of stress from adrenal cortex nutrient deficiencies, stress, sleep deprivation, pharmaceuti-
cal drugs, adrenal dysfunction, oxidative stress, stress in gen-
Omega 3 Blunts the stress response. Decreases cortisol
eral, and changes in the gut microbiota. These disruptors are
and epinephrine
1000–3000 mg depending on co-existing extremely important because suboptimal thyroid function
pathologies has far-reaching consequences.
Some consequences of low thyroid hormone include
Vitamin D 2000 IU/day
Reduces latent virus reactivation with increased
fatigue, weight gain, depression cardiovascular dysfunction
stress (including dyslipidemias and atherogenesis), glucose intoler-
ance or insulin resistance, and poor pregnancy outcomes [75,
Based on data from Ref. [54–68] 76]. Inhibitors or promoters of proper thyroid hormone
function will be divided according to the location of opera-
tion. First, at the level of the thyroid gland or at the conver-
An optional fourth leg may be necessary at times and sion of T4 to reverse T3 (RT3) or to T3, there are factors that
includes hormonal supplementation. Hormonal supplemen- contribute to or inhibit proper thyroid function. Factors con-
tation may help the adrenals recover more quickly and may tributing to proper production of thyroid hormones include
assist both the brain and adrenals to re-establish their bal- the nutrients iron, iodine, tyrosine, zinc, selenium, vitamin
ance and connection with one another [71–73]. The most A, vitamin E, vitamin B2, vitamin B3, vitamin B6, vitamin C,
common hormones that may be considered are DHEA and and vitamin D [77–84]. Factors that inhibit proper produc-
pregnenolone, but these are recommended in very low doses. tion of thyroid hormone include stress, infection, trauma,
It is strongly recommended that hormones only be used radiation, medications, fluoride and bromine (antagonist to
when the other three legs are in place and more support is iodine), toxins such as pesticides, Hg, Cd, Pb, and autoim-
needed. Fortunately, in many cases, the first three legs are mune diseases such as celiac disease [36, 37]. Minerals
satisfactory interventions to bring the hypothalamic-­ important for conversion of T4 to T3 by deiodinase enzyme
pituitary-adrenal axis back to balance. include selenium and zinc. Factors that increase conversion
of T4 to RT3 include stress, trauma, low-calorie diets, inflam-
mation and cytokines, toxins, infections, liver and/or kidney
31.3.4  A Final Word on Adrenal Dysfunction dysfunction, and certain medications. Factors that improve
cellular sensitivity to thyroid hormones include vitamin A,
The two most important aspects of addressing adrenal dys- exercise, and zinc. Factors that promote or inhibit conversion
function are to stage the patient and understand the root of T4 to T3 by a deiodinase enzyme are provided in
cause of the dysfunction. Then and only then can a personal- . Table 31.5.  
Nutritional Influences on Hormonal Health
527 31

..      Table 31.5  Factors that facilitate or inhibit deiodinase ..      Table 31.6  Assessment of abnormal thyroid function
conversion of T4 to T3
Symptoms Memory and concentration problems
Facilitate Micronutrients Diffuse headache, migraines
Vitamins: A, E, riboflavin, etc. Depression; melancholia
Minerals: selenium, potassium, iodine, iron, zinc Constipation: hard or pellet-like bowel move-
Hormones ments and decreased frequency
Cortisol Low libido
Growth hormone Reactive hypoglycemia
Testosterone Hypotension
Insulin Hypoglycemia
Glucagon Poor tolerance to stress and exercise
Melatonin Fatigue
Hair loss
Inhibit Micronutrient excesses or deficiencies Poor concentration
Selenium deficiency Cold extremities
Iodine Headaches
Other micronutrient deficiencies
Hormones Physical Dry skin, elbow keratosis, brittle nails
Excess estrogen exam Diffuse hair loss
Oral contraceptives Puffy face, swollen eyelids
Prescription medications Edema in legs, feet, hands
Excess cortisol, catecholamines Elevated cholesterol, generally LDL
Chronic illness (cytokines, free radicals) Easy bruising
Long-term hospitalization Prolonged Achilles tendon reflex
Compromised liver or kidney function Keratoderma
Poor-quality diets Enlarged thyroid gland
Deficient protein
Excess sugar Laboratory TSH Functional Conven-
Environmental toxicity testing and Free T4 ranges tional
Heavy metals ranges Free T3 ranges
Herbicides, pesticides Total T3
Anti-peroxidase TSH: (0.4–5.5)
Polycyclic aromatic hydrocarbons 0.4–2/2.5
antibodies
Anti-­ mIU/L
thyroglobulin Free T4: (9–23)
antibodies 15–23
31.4.1  Assessment Anti TSH receptor pmol/L
antibodies
rT3 Free T3: 5–7 (3–7)
For overall assessment see . Table 31.6.
 
Total T3 (TT3) pmol/L
When evaluating laboratory results for thyroid testing, Free T3/free T4
it is important to realize that most conventional laborato- Total T3: (76–181)
TT3/rT3
120–181 ng/
ries have not adopted the optimal reference ranges that CBC and ferritin
dl
have been promoted by current literature and used in inte- RBC selenium
RBC zinc
grative/functional practices. Instead they use standard ref- Thyroid
25-OH vitamin D antibodies:
erence ranges that have been developed by tabulating Serum vitamin A WNL
results from multiple patient samples who were considered Urinary fasting
normal without regard to level of dysfunction. In appropri- morning spot rT3: 11–18 (11–31)
ate circumstances, red blood cell heavy metal testing may iodine ng/dl
Celiac panel
be done for acute ongoing exposure, and urinary heavy FT3/FT4:
Toxic metals as
metals may be used for ­assessment of total body load. indicated by
>0.33
Urinary testing can be done with or without provocation TT3/RT3: >6
history and
with a chelator. However, if ordering a provoked 24-hour or physical exam
6-hour urinary test, make sure patient will tolerate this Food sensitivity
testing
challenge. A chronically ill patient may not be able to toler-
ate provocation.

essary. Special attention is directed to removing the offending

31.4.2  Treatment cause or causes and supplementing the deficiencies as appro-
priate. Recommendations include a dietary plan that is low in
Treatment should begin by first focusing on lifestyle modifi- reactive foods. Choices for the plan include foods that are
cations and supplementation. After this has been optimized, high in pre- and probiotic content and high in phytonutri-
the final intervention may include hormonal therapy, if nec- ents and balanced in the omega-6/omega-3 ratio. The plan
 528 F. Trindade

31.5  Sex Steroid Hormones

..      Table 31.7  Thyroid function and the relationship to other
hormones
Sex steroid hormones for this discussion will refer broadly to
Hormone estrogen, progesterone, and testosterone. In the author’s
experience, if insulin sensitivity, adrenal function, and thy-
Adrenal High adrenal activity impairs 5′ deiodinase
leading to higher T4, lower T3, normal or
roid status have been addressed, the sex hormones may no
elevated TSH longer need special attention or additional hormone replace-
Low adrenal activity may result in lower T4, ment. In other words, there may be imbalances in sex hor-
higher T3, normal or elevated TSH mones due to problems with insulin sensitivity, adrenal
Excess adrenaline can desensitize T3 receptors function, or thyroid status. It is important to assess sex ste-
leading to T3 resistance, higher T3, despite
symptoms of hypothyroid
roid hormones by laboratory testing since abnormalities may
With excess adrenaline, the body compensates be present in men and women of all ages and not just in the
by lowering T4 leading to symptoms of perimenopause, menopause, or andropause stages.
hypothyroid but often the patient intolerant of 7 Box 31.2 details the approach to the sex steroid hormone
 

thyroid supplementation (always balance assessment.

31 adrenals first)

Sex steroid Hypothyroidism stimulates CYP3A4 leading to

hormones increased production of 16αOHE1
Hypothyroid decreases concentration of SHBG Box 31.2  Assessment of Sex Steroid Hormone
which causes more bioavailable E2 and Balance
testosterone 55 Thorough history including past medical history, child-
Hyperthyroid increases SHBG leading to less hood and family history, hobbies
bioavailable E2 and testosterone 55 Evaluation of insulin, adrenals, thyroid, sex hormones
Hypothyroidism associated with less deactiva- (including ovarian function), steroidogenic cascade, and
tion of cortisol to cortisone (hyperthyroidism estrogen metabolism
leads to the opposite) 55 Balance all hormones in specific order as outlined
55 Consider estrogen metabolism/genomics
55 Consider the effect of hormone balancing before drugs
55 Food and lifestyle management first
55 Assessment of impact of hormones in the individual
55 Decision to give hormones and informed consent
should strive to reduce inflammation by reducing saturated 55 Consider best route of delivery
fats, damaged fats, and trans-fatty acids. Critical for the 55 Regular reassessment of hormone levels and symptoms
patient is ensuring sufficient sleep, exercise, hydration, and
stress reduction techniques. Evaluating for adequate social
and community support is key.
Key nutrients to consider supplementing include sele- It is strongly cautioned not to begin bioidentical hormone
nium, zinc, iron or ferritin, iodine, vitamin D, and vitamin A replacement without adequate evaluation first. Since women
[77–84]. Zinc and selenium are especially important miner- with increased or persistant vasomotor symptoms (VMS) are
als to consider. For example, a low T3/T4 ratio may be related at higher risk for cardiovascular disease due to insulin resis-
to impaired zinc and/or selenium status. Remember to begin tance [6, 85], it is imperative to screen for insulin resistance
with food first; Brazil nuts are particularly high in selenium prior to balancing the sex hormones. Much has been written
and zinc and may be recommended before supplements. about hormone replacement therapy with respect to poten-
When needed, supplementation has been associated with tial increased risk of heart disease and breast cancer [6, 85–
modest changes in thyroid hormones and with a normaliza- 88]. It has been stated that hormone replacement therapy
tion of T4 and RT3 plasma levels. Iron deficiency impairs should be considered in these women to avoid these increased
thyroid hormone synthesis by reducing the activity of heme-­ risks [85]. If VMS are significantly associated with insulin
dependent thyroid peroxidase. Evaluate ferritin levels by resistance, it may also be postulated that women with insulin
laboratory testing instead of iron alone and supplement with resistance would have a greater need for menopausal hor-
ferritin when levels are low. Supplementation is recom- mone treatment than those without insulin resistance. In this
mended at levels of 80–100 mg/ml in women and slightly regard, there is the possibility of a beneficial effect with
higher in men. Further, iron-deficiency anemia blunts and replacement of menopausal hormones in patients with insu-
iron supplementation improves the efficacy of iodine supple- lin resistance.
mentation [77–84]. Typical amounts to consider are sele- In women beginning in pre- and perimenopause,
nium, 200–400 mcg; zinc, 15–30 mg; vitamin D, 2000 IU; ­progesterone and testosterone levels decline before estrogen
vitamin A, 2000 IU; iodine, 150 mcg; and iron, 15–20 mg (in levels decline. For menstruating women, it is helpful to mea-
a menstruating woman). Important points to consider for sure progesterone in the luteal phase on days 19–21 of the
thyroid function and the relationship to other hormones are cycle and the estrogens during the follicular phase on days
listed in . Table 31.7.
  10–12 to evaluate the respective peaks. Further, if we focus on
Nutritional Influences on Hormonal Health
529 31
optimizing estrogen metabolism for both men and women, the anxiety and mood changes that often accompany hor-
theoretical risks from hormone replacement may be miti- monal imbalances [105]. Estrovera, or Err 731, binds to estro-
gated [89]. Daily unremitting stress is associated with early gen receptor beta, which may be protective for hormone-
decline in progesterone and estrogen in younger women. related cancers. The central functions relevant to climacteric
Because of its position at the beginning of the steroidogenic complaints are proposed to be mediated via estrogen receptor
pathway, progesterone may be diverted down the pathway to beta (ERbeta) activation [106].
the stress hormone, cortisol. This is related to the physiologic To allow for smooth estrogen metabolism, supporting
need to respond to stress for survival, which is immediate and phase 2 conjugation detoxification enzymes, especially meth-
pressing. In addition, environmental toxins compete with our ylation with activated B vitamins and supplements such as
innate hormones because they are endocrine disruptors and/ alpha-lipoic acid, N-acetyl cysteine, selenium and liposomal
or xenoestrogens  that disrupt hormone signaling. In men, glutathione, can be helpful. Studies have shown that reducing
testosterone levels are declining at much younger ages related the levels of estrogen-DNA adducts could prevent the initia-
to exposure to environmental toxins [90, 91]. tion of human cancer [107–109]. The dietary supplements
As emphasized above, if there is an imbalance in baseline N-acetylcysteine and resveratrol also inhibit formation of
insulin sensitivity,  adrenal/HPA axis function, or with thy- estrogen-DNA adducts in cultured human breast cells and in
roid gland, begin by repairing these baseline abnormalities. women [110]. These results suggest that the two supplements
However, if after fixing the root causes sex hormone replace- offer an approach to reducing the risk of developing various
ment is needed, studies show that transdermal bioidentical prevalent types of human cancer.
estrogen and testosterone, as well as micronized oral or
transdermal progesterone, are generally safe and may not
increase a woman’s risk of heart disease or breast cancer if
31.6  Conclusion
prescribed appropriately [92–98]. It is necessary to measure
hormone levels and evaluate estrogen metabolism and then
Addressing hormonal issues in a systematic way is critical to
follow these levels on a regular basis if hormone replacement
discovering the root cause of hormonal imbalance. This is
is begun to ensure safety. Use non-synthetic hormones.
most effective when addressing insulin dysfunction first, fol-
Progestins are an example of synthetic hormones which are
lowed by adrenal support, followed by addressing thyroid
associated with increased cardiovascular risks, as demon-
issues, and lastly balancing the sex steroid hormones along
strated in the Women’s Health Initiative study [86, 96].
with their metabolism. This approach allows the practitioner
Hormone level baseline assessment should include pro-
to fix underlying imbalances without resorting to hormone
gesterone, testosterone (both total and free), sex hormone-­
replacement in many, if not most, cases.
binding globulin (SHBG), albumin, estradiol, estrone, and
estriol. With values for SHBG, albumin, and total testoster-
one, the bioavailable testosterone can be calculated in men
and women. The testosterone is tightly bound to SHBG,
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 533 32

Nutritional Influences
on Reproduction:
A Functional Approach
Brandon Horn and Wendy Yu

32.1 Introduction – 534

32.2 Microenvironments and Complexity – 534

32.3 Examining the Structural Layer – 536

32.4 Examining the Functional Layer – 536

32.4.1 E nergy Production – 536
32.4.2 Energy Utilization – 537
32.4.3 Hormonal Factors – 537
32.4.4 Nutrient Factors – 539
32.4.5 Reproductive Toxicology – 540
32.4.6 Reproductive Immunology – 544
32.4.7 Exercise – 546

32.5 Examining the Informational Layer – 547

32.5.1  enetics – 547
G
32.5.2 Innate Genetic Issues – 547
32.5.3 Neural Tube Defects and Folate Supplementation – 548
32.5.4 Risk Factors of Folic Acid – 548

32.6 Acquired Genetic Issues – 549

32.7 Summary – 549

References – 550

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_32
 534 B. Horn and W. Yu

32.1  Introduction Interestingly, when ART techniques are combined with

other modalities designed to address factors influencing the
Reproduction is one of the most basic biological processes, uterine environment, significant increases in pregnancies
yet it is also among the most mysterious. On one level, human and live birth rates have been reported [5–7]. As we will
reproduction merely requires the fusion of two haploid gam- explore, the uterine and ovarian microenvironments are
etes, forming a diploid zygote. This zygote must then divide essential factors in reproduction. The status of these micro-
40 times, amassing 1.4 trillion cells in the process (assuming environments, however, is intimately entangled with the sta-
the average weight of a newborn is 3250 g) [1]. The resulting tus of the relative macroenvironment of the organism.
conglomeration of cells is then ready to enter the world as a Indeed, many reproductive pathologies are merely one
human infant. This newborn, however, is not merely a mass of aspect of a larger clinical picture. For example, endometrio-
molecules. It is a highly organized and immensely compli- sis is a condition that affects 10–15% of reproductive-age
cated network of other living organisms. Some of these organ- women and is associated with reduced fertility [8].
isms are endogenously derived (the 1.4 trillion human cells) Researchers noted a significant association between endo-
[2], while others are acquired exogenously. Of those acquired, metriosis and pigmentary traits, including an increased
some are inherited (mitochondria), some are acquired within number of cutaneous nevi, freckles, and those with sun-
the womb, and still others are acquired as the fetus is exposed sensitive skin [9]. While the precise relationship between
to the environment during and following childbirth [3]. pigment and endometriosis has yet to be elucidated, it has
been shown that women with endometriosis have a higher
32 Within the microenvironment, each of these cells has its
risk of melanoma [10]. Furthermore, both melanoma and
own nutritional requirements, need for waste management,
and defense against invaders. They all serve some unique endometriosis have been associated with environmental tox-
purpose within the larger community that is a human organ- ins, including PCB and organochlorine exposure [11]. One’s
ism. For endogenously derived cells, each cell’s purpose is ultimate toxic burden, while strongly correlated with the
expressed through its phenotype. A cell that migrates to the dose and type of toxic exposure, is also largely influenced by
heart will develop phenotypical characteristics of a cardiac one’s detoxification capacity for such toxins. In the case of
cell, whereas a cell that migrates to the liver will develop PCBs, biotransformation occurs via the cytochrome P450
characteristics of a hepatic cell. Despite clear phenotypical 1A1 enzyme (CYP1A1) [12]. It was found that individuals
differences, both cells are genetically identical. The environ- with genetic polymorphisms in the gene that codes for
ment determines a cell’s ultimate phenotypical expression, CYP1A1 (A4889G) have significantly higher risks of cancer
whether in the promotion of physiology or pathology. [13] and endometrial hyperplasia [14]. Similarly, genetic
The environment, therefore, is one of the key determina- polymorphisms in other genes, such as the GSTM1 gene
tive factors in the health of an organism. Nutrients, as largely involved in the regulation of glutathione S-transferase (and
exogenous molecular influences, make up an important part thus protection from PCBs), were associated with an
of this environment, and variations in the type and quantity increased risk of endometriosis [15]. Because GSTM1 is also
of such influences can significantly alter physiology. It is involved in detoxification of electrophilic compounds
within this context that we will explore the dynamics of including carcinogens, therapeutic drugs, and other envi-
reproduction. The goal of this chapter is to help the reader ronmental toxins and products of oxidative damage, any
understand the complexities inherent in reproduction and to findings related to issues in glutathione-mediated detoxifica-
create effective strategies for determining an appropriate tion pathways warrant an inquiry into GSTM1 and other
nutritional intervention. This chapter is not, nor is it intended polymorphisms. In the case of GSTM1, the frequency of the
to be, a comprehensive catalogue of nutritional influences on particular polymorphism rs366631 in the general population
reproduction. is 50–78% (depending on race) [16]. Therefore, it is more
likely than not that a patient presenting with endometriosis
will develop a number of seemingly unrelated pathologies.
32.2  Microenvironments and Complexity Endometriosis has also been shown to have a strong
inflammatory component in both its pathogenesis and the
Reproduction is a biological imperative and our bodies have resulting pathophysiology. Consequently, endometriosis has
evolved to survive and reproduce. As a result, the successful been associated with an increased risk of cardiovascular dis-
treatment of reproductive issues often has more to do with ease [17]. Vascular insult and atheromatous plaque progres-
removing impediments to reproduction than directly facili- sion are commonly found with endometriosis-associated
tating conception. While both strategies merit consideration coronary heart disease and can also be found in the general
within any given case, it should be noted that the direct facil- population of women with unexplained infertility [17–18].
itation of conception through assisted reproductive technol- While there are many systems affected by inflammation, an
ogies (ART), such as in vitro fertilization (IVF), even in the attempt to uncover the source of such inflammation should
youngest and most fertile population, has a success rate of be made. As inflammation is an immune-mediated response,
less than 50%. By the time a woman is 43 years old, she has a it comes as no surprise that endometriosis has been ­associated
less than 4% chance of achieving a successful pregnancy with infectious agents. Less intuitive is that infectious influ-
through ART [4]. ence is not restricted to pathogens local to the reproductive
Nutritional Influences on Reproduction: A Functional Approach
535 32
tract. Take Helicobacter pylori (H. pylori), for example. H. an isolated and exclusive disease of the reproductive system
pylori is not known to infect the genital tract or associated or HPO/HPA axis [32].
nervous or glandular structures, yet it is significantly more As the previous example illustrates, there are many etio-
prevalent among infertile men and women than among logical and pathophysiological factors involved in reproduc-
healthy controls [20]. Extra-reproductive pathogens influ- tive pathology. Many of these factors overlap and form an
encing reproduction are not limited to H. pylori. Periodontal interconnected web. Organizing the masses of information
disease, for example, was also significantly associated with can be challenging. One useful model has its roots in Chinese
endometriosis [20]. It has been subsequently hypothesized medicine, where they describe all phenomena as some com-
that systemic autoimmune disorders and possibly endome- bination of three levels: material/structural, energy/function,
triosis may be an inflammatory response to seeded peri- and informational (which includes psychospiritual factors).
odontal bacterial pathogens [20]. A variety of local pathogens While all phenomena will have some interaction with each of
have also been associated with an increased risk of develop- these factors, there tends to be a dominant factor. To illus-
ing endometriosis. Some of these include the human papil- trate this concept, let us examine a common reproductive
lomavirus, Escherichia coli, Chlamydia trachomatis, and pathology: uterine leiomyomas (fibroids).
Mycoplasma genitalium [21–22]. In addition to pathogens, A fibroid is a structural anomaly that can inhibit repro-
inflammation can be induced by autoimmunity. In women duction through a number of potential mechanisms, the pri-
with endometriosis, the presence of autoantibodies is a com- mary of which is usually some form of physical obstruction.
mon feature [23]. While hormone modulation and potentially certain phyto-
Aside from the cardiovascular, toxicological, reproduc- chemicals can inhibit the growth and even regress the tumor
tive, and immune factors, endometriosis has perhaps most [33], many of the therapeutic targets used to accomplish this
strongly been associated with endocrine pathology. Indeed, are antagonistic to reproduction. Estrogen and progesterone,
estrogen is often considered to be one of the most important for example, are known growth factors for fibroids.
factors in the pathogenesis of endometriosis [24]. What is Downregulation of ovarian steroid hormones using a GnRH
less well known is that progesterone resistance may play an agonist often results in tumor regression [34]; however,
equally important role [25]. Progesterone resistance can reproduction is not possible under such conditions and the
result from various etiologies, one of the more important of therapy is only approved in the short term. Other hormonal
which is via modulation of the endocannabinoid system and potentially nutraceutical therapies, such as epigallocate-
(ECS). The cannabinoid receptor type 1 (CB1-R), for exam- chin gallate (EGCG), work by modulating aromatase or
ple, has been found to have essential reproductive functions directly inhibiting cellular reproduction [35–36]. In cases of
[26] and appears to be responsible for progesterone’s anti-­ infertility, inhibiting cellular reproduction would be counter-
inflammatory actions. Indeed, within the reproductive tract, productive. As a result of a lack of options, fibroids suspected
the uterus contains the highest concentration of CB1-R of causing infertility are often surgically excised, yet the
ligands, and the activation of CB1-R seems to be directly 8-year recurrence rate for laparoscopic myomectomies is
involved in implantation. Altering the endocannabinoid sys- 76% [37]. Such a high recurrence rate may be the result of the
tem by inhibiting progesterone (a CB1-R ligand), or through failure to address antecedents or triggering events. Indeed,
direct exogenous ligand exposure (via cannabis use), resulted physical activity [38], lower BMI [39], intake of fruit, intake
in reproductive malfunctions [25]. of preformed vitamin A [40], and sufficient sunlight expo-
Other hormones have been associated with endometrio- sure [41] have each been independently associated with
sis as well. For example, low levels of vitamin D were found lower incidence of fibroids. In animal models, activated vita-
in women with endometriosis and associated pelvic pain min D3 (1,25(OH)2D3) shrank uterine fibroids [42], lending
[27]. Excessive exposure to thyroid hormone, for example, further weight to the epidemiological data [41]. Genetic fac-
in Graves’ disease, was also associated with endometriosis tors have also been found to play a role [429].
[28], as were genetic polymorphisms in the renin-angioten- While a number of nutrients have been explored in the
sin system [29]. treatment of fibroids, human studies are lacking. As a general
Emotional factors were also found associated with endo- proposition, correlations between animal studies and human
metriosis, with stress contributing to the development and studies are largely disappointing. A review of the highest
severity [30]. Interestingly, endometriosis patients with high impact animal studies found only 10% resulted in a treat-
stress had lower salivary cortisol than controls, leading ment approved for use in patients [43]. Thus, animal studies
researchers to postulate that the hypocortisolism may be an are not reliable predictors of human response. In addition,
adaptive response [31]. and as we’ll see later in the chapter, many nutritional supple-
While there are many other factors that can influence ments seem to have dose-dependent biphasic effects: pro-
endometriosis and reproduction in general, this example moting or inhibiting the same function. Genistein, for
illustrates the importance of approaching infertility as a example, was found either to proliferate or inhibit human
“nonrandom” occurrence. Different infertility etiologies are uterine leiomyoma cells, depending on the dose [44].
genetically and clinically linked with other diseases, and In summary, uterine fibroids have a structural
researchers suggest that we should be treating infertility ­component, being the mass itself and the potential to physi-
problems using phenomics, rather than viewing infertility as cally obstruct important aspects of reproduction. They also
 536 B. Horn and W. Yu

have a functional component, which covers the etiology and lead to ischemia and are a well-known risk factor in recur-
pathophysiology of the fibroid and includes its antecedents, rent miscarriage and suspected factors in implantation fail-
triggering events, and mediators. There are also psychologi- ure [50]. Clots are an interesting subset of structural issues
cal and informational aspects, including possible genetic because nutritional intervention can be very effective.
and stress components. Nutraceuticals such as nattokinase, lumbrokinase,
As the aforementioned example illustrates, structural Desmodium styracifolium, and Sargassum fulvellum have
abnormalities are often the result of functional or informa- strong fibrinolytic activity [51]. Many Chinese herbs have
tional problems. Therefore, when dealing with structural also been shown to inhibit a number of prothrombotic path-
issues, an attempt should always be made to identify and ways [51]. Dietary factors can also influence clotting risk,
address any confounding informational and functional issues. with red and processed meats tending to increase thrombotic
risk and fruit, vegetables, and fish decreasing risk [52].
Unfortunately, most studies incorporating meat are poorly
32.3  Examining the Structural Layer designed. Red meat from grass-fed cows, for example, has a
completely different nutritional profile than the same meat
Structure dictates function. While this is a mantra of biology, from grain-fed cows. An analysis done by the Weston A. Price
as we will discuss, the converse is also true. Structural issues Foundation with the University of Illinois found that “[t]he
can present on a macroscale, such as a uterine fibroid, or on a ratio of omega-6 to omega-3 fatty acids was over 16:1 for the
microscale, such as improper protein structures or folding. grain-fed tallow but only 1.4:1 for the grass-fed tallow.” It
32 Within reproductive pathophysiology we can roughly divide should be noted that a higher n6:n3 ratio has been found to
structural issues into direct and indirect. be associated with higher thrombotic risk [53]. Therefore,
Direct structural issues are gross anatomical abnormali- studies discussing “meat” (or any other class of foods without
ties that can change how the reproductive process functions. specifying type or source) should be approached with signifi-
Hydrosalpinx, ovarian cysts, endometriomas, fibroids, and cant skepticism.
polyps are all examples of masses that have potential for caus- Structural impingement of nerves or blood vessels may
ing direct structural issues. Within male fertility, these may also result in altered function of a variety of systems. While
relate to varicoceles and other tumors, as well as morpho- high-quality data are lacking, biological mechanisms exist
logical defects in sperm. whereby spinal or other nerve impingement may negatively
Indirect structural issues occur where structural damage impact sexual and reproductive function [54]. Where such
or morphological anomalies interfere with cellular commu- patho-mechanisms are suspected, manual manipulation
nication, often leading to over- or underproduction of hor- such as massage, chiropractic, or osteopathic manipulation
mones or other ligands. This form of structural issue has should be explored.
significant overlap with the energy/function level; however, Finally, we have structural damage to DNA. The cause of
if the structural level is not addressed, it is very difficult to such damage is often reactive oxygen species (ROS) or reac-
correct the functional aspects. Therefore, the ideal therapeu- tive nitrogen species (RNS). As will be discussed later in the
tic target is usually the structural abnormality and its ante- chapter, this can cause damage leading to poor oocyte quality
cedents. An example of this is a Leydig cell tumor (LT), or oocyte destruction.
which can secrete sex hormones resulting in reproductive
problems. In men, an LT can lead to feminization, loss of
libido, erectile dysfunction, and gynecomastia. In women, 32.4  Examining the Functional Layer
they can lead to masculinization, anovulation, amenorrhea,
clitoromegaly, and increase in musculature. Treatments Function is life. It is what separates an organism from an
aimed at inhibiting the effects of estrogen or testosterone are inanimate object. The term “function” is a concept. The
of limited benefit and destruction of the tumors is necessary means of executing that concept is energy. Therefore, energy
to stop the process [45]. is one of the most important and fundamental requirements
Not all tumors, however, should be treated surgically. for life and, as a consequence, for reproduction. Indeed, the
While a common procedure, aspiration of ovarian cysts has body seems to have evolved to suppress reproductive func-
not been found to be effective at increasing fertility outcomes tion in response to energy deficits [55]. The energy cycle has
[46] and the “effects of surgical treatment are often more four basic aspects: production, storage, delivery, and utiliza-
harmful than the cyst itself to the ovarian reserve” [47]. tion. While energy storage and delivery can be important
While tumors are one of the more common indirect factors in reproduction, we will focus this discussion on pro-
structural issues, tissue damage is another. Head injuries, for duction and utilization.
example, can cause damage to the hypothalamus, resulting in
hypopituitarism with elevated prolactin levels [48]. Scar tis-
sue from abdominal surgeries or endometriosis can lead to 32.4.1  Energy Production
pelvic adhesions and even infertility [49]. The formation of
masses in the blood (i.e., clots) are also a common cause of Efficient energy production occurs primarily through oxi-
reproductive problems [50]. These can inhibit blood flow or dative phosphorylation within the mitochondria. Indeed,
Nutritional Influences on Reproduction: A Functional Approach
537 32
the estimated number of mitochondria per cell can give us 32.4.2  Energy Utilization
some idea of the energy requirements of the function of a
given tissue. For example, a skeletal myocyte has been esti- While energy production is essential, of equal importance is
mated to contain over 3500 mitochondria [56], whereas a its utilization. We can broadly classify the use of energy
cardiac myocyte, which is active all the time, contains through the related concepts of communication and interac-
almost 7000. In contrast, the number of mitochondria in tion. Communication allows for interaction and, while a very
an oocyte (mature egg cell) is close to 800,000 [57]. The broad topic, we will narrow our focus to how the way we inter-
mitochondrial requirements of an oocyte are therefore act and process our environment influences reproduction.
orders of magnitude higher than other cells. It comes as The process of communication deals with signal distribu-
little surprise therefore, that one of the most fundamental tion, be it electrical, chemical, or otherwise. The nervous
sources of embryo failure is the inability to produce suffi- system, as a mediator of brain signaling, is intimately involved
cient energy [58]. in almost every aspect of reproduction [70]. Insults to the
While the quantity of mitochondria is certainly impor- nervous system can inhibit proper reproductive function,
tant for energy production, the quality of energy production whether from disease process, emotions, or exposure to envi-
is equally important. For proper function, mitochondria ronmental or immunological challenges [71–75]. Chemical
need both substrate and cofactors. With aerobic respiration, signaling, whether endocrine, paracrine, or autocrine, is
the substrates are pyruvate and oxygen with pyruvate being indispensable for human reproduction [76–78]. Disruption
primarily a glucose derivative resulting from glycolysis. in chemical signaling can also come from disease process,
Glycolysis, however, occurs within the cells and therefore emotions, and exposure to environmental and immunologi-
glucose must efficiently enter such cells. Suboptimal glucose cal factors [79–81]. In addition, there seem to be other com-
transport is thus correlated with poor fertility outcomes. munication and delivery mechanisms that are more
Polycystic ovary syndrome (PCOS), for example, is a condi- amorphous, such as quantum entanglement within neural
tion that affects up to 20% of women [59] and is highly asso- networks [82] and the meridian theory of Chinese medicine
ciated with insulin resistance [60]. While women with PCOS which posits a network of channels covering the entire body.
have an ordinary number of primordial follicles, the number While research is ongoing, there have been a number of
of primary and secondary follicles is significantly increased. recent studies affirming that biophysical characteristics at
However, despite the large quantity of follicles, the growth of acupuncture points are in fact different from non-­
such follicles often arrests prematurely. Without a dominant acupuncture points [83]. The modulation of these communi-
follicle, anovulation results. For those women with PCOS cation routes via acupuncture has been found to improve a
that do ovulate and achieve pregnancies, the incidence of variety of fertility issues, including improvement in markers
spontaneous abortion is as high as 73% [59]. Improved con- of poor ovarian reserve [84]; premature ovarian failure [85];
trol of glucose, however, may result in significantly improved ovulation frequency in women with PCOS [86]; sperm count,
pregnancy outcomes [61]. motility, and morphology [87–89]; and so forth.
Oxygen is essential for human life and reproduction. There are many physiological and pathological intricacies
Oxygen utilization level within the oocyte was found to be to the facilitation and inhibition of the process of communi-
a predictor of reproductive success [62]. Consequently, the cation and transformation. Some of the more important
availability, perfusion, transport, and utilization of oxygen facilitating molecules include hormones and various nutrient
should be examined in the context of reproduction. For cofactors.
example, pulmonary issues can predispose women to fer-
tility difficulties [63], as can issues with oxygen transport
[64]. Once oxygen is in the cell, the mitochondria require a 32.4.3  Hormonal Factors
number of nutrient cofactors for proper function. Electron
transport chain (ETC) cofactors include nicotinamide, The primary role of hormones is to carry particular mes-
thiamine, riboflavin, succinate, and coenzyme Q10 sages from one site to another. Sex hormones, including pro-
(CoQ10) [65]. gesterone, androgens, and estrogens, are essential to
The aerobic metabolism of energy is a delicate balance. reproduction, but there are many other hormones involved
The reduction of oxygen produces ROS, including superox- as well. Some of these include gonadotropin-releasing hor-
ide and peroxide anions, which can damage DNA and cellu- mone (GnRH), luteinizing hormone (LH), follicle-stimulat-
lar structures and is associated with fertility decline [66]. At ing hormone (FSH), prolactin (PRL), oxytocin, inhibin,
the same time, ROS and RNS are important facilitators of activin, prostaglandin F2a, PGE2, human chorionic gonado-
ovulation, folliculogenesis, implantation, and even ovarian tropin (hCG), placental lactogen, relaxin, thyroid hormones,
steroidogenesis [67]. A study measuring follicular fluid ROS DHEA, insulin, anti-Mullerian hormone, albumin, SHBG,
levels found increased ROS was a marker predictive of cortisone, melatonin, and angiotensin. While a thorough
in vitro fertilization (IVF) success [68]. Optimal ROS levels investigation of the interactions of these hormones is beyond
change depending on the location and timing of the repro- the scope of this survey, we will review selective interactions
ductive cycle and, as such, the indiscriminate use of antioxi- to further demonstrate the role of systems biology within
dants could be detrimental to fertility [69]. reproduction.
 538 B. Horn and W. Yu

During the follicular phase, the hypothalamus sends low-­ as prematurely elevated levels may suppress ovulation
frequency, high-amplitude pulses of GnRH to the anterior [101]. In the luteal phase, melatonin plays a number of
pituitary, which responds by secreting FSH. FSH then stimu- important roles, particularly in the maintenance of proges-
lates the aromatization of androgens within the granulosa terone levels and in the reduction of oxidative stress. Indeed,
cells to create more estrogen. However, LH is just as impor- melatonin’s antioxidant effects are strong enough to help
tant as it stimulates the theca cells to produce the androgens prevent premature ovarian failure in chemotherapy-treated
that are aromatized [90]. FSH also stimulates follicular females [102] and to significantly extend the reproductive
growth. As follicles grow, they produce more estrogen. life of hens [103]. As melatonin levels decline with age, the
Estrogen, in turn, helps develop the uterine lining, stimulates likelihood of poor oocyte quality due to oxidative damage
vaginal lubrication, upregulates expression of progesterone increases significantly [104]. In pregnancy, melatonin read-
receptors, and increases vasopressin and oxytocin produc- ily crosses the placental barrier and has an essential role in
tion in preparation for ovulation. With respect to FSH, estro- protecting the fetus from oxidative damage [104]. It also
gen has a bimodal effect, first inhibiting FSH through a appears to be a crucial component in proper fetal develop-
negative feedback loop until E2 levels reach 2–4 times the ment, particularly in the prevention of neurodevelopmental
early follicular level. At that point, the response of the hypo- disorders. Low levels of melatonin are associated with
thalamus switches to a positive feedback that results in a autism spectrum disorders (ASD) [104]. As melatonin
surge of gonadotropin production, though a number of fac- secretion occurs mainly at night in the absence of light, it is
tors, including insufficient oxytocin levels and elevated mela- essential to reinforce the importance of proper sleep
32 tonin levels, may inhibit the LH surge [91]. The LH surge hygiene. Minimization of nocturnal light is important to
prevents further growth of nondominant follicles and causes maintain proper melatonin levels. Exposures to as little as
final oocyte maturation to begin, a process involving the 285 lux for 2 hours were sufficient to negatively impact
renin-angiotensin system. As a result, the use of ACE inhibi- melatonin levels [105], though filtering out blue light via
tors may interfere with this process [92]. orange-tinted safety glasses seems protective [106].
Following the LH peak, the outer granulosa layer stops Following ovulation, the oocyte is released into the peri-
aromatizing androgens and, with the help of other hormones toneal cavity where the fimbriae at the end of the nearest fal-
like melatonin [93] and angiotensin and renin [94], switches lopian tube facilitate its entrance. Propulsion of sperm and
to progesterone synthesis. During ovulation, the follicle is oocytes within the fallopian tubes is accomplished through a
ruptured via the degradation of the follicular wall by enzymes complex interaction between peristaltic waves, ciliary activ-
such as collagenase, plasminogen activator, and gelatinase. ity, and the flow of tubal secretions [107]. Fertilization typi-
After release of the oocyte, the follicle (corpus luteum) pri- cally occurs in the ampulla of the fallopian tube, with sperm
marily secretes oxytocin, progesterone, estrogen, and inhibin. able to live for up to 7 days waiting for the arrival of the
Oxytocin (OT) is believed to facilitate sperm transport to oocyte [108]. While it has often been assumed that ovulation
the proper fallopian tube [95], is anxiolytic, and seems to be only occurs once per cycle, multiple batches of maturing eggs
a cofactor in angiogenesis [96]. Progesterone converts the have been observed in nearly all human subjects and multiple
endometrium to the secretory stage, thickens cervical mucus ovulations per cycle in 10% [109]. This perhaps explains why
to block sperm transit, and decreases the maternal immune the rhythm method of contraception tends to be unreliable
response. Progesterone also has anxiolytic effects, perhaps to [110], though there are other factors, such as pheromones,
help minimize the negative impact of stress on implantation that can trigger ovulation [111] and could influence rhythm
[97], and helps to control oxytocin levels. While OT seems method failures.
useful to facilitate sperm transport, continued myometrial Upon fertilization, it takes the embryo ~4–6 days to travel
contractions may interfere with implantation. Indeed, the from the fallopian tube into the uterus where it spends
use of OT antagonists following IVF was associated with ~3 days in the uterine cavity prior to implantation. During
increased implantation rates [98]. this time, the embryo is nourished solely through fluids in
Like OT, PRL has important bimodal functions in repro- the uterine cavity. Therefore, fat-soluble vitamins and iron
duction. While PRL is necessary for embryo implantation are particularly important [112]. The endometrium then
and can rescue stress-threatened pregnancies by preventing absorbs the fluids to allow contact between the blastocyst and
progesterone degradation [99], its presence in sufficient the uterus. Failure of fluid absorption (endocytosis) signifi-
quantities at the wrong time can inhibit ovulation through cantly increases implantation failure [113]. The invasion of
suppression of GnRH. Perhaps this is how vitex agnus-castus the embryo into the uterus then begins. This is an inflamma-
(VAC) improves fertility in some women, as it was found to tory process and the use of anti-inflammatory medication
lower PRL levels equivalent to the dopamine agonist bro- may be counterproductive. For example, dexamethasone
mocriptine [100]. However, caution should be exercised in administration for 4 days inhibited implantation in 80% of
administering VAC to eu-PRL individuals, as low prolactin rats given E2. However, injecting two doses of histamine
may have unwanted effects on fertility. reversed these effects. [114]. Therefore, eating fermented or
Melatonin is present in significant amounts in follicles other foods high in histamine may help facilitate implanta-
[93] and peaks during the luteal phase. The cyclical nature tion. Similarly, PGE2 reversed dexamethasone-induced
of melatonin throughout the reproductive cycle is essential implantation inhibition [114].
Nutritional Influences on Reproduction: A Functional Approach
539 32
There are many hormones involved in implantation, Reproduction requires a tremendous amount of energy
including thyroid hormone, E2, P4, PRL, CRH, melatonin, expenditure. It is estimated that over a normal gestational
and PGE2. [115–118]. If hCG or other signals are not received period with normal fetal weight gain, the caloric requirement
indicating implantation, hormone levels drop, triggering is 78,000  kcal [55]. Calories, however, are not a sufficient
menstruation. If hCG is detected, the body begins prepara- metric; the type of caloric intake is also important. Numerous
tion for a pregnancy. food substances have been found to impair fertility. For
From a treatment standpoint, there are many dietary example, trans-fatty acid intake was inversely associated with
strategies to modulate hormones. One common strategy is sperm count [127]. Replacement of 1% energy of saturated
the use of natural aromatase inhibitors, such as flavonoids. In fatty acids with 1% energy of long-chain n3-PUFAs more
particular, chrysin, naringin, naringenin, hesperetin, erio- than doubled live birth rates [128]. Caffeine consumption
dictyol, and apigenin [119–120] are among the compounds (coffee, tea, sodas, etc.) in both men and women was associ-
shown to have significant inhibitory effects on aromatase. ated with a greater than 70% increase in the risk of pregnancy
Tea polyphenols can also inhibit aromatase, with black tea loss [129] and alcohol more than doubled the risk of miscar-
having significantly more potent effects than green tea [119]. riage [130]. Study results on alcohol and caffeine, however,
A variety of other phytocompounds, particularly from a vari- have not been consistent [131]. Sugar consumption reduced
ety of herbal medicines and foods, are also effective [119]. live birth rates [132] and adding just one serving of poultry
Genistein and quercetin, on the other hand, induced aroma- per day resulted in a 32% higher chance of developing ovula-
tase with a 2.5- and 4-fold induction, respectively [121]. tory infertility [133–134]. Interestingly, no other meats had
Aromatase modulation should be attempted only relative to this effect, though both meat and fish have toxicological con-
the patient. In diseases often characterized by estrogen-­ cerns that are known to negatively impact fertility [131].
dominant states such as endometriosis, aromatase inhibition In contrast, proper nutrition has consistently been found
may be therapeutically indicated. However, in cases of andro- to increase fertility [131]. High-quality food should be free of
gen dominance, such as PCOS, this would be counterpro- pesticides and as natural as possible. Organic foods avoid
ductive. Strongly inhibiting aromatase may result in poor endocrine damage from pesticide residues. Indeed, such
reproductive outcomes, and there is some evidence that it residues were associated with fertility problems including
could induce autoimmune disease [122]. Indeed, estrogen reduced semen quality in men and a lower probability of
seems to be an important regulatory hormone for develop- pregnancy and live birth in women [7, 135]. The
ment of peripheral T regulators and therefore can help main- Mediterranean diet was examined in relationship to fertility
tain immune tolerance. Estrogen was also found to be an and found to significantly improve live birth rates [136] and
important factor in embryo implantation [123]. reduced the risk of preeclampsia [137]. On the other hand,
Cortisol is released by the adrenal glands in response to caution is warranted for patients on restrictive diets.
stress and low blood sugar. Increased cortisol levels have Carbohydrate restriction in the form of avoiding whole
been associated with untimely increases in gonadotropin and grains may be counterproductive, as whole grain intake was
progestin levels during the follicular phase, impending ovu- associated with a 51% higher probability of live birth [138].
lation and implantation [97]. It has also been associated with Consumption of fruits and vegetables was positively corre-
early pregnancy loss [124]. During pregnancy, elevated corti- lated with healthy birth weight [139], and tomato juice, in
sol is associated with intrauterine growth restriction, preterm particular, improved sperm motility [140]. Consistent use of
labor, preeclampsia, and chorioamnionitis [125]. In contrast, a prenatal multivitamin resulted in a 55% reduction in the
cortisol was also found to have beneficial effects on stimulat- risk of miscarriage [129], stillbirths [141], preeclampsia, pre-
ing hCG secretion and promoting trophoblast growth [125]. term labor, and small gestational-age babies [142]. Intake of
The adverse effects of cortisol are unlikely to stem from nor- iron, zinc, folic acid, calories, and protein was also found to
mal physiological secretion, but rather from stress-induced be higher in fertile women, specifically in the form of meat,
production. Cortisol levels are upregulated by caffeine, stress, nuts, dried fruit, and green leafy vegetables [143].
and sleep deprivation. They are downregulated by relaxation, Specific nutrients have also been found to exert impor-
massage, intercourse, magnesium, vitamin C, n3 fatty acids, tant influences on fertility; however, whether a nutrient is
and having fun or laughing. Estrogen also increases cortisol beneficial or detrimental is often dose-dependent. For exam-
levels [97]. ple, levels of iron (Fe), copper (Cu), and magnesium (Mg)
were found to be lower in males with sperm motility issues,
yet excess Fe and Cu (especially if a person is positive for
32.4.4  Nutrient Factors hemochromatosis or Wilson’s disease) both impaired sperm
parameters and could lead to impotence [144, 145]. Zinc
Nutrition is one of the most important factors in the survival (Zn) levels were found to be significantly higher in fertile
and reproduction of any organism. Indeed, nutrition pro- men than in non-fertile men, and seminal Zn levels were
vides substrates for both structure and function. In repro- positively correlated with improved sperm count and mor-
duction, proper nutrition has been found to be essential for phology [146]. High levels of Zn, however, produced the
fertility and proper fetal development [126]. To begin with, opposite effect [147]. Selenium was found to reduce the risk
nutrition provides the substrates for energy production. of miscarriage, preeclampsia, preterm labor, and gestational
 540 B. Horn and W. Yu

diabetes [142]. Deficiencies in selenium have also been asso- factors is of equal importance. These factors often arise as a
ciated with reduced sperm quality. However, too much sele- result of environmental exposures. Indeed, in modern times
nium reduced sperm quality [148–149]. where nutrients are relatively easily accessed, toxicological
Vitamin D, technically a hormone, regulates calcium, concerns have become increasingly prominent.
magnesium, and phosphate homeostasis and plays an
important role in fertility. Low levels of vitamin D are associ-
ated with a decrease in sperm count and motility, along with 32.4.5  Reproductive Toxicology
an increase in abnormal sperm morphology. High vitamin D
levels were found associated with poor sperm count, motil- There are over 80,000 chemicals registered for use in the
ity, and morphology [150]. Furthermore, elevated vitamin D United States, and 2,000 new ones introduced each year
levels in follicular fluid reduced fertilization rate and embryo [163]. While many chemicals have been found to cause
quality [150], and higher values of vitamin D were associ- reproductive harm, most of the chemicals in use have never
ated with a lower possibility of achieving pregnancy [150]. been tested. According to the New York Times,
Indeed, the activated form of vitamin D (1,25(OH)2D3) is
transferred through the placental barrier, where it can leach
»» MANY Americans assume that the chemicals in their
shampoos, detergents and other consumer products
out embryonic skeletal calcium stores, potentially compro-
have been thoroughly tested and proved to be safe. This
mising postnatal survival [150]. A significant portion of
assumption is wrong. Unlike pharmaceuticals or
vitamin D’s effects on fertility is thought to be its influence
32 on calcium homeostasis. One study examining vitamin
pesticides, industrial chemicals do not have to be tested
before they are put on the market… [Furthermore,]
D-­deficient subfertile mice found that calcium supplementa-
companies are not required to provide any safety data
tion restored fertility [151]. Indeed, calcium plays a major
when they notify the [EPA] about a new chemical, and
role in fertility as calcium ion oscillations initiate embryo-
they rarely do it voluntarily ... If the EPA does not take
genesis [152].
steps to block the new chemical within 90 days or
Magnesium (Mg) also has important influences on fertil-
suspend review until a company provides any requested
ity. Mg ions were found to preserve fertility on exposure to
data, the chemical is, by default, given a green light...
ionizing radiation [153]. Women supplementing with 300 mg
[164].
of Mg were found to have fewer instances of intrauterine
growth retardation, preterm labor, preeclampsia, gestational In such an environment, a toxicological evaluation becomes
diabetes mellitus, leg cramping, pregnancy-induced hyper- essential. Official determinations of safe levels of potentially
tension, and abnormal weight gain. The Cesarean delivery toxic substances may err by orders of magnitude. This is the
rate was 67% lower, and children born to these women had result of most toxicity studies examining isolated elements.
higher Apgar scores when compared to women taking only Real-world exposures are rarely isolated and substances con-
100 mg of Mg daily [154]. sidered harmless at low levels can become highly toxic when
Maternal intake of folic acid during pregnancy was found combined. For example, experiments where mercury was
to lower the risk of autism spectrum disorder (ASD) [155], administered at a level that kills 1% of a test population (LD1)
neural tube defects, cardiac malformations, and cleft palate and then combined with an amount of lead that kills 0.05% of
[156]. However, one report found that excessive levels of folate a test population (1/20 of LD1) killed 100% of the animals
and vitamin B12 in the blood increased autism risk by 17,600%. [165]. This is one of the reasons for adverse event reporting at
Excess levels were defined as more than 59 nanomoles per liter dosages deemed safe in controlled trials.
of folate and more than 600 picomoles per liter of B12. While A second important toxicological principle is that route
this has not yet been confirmed, a bimodal effect of folic acid of administration can exponentially increase the toxicity of
would be commensurate with other nutrients [157]. various substances. For example, safe levels of GI exposure
Vitamin C (AA) can also help protect the reproductive can be highly toxic if given parenterally. A study looking at
system from oxidative stress. It is also important during fol- the LD50 for cholinesterase inhibitors found the LD50 for
licular growth [158] and to help prevent reproductive dam- oral Ciodrin was more than 40 times higher than the LD50
age from lead and other toxins [159]. AA was found to for intravenous and more than 15 times higher than subcuta-
protect the fetus from epigenetic damage due to maternal neous administration [166]. Finally, toxicity dosage is not
smoking [160] and to help reverse testicular damage in dia- linear. Researchers examining aluminum oxyhydroxide
betic rats [161]. A dose of 500 mg/day of time-release vita- (AlO(OH)), the primary adjuvant for vaccines, found that
min C was found to almost double pregnancy rates [162]. “[n]eurobehavioural changes, including decreased activity
While many other nutrients may influence reproduction, levels and altered anxiety-like behaviour, were observed
the above examples make it clear that many nutrients can compared to controls in animals exposed to 200 μg Al/kg but
either improve or impair fertility. Clinicians should therefore not [emphasis added] at 400 and 800 μg Al/kg.” They con-
consider careful evaluation of nutrient status prior to com- cluded that “[Al] injected at low dose in mouse muscle may
mencement of a supplement regimen in support of reproduc- selectively induce long-term Al cerebral accumulation and
tive health. In addition to supporting physiology through neurotoxic effects; and that ‘the dose makes the poison’ rule
proper nutrition, avoidance or neutralization of inhibitory of classical toxicology appears to be overly simplistic” [167].
Nutritional Influences on Reproduction: A Functional Approach
541 32
It should also be mentioned that, for obvious reasons, most Mercury is highly toxic to the reproductive system and all
controlled toxicological studies (including the ones we will mercury compounds can cause fetal harm [183]. Methylated
be citing below) are done in nonhuman, animal models and mercury easily crosses the placental barrier and denatures
extrapolated to humans despite the imperfect correlation. DNA. It can also induce chromosomal aberrations, increas-
Toxins are ubiquitous in the environment with common ing aneuploidy incidence [183]. Garlic is a relatively safe
sources including food, air, water, electronics, cleaning sup- compound that effectively inhibits the embryotoxicity of
plies, pesticides, insecticides, pharmaceuticals, nutraceuti- methylmercury [184] and, given its safety and efficacy pro-
cals, and medical procedures. Reproductive toxins in food file, should be considered prophylactically for persons of
can arise “naturally” or through contamination with food reproductive age with potential mercury exposure. A variety
additives. For example, grains naturally attract mold of other compounds have also been found to attenuate the
growth. As such, cereal grains designated for consumption toxic effects of mercury compounds and should be consid-
are frequently contaminated with mycotoxins such as ered both in treatment and prophylaxis. Examples include
zearalenone that are highly toxic to the reproductive sys- selenium [185], cysteine and methionine [178], alpha-lipoic
tem, lead to the degeneration of oocytes [168], and inhibit acid [186], niacin [187], chrysin [188], and vitamin C [189].
sperm viability [169]. Rice, particularly the bran, has been Interestingly, morphine [190] and prolactin [191] were also
shown to contain high levels of arsenic (discussed further found to have protective effects.
below) [170], a compound that is highly toxic to the repro- Arsenic (As) is commonly found in water, seafood,
ductive system. Arsenic can cross the placental barrier, chicken, pork, wine, tobacco, rice, nutritional supplements,
inducing developmental toxicity and even fetal death [171]. and wood. It is highly embryotoxic and tends to cross the
It also damages male fertility, reducing testis size and inter- placental barrier, inducing irreversible defects in the devel-
fering with spermatogenesis and steroidogenesis [172], oping fetus and embryo. It also damages testicular function,
though quercetin may ameliorate some of the negative resulting in reduced count and motility [192]. Arsenic also
impact on the male reproductive system [173]. The bran of inhibits steroidogenic enzymes 3β- and 17β-hydroxysteroid
rice contains 10× the arsenic levels of polished rice; thus dehydrogenase, whose activity is essential in the production
brown rice has much higher arsenic levels than white rice. of progesterone, testosterone, and estrogen [193]. A number
In addition, proper preparation of rice can significantly of compounds have been found to inhibit arsenic-induced
reduce arsenic levels. Cooking with a water-to-rice ratio of toxicity. These compounds include vitamin C [194]; vitamin
12:1 was found to reduce arsenic levels by 57% [174]. E [195]; alpha-lipoic acid [196]; vitamin B12; carotenoids;
Other common metals that have significant reproductive flavonoids such as quercetin, naringenin, and silymarin; and
toxicity include cadmium, mercury, lead, and aluminum. organic forms of calcium, iron(II), and zinc. Of note, the
Cadmium (Cd) is found in various foods such as shellfish, inorganic forms of these metals can be problematic in combi-
mushrooms, cereal grains, chocolate, potatoes, and other nation with arsenic [197]. Amino acids, such as cysteine and
vegetables (usually acquired from the soil), as well as ciga- methionine, were all found to mitigate arsenic’s toxic effects.
rettes, gasoline combustion, fertilizers, PVC, ceramic glazes, Selenium, specifically, decreases teratogenicity of As [178].
textiles, and paints [175]. A combination of zinc and sele- Lead (Pb) is commonly found in soil, dust, drinking
nium was found to ameliorate Cd damage to ovarian tissue. water, paints in older homes, crystal, some ceramic glazes,
Vitamin C, retinol and blueberries also significantly reduced imported foods, batteries, chocolate, and nutritional supple-
the negative impact of Cd exposure. Low-protein diets on the ments [198]. Pb has been associated with sterility, spontane-
other hand increase cadmium toxicity, presumably due to ous abortions, stillbirths, and neonatal deaths [197]. It can
lower access to cysteine – necessary for metallothionein syn- also reduce semen morphology, motility, count, and volume
thesis [176–178]. [199]. Fetal exposure to Pb can result in impaired cognitive
Mercury is commonly found in seafood, fluorescent development and was even associated with an increase in
light bulbs, vaccines, contact lens solutions, makeup, and criminal arrests in early adulthood. For every 5  μg dL−1
skin creams. Dental amalgams contain 50% elemental mer- increase in blood Pb levels by 6 years of age, the risk of being
cury and may produce a significant amount of vapor, as it is arrested for a violent crime as a young adult increased by
consistently released from amalgams and absorbed by the almost 50% [200]. Omega-3 fatty acids were found to signifi-
human body [179]. Modern amalgams are higher in copper, cantly decrease brain damage due to lead exposure [201]. As
causing still higher mercury emissions [180]. While it was Pb mimics calcium, vitamin D increases Pb absorption and
previously believed that mercury released from dental its deposition into the bone and the kidneys [178].
amalgams was not harmful, new findings dispute this [181]. Phosphorus, on the other hand, decreases bone retention of
Heat can increase the release of mercury vapor, as can elec- Pb [178]. Zinc supplementation decreases Pb GI absorption
tromagnetic fields [181]. Exposure of patients, for example, and tissue accumulation [178].
to radiofrequency emissions from conventional Wi-Fi Aluminum (Al) is the third most abundant element in the
devices increased mercury release from dental amalgams earth’s crust, yet it is highly neurotoxic [202]. It is found in a
[182]. Consequently, researchers have urged pregnant wide variety of commonly used products such as baking
women with dental amalgams to minimize their exposure powder, sugar, and salt (as an anticaking agent), a bleaching
to electromagnetic fields [181]. agent in white flour, antiperspirants, lotions, infant formulas,
 542 B. Horn and W. Yu

parenteral nutrition (TPN) [203], antacids, and cheeses There are many other common chemicals that negatively
[204]. It is also contained in vaccines in biologically signifi- impact fertility. Polychlorinated biphenyls (PCBs) and diox-
cant amounts [167] routinely recommended for pregnant ins are highly toxic persistent organic pollutants (POPs).
women [205–206]. Following prenatal exposure, Al transpla- Dioxins are the primary toxic constituent of Agent Orange,
centally traverses and accumulates in the fetal tissues in for example. They are lipophilic byproducts of combustion
amounts that can adversely influence fetal development (wood, coal, petroleum, etc.) and the manufacture of chlo-
[192]. Pregnancy enhances susceptibility to Al toxicity. In rine products, such as bleach and paper manufacturing [224].
developmental studies, Al has been shown to cause bone Over 90% of human exposure is through food [225], with
abnormalities, fetal internal hemorrhaging, neurodegenera- approximately 41% of exposure from dairy products, 38%
tion, and immune system activation [192, 202, 207]. Silica from beef ingestion, and an overall load of 98% from animal
has been shown to chelate Al [208]. In one study, the con- products [226]. Dioxins can be found in much smaller
sumption of 1  L of silicon-rich mineral water daily for amounts in hygiene products such as toilet paper and diapers
12  weeks significantly reduced the body burden of Al and [227], though the contribution to disease at such low concen-
improved cognitive function in Alzheimer’s disease patients trations has not been confirmed. Dioxins can lead to ovarian
[209]. In addition, vitamin E and selenium [210], vitamin C dysfunction and have been implicated in the pathophysiol-
[211], green tea leaf extract [212], and curcumin have all ogy of endometriosis [228]. Transformation of the aryl
been shown to reduce the toxic effects of Al. hydrocarbon receptor (AhR) is the initial step of dioxin tox-
Organophosphates (OPs) and carbamates (CMs) are the icity [229]. Catechins, flavonols, and flavones are natural
32 most commonly used pesticides in agriculture and have been antagonists of AhR.  Chlorophylls, lutein, quercetin, carot-
shown to induce reproductive toxicity, developmental toxic- enoids, and green tea catechins also inhibit AhR transforma-
ity, and endocrine disruption [192]. OPs are irreversible ace- tion. Among foods, AhR transformation inhibition was
tylcholinesterase (AChE) inhibitors and operate similarly to found with spinach, citrus fruits (particularly lime, grape-
nerve gases, such as sarin. AChE inhibitors have also been fruit, and lemon), sage, rosemary, oregano, peppermint,
shown to disrupt cell replication and differentiation. OPs and clove, olive oil [230], coffee [231], and cacao [232]. However,
CMs are also potent endocrine disruptors and were found to a number of these components had biphasic activity: acting
disrupt normal sexual differentiation, ovarian function, as an AhR antagonist at low doses, while high doses had ago-
sperm production, and pregnancy [192]. OPs and CMs are nist (and therefore potentially toxic) effects [231–232]. The
common residues on a variety of foods, including peaches, biphasic activity of many substances serves as a reminder to
apples, nectarines, popcorn, pears, corn, and grapes [213]. utilize caution with aggressive dosing.
Not surprisingly, an organic diet was found to significantly PCBs are similarly lipophilic and environmentally persis-
lower dietary exposure to OPs [214]. Quercetin has been tent and travel up the food chain. They are reproductive tox-
shown to protect against multi-OP pesticides [215]. Vitamins ins that can induce a reduction in the number of ovarian
C and E [216] and lycopene [217] also have protective effects. follicles and may induce premature ovarian failure [233].
Polychlorinated aromatic hydrocarbons (PAHs) are a Semen abnormalities have also been induced by PCBs [233].
large group of chemicals that are byproducts of combustion. A study on mink found PCBs from fish ingestion caused
Typical sources include combustion of coal, wood, and bio- complete, though reversible, reproductive failure [234].
fuels for cooking, cigarette smoke, and vehicle emissions. Placental transfer also occurs with PCBs but not readily.
Food preparation is a common source as well, with PAHs Lactation, however, can be a significant source of PCB expo-
resulting from a variety of food processing techniques, sure for the neonate [235]. PCBs were widely used in elec-
including curing, drying, smoking, roasting, grilling, barbe- tronic equipment manufacturing and, prior to their use being
cuing, and refining [218]. PAHs have a broad range of anti- banned in 1979, were ubiquitous. Fortunately, environmental
fertility actions. For example, PAH exposure was found to levels have begun to decline in recent years; however, sea-
destroy oocytes [219] and damage sperm DNA [220]. It also food, meat, and dairy products are still significant sources of
has toxic effects on embryonic development [192]. Low-dose exposure. Vitamins E and C [236] and quercetin [237] were
repeated exposures were found to be substantially more toxic found to be protective. EGCG was found to inhibit PCBs
than a single high-dose exposure [219], thus emphasizing the xenoestrogenic effects as well [238]. However, as with diox-
importance of limiting dietary and environmental exposures. ins, many of the substances that ameliorated negative effects
PAHs are also xenosteroids and can significantly influence a from PCBs had biphasic effects and could inhibit or promote
wide variety of serum hormone levels, including estrogen, toxicity depending on circumstances [239].
progesterone, androgens, PRL, and LH [192]. Ellagic acid, Phthalates (PHTs) are another group of lipophilic and
epigallocathechingallate, chlorophyllin, and benzyl isothio- ubiquitous compounds used to make plastics flexible and as
cyanate were found to ameliorate toxicity from PAHs, though lubricants. Unlike PCBs, PHT is currently used everywhere.
the protective effect depended on the type of PAH [221]. Some examples include PVC pipes, paints, children’s toys, sex
Vitamin C had the paradoxical effect of increasing PAH tox- toys, food containers, sandwich bags, infant care products,
icity by interfering with superoxide dismutase in one study electronics, and cosmetics. While the primary route of expo-
[222] and, along with vitamin E, demonstrated antigenotoxic sure is through food, considerably higher levels of exposure
effects in another [223]. come from hospital environments [240]. For example, large
Nutritional Influences on Reproduction: A Functional Approach
543 32
amounts of PHT are leached from intravenous (IV) tubing public safety limits, as well as limits on further deployment of
[241] and PVC bags housing IV solution [242]. It is also untested technologies, are warranted” [260]. NIER is
added to the enteric coating in pharmaceutical pills [243]. absorbed by living tissue [261], leading to a variety of adverse
From a reproductive standpoint, PHTs easily cross the pla- effects including reproductive, immune, neurological, psy-
centa and act as anti-androgens, reducing testosterone and chiatric, and oncologic effects [260, 262–265].
negatively impacting male reproductive development. In From a reproductive standpoint, NIER has been found to
females, they also act as endocrine disruptors, inducing cause a variety of disturbances including increased miscar-
PCOS [244], endometriosis, adenomyosis, and fibroids [245], riage rates [262], preterm births [266], fetal growth abnor-
interfering with steroidogenesis, and inhibiting ovulation by malities [267], neurodevelopmental issues [268], disturbances
suppressing the LH surge. Interestingly, they were found to in semen parameters [269], and hormonal disruption [269].
act as antagonists to the G protein-coupled cannabinoid 1 The most common sources of exposure are from cell towers,
(CB1) receptor [246]. Endocannabinoids are important in power lines, transformers, power meters, mobile phones and
the regulation of successful reproduction. Plasma levels of watches, wireless routers, cordless telephones, and micro-
anandamide (AEA, an endocannabinoid ligand) fluctuate wave ovens [270]. Common mobile phone usage involves
throughout the menstrual cycle and pregnancy. Successful leaving phones in pockets, on belt clips, in bras, and resting
implantation and pregnancy seem to require lower levels of them on one’s abdomen while pregnant. The unique location
AEA, whereas higher levels are found during the follicular of the testes and temperature sensitivity makes them more
phase, and a surge of AEA occurs during active labor. Not susceptible to NIER penetration and damage. In males, NIER
surprisingly, the use of exocannabinoids (such as marijuana) has been shown to reduce seminiferous tubule diameters
has been found to increase the risk of adverse pregnancy out- [271–272] and tunica albuginea thickness [273]. It has also
comes [247]. CB1 receptors have been found in the brain tis- been found to induce changes consistent with oxidative dam-
sue of fetuses and are important contributors to neuronal age, including reductions in CAT and SOD activity [272],
diversity during early CNS development [248]. Oxidative lipid peroxidation, and DNA damage [273]. NIER can also
stress was found to play a critical role in how PHT induces decrease spermatozoa formation [271], impair motility
neurotoxic effects [249]. Selenium was found to protect the [274], create sperm aggregation [275], and decrease fertiliza-
male reproductive system from PHT damage [250], as was tion potential [276].
vitamin E [251]. Paradoxically, administration of vitamin C In females, NIER induces oxidative stress and increases
or resveratrol increased PHT-induced oxidative damage apoptosis in endometrial tissue [277–278] with significant
[252]. However, if vitamin C was combined with vitamin E, it reductions in ovarian primordial follicles [279–280] and
significantly inhibited testicular injury [253]. Finally, PHTs increases in follicular atresia, apoptosis, and stromal fibrosis
(and bisphenol A) were found to disrupt circulating vitamin [280].
D levels in pregnancy [254]. As adequate vitamin D is essen- In pregnancy, exposure to 900  MHz frequencies (com-
tial for proper reproduction, pregnancy, and fetal develop- mon in cordless and mobile phones) during pregnancy in
ment, levels should be monitored closely. Significant rats resulted in male offspring with a higher apoptotic index,
protective effects of vitamin D during pregnancy were found greater DNA oxidation levels, lower sperm motility and vital-
where serum 25(OH)D exceeded 30 ng/ml [255]. ity, and altered seminiferous tubules [281]. Female offspring
In addition to material-based functional interference, we with in utero exposure to NIER had a decreased number of
are also exposed to large amounts of electromagnetic radia- ovarian follicles [282], broken oocyte nests, binucleate pri-
tion (EMR) with potentially significant implications for mordial follicles, loose stromal cells, cytoplasmic vacuoliza-
reproduction. The electromagnetic spectrum can roughly be tion, greater follicular atresia, and chromatin condensation
divided into ionizing and nonionizing radiation at approxi- [283].
mately 2417 THz/124 nm. This falls in the upper ultraviolet Some natural substances have been examined for their
spectrum (UVC). UVB, the wavelengths responsible for tan- ability to counteract NIER-related damage. Cordyceps, a type
ning and necessary for vitamin D production (280–320 nm) of fungus rich in selenium, was shown to reduce testicular
[256], are too long for ionization, yet UVB radiation can lead damage by increasing sperm formation and decreasing apop-
to DNA damage, leading to apoptotic keratinocytes and totic spermatogenic cells [271]. Melatonin was found to pre-
increasing cancer risk [257]. vent DNA damage in male germ cells [284], and vitamins C
While the reproductive toxicity of ionizing radiation is and E protected the testes from oxidative damage with
well described [258–259], the growing body of literature increased total glutathione and glutathione peroxidase levels
demonstrating toxic effects of nonionizing radiation has not and reduced lipid peroxidation values [285]. It should also be
received widespread acknowledgment. Nonionizing radia- noted that, like many nutrients, NIER may have a biphasic
tion (NIER) is a ubiquitous, potentially deleterious modern activity that is dose-dependent. Some studies have found
environmental influence that may greatly impact both female NIER improved reproductive outcomes. For instance, rats
and male reproduction and overall health. A review of the exposed to NIER at 900 MHz had increased sperm motility
scientific literature regarding immunological effects of NIER and testosterone levels, improved sperm morphology, and
stated: “it must be concluded that the existing public safety lowered tail abnormalities, though it also had the result of
limits are inadequate to protect public health, and that new increasing precocious puberty [286]. Lastly, of particular
 544 B. Horn and W. Yu

importance is a review of the mobile phone safety literature. GLY has multiple targets of interference, including oxi-
Panagopoulos et  al. [287] observed that 50% of the studies dative damage [297]; excitotoxicity [304]; microbiome dis-
using simulated mobile signals found no effects, in sharp con- ruption [305]; inhibition of aromatase [309]; depletion of
trast to studies using real exposures to mobile signals which iron, cobalt, molybdenum, copper, tryptophan, tyrosine,
resulted in an almost 100% effect rate. The reader should note methionine, and selenomethionine [310]; disruption of the
it is inappropriate to use simulated exposures for safety data intestinal barrier [311]; and breakdown of tight junctions
when sources of real-world exposures are available. [312]. There is a paucity of studies on mitigation of GLY tox-
Glyphosate (GLY) is a now ubiquitous, broad-spectrum icity. Lignite extract was recently shown to inhibit GLY-
herbicide brought to the consumer market in Roundup. induced intestinal permeability [312]; however, the study
Exposure has been linked to a wide range of health problems was conducted by a nutraceutical company on its own prod-
including reproductive problems, autism, Parkinson’s dis- uct and should be independently verified. Despite the lack of
ease, Alzheimer’s disease, and cancer [288]. In males, it has data, evaluating patients on the above targets and addressing
been found to impair sperm motility [289–290] and concen- individual shortcomings may prove clinically useful in GLY
tration [290–291], cause testicular lesions [290], and impair mitigation.
mitochondrial function [289]. When combined with soy, While presented here, it should be noted that the evi-
GLY was associated with a decrease in testosterone levels, dence for reproductive toxicity from GLY, and the toxicity of
degeneration of Sertoli and Leydig cells, and a decrease in GLY and other chemicals in general, is the subject of intense
seminiferous tubule diameter [292]. In females, GLY resulted debate and controversy [313]. The topic has also become a
32 in changes to granulosa cells [293], abnormal uterine devel- wider political debate involving the safety of genetically
opment, and increased risk for neoplasias [294]. GLY reduced modified organisms (GMOs) as a whole. There are many
fecundity by inducing endometrial morphological abnor- studies establishing the safety of GLY and GMOs [314].
malities and decreasing the expression of estrogen and pro- However, the weight and reliability of evidence should be
gesterone receptors [295]. It also disrupted steroidogenic approached with caution [315]. With GMOs and GLY having
acute regulatory (StAR) protein expression [296]. Offspring very significant public health implications and concerns, the
had higher levels of oxidative damage, lipid peroxidation, precautionary principle should be evoked [316].
lower levels of glutathione [297], and skeletal alterations
affecting the cephalic and neural crests [298–299].
Perinatal exposure to GLY negatively impacted the set 32.4.6  Reproductive Immunology
point of the hypothalamus-pituitary-thyroid axis [300].
Neuropsychiatric effects were commonly found with predis- “One of the most remarkable aspects of reproductive biology
positions to attention-deficit hyperactivity disorder [301], is the simple fact that a healthy woman with a fully func-
anxiety [302], depression, reduced locomotor activity [302], tional immune system can successfully carry a semialloge-
and glutamate excitotoxicity in the hippocampus persisting neic pregnancy to full term without immune rejection”
throughout adulthood [303–304]. [317]. Indeed, tolerance of the rapid growth of an invasive
Finally, a curious study found GLY-induced dysbiosis, mass, from implantation through fetal development, has
characterized by reduced Firmicutes and increased been described as “pseudomalignant” or even a “physiologi-
Bacteroides ratio in female rat gut microbiota, but not in cal metastasis” [318]. A number of immune cells, such as
males [305]. Bacteroides can be commensal, mutualist, or natural killer cells (NKs), regulatory T cells (Tregs), effector
pathobiont [306]. Increased levels can lead to reproductive T cells (Teffs), and dendritic cells (DCs) populate the
pathogenic states, such as antibiotic-resistant bacterial vagi- maternal-­fetal interface [318]. For many years, it was believed
nosis [307]. Changes in vaginal microflora by pathogenic that recurrent pregnancy loss often resulted from an overac-
organisms can lead to infertility [308]. Women with asymp- tive maternal immune system. However, results obtained by
tomatic vaginosis and women with bacterial vaginosis both direct suppression of the maternal immune system were dis-
had higher incidences of infertility [308]. Low levels of appointing [317]. In contrast, studies examining the role of
microflora, Firmicutes, may contribute to infertility. In a Tregs, and particularly peripheral Tregs (pTregs), have sug-
study comparing normal vaginal flora to women with infer- gested that pTregs play a major role in governing fetal
tility, it was found that healthy women’s flora contained on immune tolerance [317] and are believed to be the primary
average 27.8% Firmicutes. Infertile women averaged only suppressors of the immune response [319]. The ability of
3.5%. Therefore, GLY may increase risk of infertility through Tregs to effect immune tolerance is dependent on the main-
modulation of the female microbiome. In addition, Group B tenance of low levels of L-tryptophan (TRP) locally [320].
Strep, Gram variable coccobacilli, and Trichomonas vaginalis This is accomplished through the metabolism of TRP by the
were found in infertile women but not in healthy women. iron-dependent enzyme indoleamine 2,-3-dioxygenase
Furthermore, 25% of a healthy woman’s flora consisted of (IDO) expressed by DCs. Perhaps paradoxically, free iron
diphtheroids and Micrococcus, whereas infertile women had prevents TRP degradation [321], potentially resulting in
none of these organisms. While E. coli and Enterococcus spp. reduced fetal tolerance.
were found in both groups, there were two to four times as The expression of IDO is enhanced by PGE2 [322], a
many in infertile women. downstream metabolite of arachidonic acid (AA) requiring
Nutritional Influences on Reproduction: A Functional Approach
545 32
cyclooxygenase 2 (COX-2) for conversion. Inhibition of sion of FoxP3, an important component of immune toler-
COX-2 has been found to constrain IDO activity [323]. ance. Other organisms were also found to increase FoxP3
Therefore COX-2 inhibitors, including NSAIDs such as aspi- expression, including Bifidobacterium infantis 35624,
rin (which irreversibly binds to COX-2 [324]), should be Lactobacillus rhamnosus GG (ATCC 53103) and
used with caution in pregnant women or those trying to con- Bifidobacterium lactis (Bb-12), Lactobacillus salivarius and
ceive. Aspirin is prescribed to many women undergoing Lactobacillus reuteri (ATCC 23272), a probiotic mixture
in vitro fertilization (IVF) under the hypothesis that it may called VSL#3, and Helicobacter pylori [335].
improve blood flow to the implantation site; however, studies Not all organisms that facilitate Treg activity are benefi-
have not found a clear benefit [325] and paradoxically it may cial for fertility. The immune interaction with microbes is
prevent successful pregnancy. COX-2 induction was found to complex and the same microbe can be pathogenic in some
be crucial in implantation [326]. In mice, for example, dele- instances and beneficial in others. H. pylori, for example, may
tion of the gene encoding for COX-2 (Ptgs2) resulted in com- upregulate Treg efficacy to prevent its own destruction. As a
plete female infertility [327], as did the removal of the PGE2 consequence, it may have a protective role in some autoim-
receptor (EP2) [328]. mune diseases [336] and in reducing stroke risk [337], while
The facilitation of Treg activity has multiple targets. Some increasing susceptibility to gastric cancer [338] and infertility
include increasing dietary AA (e.g., chicken, eggs, beef, tur- [19]. In the case of infertility, anti-H. pylori antibodies have
key, and pork [329]), facilitating AA’s conversion to PGE2 been found in the cervical mucus and there is evidence that
(via COX-2), inducing COX-2 directly, or minimizing the cross-reaction with sperm may occur inhibiting sperm pro-
use of COX-2 inhibitors. One can also directly facilitate Treg gression and thus fertility [339].
activity, for example, through the use of short-chain fatty The reproductive microbiota play an exceedingly impor-
acids (such as butyrate), although medium-chain fatty acids tant role in reproduction. Endometrial microbiota consist-
(such as coconut oil) and long-chain fatty acids (such as ing of less than 90% Lactobacillus species was found to
DHA) inhibit Treg activity [330–331]. It is noteworthy that significantly decrease implantation [60.7% vs 23.1%], preg-
plants and animals contain multiple chemical compounds nancy [70.6% vs 33.3%], ongoing pregnancy [58.8% vs
often having ligands for multiple targets that can produce 13.3%], and live birth [58.8% vs 6.7%] rates [340]. A vaginal
seemingly contradictory results. For example, butyrate can microbiome composed solely of Lactobacillus seems to pro-
inhibit COX-2 [332], suggesting that it may downregulate duce the highest chances of a successful IVF outcome [341].
Treg production, yet it was shown to increase pTregs specifi- In contrast, the isolation of Staphylococcus species or
cally [333]. Seafood can be a significant source of AA, yet it Enterobacteriaceae from the cervix or vagina resulted in
shuttles conversion of AA to PGE3 instead of PGE2 [334], substantially lower pregnancy rates [342]. Likewise, a pre-
making EPA and DHA supplementation potentially counter- ponderance of Clostridium perfringens, Bacteroides sp.,
productive in cases of immunological infertility. Staphylococcus aureus, and S. epidermis were associated
A number of other substances can modulate Treg activity. with fewer pregnancies [341].
For example, vitamins A (as retinoic acid) and D were found Chlamydia trachomatis (CT) infection is the most preva-
to increase Tregs, as was gluten [335]. In general, where lent sexually transmitted disease in the world [343], affecting
increased Tregs are found, it is often unclear whether the 1.6 million people in the United States annually [430].
substance is increasing Tregs directly or whether the Tregs Infertility is estimated to result in 3% of infected women and
are increasing as a response to control an inflammatory 2% will have adverse pregnancy outcomes [345]. It can also
immune response induced by the substance. In the case of cause male sterility [343], though the percentage of the popu-
gluten, this may be a worthwhile evaluation. Those on a lation affected is unclear due to poor testing methodology.
gluten-­free diet were found to have significantly decreased Non-­pharmaceutical interventions show significant poten-
percentages of circulating Tregs [335], suggesting that arbi- tial in treating CT infections and can be used alone or to
trarily restricting gluten may turn out to be counterproduc- potentiate standard antibiotic therapies [344]. Polyphenols,
tive to fertility. such as flavones (apigenin, luteolin, acacetin), flavonols
Another important substance in optimizing Treg func- (quercetin, myricetin, morin, rhamnetin), natural coumarins
tion is folate. Researchers found that Tregs express high levels (methoxypsoralen), and gallates, are all highly active chla-
of folate receptor 4 and folate depletion via methotrexate mydia inhibitors [344]. Lipid compounds such as capric acid,
(MTX) resulted in significantly reduced numbers of Tregs monocaprin, and lauric acid caused a greater than 10,000-
[432]. As MTX inhibits dihydrofolate reductase (DHFR), fold reduction in the infectivity titer with monocaprin having
those with genetic polymorphisms in the DHFR and/or a greater than 100,000-fold inactivation rate [344]. Peptides
MTHFR genes may also experience poor Treg survival. including melittin, isolated from bee venom, and cecropin,
Therefore, genetic and functional evaluations of folate status isolated from cecropia moths, also exhibit anti-CT proper-
can be important factors in treating infertility. ties. Vaginal lactobacilli such as L. vaginalis, L. brevis, L. gas-
Commensal microbes have also been found to facilitate seri, and L. crispatus had strong inhibitory effects on CT as
Treg activity. Probiotic mixtures such as Lactobacillus aci- well, with L. crispatus having the highest efficacy [344].
dophilus and Bifidobacterium longum were found to increase Many other infections can lead to infertility. Indeed, 15%
immune-modulating activities of Tregs by increasing expres- of male factor infertility is estimated to be due to infectious
 546 B. Horn and W. Yu

agents [19]. Some of these agents include protozoa such as nausea and vomiting being associated with reduced risk of
Toxoplasma gondii, which can cause endometritis, impaired pregnancy loss [365]. Meat (which includes poultry [366]
folliculogenesis, ovarian and uterine atrophy, amenorrhea, and fish), for example, is a common aversion, as are coffee,
and reduced semen quality [431]. Mycoplasma species, par- sour foods, beans, and rice [364]. As discussed previously,
ticularly M. hominis and M. genitalium, Ureaplasma urealyti- meats are high sources of TRP, which needs to be kept at
cum [346], Neisseria gonorrhoeae, Gardnerella vaginalis, lower levels, at least locally to maintain immune tolerance of
Trichomonas vaginalis [347], Candida albicans, Listeria the fetus. TRP is also necessary for the replication of many
monocytogenes [348], and others, have also been implicated intracellular microorganisms such as Chlamydia trachomatis
in impairing fertility and have been associated with increased [321], and an aversion to sources of high TRP may be essen-
miscarriage rates [349]. Other common organisms that were tial for suppressing the replication of such organisms. Beans
associated with increased miscarriage rates include human are high in iron, which, as discussed previously, may impair
herpesvirus, Cytomegalovirus [350], Chlamydia trachomatis TRP breakdown. Sour fruits, such as citrus, often contain
[351], Mycoplasma hominis [346], and Peptostreptococcus COX-2 inhibitors [367–369] and rice may contain significant
spp. [352]. levels of arsenic, which has been associated with spontaneous
While microbial diversity in the gut is believed to confer pregnancy loss [370]. Thus, food aversions, nausea, and vom-
health benefits [353], bacterial diversity in the vagina was iting in early pregnancy may play an important physiological
found to be associated with vaginal inflammation and defense mechanism for maintaining a healthy pregnancy.
reduced implantation [354]. Normal vaginal microbiota is Therapies to suppress these reactions, whether pharmaceuti-
32 dominated by Lactobacillus species, especially L. crispatus, L. cal or natural, should be approached with caution.
iners, L. gasseri, and L. jensenii [355]. The proportions of While the interface between immunology and infertility
various species differ among various ethnic groups and also is vast, when dealing with fertility challenges, immunology
change during pregnancy, with an increase in Lactobacillus must be carefully considered. Testing for the presence of
species and a decrease in anaerobic species as pregnancy pro- pathogenic microorganisms and addressing them with anti-
gresses [356]. microbials may be insufficient or even counterproductive.
Abnormal vaginal microbiota (AVM) composition, such While antimicrobial therapy may be necessary in some
as in bacterial vaginosis (BV), aerobic vaginitis (AV), or instances, consideration for the totality of the microbial ter-
abnormal vaginal flora (AVF), has been implicated in a vari- rain and the body as a whole is essential for optimal repro-
ety of adverse fertility and pregnancy outcomes, including ductive outcomes.
increased risk of preterm birth. While antibiotics can eradi-
cate BV in pregnancy, the increased risk of preterm birth is
not altered [357]. The destruction of beneficial bacteria may 32.4.7  Exercise
also have adverse consequences on the health of the baby,
and even a short course of antibiotics can have lasting adverse Immune modulation can also come from exercise. Low-­
consequences on the gut microbiome [358]. intensity exercise reduces cortisol levels, whereas moderate-
A review found that prophylactic antibiotics during the to high-intensity exercise increases them [371]. Indeed,
second and third trimesters, though reducing infection, do athletic women are much more likely to experience repro-
not reduce adverse pregnancy outcomes and morbidity. ductive cycle dysfunction [372]. A dose-response relation-
Instead, they result in short- and longer-term harm for chil- ship in nonobese women between vigorous physical activity
dren of mothers exposed to antibiotics, including neonatal (of 5 hours or more per week) and delayed time to conceive
death [359–360]. In contrast, prophylaxis and treatment of was found [373]. On the other hand, for overweight or obese
AVM with Lactobacillus species (Lactobacillus rhamnosus women with infertility, a combination of reduced calorie diet
HN001 and Lactobacillus acidophilus GLA-14) were found to and aerobic exercise significantly improved pregnancy rates
effectively inhibit both AV and BV with a 100% inhibition of [374]. Interestingly, the improved chances of pregnancy in
all studied pathogens (S. aureus, E. coli, G. vaginalis, and A. these women held true for natural pregnancies only. For IVF,
vaginae) after 48 hours [361]. Two studies suggested that the diet and exercise did not seem to change pregnancy chances
use of oral fermented milk or vaginally administered yogurt significantly [357]. During pregnancy, the amount of exercise
reduced the risk of preterm birth [362]. In contrast to antibi- was proportional to the risk of miscarriage, with hazard
otics, administration of probiotics during pregnancy has ratios (HR) increasing, beginning with 75 minutes of exercise
been associated with increased resistance to respiratory per week (HR 1.8) and increasing to an HR above 3 for 420+
infections, reduced IgE-associated disease burden, and minutes per week through week 18 of pregnancy [375]. After
reduced incidence of atopic eczema in children. In mothers, week 18, those exercising had reduced risk of miscarriage. It
a reduction in blood glucose and increase in glucose toler- is worth noting that even those engaging in low-impact exer-
ance have been observed [362]. cises (dancing, walking, hiking, aerobic) had twice the risk of
Other strategies to reduce microbial and immunological miscarriage. Those engaged in high-impact exercise (jog-
burden include aversions during pregnancy. Indeed, up to ging, ball games, and racket sports) had 3.6x the risk of mis-
80% of women experience some form of food aversion, nau- carriage. Swimming was the one sport that did not seem to
sea, and/or vomiting in the first trimester [363–364], with increase miscarriages, though swimming is often a source of
Nutritional Influences on Reproduction: A Functional Approach
547 32
chlorine exposure which was found to increase risk of birth (absence of sperm in semen). As a consequence, female fer-
defects [376]. For men, vigorous exercise was associated with tilization is not possible without assisted reproductive tech-
reduced fertility rates, particularly in endurance athletes nologies, specifically IVF-ICSI.
[372]; however, moderate exercise does not seem to have any
negative impact.
32.5.2  Innate Genetic Issues

32.5  Examining the Informational Layer An example of how a common genetic issue can have a wide
range of influences indirectly leading to infertility can be
Information is what gives meaning. Information is not only found with a gene involved in folate metabolism. Folate is an
messages themselves, but also how messages are interpreted essential nutrient for both fertility and pregnancy. Women
and processed. There is significant overlap between the infor- with the highest intake of folic acid reduced the chances of
mational, functional, and physical layers because informa- anovulatory infertility by 59% [384]. While fortification of
tion is what drives everything. Any physical structure foods with folic acid is controversial due to potential associa-
requires information to be built. Any function requires infor- tions with cancer and the masking of vitamin B12 deficiency
mation to instruct it. Therefore, information is central to all [385], in terms of pregnancy, folic acid fortification has been
physiological processes. It has been assumed that the brain is called one of the “most significant public health measures for
the central repository of information and thinking; however, the prevention of pregnancy-related disorders” [386].
recent advances in quantum effects are questioning this Significant sources of folates include edamame, arrowroot,
assumption [377–378]. Whether the mind is local or nonlo- chickpeas, peanuts, lentils, wheat germ, sunflower seeds,
cal to the brain, thoughts and attitude can significantly influ- spinach, avocado, broccoli, artichokes, and asparagus.
ence reproduction. For example, a woman’s level of positive One of folate’s primary functions is to help run the methio-
expectation related to motherhood and a man’s quality of nine cycle that generates S-adenosyl-L-methionine (SAM): the
integration between the wish for a child and sexual relation- primary methyl donor for most biological methylation reac-
ships were found to be significant predictors of a couple’s tions [387]. The rate-limiting step in the methyl cycle is con-
fertility status [379]. The effects of psychological stress on trolled by the enzyme 5-methylenetetrahydrofolate reductase
fertility outcomes have been studied during IVF cycles, with (MTHFR), which converts 5, 10-­methylenetetrahydrofolate
lower perceived stress at the time of embryo transfer being into 5-­methyltetrahydrofolate (5MTHF). A gene of the same
associated with improved pregnancy rates [380]. Women name codes for the MTHFR enzyme. There are a number
with higher anxiety and depression scores on the day of preg- of polymorphisms that occur in this genetic pathway, the
nancy detection were less likely to be pregnant [6], whereas most researched of which is the C665T transition (previ-
lower levels of norepinephrine and cortisol at the time of ously known as C677T). Women with a C665T mutation had
oocyte retrieval as well as lower levels of cortisol at the time reduced numbers of oocytes, lower serum estradiol concen-
of pregnancy test were associated with favorable pregnancy trations at ovulation [384], higher risk of recurrent implanta-
outcomes [6]. These findings suggest that therapy and stress tion failure [388], higher risk of neural tube defects [389], and
reduction techniques may provide important benefits to a 6.3-fold increase in early miscarriage risk [390]. Paternal
infertile couples. Indeed, a meta-analysis found psychologi- MTHFR mutation is also a risk factor for recurrent pregnancy
cal interventions improved pregnancy rates, though they loss [391]. Homozygotes have a nine-fold increase in the odds
ironically did not improve mental health measures [381]. of idiopathic male factor infertility [392].
MTHFR polymorphisms are extremely common with
around 50% of whites and Hispanics and 12% of African
32.5.1  Genetics Americans having one or more mutations. Consequently,
MTHFR-related methylation issues may be encountered fre-
Genes are a structural source of information that can be quently in a clinical setting. Methylation is essential to life as
either a direct or indirect source of infertility. Direct genetic it is one of the primary tools of epigenetic control of our
issues generally fall into two major categories: inborn and genome. It enables the body to silence a gene without modi-
acquired. Inborn faults span a wide variety of genetic syn- fying the structural composition. Methylation is also neces-
dromes, including fragile X syndrome, Kartagener’s syn- sary for immune modulation, histamine metabolism, energy
drome, myotonic dystrophy, Noonan syndrome, Klinefelter production, cellular repair, detoxification, and a number of
syndrome, 47,XYY syndrome, Y chromosome microdele- other processes. Polymorphisms in the MTHFR gene can
tions, and polymorphisms in many genes, including DAX1, reduce the efficiency of methylation, causing a number of
CBX2, NR5A1, WNT4, GNRH1, DAX1, KISS1, MTHFR both direct and indirect consequences. As methylfolate plays
[382–383], and so on. Some of these are directly responsible an important part in the metabolism of homocysteine to
for infertility and some indirect. An example of a direct methionine, an MTHFR polymorphism, particularly in the
genetic cause of infertility is Klinefelter syndrome (KS). KS is absence of adequate levels of vitamins B2 [393], B6, B12 and
a relatively common (1 in 500 men) condition characterized folic acid [394], frequently leads to elevated homocysteine
by additional X chromosomes. This leads to azoospermia (Hcy) levels. From a reproductive standpoint, elevated Hcy
 548 B. Horn and W. Yu

has been associated with poor oocyte quality [395], unex- folate deficiency and NTDs [406]. Red cell folate (RCF) was
plained female sterility [396], fertilization failure [397], subsequently found to be an independent risk factor for NTDs
recurrent pregnancy loss [398], NMDA excitotoxicity (which [407]. While folic acid has extensive data conclusively demon-
can impair early brain development) [399–400], oxidative strating its efficacy in significantly reducing the incidence of
damage [401], premature ovarian failure [402], and paternal-­ NTDs [406], other forms of folate may also be effective.
cause recurrent pregnancy loss [391]. Therefore, it is prudent The three most widely available forms of folate are folic
to test Hcy levels in patients with known or suspected meth- acid (FA), folinic acid (FLA), and 5MTHF. FA is an oxidized
ylation defects. form of folate that is often mischaracterized as an “unnatu-
Correcting an MTHFR deficiency can have far-reaching ral” or “synthetic” folate. FA, in fact, has been isolated from
effects. For example, vitamin B2 was shown to nullify the spinach, chickpeas, tomatoes, green beans, and cabbages
negative influence of MTHFR polymorphisms on Hcy levels [408]. From the standpoint of reproduction, the main advan-
[393], though its impact on other MTHFR related issues tage of FA is the volume of research establishing safety and
remains to be investigated. Currently, the most logical and efficacy, particularly in the prevention of neural tube defects
popular strategy of bypassing an MTHFR deficiency is sup- (NTDs). Studies have found FA alone reduces the risk of
plementation with 5MTHF, the metabolic end product of the NTDs by up to 70% [409], though this was at a dosage of
MTHFR enzyme. While studies have indicated 5MTHF 4 mg/day. More moderate dosages (800 μg) combined with
supplementation has theoretical benefits over folic acid sup- other vitamins and minerals, including vitamins B12, B6, and
plementation [403], clinicians frequently prescribing 5MTHF B2, reduced the risk by up to 90% [410]. The general consen-
32 have described severe negative reactions that have yet to sus of recommended periconceptional daily folate intake
appear in the medical literature [404]. While the precise ranges from 400 to 800  μg [409–410], with an assumption
mechanism of these reactions is unclear, there are reasons to that an additional 200 μg of folates will come from the diet.
believe it may involve methyl trapping [403]. For women with a previous history of NTDs, the daily rec-
Conversion of homocysteine to methionine is facilitated ommendation is 4 mg [409].
by methionine synthase (MS). MS requires methylated vita- People with MTHFR C665T polymorphisms are at an
min B12 in order to convert Hcy to methionine. Under nor- increased risk for NTDs [403], presumably due to a 30–70%
mal circumstances, vitamin B12 is methylated by 5MTHF. decrease in the activity of MTHFR and therefore in the pro-
5MTHF then loses its methyl group, becomes THF, and is duction of 5MTHF. In Europe, depending on the area, this
further metabolized into other non-methylated folates polymorphism affects one third to half of the population
required for other physiological processes including proper [411]. It is therefore a significant public health concern.
DNA and RNA synthesis. If all the cobalamin molecules are Consequently, supplemental 5MTHF has been hypothesized
pre-methylated (e.g., when supplementing with methylco- to be superior to folic acid and is being recommended as a
balamin, a popular form of vitamin B12), 5MTHF will not be substitute due to its perceived ability to bypass MTHFR
able to give its methyl group to cobalamin and consequently [412]. Unfortunately, the mechanism by which folic acid pro-
will be unable to form the other folates necessary for proper tects against NTDs is unknown and only 13% of NTDs could
physiology. One strategy to circumvent this problem is to be attributed to the MTHFR C665T mutation [413].
avoid combining 5MTHF and methylcobalamin. Instead, Recommendations for substituting FA with 5MTHF are
supplementation with the most common natural forms of based largely on serum and/or RBC folate levels achieved by
cobalamin, adenosylcobalamin or hydroxocobalamin [405], 5MTHF administration, rather than from studies on actual
may be considered, as these are unmethylated and will still NTD incidence. Such assumptions, while theoretically
require methyl groups from 5MTHF to run the methionine sound, do not account for potentially unique properties of
cycle. If methylcobalamin is required, then supplementation the different folates. For example, FA was found to have free
with the so-called “synthetic” folate (folic acid) will provide radical scavenging properties [414]. As oxidative damage is a
the other folates to varying degrees [403] and potentially well-established risk factor influencing the incidence of
avoid some of the reactions to 5MTHF. NTDs [415], the unique antioxidant properties of FA may be
a significant contributing factor in its efficacy. In such a case,
prescribing other folates could paradoxically result in a sig-
32.5.3   eural Tube Defects and Folate
N nificant increase in NTD incidence. While future studies may
Supplementation establish 5MTHF to be equivalent or even superior to FA in
reducing NTD rates, it is not supported by the current state
Appropriate access to folate is critical for proper fetal develop- of evidence.
ment. One of the great successes of targeted nutritional inter-
vention has been in the reduction of neural tube defects
(NTDs) via folic acid supplementation. NTDs are a group of 32.5.4  Risk Factors of Folic Acid
birth defects related to the brain, spine, or spinal cord, with
spina bifida and anencephaly being the most common presen- While FA is effective in reducing NTD incidence, its use is
tations. Suspicions of the NTD-folate relationship began in not without risk. Unlike 5MTHF, FA can mask symptoms
1964 when Hibbard demonstrated an association between of a vitamin B12 deficiency, especially in dosages above
Nutritional Influences on Reproduction: A Functional Approach
549 32
1 mg [409]. Vitamin B12 deficiencies can result in perma- ductive issues. Oxidative damage to sperm DNA was found
nent neurological damage. Consequently, testing serum to be an important contributory factor in the etiology of male
B12 and methylmalonic acid may be prudent when sup- infertility [418] and a likely cause of genetic diseases in off-
plementing with FA, particularly in higher doses. spring [419]. ROS, while important facilitators of oocyte
Co-administration of vitamin B12 should also be consid- maturation, ovulation, and implantation, correspond to poor
ered, taking into consideration the potential risk of methyl embryo quality where elevated levels were detected in follic-
trapping if methylated B12 is used. ular fluid [420]. ROS further leads to spontaneous aneu-
A more recent concern with supplemental FA has sur- ploidy [421] and contributes to cellular aging in general
faced with the discovery of unmetabolized folic acid [422]. Where exposure to elevated levels of ROS is likely,
(UMFA) in serum. This occurs when supplemental FA is such as in chronic inflammatory conditions, the use of anti-
used in concentrations above 200 μg [403]. The significance oxidants may be of benefit [423]. Antioxidants, such as
of UMFA is currently unclear. One group, for example, N-acetylcysteine; melatonin; vitamins A, C, and E; folic acid;
found UMFA levels associated with lower natural killer cell myoinositol; zinc; and selenium, had only weak evidence of
(NK) cytotoxicity [416]. However, this association was only improving fertility outcomes [423]. In such studies, it is rare
found in a subset of older women (60–75  years old). to find an assessment of the patients’ antioxidant status prior
Interestingly, the researchers also found a decrease in NK to treatment. There is often an assumption that antioxidants
cytotoxicity for a subset of subjects with elevated serum lev- are “good” and oxidative stress is “bad.” As a result, antioxi-
els of 5MTHF. It is unclear at this time what the significance dants may be overemphasized, leading to what has been
of these findings is. While UMFA may ultimately prove to termed in the scientific literature “antioxidative stress” (AOS)
confer certain risks, the greater issue may be with too much [422]. AOS may interfere with the immune system’s ability to
folate. What constitutes “too much” is an individual analy- fight bacteria and essential defensive mechanisms for removal
sis. Where metabolism of folates is genetically impaired of damaged cells, including those that are precancerous and
(e.g., in cases of DHFR or MTHFR deficiencies), the use of cancerous [422]. Therefore, individualized evaluations of the
FLA or 5MTHF has theoretical benefits, but lacks clinical ratio of ROS to antioxidants should be encouraged prior to
data. supplementation.
As clinical decisions at times precede evidence, in cases Another common etiology of acquired genetic issues that
where a clinician has concerns regarding DHFR and/or can have profound effects on reproduction is epigenetics
MTHFR deficiencies and folic acid is not producing desired [424]. In essence, epigenetics is a modification in the func-
biochemical changes, one may consider the use of other tion of specific genes that does not modify the DNA sequence
folates. Dosages of up to 200 μg of 5MTHF are theoretically [425]. Epigenetic changes can be stimulated by a variety of
equivalent to the first 200  μg of FA (which is completely factors including social interactions, psychological state, diet,
converted to 5MTHF prior to absorption). Where DHFR seasons, diurnal fluctuations, disease exposure, toxic chemi-
polymorphisms exist, FLA may be a second option to cals, drugs, financial status, exercise, microbiome, therapeu-
bypass the need for DHFR (see . Fig.  32.1). However, it
  tic drugs, and alternative medicine [426].
should be emphasized that, at the time of this writing, nei- Epigenetic changes involve histone modification through
ther 5MTHF nor FLA have been sufficiently established in a variety of mechanisms, the most studied of which is meth-
studies where NTDs are the outcome measure [409]. In ylation [427]. Such epigenetic modifications are heritable
mouse models, FA and FLA achieved different effects in [424]. For example, paternal diet was found to influence
preventing NTDs and dosage data on FLA in humans for insulin secretion, glucose tolerance, and lipid profiles in off-
such purposes is lacking [409]. Regardless, monitoring spring [425]. There is now increasing evidence suggesting
homocysteine levels, SAM/SAH ratios, and whole blood that environmental factors can have negative effects on epi-
histamine may be prudent when supplementing MTHFR- genetic processes controlling implantation, placentation, and
deficient patients. fetal growth [428]. Epigenetic factors that negatively impact
fertility can arise directly, such as by not having enough
access to methyl groups to methylate DNA, or indirectly,
32.6  Acquired Genetic Issues such as through modification of environmental factors, both
of which have been discussed previously. Addressing these
Acquired genetic issues are typically in the form of DNA causes requires a careful examination of the totality of a per-
damage, which results from primarily endogenous insults son’s life. However, one of the primary controllable influences
[417]. Reactive oxygen species (ROS), aldehydes from LPO, on our genes and reproductive health is nutrition.
some estrogen metabolites, methylation agents, reactive
nitrogen species, and reactive carbonyl species are some of
the common pathways to DNA damage, with the most stud- 32.7  Summary
ied being ROS and the resulting oxidative damage [417]. One
of the most important endogenous sources of ROS is mito- In summary, reproduction is perhaps the most important
chondrial, via the electron transport chain and nitric oxide biological mandate presenting unique challenges in modern
synthase reaction. ROS are implicated in a variety of repro- times. Recognizing and analyzing the interplay of biological
 550 B. Horn and W. Yu

Folic Acid
Key

Commercially available folates DHFR

Folate cycle outputs DHF

Enzymes DHFR

THF
(metabolically
active)
MTHFS

32
Purines 10 formyITHF

MTHFD1
MTHFS

SHMT
5, formyITHF
5, 10 methenyl-
(Folinic acid)
THF
[inhibits SHMT]
SHMT

5, 10 Methylene
dTMP
THF
TYMS

MTHFR

Key Methionine
5 MTHF
DHFR: Dihydrofolate reductase Cycle
SHMT: Serinehydroxymethyltransferase
TYMS: thymidylate synthase
MTHFD1: methylenetetrahydrofolate dehydrogenase
MTHFR: methylenetetrahydrofolate reductase
MTHFS: 5,10-Methenyltetrahydrofolate synthetase

..      Fig. 32.1  Selective folate metabolism

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 563 33

Lifestyle Patterns of Chronic

Disease
Sarah Harding Laidlaw

33.1 History and Definition of Chronic Disease – 564

33.2 Underlying Origins of Chronic Disease – 564

33.3 Primary Origins – 564

33.3.1  enetic – 564
G
33.3.2 Epigenetic – 564
33.3.3 Preconception and Intrauterine – 565
33.3.4 Early Life Experiences – 565

33.4 Secondary Origins – 565

33.4.1 S tress – 565
33.4.2 Smoking – 566
33.4.3 Alcohol – 566
33.4.4 Sleep – 566
33.4.5 Social Determinants – 567
33.4.6 Physical Activity – 568
33.4.7 Dietary Patterns – 568

33.5 Patterns Difficult to Control on an Individual Basis – 569

33.5.1 F ood Insecurity – 569
33.5.2 Environmental Toxins – 570
33.5.3 Legislative Policy and Chronic Disease – 571

33.6 Tertiary Origins – 571

References – 574

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_33
 564 S. H. Laidlaw

33.1  History and Definition of Chronic abnormal, but environmental influences and multiple inter-
Disease actions may determine disease occurrence. The risk of devel-
oping chronic disease is influenced by genetics and exposures
Chronic disease is a relatively new phenomenon that began to gene-altering conditions and interactions with these expo-
around the time of the industrial revolution when machines sures. Whether our inherited genomes are the primary causes
took over the work of men, with recognition beginning after of chronic diseases or just part of the equation is still being
World War II. Unhealthy lifestyle behaviors are at the root of investigated. A study of monozygotic twins from Western
the global burden of noncommunicable diseases and account European countries was used to estimate population attribut-
for about 63% of all deaths [1]. Common and costly, most able factors of 28 chronic diseases. Of 1.53 million deaths in
chronic diseases are preventable, noting that 60–70% of pri- 2000, 0.25% was attributable to genetics plus shared expo-
mary care visits in developed countries are for preventable sures. Genetic population attributable factors ranged from
conditions [2]. 3.4% for leukemia to 48.6% for asthma. Cancers had the low-
According to the World Health Organization (WHO), est population attributable factors (median, 8.26%), while
“Noncommunicable diseases (NCDs), also known as chronic neurological (median, 26.1%) and lung (median, 33.6%) dis-
diseases, are not passed from person to person. They are of eases had the highest population attributable factors [5].
long duration and generally slow progression. The four main The increasing incidence of obesity is a public health con-
types of noncommunicable diseases are cardiovascular dis- cern that has far-reaching consequences. It is associated with
eases (like heart attacks and stroke), cancers, chronic respira- the development of several of the chronic diseases that are
tory diseases (such as chronic obstructive pulmonary disease impacting health and healthcare globally. Genetic links to
and asthma) and diabetes.” [3] obesity have been identified and, combined with sensitivity
33 There has been a significant shift to noncommunicable to environmental cues, may provide at least one explanation
diseases, as noted in the 2010 Global Burden of Disease for how genetic risk for obesity may promote unhealthy eat-
(GBD) estimates. Years lived with disability (YLD) as a result ing behaviors. Using well-known obesity gene FTO rs9939609
of communicable, maternal, neonatal, and nutrition-related SNP in a sample of 78 children, ages 9–12  years, Rapuano
diseases decreased by 19.5% between 1990 and 2010, while et  al. observed that children at risk for obesity exhibited a
YLD due to chronic disease increased: cardiovascular dis- stronger response to food commercials than children not at
eases by 17.7%; chronic respiratory disease by 8.5%; neuro- risk. These results suggest that children who are genetically at
logical conditions by 12.2%; diabetes by 30.0%; and mental risk for obesity respond to reward signals stronger than those
and behavioral illnesses by 5.0% [4]. not at risk, which in turn may lead to lifelong unhealthy eat-
ing behaviors [6]. In addition, this polymorphism has been
related to increased BMI and obesity throughout life, as well
33.2  Underlying Origins of Chronic Disease as type 2 diabetes, and influences food intake and food choice
but not energy expenditure [7].
Causes of chronic disease can be loosely categorized into pri-
mary, secondary, and tertiary management groupings char-
acterized by the level of control one has over them. With 33.3.2  Epigenetic
primary causes, there is little control as they have occurred
either transgenerationally or within the womb. Secondary Recognition of the origins of chronic disease during early
causes are those that there is some control over during one’s periods of development may provide the key to understand-
lifetime such as diet, smoking, or exercise. The tertiary cate- ing, preventing, and treating chronic diseases in the future. It
gory focuses on preventing or managing the chronic disease is now well understood that early life events play a major role
based on what is known about the individual by identifying in the development of chronic disease later on. The four
such risk markers as low serum vitamin D levels, chronic critical periods for the development of obesity may very well
inflammatory markers, a low nutrient-dense diet, high intake be the same for other chronic, non-obesity-related disease.
of trans fats, and genomic risk (e.g., celiac disease) and These periods of development are prenatal, early childhood,
addressing post-diagnosis complications of these conditions. adolescence, and pregnancy [8].
The social determinant of health, defined as any non-
medical factor directly influencing health, including values,
33.3  Primary Origins attitudes, knowledge and behaviors, family, neighborhood,
and social network, has recently attracted interest among
33.3.1  Genetic researchers. Social disadvantage is compellingly related to
health throughout life [9]. Environmental factors, including
A person’s genes are one factor in determining whether diet, nurturing, and socioeconomic status, are closely linked
chronic illness develops early in life, in later years, or if at all. to one’s genetic code and have the propensity to leave bio-
Genetic predisposition to a chronic disease involves the pres- chemical marks on the genome. Factors such as physical and
ence of one or more gene mutations and or combination of geographic characteristics of neighborhoods including food
alleles. The presence of gene mutations or alleles may not be deserts, air quality, lead paint exposure, racial disparity, or
Lifestyle Patterns of Chronic Disease
565 33
inequality influence health, including neuroendocrine, devel- cose tolerance, obesity, schizophrenia, and depression and
opmental, immunologic, and vascular pathways. Information had an increased atherogenic lipid profile that was more than
can provide an adaptive advantage or a disadvantage to off- twice normal. They were more responsive to stress and were
spring depending on timing and duration of the interaction at double the rate for coronary heart disease and performed
between the individual and his or her environment. Early worse on cognitive tests. In addition, changes in reproductive
childhood social disadvantage has been shown to have an function including earlier menopause, breast cancer, and
impact on later child and adult health, socioeconomic well- changes in insulin-like growth factor were observed [14–16].
being, and cognitive ability. Under the right circumstances,
as listed above, as well as maternal behavior, environmental
signals may result in patterns of epigenetic marks in offspring 33.3.4  Early Life Experiences
that reflect those of the parent. Evidence supports the direct
impact of early life experiences on epigenetic patterns in spe- Childhood abuse and neglect as well as maternal nurturing
cific loci on the genome. Negative early life experiences have have been shown to have an adverse effect on adult cognition
been linked to differences in epigenetic patterns for genes and development of psychiatric disorders. Through rodent
related to drug addiction, mental health, and obesity [10]. studies, researchers have been able to demonstrate that rats
Telomeres, the crucial part of the human cell that influ- who were neglected in early postnatal periods exhibited
ences aging, have also been shown to be associated with envi- methylation of the brain-derived neurotrophic factor gene
ronmental and social stress. Although telomere shortening (BDNF) throughout the lifespan. As they grow up, these
may be related to normal aging, accelerated telomere short- rodents mistreat their own offspring, and these offspring also
ening has been linked to a number of acquired disease pro- have significant DNA methylation [17].
cesses, including inflammation-connected cancers and As far as other chronic illnesses, most data come from stud-
coronary artery disease. Some research has proposed that ies of prenatal famine during the Dutch Winter Famine.
stress increases the oxidative burden on the cell, damaging Although not as widely studied, famine postnatally is also asso-
and reducing telomere length [11]. ciated with a higher incidence of coronary heart disease in
women and their offspring. Children small at birth exhibited
higher levels of adipose tissue as compared to lean tissue, and
33.3.3  Preconception and Intrauterine they exhibited more insulin resistance. Small size at birth, low
weight gain during infancy, and a rapid increase in body weight/
The intrauterine period appears to be one of the most sensi- BMI during childhood are associated with metabolic syndrome,
tive times for formation of epigenetic variability influencing hypertension, and coronary heart disease in adulthood [18].
development and risk for a range of diseases that can develop A recent study that looked at the children of 5034 moth-
later in life [12]. Obesity, cardiovascular disease, type 2 dia- ers in New York State who delivered between 2008 and 2010
betes, stroke, metabolic syndrome, and osteoporosis later in assessed five developmental domains (fine motor, gross
life all appear to be related to in utero influences that result motor, communication, personal-social functioning, and
from small size and thinness at birth. Studies reviewed by problem-solving ability). The study of maternal and paternal
Barker demonstrated that retarded growth in utero and obesity, believed to be the first of its kind, established the
infancy is strongly related to cardiovascular disease mortality relationship between maternal obesity and delays in fine
and some of its known risk factors, proposing three explana- motor development, while paternal obesity associated with
tions for the findings: delays in personal-social development. The results regarding
1. Birth weight is merely a marker for adverse environmen- child development were not the only facts of interest in this
tal influences that appear later in life. study, as maternal obesity was also related to paternal obesity
2. Genetic influences early in life shown as growth failure and lower socioeconomic status. Additionally, obesity was
later appear as degenerative diseases, implying that genes associated with an increased likelihood of smoking, being
related to low birth weight are related to adult-­onset diagnosed with gestational diabetes or hypertension, and
degenerative diseases. lower likelihood of alcohol intake, multivitamin use, and fish
3. Most likely, the relationship between early retarded oil supplementation during pregnancy [19].
growth and adult disease is due to long-term effects on
physiology and metabolism caused by an unfavorable
environment during critical periods of development [13]. 33.4  Secondary Origins

The well-known Dutch Winter Famine study further revealed 33.4.1  Stress
the long-term health outcomes of approximately 40,000 chil-
dren born to mothers with gestational famine during preg- Stress affects people of all ages. Life is full of stress, and it is
nancy as a result of Nazi blockage of food supply lines during known to have both positive and negative effects on health.
World War II. Early gestation appeared to be the most vul- When stress helps the body overcome lethargy or enhance
nerable time for developing fetuses. Those conceived during performance, it can be positive. Short-term stress can boost
this period were found to be at higher risk for impaired glu- the immune system, but long-term, chronic stress resulting in
 566 S. H. Laidlaw

fatigue or inability to cope is a promoter of chronic disease and embryonic tissue nutrients, such as multivitamins and folate.
early aging. Environmental (experiential), psychological In addition, evidence is consistent that carbon monoxide
(emotional), and biological (physiological) stress can have dif- from smoking leads to lower birth weights and may be linked
ferent results on and between individuals. Chronic stress is to cognitive and neurobehavioral deficits in the infant/child.
inflammatory due to injury or infection, poor diet, quality of Residual nicotine and other chemicals left from smoking,
life including socioeconomic factors, smoking, and emotions. known as thirdhand smoke, can react with indoor pollutants
Increased stress can result in oxidative stress that depletes to create a toxic mix of cancer-causing compounds. These
nutrient stores or increases nutrient requirements as a result of compounds pose risk to non-smokers and young children. A
damage to the body from disease or injury. Emotional stress is relatively new concept, the residuals from thirdhand smoke,
a major contributing factor to six of the leading causes of death cannot be removed easily from fabrics and surfaces or from
in the United States: cancer, coronary heart disease, accidental airing out a room or restricting smoking to one location.
death, cirrhosis of the liver, respiratory diseases, and suicide. Inhaling, touching, or swallowing items exposed to third-
Chronic stress has an immunosuppressive effect that interferes hand smoke may place non-smokers and children at risk of
with the body’s ability to elicit a prompt and effective immune smoking-related diseases. This can be especially problematic
response. Longer exposure to stress also makes it less likely for infants and young children who have a tendency to put
that the body can shift from adaptive response (as in fight-or- things in their mouths. [22, 23]
flight response) and shifts to detrimental changes at the cellu-
lar level and then broader immune system function [20].
33.4.3  Alcohol

33 33.4.2  Smoking According to the Centers for Disease Control and Prevention,
alcohol is responsible for 88,000 deaths in the United States
It is widely accepted that smoking is a leading cause of mor- each year and is identified as single condition for 25 diseases
bidity and mortality, not only in the United States but world- and chronic conditions in the International Classification of
wide. Tobacco use is a modifiable risk factor for numerous Disease (ICD)-10 manual. Alcohol has been a part of human
chronic diseases including cancer, cardiovascular disease, culture since history was first recorded. It has been noted to
diabetes, inflammatory disease, and pulmonary-related ill- have both beneficial and detrimental effects on health,
nesses. A study conducted by Campos et al., in Brazil, found depending on the amount consumed. However, long-­term
that one in ten persons with chronic disease smoked, lightly excessive intake has been linked to tumors, neuropsychiatric
but daily, and also lived with someone who smoked. Most conditions, and many cardiovascular and digestive diseases,
patients had either hypertension, diabetes, or chronic kidney while short-term health risks include violence, injury, risky
disease, all comorbid conditions that are negatively impacted sexual behavior, and risk of miscarriage or preterm birth.
by cigarette smoke [21]. Excessive alcohol consumption has been identified as respon-
Smoking is considered a risk factor for chronic obstructive sible for 1  in 10 deaths among working age adults ages
pulmonary disease (COPD), although not all smokers develop 20–64 in 2010 and involves binge drinking (for women, 4 or
the disease. Use of tobacco products in persons with reflux dis- more drinks during a single occasion and 5 for men), heavy
ease is contraindicated due to its lower esophageal sphincter drinking (8 or more drinks per week for women and 15 or
pressure lowering effect and decreased salivation. Additionally, more for men), and any drinking by pregnant women or
smoking increases the risk of esophageal and lung cancer. people younger than age 21 [24–27].
Cigarette smoking also exerts a toxic effect on osteoblasts, Some people use alcohol to reduce stress or believe it is a
increasing the risk for and incidence of osteoporosis [22]. mood elevator. Social influences and norms can also prompt
There is no risk-free level of exposure to smoke. a person to drink, and, in some instances, too much. Low
Secondhand smoke, as well as smoking itself, no matter how levels of parental involvement and support have been shown
much, leads to rapid and sharp increase in endothelial dys- to increase the likelihood of adolescent alcohol use and other
function by injuring epithelium, impairing epithelial vasodi- problem behaviors, including smoking. A family history of
lation, and triggering inflammation. Powerfully addictive, alcoholism has been noted in the development of alcoholism,
cigarette smoking or low-level exposure via secondhand and studies have clearly demonstrated that alcoholism is a
smoke leads to inhalation of toxic chemicals burned during genetically complex disease, influenced by multiple genes
combustion, resulting in DNA damage, inflammation, and interacting with each other and with environmental factors
oxidative stress. Smoking or exposure to smoke during repro- to cause disease [24–27].
ductive years can affect fertility and conception and impact
fetal and child development. Tobacco smoke exposure is asso-
ciated with chromosomal damage or DNA damage resulting 33.4.4  Sleep
in reduced sperm quality, possibly leading to birth defects or
early fetal demise. Smoking may also be related to inflamma- Insufficient sleep alters the endocrine regulation of hunger,
tion in the mother as well as decreased nutrient absorption, appetite, and energy expenditure. In the short term, lack of
decreased nutrient uptake, and reduced levels of necessary sleep inhibits leptin production, suggesting a potential mech-
Lifestyle Patterns of Chronic Disease
567 33
anism for the early development of obesity related to increased Bharmal et al. have proposed main categories of upstream
fat mass [27, 28]. Sleep deprivation, shift work, and exposure factors that provide a better understanding of how these
to bright light at night can have an impact on the body’s circa- macro factors lead to poor health and inequities. Greater
dian rhythm and increase the probability of developing obe- social disadvantage appears to be dose-responsive and is
sity. A prospective cohort study of 8234 children aged 7 years associated with poorer health. This social disadvantage
and a subsample of 909 children (children in focus) with data approach is similar to, but elaborates on, those defined by the
on additional early growth-related risk factors for obesity in Commission on Social Determinants of Health:
Great Britain revealed a relationship between lack of sleep 1. Neighborhood conditions that can influence health
and obesity. Amount of sleep in children at 30 months of age through physical conditions such as air, playgrounds,
was independently correlated with obesity at 7 years of age. and safety.
Those children with the lowest amount of sleep (<10.5 hours 2. Working conditions with the ability to influence
and 10.5–10.9  hours) before age 7 were more likely to be physical, social, and psychosocial aspects of health from
obese than those recording 12 hours of sleep or more [29]. injury, sedentariness, obesity and obesity-related chronic
Obesity, in and of itself, is a risk factor for developing diseases, ventilation and air quality, imbalance of work
sleep apnea, which can further exacerbate chronic illness. The efforts and rewards, and support among and of co-­
presence of sleep apnea in obese individuals is estimated to be workers.
up to 45% of subjects observed. A review of six large studies 3. Education, which has been linked to increased knowl-
conducted worldwide suggests that 25% of individuals with a edge, resulting in better health and healthy behaviors. It
BMI between 25 kg/m2 and 28 kg/m2 have at least some mild shapes employment opportunities that determine
sleep apnea. Independent of obesity, several cardiometabolic economic resources influencing health, and it influences
abnormalities have been identified in persons with sleep health through psychological and social factors with a
apnea, including glucose intolerance and insulin resistance, perception of greater control, higher social status, and
both of which are precursors to diabetes and cardiovascular increased social support.
disease. In addition, persons with obstructive sleep apnea, 4. Attainment of income and wealth while income inequal-
have exhibited a heightend systemic inflammatory state as ity is linked with poor health due to social erosion and
indicated by increased cytokines, serum amyloid- A produc- lack of social cohesion.
tion and in some, elevations in C-reactive protein [28]. 5. Ethnicity and racism affects individual opportunities
based on race or ethnicity and perpetuates social
disadvantage in segregated neighborhoods, unsafe
33.4.5  Social Determinants housing, and low quality/poor educational
opportunities.
The Commission on Social Determinants of Health defines 6. Stress, as described above, may also be a causal factor of
social determinants of health as economic and social condi- chronic disease through accumulated injury from
tions that influence the health of people and communities. stressful socioeconomic and environmental situations
Money, power, and resources that people have, which are that trigger the release of cortisol, cytokines, and other
often influenced by policy choices, form these environments substances that can damage the immune system, vital
[30]. The factors determining the social determinants of organs, and physiological systems that lead to more
health are related to health outcomes and include: rapid onset – or progression to – chronic diseases, such
55 Early childhood development as cardiovascular disease [9].
55 Education level
55 Employment and retaining a job In addition to the social disadvantage theory, Bharmal also
55 Type of work a person does describes a life course approach to health that explores three
55 Food security life periods that are vulnerable to the effects of the risk and
55 Access to healthcare and quality of service duration of exposure to social determinants of health.
55 Housing, including neighborhood quality and safety 1. Adverse health effects of early childhood experiences
55 How much money a person earns that are related to social disadvantage that affect chil-
55 Discrimination and social support (CDC, Social dren’s cognitive, behavioral, and physical development,
Determinants of Health) in turn affecting lifelong health.
2. Intergenerational transfer of advantage has been studied
They are the conditions in which individuals are born, grow, over at least two decades. Children of socially disadvan-
live, work, and age. Notterman (2015) refers to the social taged parents have limited educational choices and are
determinants of health as any nonmedical factor directly less healthy, which translates into decreased advantage
influencing health, such as values, attitudes, knowledge, and for good health and social advantage as adults. Research
behavior [10]. Family, neighborhood, and social network on gene and environment interactions proposes that
context are external sources of influence. Social disadvan- intergenerational transmission of social advantage may
tage, risk exposure, and social inequalities are recognized as be partly explained by changes in gene expression that
having causal roles impacting health across the lifespan [9]. are passed on to future generations.
 568 S. H. Laidlaw

3. In animal studies, a potential causal link of epigenetics directly linked to physical inactivity. When excess energy
suggests that social status can regulate the expression of (calories) is consumed and not expended, the surplus is stored
genes that control the immune system. Perceived stress, as adipose tissue. Daily physical activity aids in weight loss,
occupational status, educational achievement, work balancing the intake output equation, and in improvements of
schedules, and intimate partner violence have been linked functional capacity. Physical inactivity has also been associ-
with telomere shortening, resulting in cellular aging [9]. ated with certain types of cancer, while epidemiological stud-
ies show that increased physical activity is associated with a
decreased risk of breast, colon, and prostate cancers [33].
33.4.6  Physical Activity

Lifestyle shifts, including changes in access to healthcare, 33.4.7  Dietary Patterns

migration from more rural to urban areas, transportation
accessibility, frequent job changes, access to more electronic Changes in the way people eat and live are increasingly
devices including television, concern regarding safety in impacting the health and development of chronic disease.
communities, and chronic disease are becoming more prom- Diet-related chronic diseases have increased as the American
inent in younger individuals, leaving them encumbered with diet and lifestyle has changed. A nutritional transition is
poor health for the rest of their lives. These shifts have resulted occurring, whereby traditional diets are being replaced by
in the prevalence of physical inactivity, a change that has been diets higher in processed foods, animal fats, and sugar. Rising
identified as being partly responsible for the earlier onset of incomes have increased the demand for, and prestige of, large
chronic disease. People are less physically active today than amounts of animal proteins, as well as generous sized meals.
33 they have been in past generations, with the number of daily This transition, combined with physical inactivity, is increas-
steps taken approximately 50–70% less since industrialization ing the burden of chronic disease by promoting overcon-
and the introduction of powered machinery [31]. sumption and underexercising (see 7 Chap. 2).
 

A sedentary lifestyle over years can lead to primary The standard American diet (SAD) is one high in pro-
decrease in functionality, obesity, cardiovascular disease, cessed foods, fat, sugar, and animal products and is con-
type 2 diabetes, and premature death. Furthermore, individ- sumed by a majority of the population. It contains a low
uals with a chronic disease are more likely to become less amount of fruit and vegetables, which is linked to a lower
physically active, if they were not already, which leads to intake of nutrient-dense foods that contain phytonutrients,
deconditioning and further decreases in the ability to per- antioxidants, fiber, and other health-conferring properties.
form physical activity. If this cycle is not halted, the likeli- This shift in diet began after World War II and rapidly esca-
hood for suboptimal quality of life and long-term poor health lated with convenience foods, fast foods, and sugar-­
increases significantly. containing beverages, being the norm for families who once
In order for people to enjoy health benefits, WHO recom- relied on a stay-at-home mom to prepare meals. Now work-
mends they get at least 600 MET minutes (the physiological ing mothers with limited time and a hungry family find they
measure expressing the energy cost of physical activities) of must rely on options that are quick and filling.
total activity a week. Moderate-intensity activity such as brisk A traditional diet, once the “norm,” is one centered on
walking 150 minutes/week or 75 minutes of vigorous physical plant-based foods with small amounts of animal proteins,
activity such as running meets these guidelines. A review of with sweets and desserts reserved for special occasions. These
literature citing the association between physical activity and plant-based foods maximize nutrients, while the SAD diet
the risk of breast cancer, colon cancer, diabetes, ischemic heart minimizes them. Traditional diets are also inspired by rich
disease, and ischemic stroke was completed by Kyu et al., in cultural and historical cuisines around the globe.
order to quantify the dose-response association between dis- Unfortunately, many of the healthier traditional diets are
ease risk and physical activity. They concluded that people now threatened by exposure to Western-style foods with fast
who achieved total physical activity levels several times the food and convenience foods permeating all corners of the
WHO recommendations experienced a significant reduction globe. Eating a traditional diet can bestow benefits that are
in the risk of the five diseases. Most health gains were observed health-promoting. These diets include the diet popular in
at levels of 3000–4000 MET minutes/week [32]. healthcare  – the Mediterranean diet with its emphasis on
With the exception of genetic causes, cardiovascular dis- plant-based foods, legumes, healthy fats, low fat dairy, eggs
ease is highly correlated to physical inactivity. Daily physical and poultry in small amounts, fish as the predominant source
activity reduces the risk of cardiovascular disease, and it of protein, and red meat and sweets once a week or less.
improves functional capacity. Diabetes affects more than 24 Other less well-known or practiced traditional diets include
million Americans, with another 60% having prediabetes and the African Heritage diet, Latin American diet, Asian diet,
at greater risk for developing type 2 diabetes. An increase in and more widely seen and accepted vegetarian and vegan
physical inactivity has been linked to the rising rates of type 2 diets. Of course, the foods and the preparation techniques of
diabetes with increased blood lipids, blood pressure, and glu- these diets can and have been changed to meet the American
cose intolerance. Obesity, linked to many chronic diseases taste, but if eaten as intended, they can and will confer health
including heart disease, diabetes, osteoarthritis, and cancer, is benefits on the consumer.
Lifestyle Patterns of Chronic Disease
569 33
33.5  Patterns Difficult to Control insecurity, on the other hand, is defined “as a lack of consis-
on an Individual Basis tent access to enough food for an active and healthy life and
or a household-level economic and social condition of lim-
33.5.1  Food Insecurity ited or uncertain access to adequate food.” It is further
defined as low or very low food security (. Fig. 33.1). Both
 

According to the United States Department of Agriculture low and very low food security households with children
(USDA), “Food security means access by all people at all reported similar patterns of lack of food or uncertain access
times to enough food for and active, healthy lifestyle.” Food to it. According to the USDA, “The defining characteristic of

..      Fig. 33.1  Percentage of

households reporting indicators Percentage of households reporting indicators of adullt food
of adult food insecurity, by food insecurity, by food security status, 2016
security status, 2016. (Source:
USDA, Economic Research Food secure Low food security Very low food security
Service, using data from the
December 2016 Current
Population Survey Food Security
Supplement)
Worried food would run out

Food bought did not last

Could not afford balanced meal

Cut size of meal or skipped meal

Cut or skipped meal in 3+

months

Ate less than felt should

Hungry but did not eat

Lost weight

Did not eat whole day

Did not eat whole day, 3+

months

0 20 40 60 80 100

Percent
 570 S. H. Laidlaw

very low food security is that, at times during the year, the Endocrine-disrupting chemicals (EDC), widely present in
food intake of household members is reduced and their nor- the environment, are natural or synthetic compounds which,
mal eating patterns are disrupted because the household through environmental or inappropriate developmental expo-
lacks money and other resources for food [34].” sures, alter the hormonal and homeostatic systems that enable
In 2015, some 42.2 million Americans lived in 15.8 mil- the body to communicate with and respond to the environ-
lion food-insecure households, with about 6.3 million of ment. The most commonly studied EDCs are bisphenol A
these people experiencing very low food security. Households (BPA), phthalates, atrazine (ATR), polychlorinated biphenyls
with children reported food insecurity at a significantly (PCB) and polybrominated diphenyl ethers, and DDT and
higher rate than those without children and especially so in DDE. BPA has long been used in a wide variety of manufac-
households headed by single mothers [35]. Data from several turing, food packaging, toys, and other uses and is produced
studies have demonstrated that food insufficiency is associ- and used in larger amounts than any other chemical. Resins
ated with poor dietary intake, inadequate micronutrient of BPA are found in foods and beverages regularly consumed.
intake, and poor diet quality. Over time, these factors can Phthalates and their esters are used as liquid plasticizers and
contribute to the development of chronic disease including found in everyday products such as plastics, coating, cosmet-
osteoporosis, sarcopenia, and anemia. Analysis of data from ics, and medical tubing. Atrazine is an herbicide used for
the National Health and Nutrition Examination Survey control of broadleaf grasses and has been the major herbicide
(NHANES) showed that of the 15,199 persons, approxi- used worldwide since 1959; it and its metabolites are common
mately 1256 reported some level of food insecurity and expe- groundwater contaminants. p,p’-Dichlorodiphenyltrichloro-
rienced 1 of 3 chronic diseases – diabetes, hypertension, or ethane (DDT) is an industrial and household synthetic insec-
chronic kidney disease. In the review of this data, food-­ ticide. It was used extensively until 1972, when it was banned
33 insecure individuals were more likely to have diabetes [36]. due to its effects on human health and the environment.
Food-insecure adults with diabetes were observed to have Dichlorodiphenyldichloroethylene (DDE) and dichloro-
poorer glycemic control than food-secure individuals. They diphenyldichloroethane (DDD) are metabolites of DDT and
also have a higher prevalence of metabolic syndrome and have been linked to endocrine-related chronic diseases
have diets of lower quality that contribute to risk of cardio- including endometrial, pancreatic and breast cancer, testicu-
metabolic disease. In addition, food insecurity was associ- lar tumors, and type 2 diabetes [38].
ated with several individual chronic disease risk factors Toxins during gestation have been associated with adverse
including smoking, higher concentrations of HgBA1c, higher outcomes at birth for decades. Children exposed in utero to
levels of C-reactive protein, and greater incidence of obesity thalidomide were born with limb deformities, while those
among women. It has been suggested that financially strapped born to alcoholic mothers experience fetal alcohol syndrome.
families may purchase cheap energy-dense foods that are Insufficient folate in the maternal diet may result in spina
high in calories and highly processed [37]. bifida. Methyl mercury exposure has resulted in Minamata
disease, and diethylstilbestrol (DES)-exposed children of
both sexes may have multiple reproductive disorders, certain
33.5.2  Environmental Toxins cancers, cryptorchidism, and other diseases. Increased dis-
ease risk is now being observed in the grandchildren of DES-­
The environmentally based contributors to chronic disease treated women, as well as examples of disease in those
risk are, although poorly understood, known to have a cumu- children with transgenerational exposure to BPA, PCBs, pes-
lative and dose-responsive effect. Most Americans have ticides, and other environmental toxins [38].
detectable levels of an extensive assortment of environmental Air pollution, either outdoor or indoor, is known to con-
chemicals in their bodies, including many with known tribute to respiratory diseases, cancers, cardiovascular dis-
endocrine-­disrupting, neurotoxic, and carcinogenic activi- ease, and adverse pregnancy outcomes. Air pollutants have
ties. In animal models, these are biologically and toxicologi- been categorized into four different groups: (1) gaseous pol-
cally relevant to the development of chronic diseases such as lutants such as sulfur dioxide, carbon dioxide, ozone, or vola-
cardiovascular disease, diabetes, hypertension, obesity, and tile organic compounds; (2) persistent organic pollutants
cancer [38]. including dioxin; (3) heavy metals such as lead and mercury;
Among environmental hazards are air pollution, includ- and (4) particulate matter.
ing smoking and occupational exposure, polycyclic aromatic All kinds of air pollution can affect the respiratory sys-
hydrocarbons, heavy metals, and bioaerosols linked to tem, from itchy throat and bronchoconstriction to asthma,
chronic disease through epigenetic processes, including gene emphysema, and lung cancer. Carbon monoxide affects the
methylation and histone modification. Although epigenetic organs that consume a lot of oxygen, such as the heart and
modification and transgenerational inheritance of disease brain, resulting in impaired concentration, slow reflexes, and
risk have been demonstrated in animals, definitive evidence confusion. Particulate matter has the ability to interfere with
for heritable environmentally induced epigenetic changes in blood coagulation and lung inflammation and can lead to
humans is limited. However, there are epidemiologic studies myocardial infarction or angina. Dioxin has been shown to
that establish a relationship between maternal and grandma- result in ischemic heart disease and adverse effects on the
ternal smoking and the risk for asthma in children [4]. nervous system by decreasing nerve conduction velocity and
Lifestyle Patterns of Chronic Disease
571 33
impaired mental development in children. Heavy metals Lead poisoning in children has brought significant atten-
such as lead, mercury, and arsenic have been linked to neu- tion to the topic since the 1970s. Children exposed to lead,
ropathies, due to neurotoxicity, resulting in memory distur- primarily from paint chips and dust in the environment, are
bances, sleep disorders, anger, fatigue, and other problems. at greater risk due to their developing brain and rapid uptake
Heavy metals have been associated with kidney damage and of nutrients. Children exposed to lead often exhibit cognitive
disease and dioxin with liver cell damage. During pregnancy, issues, including behavioral and learning problems, stunted
pollutants can lead to spontaneous abortion, reduced fetal growth, and mental retardation. Studies looking at the rela-
growth, and prematurity, while lead exposure is known to tionship of lead to cancer are mixed; however lead levels in
lead to congenital malformations and lesions on the develop- adults can lead to headaches, mood swings, and problems
ing brain, interfering with infant motor and cognitive func- with memory and damage peripheral nerves and kidney and
tions. Dioxins are endocrine disruptors and affect the growth reproductive function [43].
and development of the fetal nervous system [39].
33.5.3.3  Arsenic
Arsenic exposure can occur through such occupations as
33.5.3  Legislative Policy and Chronic Disease mining and smelting, the burning of arsenic-rich coal, and
from drinking contaminated water. Arsenic can enter the
33.5.3.1  Asbestos water through soil or as a result of industrial waste contami-
It is well-known that exposure to asbestos results in chronic nation and burning of fossil fuels, through the use of agricul-
lung disease, including lung cancer, mesothelioma, and tural pesticides and food additives, or through natural decay
asbestosis or fibrosis of the lung. Although its use in products of minerals in weathered rocks and soils. Arsenic in drinking
is limited, its effects will be felt well into the twenty-first cen- water is a concern throughout the world as it can cause mor-
tury. Workers who are exposed to asbestos are five times bidity and mortality from a number of diseases, including
more likely to develop lung-related diseases than non-­ skin lesions, diabetes, peripheral neuropathy, gastrointestinal
smokers not exposed, but the disease risk rises to 50 times symptoms, high blood pressure, and cardiovascular disease
more likely for those who smoke. Asbestos has been seen as [40]. The Environmental Protection Agency (EPA) updated
the principal cause of occupational cancer in the United arsenic standards in the early 2000s after considerable delay,
States and a significant cause of disease and disability from and while levels have declined, it remains present. The most
noncancer-related disease. Estimates indicate that the cumu- common source of arsenic in drinking water appears to be
lative total number of asbestos-associated deaths in the from private water wells, although contaminants may be
United States may exceed 200,000 by the year 2030 [40–42]. present in larger municipalities where the main source of
In the 1970s, some uses of asbestos were banned or oth- drinking water is from wells [44].
erwise regulated, and its importation from other countries
was dramatically reduced in light of growing evidence con-
cerning its connections to serious health conditions. 33.6  Tertiary Origins
Continued research has demonstrated the adverse effects of
asbestos, and, in 2002, the United States discontinued min- Although not an origin of chronic disease, tertiary is more
ing it. Still, asbestos remains in use in some products today aptly defined as the management of the chronic disease and
and still exists in many old buildings. As of this writing, prevention of further complications, based on what is known
although lawmakers have attempted to introduce legislation about the individual. This approach is central to the expand-
banning asbestos use, measures to do so have failed. Thus, ing field of lifestyle medicine, whereby the clinician uses risk
there is no comprehensive law governing its use in the factor markers to assess for and identify chronic disease.
United States [41]. Lifestyle medicine focuses on the prevention and treatment
of chronic disease caused by lifestyle factors including physi-
33.5.3.2  Lead cal inactivity, poor diet, tobacco use, and stress and psycho-
Lead has been used since the beginning of time and contin- social factors. Below is a table of chronic diseases with their
ues to be found in man-made and natural products, so its risk factor markers, potential origins that may help in identi-
complete elimination is virtually impossible. The use of lead fying the approach appropriate for the identified chronic dis-
in paint, gasoline, pipes, some construction materials, and ease (. Table 33.1).
 

cosmetics has been banned for a number of years. However, Noncommunicable, chronic diseases have surpassed
lead from gasoline emissions and other deposits from years communicable and infectious diseases as the cause for mor-
ago remain in the soil and will not break down or go away. bidity and mortality worldwide. More than one third of
Lead is still in use in lead-acid batteries, ammunition, cable Americans have been identified as obese, and diseases related
coverings, piping, in the manufacturing of brass and bronze, to obesity – cancer, heart disease, type 2 diabetes, and stroke –
as bearing metal in machinery, and in sheet lead. Lead com- are among the leading preventable causes of morbidity and
pounds are used in matches, some paints and ceramics, sol- death. New approaches to identify and treat these conditions
dering and building materials, and photography and as are needed to reduce the incidence of these diseases and to
catalysts to help chemical reactions [40, 43]. prevent their continued explosion. Lifestyle medicine is
 572 S. H. Laidlaw

..      Table 33.1  Chronic diseases, risk factor markers, and their potential origins

Disease Risk factor markers Primary origin [45] Secondary origin

Cardiometabolic

Obesity Weight Diet

Diabetes Glucose Type 1 diabetes – HLA-DQA1, Smoking

Heart disease HgB A1c HLA-DQB1, and HLA-DRB1 genes Stress
Lipids Psychosocial
Homocysteine Inactivity
Blood pressure

Cancer Obesity BRCA1 Diet

Diabetes BRACA2 Chemical exposure

Inflammation Multiple tumor markers Smoking

Hormonal and endocrine

Thyroid Hyperthyroid Iodine intake

Hypothyroid Drugs
Low vitamin D Infections
33 Chemicals

Hashimoto’s thyroiditis TSH HLA genes Change in sex hormones

Antithyroid antibodies CTLA-4 gene Excess iodine intake
Free T-4 test PTPN22 gene Viral infections
VDR gene Ionizing radiation
Cytokine genes
Female
Postpartum
Fetal microchimerism
Human leukocyte antigen (HLA)
complex

PCOS Thyroid function tests Possible multiple genes with Stress/anxiety

Prolactin relationship to PCOS Low socioeconomic status
Free androgen index
Fasting glucose
Fasting insulin
Elevated blood pressure
Weight
Miscarriage
Dysmenorrhea
Hirsutism
Acne

Adrenal Weight Does not have a clear pattern of Prolonged stress and/or
(Cushing disease) Blood pressure inheritance depression
Moon face Somatic genetic mutations
Cortisol levels

Autoimmune

Allergies and intolerances Physical measures – NFPA Ethnicity Environmental smoke

IgE Genetic factors are yet unknown Diet/nutrition
IgG Sleep
Air pollution

Celiac disease Type 1 diabetes Variants of the HLA-DQA1 and Diet

Weight loss HLA-DQB1 genes
Skin rash Possibly changes in other genes

Rheumatoid arthritis Red, swollen, warm joints HLA complex Smoking

Anemia Various genes Obesity
Sex Environmental pollutants
Age Viral/bacterial infections
Family history
Lifestyle Patterns of Chronic Disease
573 33

..      Table 33.1 (continued)

Disease Risk factor markers Primary origin [45] Secondary origin

Systemic lupus Joint pain Immune function-related genes Drugs

erythematosus Fatigue Viral infections
Weight loss Diet
Stress
Chemical exposures
Sunlight

Gastrointestinal

Inflammatory bowel Weight (loss) Variations in various genes related Abnormal immune response to
disease/ulcerative colitis GI function to protective function of intestine bacteria and toxins

Crohn’s disease Weight (loss) Variations in the ATG16L1, IRGM, Cigarette smoking
Anemia and NOD2 genes
IL23R gene
Variations in certain regions of
chromosome 5 and chromosome 10

Gastroesophageal reflux Weight (obesity) Polygenic basis overlapping with Alcohol

(GERD) Non-cardiac chest pain Barrett’s esophagus, but incom- Large meals
Barrett’s esophagus Dental erosion pletely understood [46] Viral infections
Hiatal hernia COPD

Ulcers Weight (loss) Many individuals with peptic ulcers H. pylori infection
Appetite loss have close relatives with ulcers, Gastritis
suggesting that genetic factors may Aspirin use Stress/severe illness
be involved but has yet to be fully Tobacco use
elucidated Alcohol
Stress

Developmental

Attention deficit hyperactiv- Behavioral problems Research suggests there may be a Exposure to lead
ity disorder (ADHD)/ genetic component as it appears to Smoking and alcohol use during
attention deficit disorder run in families pregnancy
(ADD)

Autism spectrum disorder Impaired social interaction It is believed that 50% of the risk of Drugs taken during pregnancy
Poor communication skills ASD is due to genetic variation, but Environmental toxins
Repetitive behavior exact genes are yet positively Alcohol
identified [47]

Neurological

Parkinson’s disease Tremor Mutations in LRRK2, PARK2, PARK7, Free radical production
Weight (loss) PINK1, or SNCA genes. Effect of
changes not fully understood

Alzheimer’s disease Memory loss Gene mutation passed from parent Poor diet (lack of folic acid,
Weight (loss) to child – APP, PSEN1, or PSEN2 phytonutrients, naturally
Malnutrition genes occurring nitrates, b vitamins) in
middle age

Amyotrophic lateral Dysphagia Mutations in the C9orf72, SOD1, Secondary origins do not appear
sclerosis (ALS) Muscle weakness, twitching, TARDBP, and FUS genes to affect the development of ALS
and cramping

Multiple sclerosis (MS) Muscle weakness Variations in numerous genes are Vitamin D intake
Tremors thought to cause MS – HLA-DRB1, Smoking
Difficulty walking IL7R Exposure to Epstein-Barr virus
Vision difficulties

Muscular dystrophies Progressive muscle weakness Mutations in the DMD Secondary origins do not appear
(Duchenne and Becker) Muscle wasting X-linked recessive pattern carried by to affect the development of
the mother muscular dystrophies
 574 S. H. Laidlaw

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39. Kampa M, Castanas E. Human health effects of air pollution. Environ disease shares genetic background with esophageal adenocarci-
Pollution. 2008;151:362–7. noma and Barrett’s esophagus. Hum Mol Genet. 2016;25(4):828–35.
40. Prüss-Ustün A, Vickers C, Haefliger P, Bertollini R.  Knowns and https://doi.org/10.1093/hmg/ddv512.
unknowns on burden of disease due to chemicals: a systematic 47. Yoo H.  Genetics of autism spectrum disorder: current status and
review. Environ Health. 2011;10(9). Available at http://ehjournal.­ possible clinical applications. Exper Neurobiology. 2015;24(4):257–
biomedcentral.­com/articles/10.­1186/1476-069X-10-9. Accessed 5 72. https://doi.org/10.5607/en.2015.24.4.257.
Jan 2017.
41. Asbestos.­com. National asbestos regulations. Available at https:// Additional Resources
www.­asbestos.­com/legislation/. Accessed 5 Jan 2017. Food Security and Health. Policy brief by the scientific advisory board of
42. ATSDR Case Studies in Environmental Toxicity: Asbestos toxicity. the UN Secretary General. December 28, 2016.
Available at https://www.­atsdr.­cdc.­gov/csem/asbestos_2014/docs/ Lung Cancer Fact Sheet. Available at http://www.­lung.­org/lung-health-­
asbestos.­pdf. Accessed 5 Jan 2017. and-diseases/lung-disease-lookup/lung-cancer/learn-about-lung-­
43. American Cancer Society. Lead: what is lead? Available at http:// cancer/lung-cancer-fact-sheet.­html. Accessed 7 Jan 2017.
www.­cancer.­org/cancer/cancercauses/othercarcinogens/athome/ National Institute of Environmental Health Sciences. Air pollution.
lead. Accessed 5 Jan 2017. Available at https://www.­niehs.­nih.­gov/health/topics/agents/air-­
44. Environmental Protection Agency (EPA) Drinking water regulations pollution/. Accessed 4 Jan 2017.
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drinking-water-regulations-and-contaminants. Accessed 9 Jan chronic disease. 2003. Available at http://www.­who.­int/dietphysi-
2017. calactivity/publications/trs916/en/. Accessed 31 Dec 2016.
 577 34

Circadian Rhythm: Light-Dark

Cycles
Corey B. Schuler and Kate M. Hope

34.1 Introduction – 579

34.2  ackground of Scientific Relevance to Metabolism and

B
Nutrition Status – 579

34.3 Central and Peripheral Circadian Clocks – 580

34.4  ircadian Rhythm and Disruption of the Sleep-Wake

C
Cycle –  581

34.5 Types of Circadian Rhythm Sleep Disorders (CRSDs) – 581

34.6 Treatment for Circadian Rhythm Sleep Disorders – 581

34.6.1 Light, Melatonin, and Vitamin B12 – 581

34.7 Nutrition and the Circadian System – 582

34.7.1 T he Circadian Clock System Prepares the Body for Feeding – 583
34.7.2 Coupling Between Metabolism and Clocks – 583
34.7.3 Eating Patterns: The Feeding/Fasting Cycle – 583

34.8 Time-of-Day Restricted Feeding – 584

34.9 Circadian Clock Genes – 585

34.10 P
 athophysiology Mechanisms and Relevance to Chronic
Disease Risk – 586
34.10.1  etabolism and Obesity – 586
M
34.10.2 Cancer – 586
34.10.3 Diabetes – 587
34.10.4 Cardiovascular Issues – 587
34.10.5 Renal Function – 588
34.10.6 Endocrine System – 588
34.10.7 Immune System – 588
34.10.8 Reproductive System – 588
34.10.9 Sleep Hygiene – 589

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_34
34.11 Toxin-Related Influences – 589

34.12 Key Lifestyle Influences – 589

34.13 Chronotypes and Personalized Nutrition – 590

34.14 Conclusion – 590

References – 591
Circadian Rhythm: Light-Dark Cycles
579 34
34.1  Introduction The circadian rhythm is tightly connected to energy
homeostasis and is affected by the timing of meals, as well as
Chronobiology is the study of how biological clocks control food composition and components. The clocks control
and regulate virtually every function of life. Most living energy metabolism, and the metabolic states, in return, can
organisms, including humans, have an endogenous biologi- influence the circadian clocks. In many countries where
cal clock that operates on a near 24-hour  cycle, in concert meal timing and sleep habits are not in tune with the natural
with Earth’s daily rotation and the lunar cycles. This is called circadian rhythm, metabolic disease can arise [14]. The prin-
the circadian rhythm (from the Latin “circa diem,” which ciples of chrononutrition, which studies the relationship
means “approximately a day”). This intrinsic clock regulates a between the circadian system and metabolism, have been
wide variety of functions, including sleep, arousal, feeding, shown to improve human weight loss and will likely benefit
and a myriad of metabolic processes. Indeed, it appears that people who suffer from metabolic disease, as well as the gen-
nearly all biological mechanisms are regulated by the circa- eral public [15].
dian clock system, including blood pressure, body tempera-
ture, cell division, immune function, digestion, and hormone
secretion [1]. 34.2  Background of Scientific Relevance
In humans, the master biological clock is located in the to Metabolism and Nutrition Status
suprachiasmatic nucleus (SCN) within the anterior hypo-
thalamus of the brain. The SCN receives photic input from As the saying goes, “You are what you eat,” however, research
the retina each day, which serves to reset the clock. The mas- indicates that we may need to add a companion axiom that
ter clock then coordinates the peripheral clocks which are states, “You are when you eat,” as well. Food has been shown
present in nearly all cells of the body, by way of a common set to be a strong driver of circadian rhythms, and a disruption
of clock genes that work in various negative feedback loops in metabolism can occur if food consumption is not in phase
to create the circadian oscillations that regulate metabolism with the light-dark cycle [5]. The term “chrononutrition”
[1–3]. Functional genomics have established that these circa- refers to the timing of food ingestion in coordination with
dian clocks govern a large portion of the human genome. the daily circadian rhythm. Time-specific food intake has
Though circadian rhythms are endogenous in nature and been shown to have distinct consequences on physiology,
regulated by the clock genes, they can be entrained or and the circadian clock system provides a critical connec-
adjusted by zeitgebers (from the German, “time giver”), tion between nutrition and an organism’s homeostasis [16].
which are external cues from the environment. Zeitgebers Meal timing can affect the sleep-wake cycle, core body tem-
include light, temperature, redox cycles, diet, exercise, and perature, performance, alertness, and hormone levels, and it
social contacts [4, 5]. Disruptions in the circadian coordina- appears to be connected to obesity and metabolic patholo-
tion, whether environmental or genetic, can cause metabolic gies [16].
imbalances, leading to sleep issues, which may eventually In addition to the timing, the type and quality of macro-
affect the nervous, endocrine, cardiovascular, and immune nutrients and micronutrients have the capability of function-
systems. This can result in dyslipidemia, obesity, hyperten- ing as zeitgebers by modulating clock proteins or nuclear
sion, inflammation, and mental health disorders [6]. Growing receptors. The use of targeted nutrients based on SNPs (single
evidence also shows support for the idea that circadian dis- nucleotide polymorphisms) in human clock genes, as well as
ruption from shift work, chronic jet lag, or artificial light a person’s specific chronotype, has the potential for clinical
exposure at night may be risk factors for the development of utilization [5]. Nutrients can either disrupt or restore the
cancer [7–9]. synchronization between the peripheral clocks and the
Circadian rhythm sleep disorders (CRSDs) or circadian suprachiasmatic nucleus (SCN), also known as the central
sleep disorders are clinically diagnosed disorders that arise pacemaker in the brain.
from abnormalities in the length, timing, or alignment to the The SCN is a network of neurons. It is a wing-shaped
day-night cycle. These include delayed sleep phase syndrome structure located within the hypothalamus gland that sits
(DSPS), advanced sleep phase syndrome (ASPS), non-24- directly above the optic chiasm. This neural network consists
hour sleep-wake disorder (Non-24), irregular sleep-wake of thousands of neurons, and it sends out signals that keep
disorder (ISWD), shift work disorder, and jet lag disorder the rest of the body on a near 24-hour schedule.
[10]. The role of the microbiome is being explored for its role
The gold-standard measures of circadian rhythm in in circadian rhythm. A large portion of the body’s microbiota
humans have been core body temperature and salivary or is located in the gastrointestinal tract, a site that has been
plasma melatonin levels [4]. The SCN regulates the secretion shown to have a powerful circadian clock. The microbiota
of the hormone melatonin (N-acetyl-5-methoxytryptamine) participates in the daily cycles of digestion, and changes in its
by the pineal gland in response to the environmental light-­ levels and composition can have an impact on the system-­
dark cycle, inducing sleep. Abnormal oscillations in melato- wide cyclic homeostasis of the body [16]. An appreciation of
nin secretion can affect sleep patterns [11]. Bright light the circadian system has many implications for nutritional
exposure and melatonin therapy have been shown to be effec- science and may ultimately help reduce the burden of chronic
tive treatments for circadian rhythm sleep disorders [12, 13]. disease [17].
 580 C. B. Schuler and K. M. Hope

34.3  Central and Peripheral Circadian Clocks local clocks, are found in every cell, tissue, and organ [2, 3].
While the central clock is entrained by light, the peripheral
Even without external cues from the environment, humans clocks are entrained by feeding cues and dominate local
maintain a sleep-wake rhythm that is very close to 24 hours. metabolic rhythms including glucose, lipid homeostasis, and
In mammals, the central circadian clock that regulates this hormonal secretion. Nutrients and meal timing can affect the
rhythm is the SCN. This master pacemaker regulates rhythms clock system. Thus, a current view for the adaptive signifi-
such as the sleep-wake cycle, the autonomic nervous system, cance of circadian clocks is their basic role in coordinating
body temperature, gene expression, and hormone secretion, metabolism [18] (. Fig. 34.1).
 

including melatonin [17]. There is also evidence that the cell The master circadian clock is located in the suprachias-
cycle is regulated via the day-night cycle, and numerous matic nucleus (SCN) in the hypothalamus. This master clock
studies have shown that cell division is governed by a circa- is entrained to the 24-hour day cycle by light which enters the
dian variation in mammalian tissues, including the epithelia retina, and it dominates activity rhythms. The central circa-
of the tongue, skin, oral mucosa, intestine, esophagus, stom- dian clock sends signals to peripheral clocks located in cells
ach, duodenum, jejunum, rectum, as well as the bone mar- throughout the body. The peripheral clocks are entrained by
row, and pancreas [3]. feeding cues that dominate local metabolic rhythms. Both
However, without time cues, the internal clock’s period nutrients and meal timing can affect the clock system.
is actually about 24.2 hours, so it must be reset or entrained Chrononutrition has two facets: (1) nutrients and substances,
every day to the 24-hour day, to keep the organism in sync for example, caffeine, can alter the periodicity of the clock,
with the external world [17]. The SCN is entrained by light and high-fat diets can affect the rhythm of lipogenesis, circu-
cues that enter the retina. The retina transfers information lating lipids, and feeding behavior and (2) meal-timing can
about light and darkness to the SCN, which then synchro- affect the clock system, for example, skipping breakfast or
nizes a phase of rhythms with the external environment. nocturnal eating can increase the risk of obesity, whereas
34 This is orchestrated through a monosynaptic pathway from regular or time-restricted eating can synchronize the clock
photosensitive cells in the retina that take photic input to system and offset metabolic disorders.
the SCN. Then, by way of a multisynaptic pathway, informa- Synchronicity between the central and peripheral clocks
tion is transferred from the SCN to the pineal gland. The appears to be important for metabolic health. It is shown that
pineal gland synthesizes melatonin, a neurotransmitter-like workers on the night shift or a rotating schedule have a greater
substance that regulates circadian rhythms and sleeping risk for type 2 diabetes, obesity, and cardiovascular disease. If
patterns. the light-entrainable pacemaker of the SCN is out of sync
The central circadian clock also sends signals to periph- with the food-entrainable oscillators of the peripheral tissues,
eral clocks throughout the body. The peripheral clocks, or then there may be a disruption in the energy balance [5].

..      Fig. 34.1  The circadian clock Light

system and chrononutrition. 12 (1) Chrono-nutrition
(Reprinted from Oike et al. [14]. Central clock Caffeine (1) Clock regulation
With permission from Springer (SCN) ex. High-fat diet (HFD), Caffeine
Nature) 6 18 (2) Meal-time effects
ex. Skipping breakfast (SB)
Nocturnal eating (NE)
24

Peripheral clocks
Feeding Regular/Time-restricted feeding
(Most Tissues)
rhythm
Synchronization
12 (2)
SB&NE

6 18
Nutrients Circulating
fat/Lipids Amplified rhythms
Healthy
24
Irregular/Unusual feeding

(1) Desynchronization
Metabolic rhythms HFD
Lipogenesis, Thermogenesis

Attenuated rhythms
Metabolic disorders
Circadian Rhythm: Light-Dark Cycles
581 34
34.4  Circadian Rhythm and Disruption ular cycles. Shift work and jet lag are two examples of this.
of the Sleep-Wake Cycle Not all shift workers have sleep difficulty as the ability to cope
with shifting circadian patterns varies between individuals
Identifying circadian rhythm sleep disorders or functional [31]. Similarly, not all travelers suffer from jet lag. Eastward
versions of these disorders can be an important part of nutri- travel is often more problematic than westward travel.
tional management. Medical care often overlooks functional Irregular sleep-wake pattern also can occur in those with
sleep disorders and is not well-equipped to support sleep dis- developmental conditions, brain injury, and dementia and
orders non-pharmacologically. those in institutional care [32–35].
Initial assessment can identify clues to the functional or Sleep Apnea is not recognized as a circadian rhythm sleep
pathologic state. Either on intake documents or initial inter- disorder per se. However, it can dramatically affect circadian
view, questions regarding diurnal preference (is the client a patterns, may be affected by diurnal patterns, is a common
“night owl” or “morning lark”?) and whether or not they nap sleep disorder, and can be modified, in part, by nutritional
may be important regardless of the presenting complaint or interventions. Poor sleep quality causes daytime sleepiness
health goal. Excessive daytime sleepiness and sleep depriva- and affects both wake timing and normal somnolence. Sleep
tion are two common complaints in nutrition practice. Not apnea severity is described by the average number of respira-
only do these result in metabolic consequences but also poor tory events per hour of sleep (frequency), but also the dura-
decision-making as it pertains to healthy choices. tion of each event can be monitored. At a circadian phase
corresponding to early morning, apnea durations are longest
and frequency was low. In the late afternoon and early eve-
34.5  Types of Circadian Rhythm Sleep ning, event durations are shortest and frequency is high [36].
Disorders (CRSDs) This may be due to the concept that respiratory plasticity or
neuronal control of respiration is modulated by a circadian
As a practical note when speaking about circadian rhythm, rhythm [37]. Also, upper airway muscle activity, which helps
the term delayed is used to mean a later-than-usual onset of maintain upper airway patency, is also modulated by a circa-
sleep. If normal onset of sleep is 10 p.m., then a delayed onset dian rhythm [38, 39]. Prescribing a sleep schedule and pos-
may mean an 11 p.m. or later sleep onset. The term advanced sibly promoting daytime napping may be involved in
suggests the opposite and is used to mean an earlier-than-­ managing sleep apnea as it pertains to breathing stability
usual onset of sleep. This is important when evaluating thera- [37]. Addressing excess body weight and inflammation are
peutics and methods that shift the circadian pattern and is key nutritional interventions to support individuals with
relevant in CRSD nomenclature. sleep apnea [40, 41].
Delayed Sleep Phase Syndrome (DSPS) is thought to
be the most common and similarly most understood
CRSD. Typically, the delay is 3–6 hours. These clients are often 34.6  Treatment for Circadian Rhythm Sleep
awake until 2–6 a.m. and wake up between 10 a.m. and 1 p.m. Disorders
or at least would if allowed. When a conventional wake time
in those with DSPS is enforced, they often suffer from sleep 34.6.1  Light, Melatonin, and Vitamin B12
deprivation [19]. Prevalence of DSPS in those with chronic
insomnia is 5–10% but only 0.13–0.17% of the general popula- Treatments are limited for circadian rhythm sleep disorders
tion [20–22]. Polymorphisms in circadian rhythm genes, such because of a lack of ability to assess circadian function in a
as Human Per3 (hPer3), arylalkylamine N-­acetyltransferase, practical and meaningful way, and there are limited random-
HLA, and Clock, may play a role is DSPS [23–27]. ized controlled clinical trials, especially in regard to func-
Advanced Sleep Phase Syndrome (ASPS) can be clinically tional alterations. In various combinations of dosing and
overlooked as a CRSD. Individuals with ASPS wake up early timing, light, melatonin, and vitamin B12 routinely appear to
without much effort. Following their circadian pattern, they support circadian rhythm.
may choose sleep onset at 6–9 p.m. However, social pressures Melatonin is not corrective and cannot be relied upon as
may delay their preferred bedtime and cause chronic sleep a sole tool in the management of DSPS as treatment shows a
deprivation. Advancement in the phase of sleep-wake cycle is wide variability among subjects [42–45]. Dosage trial and
commonly seen with aging [28]. Prevalence is thought to be error is often required over the course of several months. The
exceedingly rare [22]. Polymorphisms in circadian clock lowest effective dose is recommended.
gene hPer2 have been identified [29]. Vitamin B12 likely acts to enhance the entraining light
Non-24-Hour Sleep Pattern is a CRSD that is primarily signal to the circadian pacemaker (SCN). Whether methyl-
reported in blind individuals with no light perception. Delays cobalamin is the right form is debatable. Cyanocobalamin,
or advances may result since the SCN does not respond to hydroxocobalamin, and adenosylcobalamin may be con-
dark-light cycles. Up to 70% of blind individuals complain of verted to methylcobalamin. If a clinician is tracking homo-
chronic sleep disruption [30]. cysteine as a functional marker, methylcobalamin would
Irregular Sleep-Wake Pattern as a CRSD includes those have to be used in order to note treatment effectiveness
with poor sleep hygiene or those who voluntarily have irreg- . Table 34.1.
 
 582 C. B. Schuler and K. M. Hope

..      Table 34.1  Dosing light, melatonin, and vitamin B12 for disordered sleeping

Condition Light Melatonin Vitamin B12

Delayed sleep phase Early morning bright light (2500 lux) Moderate dose (3–6 mg) Dosed according to clinical
syndrome for 2 hours between 5 p.m. and 7 p.m. for need (1.5–4.5 mg methylco-
1 month followed by balamin)
moderate dose at 7:30 p.m. for
two additional months

Advanced sleep phase Early evening bright light (2500 lux) for Low dose (0.3–0.9) early
syndrome 2 hours morning

Non-24-­hour sleep pattern If sighted or blind with light percep- High dose (10 mg) before bed Dosed according to clinical
tion, bright light (2500 lux) for 2 hours for entrainment need (1.5–4.5 mg methylco-
Low dose (0.5 mg) at night balamin)

Irregular sleep-wake pattern Bright light (1200–10,000 lux) for Moderate–high dose
shift work disorder 3–6 hours during the night shift or (3–10 mg) at bedtime after
20 minutes per hour night shift for 2–6 days

Irregular sleep-wake pattern Avoid bright light in the morning; get Moderate dose (2–5 mg) at
jet lag (eastbound) as much as possible in the afternoon bedtime

Irregular sleep-wake pattern Stay awake while it is daylight at the

jet lag (westbound) destination; sleep when it gets dark

Irregular sleep-wake pattern Early morning bright light (2500 lux) Low–high dose (0.3–10 mg) Dosed according to clinical
34 (other) for 2 hours before bed need (1.5–4.5 mg methylco-
balamin)

Sleep apnea Need determined by chronotype Moderate dose (2–5 mg) at

bedtime

Some nutritional interventions may be applicable to vir- 34.7  Nutrition and the Circadian System
tually all aberrant circadian patterns. Assessment for the
applicability in individual patients of these interventions The circadian clock directs when we are active, when we
may provide a useful clinical roadmap. Inflammatory signals sleep, and, to a great extent, when we eat. This system main-
have profound effects on circadian clocks. Essential fatty tains the rhythm in the endocrine and metabolic pathways
acid balance and natural substances that target NF-KappaB required for our body’s homeostasis. A wide range of meta-
and AMPK (5′ adenosine monophosphate-activated protein bolic pathways are controlled by the clock system, whose
kinase) can be considered [46, 47]. As examples, omega-3 daily fluctuations are affected by the food we ingest [54].
fatty acids such as eicosapentaenoic and docosahexaenoic Today’s modern lifestyle, which includes artificial lighting
acids (EPA and DHA), turmeric, and berberine, respectively, and ready-made, easy-to-access snacks, may place an evolu-
can be considered. Red blood cell fatty acid analysis, clini- tionary stress on our bodies that can impact our diet and
cally actionable markers of inflammation including health. The complex circadian system optimizes behavior
C-­reactive protein and erythrocyte sedimentation rate and physiology according to the time of day and is organized
(ESR), and blood sugar dysregulation markers such as with a central clock in the SCN primarily entrained by light.
hemoglobin A1c, fasting glucose, and fasting insulin can be Patients are commonly exposed to less light during the day
used to identify these opportunities for intervention. and more light at night because of artificial lighting. This fur-
Supplements of and foods rich in magnesium and the other ther impairs the circadian system and disrupts sleep.
B vitamins beyond B12 can be included in the management Disturbed sleep thus results in widespread deleterious effects
of individuals with circadian rhythm sleep disorders [48, on metabolic health. As an example, sleep disruption pro-
49]. The type and dose of each require individualized clinical motes increased energy intake, reduced energy expenditure,
evaluation and a trial of therapy. Dietary management of cir- insulin resistance in some individuals, and an increased pro-
cadian rhythm disorders may include the inclusion of phyto- pensity to make less healthy food choices.
nutrients such as polyphenol- and flavonoid-rich vegetables The human biological clock can be disrupted or
and spices [50, 51]. Additionally, nutrition professionals adjusted, depending on environmental factors, including
must consider macronutrient choices that support glycemic not only the pattern of day and night, but the rhythmic
balance [52, 53]. intake of food [16].
Circadian Rhythm: Light-Dark Cycles
583 34
34.7.1  The Circadian Clock System Prepares according to the gut cycles. Thus, the circadian clock is an
the Body for Feeding integral player between food and the intestinal system.
The circadian clock also controls rhythms in the blood
The circadian clock system readies the body for daytime concentrations of many nutrients, for example, glucose and
feeding. Gastrointestinal motility and gastric emptying peak lipids [57]. Due to the clock-controlled regulation of the gas-
in the morning, and animal studies have shown that the clock trointestinal system, practitioners may want to consider the
regulates the action of bile acids and nutrient transporters timing of nutritional testing. There has been some interesting
which optimize digestion [17]. In addition, the gut microbi- research with rodent models and the timing of food intake
ota exhibit daily circadian oscillations, which are time-of-day and allergies. It was shown that exposure to food antigens
specific in order to perform certain functions. The intestinal during the resting phase produced more severe food allergy
cells have a circadian clock that scientists are now investigat- symptoms [58].
ing in order to discover its physiological pathway. The gut The circadian system regulates energy storage in the
clock reacts to the rhythmic intake of food, and it has been body’s tissues. To a large extent, appetite is clock-controlled.
shown that the microbiota participate in food processing and There is a bimodal daily peak of insulin within the active
react with the intestinal clock [16]. Energy metabolism is phase, and diet-induced thermogenesis is rhythmically regu-
enhanced by the gut microbes during the active phase, while lated and peaks in the morning. Hunger is typically lower in
detoxification occurs more often in the resting phase [17, 55]. the morning and higher at night. This may be of importance
There is a complex connection between the circadian rhythm when discussing obesity, since delayed bedtimes allow more
and the microbiome, and a disruption in the clock system time for food consumption when the appetite is higher. Some
can have a disorganizing effect on the gut microbes [56]. This suggest that consuming a greater percentage of food in the
information lends itself to recommendations of avoiding morning may encourage a negative energy balance and a
high-fat meals in the evening and also ensuring micronutrient-­ decrease in body mass [17, 59]. This works to the extent that
rich evening meals to support detoxification during rest a patient does, in fact, reduce portions in the evening rather
(. Fig. 34.2).
 
than simply consuming more in the morning and allowing
The intestinal cells have a circadian clock that research is natural appetite and satiety to control excess eating at night.
showing is connected to the central clock in the SCN. The gut Encouraging self-awareness of a satiety index may be a cen-
clock responds to the rhythmic intake of food, and it has tral principle in medical nutrition therapy when these tools
been demonstrated that the microbiota participate in food are used.
processing and react to the intestinal clock. The action is
bidirectional, in that the gut clock needs the microbiota to
function correctly, and the gut bacterial levels fluctuate 34.7.2  Coupling Between Metabolism
and Clocks

Central circadian clock Food intake The light-dark cycle entrains the central clock in the SCN
and governs activity-related rhythms such as the sleep-wake
cycle, core body temperature, the autonomic nervous system,
and melatonin production, whereas the peripheral clocks,
present in most tissues including the brain, are entrained by
the feeding and fasting cycles. The peripheral clocks oversee
local physiological processes such as glucose and lipid levels,
hormone secretion, digestive functions, and the immune
Daily oscillation in microbiota response [14, 60].
Recent studies have shown that the peripheral circadian
oscillations respond differently to dietary cues than those of
the SCN and that an irregular feeding schedule can cause a
decoupling between the SCN and the peripheral system. A
desynchronization or decoupling among the clocks is thought
Gut microbiota to result in the development of cancer, metabolic, and psy-
chiatric disorders [14].

Gut epithelium
34.7.3  Eating Patterns: The Feeding/Fasting
Cycle
Gut circadian clock

..      Fig. 34.2  The connection between the microbiota and the gut
The circadian system primes organisms to feed at specific
circadian clock. (Reprinted from Asher and Sassone-Corsi [16]. With times, and if feeding occurs outside the normal boundaries,
Elsevier) negative health consequences may result [17, 61]. Studies in
 584 C. B. Schuler and K. M. Hope

both humans and animals suggest that the timing of meals independent of lighting conditions. For the most part, the
may be related to diabetes, obesity, and impaired cognitive SCN clock is controlled by the light-dark cycle, whereas the
function via the peripheral clock network and metabolism peripheral clock rhythms are affected by feeding cycles.
[17, 61]. In humans, skipping meals, especially breakfast, has Time-of-day restricted feeding (TRF), where food availabil-
been shown to be associated with obesity and other meta- ity is restricted to a smaller window during the day, has been
bolic issues. On the flip side, eating later at night can disrupt shown to entrain the circadian rhythm in peripheral tissues
the rhythm of meal timing and sleep onset and has also been without disrupting the clock rhythm of the SCN [62, 65]. The
associated with weight gain. Though conclusive data is some- effect of restricted feeding is not the same as caloric restric-
what limited, there have been many studies on the effects of tion, which can affect the phase of circadian rhythms in the
the fasting/feeding cycle on the circadian rhythm. Rodent central pacemaker [5].
studies show that fasting during the early “activity” phase A number of studies show the beneficial effects of restrict-
(which for them is nighttime, since rodents are nocturnal) ing food intake to a discrete window of time within the daily
results in an increase in both body weight and hepatic lipid active cycle (daylight for humans). There have been several
deposition. This early nocturnal fasting disrupts the periph- human epidemiological studies that exhibited a correlation
eral clock system and results in de novo lipid synthesis and a between eating pattern and obesity. When food is restricted
tendency toward obesity. This is akin to skipping breakfast in to a smaller time frame within the active period, increase in
humans [62]. glucose tolerance, reduction in insulin resistance, and
There have been a number of studies that show the decrease in serum lipid levels have been shown. This has
importance of eating a meal upon the beginning of the active implications for reducing the risk of developing obesity
phase to prevent obesity. Thus, one could make an argument [16, 66] (. Fig. 34.3).
 

for eating on a regular schedule, during the normal “active There is a wide body of evidence that shows that when
phase” (or light phase for humans) for proper peripheral food is restricted to a discrete window of time within the
34 clock management and optimal health [62]. Human studies daily cycle, various metabolic processes are improved. When
have compared isocaloric weight-loss groups and have found food is restricted to a smaller time frame within the active
there was a greater improvement in metabolic markers in the period, an increase in glucose tolerance, a reduction in insu-
group given the larger breakfast and a smaller dinner, rather lin resistance, and a decrease in serum lipid levels have been
than vice versa. Other studies have found a correlation shown. This has implications for reducing the risk of devel-
between earlier meal times and a decrease in serum lipid lev- oping obesity.
els. Evidence also shows that the consumption of breakfast In a study of overweight and obese women, those who
among adolescents is inversely associated with weight gain consumed a larger percentage of daily calories earlier in the
[63]. In addition, time-delayed eating, as in nighttime eating, day lost more weight than those eating later in the day [67].
is positively associated with an elevated body mass index These findings are consistent with others that show that ear-
(BMI) [14, 16]. In studies of both rats and humans, it was lier lunch consumption is associated with greater weight loss
found that there was an affinity toward higher fat foods in the after 20 weeks [17].
evening compared to morning. Though studies are not con- Restricting the delivery of nutrients in a rhythmic fashion
clusive, this preference may indicate an association between may help to reset the peripheral clocks, which could poten-
late-night feeding and obesity [16]. tially have a positive impact on the immune system. Some

34.8  Time-of-Day Restricted Feeding

The eating pattern of humans in modern societies typically

consists of three meals and a few snacks every day. This is Circadian time
abnormal from an evolutionary perspective, where research 0 4 8 12 16 20 24
shows hunter-gatherers eating intermittently. The body
Discrete windows of food availability
evolved to take up and store glucose (liver glycogen stores)
and longer-lasting energy substrates, such as fatty acids in
adipose tissue, and was designed for a diurnal rhythm of
activity/rest and feeding/fasting. Modern lifestyle, with arti-
ficial light and erratic eating patterns, can upset our ­biological Time-restricted feeding
circadian system [64].
The timing of meals seems to be a significant zeitgeber for
Beneficial metabolic effects
the oscillations in the peripheral clocks and could be seen as
Reduced insulin resistance
an important factor in regulating metabolism. Though the Increased glucose tolerance
mechanisms by which an irregular feeding time affects the
metabolism are not completely known, the evidence suggests ..      Fig. 34.3  The benefits of time-of-day restricted feeding (TRF).
that differential meal timing may alter the circadian cycle (Reprinted from Asher and Sassone-Corsi [16]. With Elsevier)
Circadian Rhythm: Light-Dark Cycles
585 34
emerging research with both human and animal models achieved without the deleterious effects if the fasting window
shows improved health with intermittent energy restriction began in the early evening and breakfast was consumed on a
of as little as 16 hours (an 8-hour eating window). Here there regular basis.
is a shift to fat metabolism and ketone production, which can
stimulate adaptive cellular stress response and repair molec-
ular damage [64]. Circadian dysregulation can induce 34.9  Circadian Clock Genes
adverse health effects as well as hamper recovery. When deal-
ing with ill patients in the ICU or those who are on enteral Within the neurons of the SCN, there are a number of genes
feeding, restoring their day-night cycle might help realign that are activated or inhibited in a regular pattern over the
their biological rhythms during the recovery phase to course of a day. The fluctuations act as molecular gears of the
improve outcomes [2]. biological clock which regulates the 24-hour  cycle. These
Practitioners who develop nutritional plans for clients molecular oscillations work in a negative feedback fashion,
should not ignore the impact of the circadian rhythm on whereby the protein product of a gene turns off production of
nutrition and health. The timing of meals has shown to affect more protein.
body weight and the risk of obesity in humans [14, 68, 69]. At the core of the molecular network are transcription
Though not conclusive, it appears late meals and skipping factors that drive expression and regulate the biological func-
breakfast encourage a gain in body weight and propensity tion of the master circadian genes, CLOCK and BMAL1. The
toward obesity. Eating a larger breakfast and a smaller dinner transcription of a large number of clock-controlled genes
may lead to better markers for fasting glucose, insulin, ghre- also directs the transcription of their own repressors, period
lin, as well as improved mean hunger and satiety scores [14, (PER) and cryptochrome (CRY), which create a self-­regulated
67]. Early mealtimes are also shown to reduce triglycerides feedback loop. During daytime, the per and cry genes create
and LDL levels in serum [65]. In addition, restricting the the PER and CRY repressors, which accumulate over the day.
consumption of food to a smaller window during the active This eventually inhibits the CLOCK-BMAL1-driven tran-
period may be beneficial to health [64]. scription of per and cry. Then the degradation of PER and
Intermittent fasting (IF) is popular in the health and fit- CRY allows the CLOCK-BMAL1 transcription to proceed
ness field today. Practitioners often recommend a 12- to once again. This creates the cycling in the circadian gene
16-hour fast, and many studies show a positive effect on expression [16, 75]. Additional clock genes or clock-­
weight loss [70–72]. However, breakfast is the meal most controlled genes, such as Rev-erb∝/ß, Ror∝/ß, Dpb, Dec1/2,
often skipped. Though positive weight loss may occur when CK1ε/δ, and NPAS2, also work to sustain mammalian circa-
breakfast is removed, evidence indicates that for overall dian clocks [14] (. Fig. 34.4).
 

health and weight management, it is better to eat breakfast CLOCK and BMAL1 are transcriptional activators that
[63, 73]. This is keeping with the idea that it is more advanta- dimerize to stimulate the expression of many clock-­controlled
geous to consume one’s daily calories within the active (day- genes (CCGs) with E-box promoter elements in their pro-
light) cycle [16]. Recent evidence demonstrates that when moters. CLOCK:BMAL1 also stimulate the expression of the
the first meal of the day is missed, neuroendocrine parame- Period (Per) and Cryptochromes (Cry) gene families. PER
ters may be negatively affected. In one study, levels of testos- and CRY protein levels become elevated during the night.
terone and IGF-1 were shown to be reduced, as was leptin They dimerize and translocate to the nucleus to repress
[74]. Another study in men found that omitting breakfast led CLOCK:BMAL1-mediated transcription. PERs and CRYs
to an increased risk of type 2 diabetes [73]. It is worth specu- undergo a number of posttranslational modifications that
lating if perhaps the benefits of intermittent fasting could be cause their degradation, which then allows them to start a

..      Fig. 34.4  The molecular Day Night

organization of the circadian CRY
clock. (Reprinted from Asher and P
PER
Sassone-Corsi [16]. With Elsevier)

Per
CLOCK BMAL1 Cry CLOCK BMAL1
E-box Rev-erb E-box
CCGs
REV-
ERB Bmal1
RRE RRE
Ub
CRY
Ub
PER
 586 C. B. Schuler and K. M. Hope

new circadian cycle. Another loop involves the proteins beyond these conditions, such as preventing morbidity and
REV-ERBa/b, whose levels increase during the day and bind reducing mortality in relation to other pathologies such as
to specific responsive promoter elements (RRE), inhibiting aging [16].
Bmal1 transcription. At night, REV-ERBa protein levels There is a daily cyclic control over glucose metabolism
decrease, allowing Bmal1 transcription to take place. These [64, 79]. Glucose tolerance and the action of insulin vary
regulatory loops operate in most cells and control a large per- throughout the day. Glucose tolerance is reduced in the eve-
centage of the human genome. ning, as opposed to the morning hours, because insulin
Disruption in the feeding/fasting cycle can impact the cir- secretion is lower, and insulin sensitivity is diminished dur-
cadian clock genes. In mice, early nocturnal fasting (which ing the nighttime. Glucose levels peak right before the “active
correlates with skipping breakfast in humans) alters lipid period” or daytime hours [64]. Insulin sensitivity has a
metabolism and the peripheral clocks. It increases caloric bimodal peak during the daytime phase, and appetite is actu-
intake and alters lipogenesis at the levels of transcriptional and ally lowest in the morning [17, 59, 79]. Thermogenesis also
metabolic cycling, changing the expression of clock genes has a circadian rhythm that is induced by the diet and peaks
such as CLOCK, BMAL1, Cry1, and Per2 [62]. Single nucleo- in the morning. Nutrition professionals may want to recom-
tide polymorphisms (SNPs) in CLOCK have been associated mend a larger percentage of dietary energy during the early
with non-alcoholic steatohepatitis, metabolic syndrome, small hours of the active phase. This will encourage a negative
dense low-density lipoprotein levels, obesity, and diabetes. energy balance, which is the principle determining factor of
One of the most studied associations is that of obesity. So far, reducing body mass [17, 80].
eight common CLOCK SNPs have been associated with obe- Poor-quality sleep and reduced sleep duration are linked
sity, and three of them are linked with energy intakes [17, 76]. with impairment of glucose tolerance, along with reduced
Disruption of the molecular clock can produce metabolic insulin response following a glucose challenge. Studies with
disturbances, a fact which is supported by some observa- shift workers have revealed that, with a disruption in the
34 tional studies [7, 9, 57]. Nutritional interventions, such as light-dark cycle, the risks of metabolic dysfunction, cardio-
caloric restriction, may hold promise in mediating some vascular disease, stroke, obesity, and cancer all increase.
beneficial effects [17]. Rodent models suggest that a calorie-­ Evidence also shows a rise in BMI when there is a discrep-
restricted diet reprograms the circadian clocks both tran- ancy between the natural circadian clock and one’s social
scriptionally and posttranscriptionally. It appears that the clock. In a compelling clinical study, volunteers were put on a
transcription factor BMAL1 is important for the reprogram- cycle that was shifted 12 hours from their normal sleep-wake
ming of the clock [77]. cycle. The subjects exhibited increased glucose, decreased
Further study of clock genes and their alterations will leptin, and elevated blood pressure. Their postprandial glu-
expand our knowledge of the molecular workings of the cir- cose response was similar to a prediabetic patient [64, 79].
cadian clock that could lead to potential therapies for treating In mouse studies, feeding at the incorrect time in the
metabolic, sleep, and neuropsychiatric disorders. Of particu- light-dark cycle can elevate the obesogenic effects of a high-­
lar interest is identifying the at-risk CLOCK genotypes, who calorie diet, due to the desynchronization of the hormonal
may be more susceptible to overeating and gaining weight and molecular rhythms in maintaining energy balance [64,
when they experience shorter sleep time [76]. 81]. While feeding a high-fat diet during the rest phase leads
to weight gain, restricting feeding to the active phase leads to
an improvement in obesity and metabolic disorders.
34.10  Pathophysiology Mechanisms Directing therapy toward weight loss in obese and over-
and Relevance to Chronic Disease Risk weight patients may improve sleep, such as is the case with
sleep apnea [40]. The potential positive effects of normalizing
34.10.1  Metabolism and Obesity body composition include improved glucose tolerance, nor-
malized lipid markers and reduced blood pressure, reduced
A large body of evidence shows that cellular metabolism is inflammation, and reduced stress to the circadian system.
intimately interconnected with the circadian clock [16, 64, Obesity and related metabolic sequelae, including cardiovas-
78]. Some say it may be due to an evolutionary advantage cular disease, accelerated aging, diabetes, cancer, and neuro-
that separates the anabolic and catabolic reactions of the degenerative diseases, are conditions of increased oxidative
body during different times of the day, such as gluconeogen- stress. It has been proposed that oxidative stress and circa-
esis and glycolysis. This way, the metabolic cycles are aligned dian rhythm be supported simultaneously when one or both
to the sleep-wake cycle. The circadian clock mechanism clinical challenges are identified [82].
influences homeostasis over a wide range of processes includ-
ing glucose and lipid metabolism, body temperature, endo-
crine hormone secretion, and cardiovascular health [64]. 34.10.2  Cancer
Numerous studies have focused on the connection
between the scheduling of meals and such pathologies as In human and rodent studies, abnormal circadian rhythms
obesity and diabetes [60, 62, 63]. It can be conjectured that have been associated with a greater risk of both the develop-
“optimal” feeding schedules may also provide health benefits ment and progression of cancer. A disruption in the light-­
Circadian Rhythm: Light-Dark Cycles
587 34
dark cycle can result in poorer outcomes for cancer patients. secretion of melatonin may be a key to the development of
Faster tumor growth and shorter survival times are seen when type 2 diabetes [84, 90].
the rhythm is unbalanced. Shift work, with the attendant dis- In humans, a study demonstrated that two SNPs in the
ruption of the natural circadian rhythm, is a significant and clock gene, BMAL1, led to a greater risk of gestational diabe-
independent risk factor for the development of a variety of tes mellitus in women. Other recent work has illustrated a
cancers. Studies in women with breast cancer show that those role for Cry1 and Cry2 in diabetes. In addition, there is ongo-
whose cortisol rhythms were off due to circadian disruption ing research exploring the use of Cry1/2 agonists to treat the
had a poorer survival rate [7]. It is believed that the prolonged disease. Continued exploration into the physiological signifi-
disturbance of the circadian clock system may lead not only cance of the gene interactions may lead to therapies that suc-
to cancers of the breast and prostate but to other types of can- cessfully target the circadian clock for the treatment of
cers, such as ovarian, kidney, brain, colorectal, lung, head and diabetes and other metabolic disorders [84].
neck, pancreatic, and hematological cancers [9].
Interventions that target the circadian timing system hold
promise for potential therapies that may help improve the 34.10.4  Cardiovascular Issues
quality of life and survival in cancer patients [9]. In addition,
the altered expression of various clock genes may be an Sleeping for less than 7 hours per night is associated with a
important mechanism contributing to the progression of higher risk of cardiovascular disease and poor cardiovascular
cancer and is an area of further research interest. Practitioners health outcomes, such as hypertension, hypercholesterolemia,
can work with their cancer patients to regulate the timing of myocardial infarction, and cerebrovascular events [83]. Several
meals in concert with the natural circadian rhythm. An orga- studies in both rodents and humans have shown the impor-
nized feeding routine within the normal rhythm of the light- tance of the circadian clock in cardiovascular disease, due to
dark cycle will help maintain homeostasis, which may lead to different cardiovascular phenotypes associated with circadian
more favorable outcomes. disruption or desynchronization [84, 91–93]. The desynchro-
nizing of the clock system is often caused by rotating shift work
or chronic jet lag [84]. There is mounting evidence that shows
34.10.3  Diabetes the importance of maintaining healthy circadian function for
cardiovascular health. An area of active investigation is the
Evidence is accumulating that inadequate sleep may be a risk regulation of blood pressure. Circadian clock proteins regulate
factor for type 2 diabetes. Short duration of stage 3 and 4 the “dipping” of blood pressure at night (by about 10%) and its
NREM (non-rapid eye movement) sleep has been shown to rise in the morning. The mechanism is unknown, but many
increase insulin resistance. In clinical studies, decreased glu- people with hypertension, type 2 diabetes, and chronic kidney
cose tolerance was observed in adults after several nights of disease do not experience this effect. It is likely that a combina-
sleeping only 4–5  hours per night. These preliminary find- tion of sympathetic nervous system activity, hormone signal-
ings indicate that there may be a relationship between the ing, nitric oxide, and sodium reabsorption together contributes
time spent in slow-wave, deep sleep, and the circadian to the circadian control of blood pressure [84].
rhythm of glucose metabolism [83]. As with blood pressure, heart rate decreases at night and
Studies involving circadian clock genes suggest a role for rises during the day. The exact mechanism for the circadian
the clock proteins in diabetes. In animal models, circadian control of the heart rate is not yet fully understood, but per-
desynchronization results in a faster onset of type 1 diabetes. oxisome proliferator-activated receptor-gamma has been
In this case, the overexpression of human islet amyloid poly- suggested, by way of an unknown pathway involving
peptide leads to pancreatic beta-cell failure. Other rodent BMAL1 in the endothelium. It has been demonstrated that
studies show that when the SCN is ablated, the circadian the circadian clock controls numerous intracellular calcium
rhythm of glucose uptake is lost, leading to hepatic insulin channels that are important for heart rate regulation.
resistance [84–86]. Myocardial repolarization also appears to be controlled by
Other investigations show that constant light exposure circadian rhythm [84].
disrupts the circadian rhythmicity, resulting in insulin resis- The incidence of heart attack and stroke peaks in the
tance [84, 87]. Melatonin is regulated by the light-dark cycle, morning, attributing to the rise in blood pressure and heart
and evidence for its role in diabetes comes from research that rate occurring at that time. Human studies show that infarct
identified a SNP near the melatonin receptor 1B gene. This size and myocardial injury both display circadian oscilla-
gene encodes the melatonin 2 receptor, which is linked with tions, with the highest damage early in the day [84]. Cardiac
increased fasting glucose and a greater incidence of type 2 remodeling occurs during sleep, and a desynchronization
diabetes in white Europeans and Asians [84, 88, 89]. leads to an increased risk of cardiovascular events. Studies
Melatonin is secreted in a diurnal fashion and influences with shift workers who have rotating schedules show an
insulin secretion. The circadian secretion of insulin from the increased risk for cardiac issues [94–98]. Those who suffer
pancreas is also clock-driven. Evidence suggests a connec- from chronic jet lag may have similar risks due to desynchro-
tion between melatonin and the control of glucose-stimu- nization. Therefore, it is important to maintain a healthy cir-
lated insulin secretion. The dysregulation of the circadian cadian rhythm for cardiovascular health [84].
 588 C. B. Schuler and K. M. Hope

34.10.5  Renal Function 34.10.7  Immune System

Many processes in the kidney follow a circadian rhythm The circadian system is an important component of the
including renal blood flow, glomerular filtration rate, as well hypothalamic-immune communication. Disruption of this
as potassium and sodium excretion. The clock gene, Per1, is rhythmic process has been linked to immune dysregulation,
involved with the epithelial sodium channel (ENaC) in the and studies show that the circadian clock genes are involved
renal collecting duct, which is a key mediator of sodium in the immune response. Interactions between the HPA axis
reabsorption and blood volume control by the kidney. Per1 and the circadian clock system are seen in the regulation of
also regulates multiple genes involved in sodium reabsorp- immune function. The circadian oscillation of numerous
tion [99]. In one human study, it was found that Per1 was cytokines has been observed in humans, including interleu-
upregulated 1.7-fold in the renal medulla of kidneys in kin-­1 beta (IL-1beta), IL-6, interferon (IFN)-gamma, and
patients with hypertension, compared with normotensive TNF-alpha in T- and B-lymphocytes and natural killer cells.
controls [100]. Thus, it is suggested that Per1 may play a role In animal models, those with clock gene mutations display
in blood pressure control in humans. dysfunctional immune systems, including disrupted circa-
dian rhythm in leukocytes and cytokine production, altered
response to lipopolysaccharide (LPS)-induced endotoxic
34.10.6  Endocrine System shock, and the defective development of B-lymphocytes
[101]. Activation of the HPA axis and the resulting release of
The circadian clock is a key regulator of the endocrine sys- glucocorticoids strongly influence immune activity and the
tem, and conversely, the endocrine system plays a role in the inflammatory response [101].
synchronization and regulation of the peripheral circadian Sleep deprivation can evoke an acute stress response within
clocks. A mutual physiologic interaction between the circa- an organism, and sleep loss can be a risk factor for impaired
34 dian clock system and the hypothalamic-pituitary-adrenal immune function. A number of studies have indicated that
axis (HPA axis) is orchestrated by the Clock/Bmal1 tran- under normal sleep-wake and lighting conditions, circulating
scription factors, along with the glucocorticoids and gluco- blood cell populations follow a diurnal rhythm. If sleep-
corticoid receptors. This serves to manage the adaptations deprived, however, granulocyte levels and their rhythmicity
not only to the day-night cycles but to the variety of stress are disrupted, and these changes reflect the body’s immediate
stimuli the body is exposed to on a daily basis. The circadian immune response when exposed to a stressor [105]. In a
clock system and the body’s stress response system are both rodent model of chronic jet lag, research demonstrated that
crucial for survival, and they communicate with each other natural killer cell activity is compromised [84, 106].
on many levels to constantly adjust the various physiological
activities. Dysregulation in either system may lead to similar
pathologies [101]. 34.10.8  Reproductive System
The glucocorticoids, steroid hormones produced in the
adrenal glands, are involved in reducing inflammation, and Recent studies have added to the knowledge of molecular
they play a part in stress response, metabolism, and the func- circadian rhythm activity in the reproductive system. Most of
tion of the neurological and cardiovascular systems. the work has explored the role of the central clock system in
Glucocorticoids are thought to synchronize the circadian the female reproductive cycle; however, newer work has also
clock, as studies demonstrate that they can entrain the revealed the existence of a testicular clock [84]. Daily and
peripheral circadian oscillators [102]. Glucocorticoid levels seasonal environmental signals impact fertility through the
are tightly regulated, and they express a daily rhythm, with clock system, as it coordinates the various processes involved
their highest levels occurring in the early morning and their in sex hormone production, ovulation, spermatogenesis,
lowest in the late evening (in diurnal animals). The SCN, mating, embryo development, and childbirth [107, 108].
under the control of daily light input, regulates the rhythmic In females, the reproductive clock is involved in the neu-
secretion of glucocorticoids from the adrenal glands by influ- rons that express gonadotropin-releasing peptide hormone
encing the activity of the HPA axis. The glucocorticoids, in (GnRH). GnRH is responsible for releasing follicle-­
turn, phase-­delay the peripheral clocks via the clock genes. stimulating hormone and luteinizing hormone from the
This process is important for the body’s adaptation and anterior pituitary gland. GnRH displays a circadian pattern.
response to stress. A regulatory feedback loop is enacted by The central SCN clock appears to have control over the
the peripheral clocks through the interaction of Clock/Bmal1 peripheral ovarian clock. Animal models show the oscilla-
and the glucocorticoid receptors of the central clock on the tion of clock genes in the ovaries, and those with mutations
HPA axis [101]. in BMAL1 and CLOCK show decreased fertility. It is inter-
Numerous in vitro studies show that synthetic glucocorti- esting to note that the existence of the circadian clock in the
coids can synchronize cell cultures via the circadian gene placenta has been found; however, the significance remains
expression. In animal models, the administration of hydro- to be seen [84].
cortisone synchronized circadian gene expression in the lung, Circadian clock gene expression has been discovered in
pineal gland, salivary gland, cornea, and liver [102–104]. the male reproductive system, and it is demonstrated that the
Circadian Rhythm: Light-Dark Cycles
589 34
proteins CLOCK and BMAL1 are involved in the develop- greater desire and consumption of palatable food through the
ment and physiology of the chromatoid body in the male endocannabinoid receptor system [118]. Though the study of
germ cells, which are crucial to spermatogenesis [107]. In incorporating sleep hygiene into weight loss programs is in
rodent studies, BMAL1 was shown to be necessary for fertil- its infancy, research has demonstrated better weight manage-
ity and proper testosterone production. Other animal models ment when a sleep component is added [119–121]. This may
show that clock gene mutations influence reproductive func- provide some insight to nutritionists and health professionals
tion [107, 109, 110]. who are helping patients with weight issues [83].
There is growing consideration that keeping in tune with
the body’s natural circadian rhythm is advantageous for
34.10.9  Sleep Hygiene health. Developing a regular daily routine that includes opti-
mal meal timing, exercise, and sleep habits may contribute to
The concept of proper sleep hygiene is currently attracting a proper weight management and ward off chronic disease.
good deal of attention in the health field. Many professionals
recommend consistent daily rituals, including an ideal bed-
time environment that pays attention to all the senses. 34.11  Toxin-Related Influences
Human circadian rhythms were entrained by the light-­
dark pattern of the solar day. Since the development of elec- Caffeine, while the most common drug used to combat day-
tric lights, exposure to nighttime lighting makes it more time sleepiness, disrupts circadian rhythm. In fact, caffeine
difficult for the body to synchronize biological processes can shift sleep onset forward by as much as 45–60 minutes
[111]. The natural effect of darkness on the initiation and even when consumed 6 hours prior to a scheduled sleep time.
maintenance of sleep may be disrupted by the bright lights Later consumption can have even more profound effects on
from modern media displays, such as phones, tablets, televi- sleep time [122]. Those with circadian pattern concerns
sions, and computers. Both bright lights and stimulating con- should be counseled to reduce or eliminate caffeine or, at
tent curb the natural decrease in body temperature and heart minimum, limit use to only early in the day. While medi-
rate, thereby affecting the inclination to sleep. Research cal and nutrition professionals may take this information for
shows exposure to bright light at night can decrease melato- granted, consumption statistics suggest that patients are using
nin production and circumvent the physiologic sleep pro- caffeine at all times of the day. A population-based study of
cesses [83]. Lowering lights at night, turning off displays, and adults estimated that 90% of individuals consume caffeine in
sleeping in a darkened room can encourage the natural sleep the afternoon between noon and 6 p.m. and 68.5% of people
cycle [83]. consume caffeine in the evening between 6  p.m. and mid-
The brain processes sounds even while the body sleeps. night [123]. Forward shifts of sleep time and artificial waking
Some sounds can be disruptive, but some may be soothing times can further lead to reliance upon caffeine. The effects
and may help induce sleep [83]. Earplugs can help protect of caffeine are quickly adapted to thus further increasing the
from disruptive noise, while on the other hand, a sound dose required for a cognitive benefit [124, 125].
machine producing soothing nature sounds like a waterfall Of particular interest in circadian patterns is the influ-
may help some people fall asleep more quickly [112]. ence of heavy metals, such as cadmium. Cadmium changes
Aromatherapy offers a safe, cost-effective intervention the expression of various circadian rhythm-related genes,
that can aid in decreasing some of the negative impacts of including Bmal1, Per1, Per2, Cry1, and Cry2, and disrupts
lack of sleep. Natural essential oils that contain sedative or virtually every hormone secreted by the pituitary gland in
hypnotic properties are encouraging as a sleep therapy. animal models, even at low doses via drinking water.
Numerous studies, including some randomized controlled Melatonin has been shown to reduce these toxic effects
trials, have shown that essential oils, especially lavender, can including disruption of prolactin, luteinizing hormone, thy-
improve sleep issues [113–116]. Exercise is a healthy activ- roid stimulating hormone, and corticosterone [126].
ity that can reduce the risk of cardiovascular disease and Melatonin’s protective effect may be derived from supple-
other chronic issues. The National Sleep Foundation states mental use or from endogenous production. However, if
that exercise is a non-pharmacological intervention that can endogenous melatonin is shunted toward cadmium amelio-
improve the quality of sleep. However, the timing of exercise ration, less is available for other functions, in particular its
may affect sleep quality. Studies have shown that moderate key role in circadian control. Melatonin serves as a suicidal
aerobic exercise in the morning, as opposed to later in the antioxidant and is not recycled by additional antioxidants as
evening, results in longer periods of deep sleep and shorter is the case with vitamins C and E, coenzyme Q10, and others.
sleep-onset latency. In addition, morning exercise is demon-
strated to optimize blood pressure changes that lead to an
improvement in sleep architecture [117]. Information is lack- 34.12  Key Lifestyle Influences
ing regarding the timing of meals and sleep quality, except
that, as discussed in an earlier section, later bedtimes result Alcohol affects circadian patterns with both acute and
in an increased food intake during the late-night hours. chronic use [127]. Ethanol impairs sleep, and sleep problems
Current studies are finding that sleep restriction may lead to often contribute to relapse drinking [128–132]. In one study,
 590 C. B. Schuler and K. M. Hope

healthy subjects who consumed a significant amount of alco- of clock gene SNPs in response to diet. Knowledge of gene
hol over the course of a day did not see changes in cortisol variants in the circadian clock system may help practitioners
levels but did see increases in testosterone [133]. In a similar design successful personalized nutrition [17].
binge replication study, alcohol dramatically decreased noc-
turnal thyroid stimulating hormone (TSH) secretion [134].
If cessation is suggested, a significant time period of 34.14  Conclusion
1 week or more should be used to determine the effectiveness
of cessation on circadian patterns since alcohol withdrawal Circadian rhythm disorders and disruptions in sleep habits
can have its own set of repercussions to diurnal chemical may be overlooked or dismissed in clinical practice. The evi-
secretion and its effects. Of particular interest is that when dence of detrimental effects on metabolic function and
alcoholics abstain from alcohol, a delay in the nocturnal rise dietary choices are accumulating. Emphasis on supporting
of melatonin occurs [135]. Thus, during cessation, supple- circadian system function and addressing sleep disruption
mental melatonin may support sleep and reduce the propen- may significantly enhance health and productivity for many
sity for relapse that often occurs as subjects rely on alcohol as individuals.
a sleep aid. In non-addicted individuals, alcohol also shows a Biochemical assessment of individuals who may have cir-
suppression of melatonin secretion in a dose-dependent cadian rhythm dysfunction includes evaluation of the HPA
manner [136]. axis via saliva or urinary parameters; inflammation markers
This is not the only place in the scientific literature where such as C-reactive protein (CRP) or erythrocyte sedimen-
melatonin and alcohol intersect. Of specific interests to nutri- tation rate (ESR); DHEA-S; glycemic handling markers,
tion professionals, melatonin may counteract some of the including hemoglobin A1c, fasting glucose, and insulin;
effects that alcohol has on duodenal paracellular permeabil- and B-vitamin status as estimated by homocysteine, meth-
ity [137]. Intestinal hyperpermeability, while not exclusively ylmalonic acid, and a complete blood count. Advanced bio-
34 related to circadian patterns, is implicated in a variety of chemical assessment may include heavy metal testing, such
chronic health conditions. Alcohol consumption appears to as a provoked urinary sample or urinary porphyrins, genetic
decrease endogenous daytime glutamate signaling to the analysis, and red blood cell fatty acids. Markers for gastro-
SCN, which may or may not be a clinically actionable mecha- intestinal microbiotic dysbiosis and antioxidant status may
nism [127]. Brain-derived neurotrophic factor (BDNF) can further inform treatment strategies and promote treatment
be increased via a Mediterranean-style diet [138], physical adherence.
activity [139], intermittent fasting [140], and caloric restric- Included in an interview in such a case should be the
tion [141, 142]. Per2 abnormalities may predispose individu- exploration of the regularity or irregularity of sleep and wake
als to alcohol dependence [143]. Of interest for preventative times, as well as sleep hygiene, including bedtime routine,
models of care, those with abnormal circadian patterns may light and sound exposures, electromagnetic frequency (EMF)
be good candidates for screening and preventative counsel- exposure [146, 147], coping mechanisms, and stress influ-
ing for alcohol or other drug use and abuse. ences, such as the Holmes and Rahe Personal Stress Inventory.
Nutrition professionals should fully investigate alcohol Dietary intake assessment should include timing of meals to
consumption patterns among those with known circadian determine the normal eating window. Clinical assessment
and/or sleep challenges and thyroid disorders. Those with may include stress, depression and anxiety screening ques-
gastrointestinal disorders may additionally benefit from such tionnaires, and sleep questionnaires such as the Pittsburgh
investigation. Some patients will benefit from abstinence Sleep Quality Index (PSQI).
even in the absence of addiction. Integrative physicians and nutrition professionals wish-
ing to optimize the circadian system may consider emphasiz-
ing eating upon arising, minimizing the eating window on a
34.13  Chronotypes and Personalized daily basis to 8–12 hours, cautioning against high-fat evening
Nutrition meals, prudent use of melatonin and vitamin B12 as needed,
and moderation or abstinence of alcohol and caffeine, espe-
With today’s interest in personalized nutrition, understand- cially in the last 6–8  hours before bed. Antioxidant- and
ing an individual’s chronotype may be helpful in developing mineral-rich foods should be promoted, and supplemental
a personal diet and lifestyle plan. A person is classified by use of bioavailable turmeric, berberine, and other botanicals
chronotype according to preference for when to sleep and may offer additional support given the outcomes of inflam-
when to be active. If laboratory investigations of an individu- matory and glycemic markers.
al’s internal time clock are not practical, a questionnaire may Increasing genetic and genomic screening may further
be used to estimate chronotype. These include the inform clinicians how aggressive these and other interven-
Morningness-­Eveningness Questionnaire and the Munich tions should be. Chrononutrition is still a promising yet
Chronotype Questionnaire Test [144, 145]. If a person’s chro- underdeveloped science and clinical practice. Best practices
notype influences physiological processes, then it may be are still evolving, and further intervention strategies await.
important to consider chronotype when developing a nutri- Satisfactory chronic disease care on the whole is an unmet
tional plan. Recent studies are beginning to explore the role medical need. While there are numerous contributing factors
Circadian Rhythm: Light-Dark Cycles
591 34
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 595 35

Nutrition with Movement
for Better Energy and Health
Peter Wilhelmsson

35.1 Background – 596

35.1.1 Integrating Nutrition and Movement – 596

35.2  hysiological Mechanisms Associated with Exercise

P
and Nutrition – 597
35.2.1  xygen Plays a Key Role – 597
O
35.2.2 Nutrients Play a Key Role – 600
35.2.3 MET: Powerful Prevention and Treatment of Chronic Disease – 602

35.3 MET and Nutrients for People with Various Conditions – 606

35.3.1  ommonalities Across Conditions – 606
C
35.3.2 Sarcopenia – 608

References – 610

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_35
 596 P. Wilhelmsson

»» Exercise is king. Nutrition is queen. Put them together The addition of consistent MET will complement and
and you’ve got a kingdom. –Jack LaLanne make other lifestyle habits or therapies more effective,
whether they are stress management, dietary habits, supple-
ment intake, or even use of pharmaceutical drugs. Our phys-
35.1  Background iology depends on movement for basic and optimal function.
Daily movement and exercise provide good circulation to
Inactivity and poor nutrition are major drivers of chronic facilitate normal physiological and biochemical functions.
disease risk, suffering, and early mortality. Physical inactivity People often underestimate the power of changing small
is the fourth-leading risk factor for global mortality (6% of habits, such as drinking a couple of glasses of water every
deaths), trailing only hypertension (13%), tobacco use (9%), morning, using public transportation, using a standing
and hyperglycemia (6%). Approximately 3.2 million annual workplace, eating a salad every day, taking a daily walk, or
deaths are linked to insufficient physical activity. In fact, just doing a little more daily stretching and activity. In the
inactivity is a greater mortality risk than being overweight or public health arena, larger populations making a few small,
obese (5% of global mortality). positive changes produce tremendous health effects, health-
In 2008, 31 percent of adults worldwide – slightly more care savings, and increased productivity. According to a
women than men – were considered inactive. In the American study in Australia, walking and moving for 35 minutes per
and European-Mediterranean populations, about half of the day has a positive effect on health and survival. The study
women and 40 percent of men were insufficiently active. showed people in the city of Melbourne alone had 272 fewer
Southeast Asia had the lowest percentages of inactive popula- deaths per year, 903 fewer cases of chronic disease and a sav-
tions, with men at 15 percent and women at 19 percent [1]. ings of $12.2 million when they used public transport instead
As will be highlighted in this chapter, most health condi- of taking a car [3]. This and other studies show how everyday
tions can be improved with movement and exercise training exercise and movement, even walking to the subway or to
(MET) or a combination of MET and other lifestyle medicine work every day, has a positive effect on health.
therapies. One challenge in the public health arena, preven-
tive medicine, and disease-oriented medicine is how to 35.1.1.1  Movement and Detoxification
35 inspire, educate, organize, and follow up on lifestyle medicine We are surrounded and affected by daily toxins. In the past
therapies. People will always look for quick fixes, but how do 80 years, we have been subjected to more than 100,000 new
we educate, inspire, and motivate them to establish and main- chemicals [4]. At least 62,000 of these chemicals have shown
tain lifestyle habits that promote health instead of disease? to be transported by our cell membranes and enter our cells.
Inactivity, poor food choices, alcohol abuse, smoking, and Most of these are toxic to our cells and mitochondria, and
poor stress management are commonly listed as drivers of they can affect and disturb our hormones. These chemicals
chronic disease. The functional medicine model adds environ- are everywhere, in air, water, food, cosmetics, pharmaceuti-
mental toxins as another risk factor. The more we can identify cals, personal care products, cleaning products, fuel, receipts,
and rectify these causes of chronic disease, the more momen- plastic bottles, and more.
tum is created and the more success we will have with indi- Why is MET so important for detox? Exercise increases
vidual patients. As a result, we will see lower healthcare costs. thyroid activity, whole-body metabolism, perspiration, lym-
phatic circulation, and bowel movement so that all these
functions become more efficient in cleaning out waste.
35.1.1  Integrating Nutrition and Movement 55 MET activates the lymphatic system and helps with
filtration of toxins through the lymph nodes and
In the same way, one should not separate the soul and body contributes to a better cleanse of interstitial tissue fluid.
and one should not separate movement and nutrition. They 55 MET increases sweating, which carries toxins from the
influence each other. You cannot treat nutrient deficiencies inside of the body to the outside of the body, where it
with exercise, and you cannot treat inactivity with nutrition. evaporated or wiped off by clothes, towels, etc. The more
Both are needed all the time. you move and sweat, the more you get rid of environ-
Administering the correct dosages of movement and mental toxins which relieve the kidneys and liver for the
exercise training (MET) will make everything else work bet- detoxification process.
ter. Even dietary supplements like fish oil work better when 55 MET increases the activities of autophagosomes and the
combined with movement and exercise [2]. This 2014 study “cleaning process” that helps to break down and remove or
in Neuropsychologia showed a difference in cognitive func- recycle the old worn-out cell components. The same
tion between patients who took omega-3 supplements and applies to “urban workers” in the brain which are primar-
exercised. They also saw that the omega-6 to omega-3 ratio ily active at night thanks to the movements through the
improved by adding exercise to omega-3 intake. This shows lymphatic system of the brain, the so-called glymphatic
the positive potential of combining the intake of nutrients with system (lymphatic system in glial cells). Activity during
movement and exercise. The transport, uptake, and function of the daytime combined with a good night of sleep has
nutrients with or without different levels of exercise and oxy- shown to optimize this glymphatic cleaning process, that
genation of the cells may differ, according to the previous study. is so valuable for removing debris from the brain.
Nutrition with Movement for Better Energy and Health
597 35
55 Increased oxygenation of cells occurs by exercise and
makes the combination of circulation and nourishment
to the citric acid cycle help bind and displace toxins.
55 The balance of redox status. Consistent moderate MET
helps maintain a healthy redox balance. Both under-
exercise and overtraining create problems with redox
balance and an abundance of free radicals, accelerating
the aging process and increasing the risk of developing
chronic disease. Exercise induces increases in superoxide
dismutase and other markers. MET and aerobic capacity
are important factors in maintaining balance in redox
status [5].

To further optimize the expelling of toxins through sweating,

make sure you shower directly after you work out, and even
better, shower and take a 15–30-minute post-­workout sauna
or hot bath.

35.1.1.2  Sitting Is the New Smoking

Over the last 10  years, many studies have concluded that
excessive sitting is a major risk for mortality or chronic dis-
ease, independent from MET. Many people who have transi-
tioned from a sitting work desk to a standing work desk can
attest to that it is one of the easiest changes one can make to
decrease the risk of mortality and chronic disease. A meta-­
analysis in 2015 concluded that sedentary time, primarily
hours of sitting time, was independently associated with a
greater risk for all-cause mortality [6]. Even if someone gets ..      Fig. 35.1  Sitting upright, standing, and walking at workplace
the widely recommended 30 minutes of daily exercise, being
active in the remaining approximate 6500 waking minutes of
the week makes a greater difference. An international mobile 35.2   hysiological Mechanisms Associated
P
health (mHealth) program for studying obesity, inactivity, and with Exercise and Nutrition
sitting showed improvement when these people could stand
and move more [7]. In fact, reduced sitting time may have a 35.2.1  Oxygen Plays a Key Role
positive impact on psychological and physical health [8].
Sitting and watching TV is more dangerous than just sit- 35.2.1.1  Oxygen, Nutrition, and Movement
ting and working because watching TV is often associated We eat 4 pounds of food and drink 4 quarts of fluid a day, but
with snacking on processed foods. Every hour of TV viewing in that same time, we take in 7.5 pounds of oxygen and pro-
after the age of 25 takes 22 minutes off a person’s life [9, 10]. duce waste from the burning of oxygen in biochemical reac-
Sitting with one’s upper back hunched forward also restricts tions. About 3% of this oxygen intake ends up as free radicals
the flow of oxygen and induces shallow breathing. Shallow due to by-products from energy production. These free radi-
breathing and stress breathing are common in modern soci- cals are complexed by our own production and even by the
eties. Deep breathing exercises contribute to increased oxy- external reserve of antioxidants we ingest from foods, super-
genation of the tissues, improvement in blood and lymphatic foods, and supplements.
flow, and better digestive functions. Aerobic exercise There is a tendency for oxygen deprivation in the modern
improves the heart’s blood-pumping capacity, as well as the world, primarily because of our sedentary lifestyle. Boosting
capacity of the lungs. Both aerobic and anaerobic exercises the production and transport of oxygen stimulates the synthe-
have been shown to increase our capacity to better quench sis and activity of white blood cells, resulting in a stronger
oxidative stress and improve redox balance [11]. Standing, immune system. Increasing oxygen levels may be the principal
walking, and MET with good posture increase the vital flow method to combat damage caused by aging and to discourage
of oxygen to tissues. Transitioning to a standing desk is a the growth of abundant number of anaerobic bacteria, yeast,
simple change to decrease sedentary time. At a standing work and cancer cells. Production of energy and the use of oxygen
desk, it is easier to move, fidget, stretch, and maintain good are controlled tightly and influenced a great deal by
posture, all of which improve oxygenation to the tissues. MET. Oxygenation to muscle cells can increase nearly 15 times
Transition to better sitting positions at work is a good first through intensive training as compared to a resting state, such
step. Standing and working or walking and working are ideal as sitting. In a resting state, the body uses about 0.21 L of oxy-
(. Fig. 35.1).
  gen per minute, compared to the approximate 2.5  L/minute
 598 P. Wilhelmsson

rate from brisk walking and the 3.0 L/minute rate from run- oxygen to our mitochondria for energy production and the
ning. The total cardiac output of blood in a resting state is disposal or recycling of waste products through aerophagia
approximately 5 L/minute, but that rapidly increases to about or biotransformation through, for example, the cytochrome
25 L/minute when engaging in vigorous MET. p450 system. But this flow of life can easily be sabotaged, and
The heart must work against gravity to pump blood up to one may become limited or incapacitated.
the brain, the body’s largest consumer of oxygen. One of the However, we can produce ATP energy units through the
main causes of mental deterioration with age is hardening anaerobic system, which does not need oxygen. This system
arteries and high blood pressure, both of which result from can produce energy for a short or limited time, but is not as
decreased nitric oxide production/supply, oxidized lipids, effective as the aerobic system and creates excess lactic acid
chronic inflammation, autoimmunity, or other sources of in the process. It may be viewed as a Plan B system for long-­
endothelial dysfunction. Years of inactivity, especially cou- term energy production, but it is used as a Plan A system for
pled with poor nutrition habits, lead to endothelial dysfunc- sprint athletes and short interval exercise training.
tion and a decreased oxygen supply to the brain. Thus, a Both physically fit and unfit people feel a burning pain
major step in reducing mental deterioration over time may when they do intense exercise that their body is unaccus-
be consistently increasing the oxygen to the brain. In addi- tomed to. A well-trained athlete, by contrast, is more efficient
tion, exercise has been shown to increase brain plasticity at converting excess lactic acid to glucose so the excess lactate
through the increased production and expression of brain-­ content and the workout “burn” is reduced.
derived neurotrophic factor (BDNF) [12]. Good production of nitric oxide (NO) allows the endothe-
Aerobic exercise increases the efficiency of the lungs in lial tissue to be softer and more flexible. This enables more oxy-
transporting oxygen into the blood and trains the heart to gen to reach the muscle cells for growth, function, and good
increase oxygen-rich blood to the body. Combining aerobic ATP production. The enzyme nitric oxide synthase (NOS)
and resistance training lowers blood sugar levels and leads to produces nitric oxide by regulation of the protein caveolin.
a rise in the number of mitochondria in muscle tissue. Nitric oxide (NO) is formed primarily in endothelial tissue.
Improved insulin sensitivity and glucose transport mean less Nitrate-rich vegetables and the body’s production of
glycation. Oxygen increases insulin sensitivity, particularly in nitric oxide and arginine are important precursors to form
35 muscle cells, efficiently transporting glucose as an easy fuel NO. Endothelial nitric oxide synthase (eNOS) keeps the car-
source for production of ATP energy for the muscles. A com- diovascular system healthy. Arginine from food or supple-
bination of aerobic and resistance exercise also increases the ments helps to synthesize eNOS, and citrulline keeps it
oxygen-carrying efficiency of hemoglobin and speeds up the circulating in the blood. Optimal NO production supports
general metabolism. It keeps the glucose, nutrients, and oxy- relaxed and healthier blood vessels, enabling better transport
gen in the blood moving quickly through the system and of oxygen to the cells. NO also has an anti-inflammatory
saturating the body’s tissues and cells. effect and helps prevent blood clots [14]. Many endurance
Exercise training increases the transport and use of glucose athletes drink beetroot juice or take nitrate-rich supplements
in the cells and mitochondria by as much as 20 times. Inactivity to improve their performance through increased blood flow
contributes to insulin resistance by continually having too and oxygenation of muscle tissues.
much glucose in the blood that must be transported by insulin Production of NO decreases with age, and most people
into the cells or stored as glycogen or fat. Too much glucose eat few nitrate-rich plants, such as arugula, spinach, kale,
creates an oxygen deprivation in which disease and pathogens pomegranate seeds, and beetroot. Furthermore, when we are
can take root. Red blood cells contain hemoglobin molecules out of balance, we can produce too much of a toxic form of
with an iron atom. A lack of red blood cell function means the NO called peroxynitrite. Peroxynitrite increases the risk of
body is deprived of oxygen. Hence, MET together with a low- cardiovascular disease and diabetes, additionally poisons our
glycemic, high-fiber, and mineral-rich diet build strong hemo- mitochondria, and reduces the production of ATP [15]. Poor
globin, increase blood flow, and ensure a highly oxygenated NO production, along with other factors like a slow metabo-
body. Proper oxygenation and adequate nutrient status ensure lism, creates a poor blood circulation.
that all tissues are healthy. A copper and/or zinc deficiency
increases glycation of hemoglobin and lowers the thyroid
function, which is copper- and zinc-dependent [13]. Box 35.1  Common Symptoms Associated with Poor
Circulation
35.2.1.2   xygen, ATP Production,
O 55 Coldness in extremities, regardless of environment but
worse when it is cold outside
and Nitric Oxide 55 Headaches, including migraines
A good example of the synergy of movement and nutrition is 55 Brain fog and poor concentration
how all our cells produce adenosine triphosphate (ATP), our 55 Varicose veins
55 Swelling and water retention, especially in the ankles,
vital energy currency. To create ATP, the mitochondria must
neck region, and upper arms
have access to oxygen. Hence, a major task for our respira- 55 Fatigue
tory and circulatory system is to deliver oxygen to the tissues 55 Numbness in extremities that is not related to a pinched
so that our mitochondria can access it for energy. A basic nerve
prerequisite for health is a proper supply of nutrients and
Nutrition with Movement for Better Energy and Health
599 35
35.2.1.3  The Glymphatic System
A study published in a 2015 issue of Nature changed our
understanding of anatomy and physiology by introducing a
system of lymphatic vessels that circulate to the brain that
had not been widely known or proven [16]. This study sug-
gests we have underestimated the effects of the lymphatic
system in health and disease, particularly brain health. The
lymphatic system has been shown to play a major role in the
immune system that influences neurological diseases. It has
also been shown to be vital to brain health by increasing
transport of oxygen and nutrients to the brain cells and by
helping to carry away waste products that are a natural con-
sequence of normal brain functioning. “In Alzheimer’s, there
are accumulations of big protein chunks in the brain,” lead
author Jonathan Kipnis said in a press release [17]. “We think Lymphatic system Lymphatic and glymphatic system
they may be accumulating in the brain because they’re not pre - 2015 post - 2015
being efficiently removed by these vessels.” In other words,
..      Fig. 35.2  Recent discovery in glymphatic anatomy and drainage
increased lymphatic circulation and drainage by the glym-
phatic channels of the brain are important to brain health
and prevention of cognitive impairment diseases. Old and lymphatic flow hampers the filtering of waste products and
new illustrations of the lymphatic system show a stark con- extracellular debris. Restoring and ensuring healthy blood
trast of how limited our knowledge has been of the vast func- and lymphatic circulation through MET is key to all physio-
tions of the lymphatic-glymphatic system. The following logical, psychological, and biochemical functions.
pictures tell a thousand words (. Fig. 35.2):
 

The new discovery emphasizes the importance of exercise 35.2.1.4   athophysiology Resulting from Lack
P
and breathing in stimulating the flow of lymphatic and glym- of Oxygen and Energy
phatic fluids to and through the brain, increasing oxygen- Nothing is more fundamental to life than respiration – the
ation of tissues and drainage of metabolic by-products. intake of oxygen and release of carbon dioxide. Healthy red
There is no central pump for the lymphatic system. blood cells (erythrocytes) absorb oxygen from the lungs for
Lymphatic fluid is pumped through both movement and delivery to cellular tissues by a vast capillary network
breathing. Diaphragm movement during deep breathing and throughout the body. To support this process, the bone mar-
physical activity are important stimuli for the lymphatic sys- row produces a continuous supply of new blood cells, giving
tem. Adequate MET support a well-functioning lymph sys- birth to two million new red blood cells every second. Each
tem. Massage, skin brushing, saunas, and other therapies also day, the body produces more than 200 billion new red blood
contribute to lymphatic flow. The lymphatic system’s move- cells, and at any given moment, there are more than 25 tril-
ment is so important to do abdominal ­breathing versus shal- lion blood cells in circulation.
low chest breathing. Another reason is that abdominal Good blood circulation enriches the blood and cells
breathing keeps you calmer and makes sure you spend more with oxygen, transports nutrients throughout the body,
time during the day in the parasympathetic dominant state. helps manage waste production, improves muscle recovery,
This ensures that you are not in a sympathetic-­dominant-­ and accelerates healing. When circulation is compromised
stimulated state of stress for a long time. by aging, sitting too much, inactivity, disease, or other fac-
Both abdominal breathing and increased circulation tors, the muscles may atrophy, and numbness and tingling
through exercise oxygenate muscle cells via the citric acid can occur. Poor circulation increases the risk for serious
cycle. MET stimulates the movement of fluids in the lym- health threats, including stroke, hypertension, and kidney
phatic vessels and helps to transport waste from the cells. failure.
Evidence from the 2015 study in Nature suggests breathing Over time, consistent MET strengthens the vessels and
and movement have a greater impact on brain health than the heart. One reward of consistent MET is a stronger
previously thought. The reason this was overlooked is that heart and a lower pulse. A pulse below 62 beats per minute
the tiny lymphatic vessels are so intimately wrapped in the and a blood pressure under 120/80 are generally consid-
blood vessels, which move from the throat and sinuses ered protective signs that decrease your risk for chronic
through the brain. Drainage of waste by the glymphatic sys- disease, especially cardiovascular disease. Even your risk
tem works together with movement of the cranial spinal for psychological disturbances, substance abuse and vio-
fluid. This extra movement of waste by the glymphatic system lent behavior are reduced by MET, according to a 2016
may partly explain why regular exercise has a protective Karolinska Institute study conducted on one million
effect against dementia and neurological diseases. Swedish men [18].
Poor lymphatic flow and blood perfusion due to inactiv- A strong heart and healthy endothelial tissue contribute
ity contribute to crippled ATP energy production. The poor to excellent blood flow, requiring less work to transport
 600 P. Wilhelmsson

nutrients, carry away waste products and oxygenate the cells. 55 Vitamin E helps transport oxygen to the blood cells.
Hypertension is still considered the largest risk factor for car- 55 Vitamin K2 increases the oxygen-carrying capacity of
diovascular diseases and the combination of a healthy diet, the hemoglobin in red blood cells. Vitamin K2 and
an appropriate MET program and improved stress reduction nitrates in foods, amino acids arginine, and citrulline
may improve health and decrease mortality risk. and nitrates eaten in a plant-based diet through the
intake of spinach, red beets, pomegranates, arugula, and
other nitrate- and chlorophyll-rich greens all aid in the
35.2.2  Nutrients Play a Key Role status of healthy endothelial cells. This increases blood
flow and oxygen transport. Inactivity, lack of chlorophyll
35.2.2.1   ey Nutrient Patterns for Better
K and minerals, lower oxygen levels in the air, and air
Energy and Health pollution all contribute to low oxygen.
Macronutrients, carbohydrates, amino acids, or fats are 55 Magnesium enhances the binding of oxygen to heme
needed for conversion into fuel for the citric acid cycle. proteins and gives red blood cells the flexibility to enter
Nutrients such as citric acid, malic acid, and fumaric acid are tiny capillaries. Magnesium also stimulates the movement
needed for the cycle to create energy, which will enter the final of oxygen atoms from the bloodstream to the cells and
stage of energy production, oxidative phosphorylation. B vita- prevents blood vessels from constricting and platelets
mins and metabolites NAD and NADH are needed as cofac- from sticking together. Calcium and magnesium aid in
tors in the citric acid cycle. Magnesium and coenzyme Q10 are the transport of oxygen into the cell. Magnesium is also
important for oxidative phosphorylation to work. Antioxidants needed to shift calcium in and out of cells, thereby provid-
are needed in the body to take care of the free radicals pro- ing the correct pH for high-cellular oxygen. Magnesium-
duced as a waste product from the production of energy. deficient individuals use more oxygen during physical
Nitrates are needed for optimal production of nitric oxide, activity, which in turn produces more free radicals.
which provides optimum oxygenation to the cells. B vitamins 55 Antioxidants found in foods, phytochemicals, amino
and other nutrients may be needed to ensure that the methyla- acids, vitamins, and minerals help the body use oxygen
tion and other cellular functions work and keep our mito- better and protect against damage by free radicals formed
35 chondria, DNA, and RNA in balance. Oxygen is needed for when excess oxygen is produced in intense exercise or
the whole process of aerobic energy production to work at all. overexertion. Copper, manganese, and zinc are used by
For blood to be able to carry oxygen to the cells, it needs the body to synthesize superoxide dismutase, a potent
hemoglobin. In adult men, hemoglobin concentrations can antioxidant enzyme. This is extremely important in the
range from 13.5 to 18 g/100 ml of blood. In adult women, the body’s defense against oxidation and the accumulation of
concentrations vary from 11.5 to 16.4 g. The following factors excess glycation, so-called aggregated glycation end
are among the most important reasons that affect the amount products which contribute to systemic oxidative stress
of hemoglobin in erythrocytes: nutrients such as iron, vita- and disturb the proper function of proteins.
min B12, folic acid, and the availability of nitrates, proteins,
fatty acids, elevation, and oxygen supply. The most important
factor, however, is movement and exercise. Well-trained elite 35.2.2.3  Nutrients for ATP Production
athletes usually have very high hemoglobin levels and thus What can affect or limit ATP production? Energy production
have an excellent transport of oxygen to the muscle cells. will gradually become less efficient with aging, especially
Through the combination of MET and nutrition, as well as after one is in their 40s. Infections, such as mycoplasma
certain genetic and epigenetic factors, you reach optimal trans- infections and Lyme disease, meningitis, heavy metal poi-
port of oxygen to the muscle cells. With moderate to intense soning, and poisoning from chemicals or plastics, can all
MET, you can produce at least 30 times as much ATP com- limit ATP energy production. Lack of oxygen and ATP-rich
pared to a resting state. During intense exercise, such as sprint nutrients, such as, CoQ10, B2, NADH (niacin metabolite),
intensity training (SIT), you can use more than 1000 times B5, B6, and magnesium, may also limit energy production.
more ATP than in the resting state. After 10–15 seconds, the The bases for protecting and optimizing the mitochondria
normal ATP production takes place through anaerobic and are lifestyle factors, access to optimal amounts of oxygen,
aerobic combination, instead of only via anaerobic metabolism. macro- and micro-nutrients and minimal exposure, and
storage of environmental toxins.
It has been found that the coenzyme Q10, the active form
35.2.2.2  Nutrients for Oxygen Transport of folate (5-methyltetrahydrofolate, 5-MTHF), grape seed
Here are some of the ways that nutrients and oxygen work extract, lipoic acid, melatonin, artichoke, the herb selfheal
hand in hand: (Prunella vulgaris), and naturally occurring polyphenols and
55 The B vitamins B12 and folate are necessary to produce other phytochemicals present in beetroot, olives, olive oil,
red blood cells. tomatoes, cocoa, ginkgo biloba, pomegranate, and hawthorn
55 Iron is important for the transport of nutrients and oxygen berries all contribute to normal NO production. These pro-
through healthy hemoglobin transport in the blood. mote good circulation and oxygenation and also provide pro-
55 Vitamin C is essential to the uptake and utilization of iron. tection from the overproduction of peroxynitrite. Nutrition
Nutrition with Movement for Better Energy and Health
601 35
for better absorption of oxygen can be found in nitrate-rich Another way it helps is by influencing insulin pathways and
vegetables (e.g., arugula, kale, beets, etc.), arginine, citrulline, modulating inflammation-signaling pathways. Modulation
CoQ10, magnesium bisglycinate, B-complex vitamins, and of these pathways is dose-dependent [19]. Aside from inac-
vitamin E complex. tivity, other lifestyle factors reported to impact insulin resis-
tance are xenoestrogens, obesity, stress, and dietary factors.
Even though one can approach the challenges of insulin
Box 35.2  Twelve Tips for Better Mitochondrial Health resistance with weight reduction, biotransformation/detoxi-
1. Regular physical activity equivalent to at least 12,000 steps
fication of chemicals, caloric or dietary restrictions, or use of
per day.
2. A plant-based diet with a low-glycemic index. supplements such as chromium and cinnamon extract, MET
3. Avoid gluten and possibly other substances/foods that you or pharmaceutical therapies such as metformin, a more ideal
may be allergic or oversensitive to. approach is to use a combination of lifestyle therapies to
4. Frequent mild detox and detox cures for a few weeks, sev- affect improvement either before or in conjunction with food
eral times a year.
supplement or pharmaceutical support. A simple but consis-
5. Abdominal breathing and, if possible, treatment for the
lymphatic system through massage, sacro-cranial treat- tent lifestyle support program has been shown to be very
ment, dry brushing, saunas, and relaxing Epsom salt or effective in affecting positive change. One 2002 study showed
herbal baths. better improvement with lower costs compared to taking the
6. Extra intake of nitrates from arugula, spinach, beets, pome- pharmaceutical metformin [20].
granate, and supplements of nitrates from concentrated
A healthy and fit person can really enjoy a great level of
red beet juice or juice-concentrated powders or capsules.
7. Good sleep, staying calm, and using a stress management aerobic fitness by doing 45–120  minutes of MET, but this
program as an everyday part of life. dose is too much, of course, for one who is not well-trained,
8. Use clean-toxic-free products in terms of hygiene, cosmet- or for a person with pathology or strong risks for problems,
ics, food, etc. and gradually chelate accumulated heavy such as those who are obese, take lots of medications, or have
metals and chemicals in tissues by eating organic veggies,
past or current cardiovascular diseases. A study conducted at
sprouts and regularly using spices such as tumeric, cay-
enne, cilantro, rosemary, oregano and basil. Regular use of Mayo Clinic in 2012 found that, for cardiovascular patients,
green superfood powders such as chlorella, spirulina and the optimal dose is more likely to be 30  minutes a day of
wheat grass is a great way to gentle move out toxins from moderate training instead of the 60–90 minutes for the very
the body. fit. For these cardiovascular patients, too much oxidative
9. Mitochondrial-supportive supplements, such as CoQ10,
stress is initiated with 60-minute moderate or vigorous
ribose, L-carnitine, acetyl L-carnitine, resveratrol, vitamin B
complex, magnesium, and lipoic acid. MET. The strongest risks are at a sustained effort of vigorous
10. Extra methylation supplements if necessary and if there are exercise such as long interval training [21].
gene deviation (DNA testing) and elevated homocysteine
levels above 8 from blood testing: Vitamin B6, B12, folic
acid, choline, betaine, trimethylglycine, or SAMe supple-
mentation will most likely improve homocystein levels and Box 35.3  Improvement of Cardiometabolic Markers
methylation functions. The following cardiometabolic markers have been shown to be
11. Acupuncture for better energy. improved by regular exercise training:
12. Adaptogenic herbs: Astragalus, ashwaganda, eleuthrococ- 55 Lipid, inflammation, and glucose profile:
cus root, arctic root, ginseng. 55 Trigylceride (Tg)
The addition of nutrients, herbs, or low-dose aspirin that 55 HDL
counteract blood viscosity. The most common blood thin- 55 LDL
ning supplements are omega-3 fatty acids, garlic, gingko, 55 Fasting glucose, glucose stress test
and meadowsweet. These are especially valuable for elderly 55 Fasting insulin, insulin stress test
people, or those at cardiovascular risk. 55 HbA1C (long-term sugar management)
55 Hs CRP
55 Uric acid
55 Homocysteine
55 Fibrinogen
35.2.2.4  Unique Considerations 55 Lp_PLA2
for Cardiometabolic Syndrome 55 VAP advanced lipid profile:
55 Apo B, Apo A1 and or Apo B/A1 quota
Cardiometabolic syndrome is a term which recognizes the 55 VLDL 3
common development of cardiovascular diseases due to an 55 HDL 2
etiology of the combination of insulin resistance, obesity, and 55 Lp (a)
inflammation. From a functional medicine perspective, we 55 GGT (oxidative stress/toxicity marker)
would add other contributing factors such as inactivity,
nutritional imbalances, and toxicity.
Insulin resistance and glycemic control are influenced by The level of intensity of aerobic training estimated to improve
many mechanisms. MET seems to be one of the most effec- cardiorespiratory fitness has been 69% exertion of maximum
tive strategies in helping the body maintain healthy blood heart rate (max HR). This is considered to be moderate train-
sugar. MET stimulates 5’-AMP-activated kinase that influ- ing pace, where you can carry on a strained conversation, or
ences GLUT4 glucose transport of glucose inside the cell. a 6–7 out of 10 on the scale of exertion, a 13–15 on the Borg
 602 P. Wilhelmsson

scale of 1–20 of exertion. This level of exertion is also consid- 35.2.3.1  Types of MET
ered the minimal effective dose for improving cardiorespira- Integrated standing, movement, and exercise training
tory fitness. It is also a rate where you are burning about 45% (ISMET) is a vital part of a holistic and integrative lifestyle
fat and 55% carbohydrates as fuel. strategy to promote healthy aging and decrease the ravages of
chronic disease. Standing, movement, and exercise training
Box 35.4  Functional Medicine Causative or
maintain or upgrade normal physiological and biochemical
Contributing Factors
functions, thereby preventing breakdown of function and
55 Insulin resistance development of progressive pathology.
55 Toxicity ISMET should be part of a holistic lifestyle prescription
55 Oxidative stress and support system like that which has been repeatedly imple-
55 Inflammation mented by Dr. Dean Ornish. In several of his studies, where
55 Endothelial dysfunction, dyslipidemia
55 Hormonal
movement and exercise training (MET), meditation, nutrition,
55 Genetic, epigenetic factors supplementation, and psychosocial support are implemented
55 Dysimmunity, autoimmunity as an integrative system, intensive lifestyle changes may affect
55 Energy, mitochondrial dysfunction the progression of prostate cancer [26]. Depending on the
55 Microbiome patient-doctor/lifestyle coach interaction, a comprehensive
55 Structural
55 Tissue Perfusion—blood and lymph and maintenance
lifestyle program can be suggested and negotiated, with the
of muscle mass proper support system, inspiration, and knowledge to imple-
55 Emotional, mental, spiritual ment the program. In integrative and functional medicine, the
increasing model has shown that it takes a team or network of
professionals or lay coaches to help the patient turn their life
In addition to the challenges of the pathophysiology of the around and integrate new habits of health into their lives.
combination of insulin resistance and cardiovascular irregu- ISMET is as an important part of these regenerative changes
larities or dysfunction, a functional medicine-trained nutri- and strategies as dietary changes or psychosocial changes. These
tionist will also investigate other underlying processes, which types of integrated comprehensive programs have been shown
35 may be important parts of the etiology or contribute to the to often be effective in various types of chronic disease [27].
problems. Most of these processes will be influenced by Although setting a goal of walking the equivalent of more
increases in various types of physical activity. I have even than 10,000 steps daily is admirable, and will improve your
added tissue perfusion, increased cardio conditioning, and health or disease status, setting more specific goals for whole
increased muscle mass as a solution to one of these func- body training is even better. The integrative model I am rec-
tional medicine links in the causal chain of chronic disease. ommending with the acronym, ISMET, involves improve-
Regardless of the mechanisms and processes, people are most ments in the following areas:
concerned about the length and quality of their lives. The 1. More standing, less sitting, the 12–12 rule (12 hours sleep-
bottom line is that MET gives you the most “bang for your ing and sitting, 12 hours standing, moving or exercising)
buck.” Better aerobic conditioning gives you not only a lon- 2. More habits of incidental movement
ger life but a better quality of life. 3. Walking and play, hobbies, and extra activities
55 Among other things, VO2 max is correlated with both 4. Exercise training, both planned and spontaneous
lowered morbidity and mortality [22].
55 Chromosome telomere length, which is a predictor of The planned or habitual MET can be a combination of aero-
health and longevity, is spared for those who have a bic and anaerobic activities and can include a combination of
better VO2 max [23]. dancing, playing, endurance training, interval training,
55 Telomere length (mitochondrial mitogenesis) is strength/resistance training, and flexibility and balance train-
increased by exercise [24]. ing (i.e., yoga, stretching). If possible, spend some of this
55 Epigenetic studies show that activity helps modify DNA time in a natural environment, such as beaches or paths
signaling [25]. through wooded areas or near lakes. Nature deficit disorder,
as identified in 2005 by the author Richard Louv in the book,
Last Child in the Woods, emphasized the added bonus of
35.2.3   ET: Powerful Prevention
M health benefits and joy in playing, moving, and exercising in
and Treatment of Chronic Disease a natural environment.

Not only is MET vital for prevention of disease and reha-

bilitation of injuries; it is often very powerful for alleviating
Box 35.5  Good Tips for Starters, from Inactivity
suffering, increasing quality of life, restoring function, and
to Active Movers
assisting in improving states of pathophysiology. The Some good tips for those who are starting to exercise:
following are only a few of the many chronic disease states 55 Start slow and start small.
where MET has shown to be a valuable in conjunction with 55 Work out at a time of the day when you have more energy.
other treatments.
Nutrition with Movement for Better Energy and Health
603 35

55 Find activities that bring you joy or connection with

people, your tribe.
55 Be comfortable and use the right clothing, shoes, and
Balance
gear.
55 Reward yourself for successes and consistency.
55 Make exercise a social activity with friends or commu-
nity groups. Community exercise groups are effective. Flexibility
This has been demonstrated repeatedly in lifestyle
support groups, such as those formed at Saddleback
Church, called The Daniel Plan (7 www.­danielplan.­com).
 

55 Use apps, technology, and tracking devices to see Strength

improvements and for coaching.
55 Keep gradually increasing the MET dose as your motiva-
tion and goals grow, but be careful, gain knowledge and
experience before doing extreme sports. Extreme exercise,
Conditioning
such as triathlon training and competition, can easily
cause too much oxidative stress, gastrointestinal
disruption, inflammation, injury, hormonal disturbances,
anemia, eating disorders, osteopenia, etc.
..      Fig. 35.3  MET pyramid

35.2.3.2   ey Exercise Patterns for Better

K
Energy and Health Walking is a great place to start for an inactive person
Traditional exercise trainings, such as yoga, tai chi, and who wants to become active. One can always start low and go
qigong, have proven through centuries of use to be important slow to avoid pain and injury. If one has a difficult time tak-
for both the health and well-being of individuals and cul- ing an extra 30–60-minute walk every morning or evening,
tures. One of several thousand studies on these ancient prac- taking 3–6 shorter walks will accomplish a similar result.
tices shows increased quality of life for the elderly [28]. These Using a pedometer or step monitor is one of the easiest track-
practices not only involve movement but also concentration, ing tools for your health. Devices worn on the belt, wrist, or
balance, stretching, meditation, breathing, and stress man- as a wristwatch can measure the amounts of steps the wearer
agement. These are an excellent complement to aerobic con- takes per day. Minimal recommendations usually suggest
ditioning training, which is the base of the MET pyramid. 4000 steps of incidental activity and 3000 steps of walking,
for a daily total of 7000. A 30-minute power walk will give
you about 4000 steps.
According to many public health recommendations, you
Box 35.6  ET Training Pyramid should create a habit where you spend at least 30 minutes a
Cardio or aerobic training is the base of the pyramid of training.
It is important that everyone has a basic level or energy and
day walking 5  days per week to accumulate at least 15,000
endurance. The next three levels are maintaining the goals of weekly steps [29]. This recommendation, while modest, is
having strength, flexibility, and balance. These levels provide deemed sufficient for creating better health and decreasing
great fitness focuses for goals to help prevent sarcopenia, risks for chronic disease. A breakthrough book in this field,
accidents, falls, and development of chronic disease Biomarkers, was published in 1992 by Evans and Rosenberg
(. Fig. 35.3).
at Tufts University. This book shows that even walking
 

30–60 minutes five times per week, when started by obese/

overweight individuals, improves key biomarkers of health
Many people struggle with scheduling movement and MET and disease. These improvements are easy to track and mea-
into their daily lives; but by simply increasing your amount of sure with blood tests, a tape measure and bio impedance cal-
incidental activities and planning regular MET sessions, you culations.
can enjoy more movement and health. All it takes are a few Exercise goals and types vary quite a bit depending on
small changes of habit, like parking farther from work, taking one’s situation and personal wishes. To make progress with
public transportation, bicycling more, walking to nearby obesity, one most often needs to exercise more than those
neighbors’ homes or stores, walks and talks with colleagues who are just looking for a minimal amount of exercise or
or friends, taking the stairs regularly, more play with the kids steps for general health. Eating the right amounts and kinds
or grandkids, walking somewhere in the building every hour of nutritious foods is also important.
at your workplace, and more house cleaning, yard work, or As seen below, certain levels of movement and exercise
gardening. Such changes can add the equivalent of 2000– training have positive effects on insulin resistance and meta-
6000 steps per day. After a few weeks, it has become a lifestyle bolic resistance. However, consistency is the most important
habit and you don’t notice it. It is now on autopilot. This is key. Even modest progress can be noticed when you are
especially important if you have an occupation, workplace, or walking every day. The best form of exercise is that which you
home environment that is not conducive to movement. do consistently.
 604 P. Wilhelmsson

INACTIVITY OBESITY

CHRONIC INFLAMMATION

35
Adipose Tissue Immune Cells Brain Cells Systemic Cytokine
Elevation

Insulin Resistance/ Artherosclerosis Alzheimers/ Cancer

Type 2 Diabetes Parkinsons

..      Fig. 35.4  The role of nutrition and exercise in the mechanisms of pathology or in pathophysiology. (Reprinted from Handschin and
Spiegelman [39]. With permission from Springer Nature)

Box 35.7  Step Goals Taking 7000–10,000 steps per day from incidental activities,
The following is a guideline for amounts of steps to aim for each movement, and walks should be seen as the minimal amount
day, on average. This includes incidental activities, walking, of effort for combined daily movement and planned exercise
play, and planned movement and exercise training (MET): time. If you do a moderate-to-intense gym workout, dancing,
55 Inactivity contributing to chronic disease (<5500 steps
daily)
aerobics, or strength training, you can count that as 2000–
55 Some improvements in immunity functions and health 4000 equivalent steps per half hour, depending on the level of
markers (>7000 steps daily) intensity/challenge.
55 Metabolic syndrome/insulin resistance improvement A more optimal number of steps per day would be
(>8000 steps day) 12,000–20,000 steps with combined, incidental movement,
55 BMI-defined weight status improvement (>10,000 steps
daily)
play, walks, and MET (planned movement and exercise
55 Optimal daily steps matching our physiological needs and training). The more natural and healthy cultures on the
our historical past (>14,000 steps daily) planet, the “Blue Zone” communities, have a daily average
of 18,000–24,000 steps movement. This also reflects the
Nutrition with Movement for Better Energy and Health
605 35
amount of movement many of our ancestors had many cen-
turies ago. These goals should also be an excellent comple- Box 35.9  Types of Exercise Training
ment to the habit of sitting less. The following flow chart can depict basic types of training that
My recommendation is the 12–12 rule. Out of your can be combined and coordinated for whole-body MET. These
play different roles in building physical and psychological
daily 24 hours, spend 12 of them sleeping and sitting, and health and resilience. Together with my 12–12 recipe for more
spend the other 12 moving and standing. Moving more at standing and movement, these areas illustrate the ISMET
work and home, exercising regularly and using a model:
standing work desk are some measures that can help you 55 Aerobic training builds endurance and cardiovascular
reach the 12–12 balance for greater health. MET should be and psychological health.
55 Anaerobic training such as sprint intensity training (SIT)
put in a context of good technique, body posture, and lots or high-intensity interval training (HIIT) builds and
of standing during the day. I refer to this healthy habit as maintains muscle mass, speed, stimulating hormone
integrated standing, movement, and exercise training production, and a healthy metabolism.
(ISMET). 55 Flexibility and balance training, such as tai chi and yoga,
balances muscles and enhances breathing, flexibility,
and balance.
55 Strength and resistance training builds strength and
power, stimulating hormone production and protects
Box 35.8  Get the Blood Flowing and Keep from sarcopenia.
It Flowing 55 Play, gardening, dance, and sports activities can balance
55 More standing and less sitting. No more than 4 hours other times of training and bring extra fun and variation
per day sitting, 7–8 hours of sleeping, and the rest of the to the mix of MET.
time should be standing or moving. The 12–12 rule of
ISMET.
55 Movement improvement, incidental activity producing
>6000 steps daily. Physical therapy and targeted training are specialized train-
55 Planned exercise at least 4 hours a week, whether at the ings to achieve specific physical goals or target specific mus-
gym, dance studio, in the outdoors, or at home looking cles, muscle groups, or function.
and following a DVD/online workout program. For two to
Moderate aerobic exercise training, high-intensity inter-
four sessions per week, transition from walking to power
walking, Nordic walking (walking with poles), cardio val training (HIIT), and sprint intensity training (SIT) have
workouts, running, biking, swimming, spin cycling, or been shown to be effective in improving the symptoms and
cross training for a more strenuous workout. progression of chronic diseases. Different forms, doses, and
55 Fidget and move at a standing desk. Taking a break combinations of these are appropriate for different individu-
every hour for some walking, doing squats, stretching,
als and needs. HIIT can be twice as effective as moderate-­
yoga poses, or having a walk-and-talk meeting with a
colleague. intensity aerobic training for people with lifestyle-induced
55 Lots of little movements and stretching throughout the diseases [30].
day. Keeping all body parts moving every day. A good Dr. Phil Maffatone, who has trained over 10,000 amateur
stretching program like yoga helps stimulate blood flow and elite athletes, recommends that at least 80% of your
and balance to all parts of the body.
training time should be in the low-moderate fat-burning
55 Consuming more spices like cayenne, cardamom,
ginger, garlic, rosemary, sage, and pepper to stimulate endurance zone, which he basically calculates with 180 minus
and assist in increased blood flow and perfusion of the your age. When you do your MET, you can mix up the above
tissues. types of training, so that each of these types is done each
week. When time is an issue, you can get a great workout in
15–20 minutes with HIIT or SIT workouts.
The best types of ISMET exercise programs are the ones you
do consistently. It is ideal if your planned exercise training
contains some of the following ingredients: Box 35.10  Training Zones
55 Personal health and fitness goals. The number 220, minus your age, is the most common way to,
on a gross level, estimate the maximum pulse/heart rate (max
55 Social support, exercising with friends.
HR) or the liverpool model for calculating your max HR which is
55 Competition, if it challenges you and motivates you. The often a little more accurate. Take 217 minus your age times 0.85.
FITTPRO model, found at 7 www.­exerciseismedicine.­
 
The following are the amounts of effort and heart rate that give
org, can give basic guidelines about frequency (5–7× different kinds of advantage:
weekly), intensity (50–70% mHR), type of exercise 55 50–75% of your max HR for aerobic conditioning and
endurance training (55–65% of this is the max fat burning
(mixing aerobic, resistance, and strength), duration
zone). Long MET sessions of 1–3 hours
(30–60 minutes), and suggestions for increasing these 55 75–95% max HR for medium to hard training, where sprint-
factors by 10 percent per week. ing and intervals are done. Short-duration MET training.
55 Overcoming or improving states of illness, personalized 15–60 minutes including warm-ups and cool down
goals, and programs.
 606 P. Wilhelmsson

increased temptations that distract from ISMET, while mak-

Box 35.11  Training Intensity ing available technology  – such as wearable-monitoring
Training intensity guidelines vary but are also, for the most part, devices – that will drive and increase the efficacy of personal-
similar. ACSMs (American College of Sports Medicine)
ized lifestyle medicine programs. As the science and moni-
guidelines and other organizations (7 www.­acefitness.­org) can
toring technology evolve, we will be able to prove to ourselves
 

be summarized as the following:

55 220 minus age and then the following level of effort and others the value of ISMET and lifestyle medicine.
(Borg scale of 1–20 and percentage of max heart rate):
55 Low effort, Borg scale: 9–12: 50–63% of max HR (you can 35.2.3.5   oth Undertraining and Overtraining
B
sing) Can Lead to Higher Disease Risk
55 Moderate: Borg scale: 13–14, 64–76% of max HR (you can
talk) The effects of physical activity on markers on specific IGF-1
55 High/intense effort: Borg scale: 16–18, 77–93% max HR markers for disease prevention can be seen in a study from
(you cannot talk) Poland conducted in 2015. The study demonstrated that
MET has a positive effect on the balance of IGF-1 and IGFBP
in the blood, therefore contributing to prevention of disease
35.2.3.3  Fitness and Lifestyle Assessments through the proper regulation of these important signaling
Fitness assessments are offered in many training centers and molecules. The majority of these studies indicate that
gyms. There are also plenty of these available online or in mechanical loading is a key mechanism linking IGF-1/
books or clinic brochures. One of the simplest is doing the IGFBPs concentration and selected chronic diseases develop-
following four easy tests that can assess your fitness, but these ment. The duration and intensity of physical activity have a
fitness tests and others should be combined with anthropo- significant impact on IGF-1 and IGFBP serum. The highest
metric testing, a physical exam and lab analysis for a more concentration of IGF-1 in serum was after eccentric training.
comprehensive personal analysis. “Overtraining” increases unfavorable and unbound IGF-1
1. The push-up test (measures muscular strength and levels and contributes to the increased incidence of hormone-­
endurance) cancer and osteoarthritis. Irregularity of the GH/IGF-1 axis
2. The crunch test (measures abdominal strength and may affect the development of rheumatic diseases, metabolic
35 endurance) syndrome, and cardiovascular diseases [32].
3. The 3-minute step test (measures aerobic fitness)
4. The 1-mile walk test (measures aerobic fitness) 35.2.3.6   ingle Exercise Training, Combined
S
Exercise Training, and Lifestyle
Nutritionists, dieticians, and lifestyle coaches can use clinical
questionnaires to evaluate the ISMET status of the client/
Programs
patient and then follow up with coaching, either online or via Many studies show examples of improved insulin resistance,
office visits. There are many online questionnaires, including decreased metabolic syndrome and decreased diabetes markers,
ones accessible in the functional medicine tool kit for those and pathology with exercise training. However, these studies can
who become members of the institute for functional medi- also be looked at comparing the effects of endurance training,
cine (7 www.­functionalmedicine.­org).
 
strength training, and total lifestyle programs. One study with
250 adults showed benefits with both endurance training and
strength training, but the improvements were even greater when
35.2.3.4  Integrative Lifestyle Therapies these two were combined. Even more improvement came after
Integrated standing, movement, and exercise training (ISMET) combining endurance and strength training and using a more
is a vital part of a holistic and integrative lifestyle strategy to comprehensive exercise, diet, and lifestyle program [33].
promote healthy aging and decrease the ravages of chronic Several lifestyle intervention programs have demon-
disease. Standing, movement, and exercise training maintain strated that a comprehensive program including diet and
or upgrade normal physiological and biochemical functions, exercise is much more cost-effective and successful than
thereby preventing breakdown of function and development pharmaceutical intervention with the drug metformin for
of progressive pathology. ISMET can be part of an integrative the treatment of diabetes [34, 35].
system of overall lifestyle changes that include meditation,
nutrition, supplementation, and psychosocial support.
It would be great if we can expand our recommendations 35.3   ET and Nutrients for People
M
from nutrition programs to comprehensive lifestyle pro- with Various Conditions
grams, such as the ones that Dr. Dean Ornish has repeatedly
shown are very powerful [31]. 35.3.1  Commonalities Across Conditions
Incorporating an integrated lifestyle program that
includes a personalized ISMET strategy will be more com- 35.3.1.1   herapeutic MET for Rehabilitation
T
mon in the days and years to come as the science and experi- (TMETR)
ences emerge that confirm the efficacy and power of patient/ Most hospitals and many clinics and private practices have
consumer driven self-care and healthcare. The convenience programs for rehabilitation of sports injuries; auto-, home-,
of the information and technology revolution will both bring or work-related accidents; war casualties; and various forms
Nutrition with Movement for Better Energy and Health
607 35
of physical limitations or handicaps. This can involve the use 35.3.1.3   nique Considerations for Inflamm-­
U
of many physical modalities, machines, body work, exercise Aging, Cardiometabolic Disease,
prescriptions, and surgical procedures that are used by many Dementia, Sarcopenia and NAFLD
different types of trained professionals. That which is in its In the following sections, we will investigate four chronic
infancy, however, is the aggressive use of TMETR for chronic complex conditions that cause a great deal of suffering and
disease unrelated to acute accidents or injuries. a huge strain on our healthcare system. These are also mod-
Although the American College of Sports Medicine els of how an integrative lifestyle program, including diet,
(7 www.­acsm.­org) and institutions in many countries, includ-
 
MET, and food supplementation, can be combined to
ing my own country of Sweden, have some guidelines (7 www.­  
achieve very good results. These four conditions are cardio-
fyss.­se) for TMETR for specific chronic conditions, these are metabolic syndrome, dementia/Alzheimer’s, sarcopenia,
seldom used in the clinical practice. Primarily, as with person- and nonalcoholic fatty liver disease (NAFLD). Their com-
alized nutrition programs, there is no or very little training of mon etiology is a combination of underlying causes such as
doctors, nurses, dietitians, health coaches, chiropractors, toxicity, chronic insulin resistance, toxicity, and inflamma-
physical therapists, or acupuncturists, concerning the use of tion that are causative or a result of these problems. If we
exercise prescriptions. The field of TMETR for chronic disease scratch below the surface of these conditions, we will find
states is still very young, especially compared to the use of the same culprits that are causative: insulin resistance,
TMETR in physical rehabilitation from injuries. Until the inflammation, toxicity and obesity, inactivity, poor stress
value of TMETR for chronic disease application is further management, poor food choices, cigarette smoking or tox-
studied, used, and incorporated into health professional train- ins in the environment, and other lifestyle factors. These
ing, the use of TMETR will be an underutilized powerful asset factors potentiated by genetic and epigenetic factors often
in the similar way personalized nutrition has been. lead to years of suffering from chronic diseases that trans-
I will present information that introduces and validates gress across body systems and disease. First, however, let us
TMETR not only for injuries but primarily for chronic dis- examine the process of chronic inflammation on disease
ease states. In the functional medicine model, as eloquently etiology and progression.
stated by one of the pioneers in medicine, William Osler, Inflammation control: moderate MET decreases the risk
“The good physician treats the disease, the great physician of chronic inflammation. Moderate endurance and strength
treats the patient who has the disease.” We are more inter- training have been shown to decrease chronic inflammation,
ested in understanding and caring for the patient than for the and flexibility and balance exercise practices, such as yoga,
disease. “The patient is more important than the disease the have been shown to lower inflammation markers. Ambarish
patient has.” Following some guidelines of aerobic and Vijayaraghava and his research colleagues revealed in a fasci-
strength training for a disease state is helpful, but ultimately nating study that, “Regular practice of yoga lowers basal
that information and recommendation must be adjusted to TNF-α and IL-6 levels. It also reduces the extent of increase
each patient. So TMETR must ultimately be personalized to of TNF-α and IL-6 to a physical challenge of moderate exer-
the living situation, family and support group, limitations, cise and strenuous exercise” [37].
possibilities, socioeconomic status, motivations, goals, and The nutrient and oxygen needs of the mitochondria
aspirations of the unique person with the disease. are very important also to prevent mitochondrial inflamm-­
aging, a chronic low-grade inflammation leading to dys-
functional mitochondria and oxidative stress. The
Box 35.12  Seven Great Goals for TMETR Is to Restore
microRNAs are involved in this process, which is hypoth-
Health
esized in an article in Experimental Gerontology from 2014
1. Personalize, communicate, and coach the TMETR.
2. Alleviate suffering. [38].
3. Halt and reverse pathology. This chronic inflamm-aging in the mitochondria, which
4. Restore and improve function. occurs in some hard-training athletes, can perhaps account
5. Improve quality of life. for damage to heart and muscle cells from overtraining.
6. Build resilience/organ reserve/organ capacity.
Intense exercise for long periods of time increases the risk of
7. Reduce risk for chronic disease reoccurrence.
chronic inflammation [39].
Elite training runs the risk of both injuries and chronic
inflammation, if the training, sleep, and nutrition proto-
35.3.1.2  MET and Physical Therapies for Injuries
cols are not carefully planned and monitored. Antioxidant
MET and correct physical therapy is a very important adjunct and anti-inflammatory foods and supplements can
to knee surgeries and other medical procedures. Many times, balance this and protect from meta-inflammation or
the correct use of MET and physical therapy can substitute injuries.
for surgery and bring as good as or better results than surgery The big culprit in creating chronic inflammation in our
and at a much lower cost. According to medical investigator society is not overtraining but inactivity, in combination with
Norman Swan, about 20% percent of knee replacement costs inflammation-stimulating processed foods. The following
(over $1 billion) incurred by the Australian healthcare sys- illustration shows how inactivity and obesity contribute to
tem were unnecessary [36]. inflammation (. Fig. 35.4).
 
 608 P. Wilhelmsson

ity risk. At age 75, the loss of strength per year, without
Box 35.13  Impact of Sarcopenia extra strength training, is two to five times faster than loss
55 On an individual level: of muscle mass [41].
55 Sarcopenia greatly diminishes independence and quality
Strength training or resistance exercise, the act of loading
of life.
55 Sarcopenia reduces individual health and happiness. muscle against an external force, remains the most effective
55 Sarcopenia increases the processes of inflammation and form of exercise in counteracting decreased function and
insulin resistance that underlie the progression of many sarcopenia. Because aging is associated with declines in hor-
types of diseases. mones, muscle mass, muscle function, and aerobic capacity,
55 On a societal or public health level:
more resistance training is needed [42].
55 Sarcopenia increases the risk of all-cause mortality and
disability. Per figures from the Journal of the American Geriatric
55 Sarcopenia puts every patient who has surgery at greater Society, “The estimated direct healthcare cost attributable to
risk of complications. sarcopenia in the United States in 2000 was $18.5 billion
($10.8 billion in men, $7.7 billion in women), which repre-
sented about 1.5% of total healthcare expenditures for that
year. The excess healthcare expenditures were $860 for every
35.3.2  Sarcopenia man with sarcopenia and $933 for every sarcopenic woman.
A 10% reduction in sarcopenia prevalence would result in
Sarcopenia, the loss of muscle tissue that is primarily a by-­ savings of $1.1 billion (dollars adjusted to 2000 rate) per year
product of the aging process and inactivity, contributes to in U.S. healthcare costs” [43].
obesity, diabetes, dementia, and the cardiometabolic syn-
drome. The main cause of sarcopenia is physical inactivity, 35.3.2.1  Unique Considerations for Dementia
especially lack of resistance training. Muscle loss and fat gain Alzheimer’s has been referred to as type 3 diabetes by some
is reversed by fitness and resistance training. researchers and doctors because of the similar underlying
Sarcopenia and the aging process are associated with less pathophysiology and processes that lead to both diabetes
efficient function of the mitochondria, the effects of which type 2 and dementia/Alzheimer’s disease. Insulin resis-
35 were well summarized in an article by Marita Rippo et al. in tance, toxicity, inactivity, obesity, oxidative stress, and obe-
Experimental Gerontology in 2014. “Mitochondria are inti- sity have been closely correlated with both diabetes and
mately involved in the aging process. The decline of autopha- dementia.
gic clearance during aging affects the equilibrium between MET has been shown to be one of the best strategies to
mitochondrial fusion and fission, leading to a build-up of decrease cognitive decline [44]. Reductions of mean blood
dysfunctional mitochondria, oxidative stress, chronic low-­ flow values are significantly correlated with the severity of
grade inflammation and increased apoptosis rates, the main dementia [45]. Increased oxygenation through MET has
hallmarks of aging” [40]. many advantages for keeping brain tissue healthier. Recent
results show that MET also helps move glymphatics, which
carry away waste products and cellular debris that accu-
Box 35.14  Multifactorial Causes of Sarcopenia mulate from an aging brain. MET has also specifically been
Like most chronic conditions associated with aging, shown to affect hippocampal-­dependent cognition and to
sarcopenia has some multifactorial causes associated with increase blood perfusion to these areas [46]. High-flavanol
the following imbalances:
cocoa has also been shown to improve memory by stimu-
55 Hormonal changes (decreased levels of testosterone,
human growth hormone, DHEA, etc.) lating the input region of the hippocampus, the dentate
55 Chronic inflammation gyrus [47]. In addition to a bigger and healthier hippocam-
55 Ectopic fat deposition pus, MET stimulates the production of brain-derived neu-
55 Decreased satellite cell health rotrophic factors (BDNFs) that appear to influence energy
55 Blunted responses to anabolic stimuli
metabolism, appetite, and important aspects of neurocog-
55 Decreased metabolism
55 Inactivity nitive function [48]. Not only that, but a study from
Karolinska Institute in Stockholm has shown that there is
indeed an antidepressant effect from running that is asso-
ciated with an increase of hippocampal cells [49]. In addi-
Without MET, especially strength training, both muscle tion to the benefits to the hippocampus, different types of
mass and strength decline every year after the age of 50, and MET affect different parts of the brain. According to a
it accelerates after age 70. Muscle mass declines at the aver- Canadian study of elderly women, resistance training had a
age rate of 0.9% in men and 0.65% per year in women after more profound effect on staving off cognitive decline com-
age 75, doubling the rate of loss per year from 10 to 15 years pared to exercise programs designed to tone and balance
earlier. Loss of muscle mass is usually more pronounced in the body [50].
the lower extremities, an influential factor in age-related According to an article by Teal Burrell, different types of
functional impairment there. This often results in move- exercises affect different parts of the brain to a lesser and
ment restriction, poor quality of life, disability, and mortal- stronger degree [51]. Neuroimaging techniques such as
Nutrition with Movement for Better Energy and Health
609 35
MRI and SPEC scans confirm the positive influences of during and after your 2–3 toughest weight training, SIT, or
increased blood flow to the brain. Some of these effects HIIT sessions. A plant-based healthy diet and the daily intake
include improved performance across cognitive domains of omega-3 supplements and good multivitamin and mineral
and core functions that improve executive decisions [52]. supplements are a great complement to your exercise plan for
Dr. Daniel Amen, a neurologist who has done more than decreasing the risk of inflammation and injury.
120,000 SPEC scans, affirms the strong positive effects of
MET and other lifestyle improvements as highly restorative 35.3.2.3   nique Considerations for
U
for damaged or low-­functioning brains. MET gives us bet- Nonalcoholic Fatty Liver Disease
ter cognition and protection against dementia, and there is NAFLD
a dose-response relationship [53, 54]. Not only does MET Like many other recognized lifestyle diseases, such as diabe-
sharpen the aging mind, it keeps people happier in their tes, cardiovascular disease, and dementia, nonalcoholic fatty
golden years. The elderly who do MET have less depression, liver disease is increasing in epidemic proportions where cul-
better moods, higher self-esteem, and self-confidence. They tures have adopted the modern lifestyle of inactivity and
also sleep better, enjoy more energy, and have better resil- indulgence in junk foods. These problems have seen a dra-
ience [55]. matic increase in the last 20 years all over the world in places
that have adopted the Western lifestyle. In the United States
35.3.2.2  Unique Considerations for Sarcopenia alone, the increase has been dramatic, increasing by 170% in
Consistent exercise training is the primary treatment to pre- the brief period of 2004–2013 [60].
vent and affect sarcopenia. A balance of endurance and pri- The 2004 documentary film, Super Size Me, by Morgan
marily strength exercises at least 3 days per week is usually Spurlock demonstrated the power of junk foods and healthy
effective. It is never too late to start. Older people get just as foods on our health outcomes and specifically on the
much out of MET as younger people [56]. Casual walks and increase and decrease of liver enzymes. This movie brought
light physical activity will not do much for reversing sarcope- the message loud and clear that the intake of substances
nia. A study on the elderly in Iceland illustrated that moder- other than alcohol can elevate your liver enzymes and
ate to vigorous physical activity is needed to be done threaten your health. In the movie, the host was shocked
consistently at least three times per week for effective results that eating three fast food meals daily resulted in elevated
on the elderly [57]. liver enzymes within a few weeks, starting on the path of
The older one is the more important it is to engage in liver pathology. A healthy plant-based diet reversed this
muscle sparing and muscle building. In a 1994 study pre- progression within several months. Not only has a plant-
sented in The New England Journal of Medicine, high-­intensity based diet been demonstrated to reverse fatty liver damage,
resistance exercise training is shown to be a feasible and so have many herbs, phytonutrients, and exercise training.
effective means of countering muscle weakness and physical Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic
frailty in very elderly people. In contrast, multi-nutrient steatohepatitis (NASH) have been shown to be very respon-
supplementation without concomitant exercise does not sive to diet, exercise training, and nutritional supplements.
reduce muscle weakness or physical frailty [58]. Lifestyle therapies have been shown to have a positive effect
The best approach is to engage in endurance training, on decreasing the progression of this common and rising
strength training, and yoga or stretching for flexibility, bal- chronic disease process.
ance, and core strength. When possible, Nordic walking is There are studies showing the ability of herbs and nutri-
preferable to normal walking. Walking at a more strained ents in protecting liver cells. Isoflavone-rich supplements
rate with poles helps activate more muscles, your metabo- alone have been shown to protect against fatty liver disease
lism, and more hormones. Taking a 30–60-minute walk daily through various pathways which modulate fructose produc-
is great, but make it a power walk or Nordic-power walk tion, fatty acid β-oxidation, lipid synthesis, and oxidative
every other day. If you swim, bike, row, or run, make every stress [61]. In addition, studies show there can be beneficial
other session a moderate to vigorous one and make sure to effects of probiotics and prebiotics in protecting liver cells
warm up before and after. Three sessions of 45–60  minute from development of NAFLD by regulating the intestinal
moderate to vigorous workouts per week that include barrier function [62].
strength training and HIIT or SIT seem to be a great goal to Different kinds of MET, whether endurance, strength,
shoot for, since it both deals with the ravages of sarcopenia HIIT, or flexibility and balance, have been shown to have
and puts the brakes on brain aging. Remember though the positive effects on degeneration due to the improved milieu
12–12 goal: 12 hours a day sleeping and sitting and 12 hours surrounding and within the tissue. The increase in oxygen
standing and moving. and nutrients are used for restoration and regeneration of
The combination of exercise training and supplementa- liver cells and tissue. One study by Takahashi shows that
tion reinforces the effects each can have on improving resistance exercise comprising squats and push-ups helps to
strength, balance, and speed. Protein, creatine, vitamin D, improve the characteristics of metabolic syndrome in patients
and calcium together showed a positive effect [59]. Sufficient with nonalcoholic fatty liver disease [63].
protein drinks during or after the workout will help build Endurance training, such as aerobic swimming training,
muscle. Use branched-chain amino acids or whey protein can prevent NAFLD via the regulation of fatty acid trans-
 610 P. Wilhelmsson

port-, lipogenesis-, and β-oxidation-associated genes. In 35.3.2.7  Unique Considerations

addition, the benefits from aerobic swimming training were for Parkinson’s
achieved partly through the PANDER-AKT-FOXO1 path- More and more Parkinson’s (PD) patients are turning to the
way [64]. gym and their bicycles to improve their disease symptoms
and the quality of their lives. Results can be astounding and
35.3.2.4   nique Considerations for Spinal
U powerful sometimes, as reported by many doctors and
Cord Injuries patients and in a study reported in the Clinical Journal of
The practice and science of the rehabilitation of spinal cord Sports Medicine. “The results of the present research synthe-
injuries, accidents, and traumas have been investigated thor- sis support the hypothesis that patients with PD improve
oughly in the last century. The advances during the last their physical performance and activities of daily living
decade of advanced stem cell and other modern techniques through exercise. Future studies should include the develop-
are a big boost to the tried-and-tested combination of physi- ment of standardized exercise programs specific for prob-
cal therapy, MET, therapeutic modalities, and surgery to lems associated with PD as well as standardized testing
bring relief for spinal cord injuries, to help accident-injured methods for measuring improvements in PD patients” [72].
patients, or to work athletes back into shape. Many studies
have been done over the years to show the advantage of the 35.3.2.8  Unique Considerations for MS
value of combining physical therapy, movement, and pulse It is not only walking that is important for multiple sclerosis
current for injury and trauma rehab [65]. (MS) patients but walking downhill may be even more help-
Another study shows the value of MET for not only help- ful. The stimulation and firing of certain nerves and muscle
ing with a spinal cord injury but the other pathologies or groups during downhill walking seem to have a powerful
risks that can accompany the injury. The increased risk of effect. According to a study reported in International Journal
cardiovascular - and other chronic disease in persons of MD Care 2016 “After the intervention, significant improve-
inflicted with spinal cord injuries can be improved by consis- ment was found in the downhill group versus the uphill
tent MET [66]. group in terms of fatigue, mobility, and disability indices;
The goals of physical therapy and MET should be not
35 only to improve function after accidents, handicaps, or inju-
functional activities; balance indices; and quadriceps isomet-
ric torque (P <0.05). The results were stable at 4-week follow-
ries but also to decrease the risk of chronic diseases that can ­up” [73].
increase in the future.
35.3.2.9  Unique Considerations
35.3.2.5  Unique Considerations for Schizophrenia
for Rheumatoid Arthritis RA MET seems to be very beneficial for those afflicted by
MET especially resistance and strength training, has been schizophrenia, especially resistance training, according to a
shown to be a safe and effective means of restoring muscle study from Brazil. “In this sample of patients with schizo-
mass and functional capacity in patients with established and phrenia, 20 weeks of resistance or concurrent exercise pro-
chronic rheumatoid arthritis (RA). The authors of a study of gram improved disease symptoms, strength, and quality of
the effects of resistance training for appropriate RA patients life [74].
recommend programs similar to theirs be included in disease
management [67].
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2014;20(23):7381–91. www.­ecotherapyheals.­org
63. Takahashi A, Abe K, Usami K, et al. Simple resistance exercise helps www.­ecsm.­org. ACSMs Exercise Management for Persons with Chronic
patients with non-alcoholic fatty liver disease. Int J Sports Med. Diseases and Disabilities 3rd edition.
2015;36(10):848–52. www.­i deafit.­c om/fitness-library/hiit-vs-continuous-endurance-
64. Wu H, Jin M, Han D, Zhou M, Mei X, Guan Y, Liu C. Protective effects training-battle-of-the-aerobic-titans
of aerobic swimming training on high-fat diet induced nonalco- www.­richardlouv.­org
holic fatty liver disease: regulation of lipid metabolism via PANDER-­ www.­shinrin-yoku.­org
AKT pathway. Biochem Biophys Res Commun. 2015;458(4):862–8.
 613 36

Mental, Emotional,
and Spiritual Imbalances
Muffit L. Jensen

36.1 Mind-Body Techniques – 614

36.2 Six Common Mind-Body Techniques – 614

36.2.1  euro Emotional Technique (NET) – 614
N
36.2.2 Biofeedback – 615
36.2.3 Neurofeedback – 615
36.2.4 Cognitive Behavioral Therapy – 615
36.2.5 Emotional Freedom Technique (EFT) – 616
36.2.6 Hypnotherapy – 616

36.3 Summary – 616

References – 617

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_36
 614 M. L. Jensen

After careful review of the Functional Medicine Matrix (IFM

Matrix) and the Medical Symptoms Questionnaire (MSQ),
you have determined that part of the patient’s clinical picture
has an emotional or mental component. Along with the nutri-
tional treatment plan, the patient may require another form of
care or a multidisciplinary approach. If this is the case, it is
time to consider some form of psychotherapy or a type of Mind Body
complementary or alternative mind-body medicine. In order
to understand how the brain affects the body, creating or Whole
potentiating illness, we must examine some of the research. Wellness
Research of modern mind-body medicine dates back to
the 1960s, although the concept has been recognized as far
back as Hippocrates.
»» Disease is not an entity, but a fluctuating condition of Spirit
the patient’s body, a battle between the substance of the
disease and the natural self-healing tendency of the
body. –Hippocrates

A psychiatrist, George Solomon, began to investigate the

impact that emotions had on inflammation and the immune
system in general. This new field was called psychoneuroim- ..      Fig. 36.1  The overlap of integrating mind, body, and spirit to
create whole wellness
munology [1].
Dr. Candace Pert (1946–2013) was a significant contribu-
tor to the emergence of mind-body medicine as an area of
legitimate scientific research in the 1980s. She has been called techniques are to reduce stress hormone levels and to reset
“The Mother of Psychoneuroimmunology” and “The Goddess emotional cellular memory, so that the body is better able to
of Neuroscience” by her many fans. To her colleagues, she fight off illness.
36 was an internationally recognized neuroscientist and phar- Some conditions that mind-body techniques may be
macologist who published more than 250 research articles helpful for include:
and many books on how the brain, endocrine, immune sys- 55 Anxiety
tem, and many other organs and systems interact to create 55 Asthma
disease processes or with the correct interventions create 55 Autoimmune disorders
wellness through peptide/receptor cellular communication. 55 Cancer
“A feeling sparked in our mind or body will translate as a 55 Coronary heart disease
peptide being released somewhere. Brain, organs, tissues, 55 Depression
skin, muscle and endocrine glands all have peptide receptors 55 Fibromyalgia
on them and can retrieve, repress or store emotional infor- 55 General eating disorders
mation (memories) and or behaviors,” she wrote. “You can 55 Hypertension
access emotional memory anywhere in the peptide/receptor 55 Insomnia
network in any number of ways. I think unexpressed emo- 55 Menopause
tions are literally lodged in the body [2].” 55 Mental health issues
Emotions, largely ignored within the traditional confines 55 Obesity
of science and medicine, are actually the key to understand- 55 Pain (acute and chronic)
ing psychoneuroimmunology and its emerging picture of 55 Poststroke
how the body and mind affect each other. By examining and 55 Stomach and intestinal problems
treating the triad of mind, body, and spirit, we can close the 55 Weight loss
gap and acquire a positive result that of whole wellness
(. Fig. 36.1).
 

36.2  Six Common Mind-Body Techniques

36.1  Mind-Body Techniques 36.2.1  Neuro Emotional Technique (NET)

Mind-body techniques aid in the management of pain and 36.2.1.1  What Is It?
many other diseases because they reduce anxiety, encourage NET uses a methodology of finding and removing neuro-
relaxation, improve coping skills, and ease tension. Managing logical imbalances related to the physiology of unresolved
stress will decrease stress hormones and increase good emo- stress. NET is a tool that can help improve many behavioral
tion-modulating neuropeptides. The goals of mind-body and physical conditions.
Mental, Emotional, and Spiritual Imbalances
615 36
36.2.1.2  How Does It Work? learn to make changes so subtle that at first, they cannot be
NET is based on the physiological foundations of stress-­ consciously perceived. With practice, the new responses and
related responses. As discovered in the late 1970s, emotional behaviors can help to bring relief and improvement to a vari-
responses are composed of neuropeptides (amino acid ety of disorders.
chains) and their receptors, which lie on neurons and other
cells of remote tissues in the body. The neuropeptides are
ejected from the neuron and carry the encoded information 36.2.3  Neurofeedback
to other sites within the body. These neuropeptides are in a
category of neurochemicals known as Information Substances 36.2.3.1  What Is It?
(IS), which are released at times of stress-related arousal and Neurofeedback is a natural, self-regulating approach that
become attached to remotely positioned neuroreceptors. helps restore the brain’s ability to function in the way it was
Significantly, this process also happens when a person recalls designed to function. Also known as EEG biofeedback, brain
to memory an event in which a stress originally occurred. training and brain computer interface (BCI), neurofeedback
This is a key factor in the NET treatment. Thus, the physio- utilizes the operant conditioning learning model to achieve
logical status of the body is emotionally replicating a similar self-regulation. Additionally, monitoring the brain’s bioelec-
physiological state that was found in the original condition- trical system also advises us of chemical activity within the
ing event by the process of remembering. It is at this point brain. It is a safe, noninvasive, painless learning procedure
that the practitioner applies the principles of the technique to during which sensors are placed on the surface of the patient’s
then “reset/erase” the original event through the nervous sys- head.
tem. This technique is highly effective, although currently
taught to chiropractors, acupuncturists, and psychothera- 36.2.3.2  How Does It Work?
pists only. This technique is worth a co-­referral to a trained A neurofeedback session involves the client sitting in a com-
practitioner within the interdisciplinary team. fortable chair in a quiet room. He or she will have electrodes
The ONE Research Foundation was established in 1993 placed on the area of the scalp where the training will occur,
by Neuro Emotional Technique (NET) founder Scott which is determined by the QEEG interpretation. The sen-
Walker, D.C., to raise funds for research to demonstrate sors record brain electrical activation levels and enable par-
empirically the validity of the BioPsychoSocial (BPS) model ticipants to learn to improve mental performance, normalize
as an effective methodology for intervening in a broad behavior, and/or stabilize mood. The information is displayed
spectrum of physical, emotional, and psychological condi- on a computer screen, together with sounds, which change
tions. The ONE Research Foundation (ONE) is comprised according to the brain’s activity levels. Therefore, the patient
of individuals who are committed to the natural noninva- can read, understand, and influence his or her brainwave
sive healing of the mind and body. ONE is a nonprofit activity. Once the patient learns to access and regulate the
501(c)(3) dedicated to making these natural methods avail- brain more effectively, symptoms begin to improve or perfor-
able to all as the standard of care [3]. mance optimizes. The visual feedback on the computer
screen and auditory feedback through speakers or head-
phones are positive reinforcement. Creating these reward
36.2.2  Biofeedback parameters involves skill and training. It is perhaps the big-
gest breakthrough in noninvasive medicine in the last
36.2.2.1  What Is It? 50 years.
Biofeedback is a noninvasive drug-free form of treatment. It Medical conditions that have been found to benefit most
is a process that enables an individual to learn how to change from neurofeedback assessment and treatments include
physiological activity for the purposes of improving health autism, ADHD/ADD, mood disorders, postanesthesia, head
and performance. Precise instruments measure physiological injury, PTSD, sleep interruption, and stroke rehabilitation [4].
activity such as heart function, breathing, muscle activity,
and skin temperature. These instruments rapidly and accu-
rately “feedback” information to the user. The presentation of 36.2.4  Cognitive Behavioral Therapy
this information, often in conjunction with changes in think-
ing, emotions, and behavior, supports desired physiological 36.2.4.1  What Is It?
changes. Over time, these changes can endure without con- Cognitive behavioral therapy is a psychosocial intervention
tinued use of an instrument. that is among the most widely used evidence-based practices
for treating mental disorders. Guided by empirical research,
36.2.2.2  How Does It Work? CBT focuses on the development of personal coping strate-
The therapist attaches sensors or electrodes to the body. gies that target solving current problems and changing
These sensors provide a variety of readings  – feedback  – unhelpful patterns in cognitions, behaviors, and emotional
which is displayed on equipment, usually a television moni- regulation. It was originally designed to treat depression and
tor, for the patient to see. With this information, patients can is now used for a number of mental health conditions.
 616 M. L. Jensen

36.2.4.2  How Does It Work? emotional intensity. Proponents of EFT and other similar
Cognitive behavioral therapy requires the patient and ther- treatments believe that tapping/stimulating acupuncture
apist to work as a team, collaborating to solve problems. points provides the basis for significant improvement in
Rather than waiting for problems to get better after talking psychological problems [6].
about them repeatedly from week to week, patients can
take an active role in their own treatment, using self-help
assignments and CBT tools between sessions to speed up 36.2.6  Hypnotherapy
the process of change. Each session is focused on identify-
ing ways of thinking differently and unlearning unwanted 36.2.6.1  What Is It?
reactions. Hypnotherapy is a form of psychotherapy that is used to cre-
In adults, CBT has been shown to have effectiveness ate subconscious change in a patient in the form of new
and a role in the treatment plans for anxiety disorders, responses, thoughts, attitudes, behaviors, or feelings. It is
depression, eating disorders, chronic low back pain, per- undertaken with a subject in hypnosis.
sonality disorders, psychosis, schizophrenia, and sub-
stance use disorders, in the adjustment, depression, and 36.2.6.2  How Does It Work?
anxiety associated with fibromyalgia and with postspinal The therapist consults with clients to determine the nature
cord injuries [5]. of their problems and prepares them to enter a hypnotic
state by explaining how hypnosis works and what they will
experience. He or she will then induce the client into a hyp-
36.2.5  Emotional Freedom Technique (EFT) notic state using individualized methods and techniques of
hypnosis based on interpretation of test results and analysis
36.2.5.1  What Is It? of the client’s problem. A person who is hypnotized displays
Emotional freedom technique, also known as tapping. certain unusual behavior characteristics and propensities,
EFT combines the physical benefits of acupuncture with compared with a non-hypnotized subject, most notably
the cognitive benefits of the traditional talk therapy for a heightened suggestibility and responsiveness. The goal of
much faster result. Most aspects of our lives are not work- hypnotherapy is to increase motivation or alter behavior
ing the way we would like due to a disruption in the body’s patterns. The therapist may train the client in self-hypnosis
36 energy system. This may be from a past trauma or memo- conditioning.
ries which cause negativity, anxiety, stress, physical pain,
and unresolved emotional issues. EFT is an amazing heal-
ing tool and can help reset the subconscious mind and 36.3  Summary
eliminate old beliefs that patients may not realize they are
holding onto. The above techniques are only a few of the many wonderful
complementary techniques available. See . Fig. 36.2 for other
 

36.2.5.2  How Does It Work? suggestions. Although some modalities do not have a strong
According to the EFT manual, the procedure consists of the evidence base, they have historical recognition of value, some
participant rating the emotional intensity of their reaction as far back as thousands of years in traditional medical prac-
on a Subjective Units of Distress Scale (SUDS) (a Likert tice. Just because they are not researched in a RCT format
scale for subjective measures of distress, calibrated 0–10) doesn’t mean that they are not highly effective. The way we
and then repeating an orienting affirmation while rubbing live, how we think, what we eat, and how we feel affect our
or tapping specific points on the body. It’s a similar approach health. The value of these therapies as part of the patient’s
to acupuncture, but instead of needles, we tap on the main treatment plan is truly worthwhile. You may be asking at this
energy spots on our body, called meridians, to release nega- point, “what technique should I choose for the patient?” The
tive emotions. Some practitioners incorporate eye move- simple answer is: the best technique is the one that the patient
ments or other tasks. The emotional intensity is then likes and will do. Always remember, “there is a cork for every
rescored and repeated until no changes are noted in the bottle.”
Mental, Emotional, and Spiritual Imbalances
617 36

Meditation

Tai Chi
Chiropractic

Reflexology
Prayer
Massage

Acupuncture

Qi Gong Salt Rooms

Aroma Therapy
Yoga
Spiritual
Guidance
FlowerEssences
Reiki

Stress
Music Therapy Reduction

Breathing
Techniques

..      Fig. 36.2  Further suggestions for mind-body techniques not discussed that are commonly used in integrative medicine

References
4 . Psychology Today. Neurofeedback. 2019. https://www.­
psychologytoday.­com/us/therapy-types/neurofeedback. Accessed
March 2019.
1. Solomon GF, Moos RH. Emotions, immunity, and disease: a specula-
5. Cognitive behavioral therapy. (n.d.). Retrieved 19 July 2017, from
tive theoretical integration. Arch Gen Psychiatry. 1964;11:657–74.
Wikipedia: The Free Encyclopedia: http://en.­wikipedia.­org/wiki/
2. Pert C. Molecules of emotion: the science behind mind-body medi-
Cognitive_behavioral_therapy.
cine (paperback). New York: Simon & Schuster; 1999.
6. Hypnotherapy. (n.d.). Retrieved 19 July 2017, from Wikipedia: The
3.
NetMindBody. Home page. https://www.­netmindbody.­com/.
Free Encyclopedia: http://en.­wikipedia.­org/wiki/Hypnotherapy.
Accessed March 2019.
 619 III

IFMNT Nutrition Care

Process
Contents

Chapter 37 The IFMNT Practitioner – 621

Robin L. Foroutan

Chapter 38 The Patient Story and Relationship-Centered Care – 633

Leigh Wagner

Chapter 39 The Nutrition-Focused Physical Exam – 637

Mary R. Fry

Chapter 40 Modifiable Lifestyle Factors: Exercise, Sleep,

Stress, and Relationships – 695
Margaret Christensen

Chapter 41 Developing Interventions to Address Priorities: Food,

Dietary Supplements, Lifestyle, and Referrals – 715
Aarti Batavia

Chapter 42 Therapeutic Diets – 743

Tracey Long and Leigh Wagner

Chapter 43 Dietary Supplements: Understanding the Complexity of

Use and Applications to Health – 755
Eric R. Secor

Chapter 44 Clinical Approaches to Monitoring and Evaluation of the

Chronic Disease Client – 769
Cynthia Bartok and Kelly Morrow

Chapter 45 Ayurvedic Approach in Chronic Disease

Management – 783
Sangeeta Shrivastava, Pushpa Soundararajan,
and Anjula Agrawal
 621 37

The IFMNT Practitioner

Robin L. Foroutan

37.1 Who Is the IFMNT Practitioner? – 622

37.2 What About Their Approach Sets Them Apart? – 622

37.3 The Functional Medicine Matrix – 624

37.4  pportunities for Education (Certification, Credentialing,

O
and Other Accredited Programs) – 624

37.5  ajor Advocate for Development of IFMNT: Dietitians

M
in Integrative and Functional Medicine (DIFM) – 625

37.6 Standards of Practice and Professional Performance – 627

37.7 The IFMNT Radial – 628

37.7.1  ey Area: Food, Lifestyle, Environment – 628
K
37.7.2 Key Area: Nutrition Physical Signs and Symptoms – 628
37.7.3 Key Area: Biomarkers – 629
37.7.4 Key Area: Metabolic Pathways & Networks – 630
37.7.5 Key Area: Systems – 630
37.7.6 Precipitating Factors – 630
37.7.7 IFMNT Radial Summary – 630

37.8 Summary – 630

References – 631

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_37
 622 R. L. Foroutan

37.1 Who Is the IFMNT Practitioner? started to revolutionize medical institutions in ways that
were difficult to imagine only a decade ago.
Integrative and Functional Medical Nutrition Therapy Integrative and Functional  Medicine has become better
(IFMNT) is a term championed by the Executive Committee accepted by both conventional institutions and health profes-
of Dietitians in Integrative and Functional Medicine sionals in recent years, further encouraging the growth and
(DIFM), a dietetic practice group of the Academy of interest of the Integrative-Functional Medical paradigm, of
Nutrition and Dietetics. DIFM and others in the Integrative which IFMNT is an important part. One example is the
and Functional Medicine arena have used IFMNT as a spe- recent opening of the Cleveland Clinic’s Center for Integrative
cific approach to medical nutrition therapy (MNT) that & Lifestyle Medicine, with its expressed dedication to address
incorporates both Integrative and Functional Medicine “the increasing demand for integrative healthcare by
methodology  to deliver a “food as medicine” approach researching and providing access to practices that address the
to nutrition care. This style of care requires education and physical as well as lifestyle, emotional, and spiritual needs of
training beyond the core nutrition curriculum that exists patients.” Similarly, New  York Presbyterian created the
for traditionally trained medical and allied healthcare prac- Integrative Health and Wellbeing program in conjunction
titioners, such as the required educational competencies for with Weill Cornell Medical Center, which employs an inter-
registered dietitians-nutritionists as determined by the disciplinary team including medical doctors, registered dieti-
Accreditation Council for Education in Nutrition and tian nutritionists, licensed acupuncturists, and nurses. These
Dietetics (ACEND), the accrediting body of the Academy types of institutions have the potential to measurably change
of Nutrition and Dietetics. the kind of health and medical interventions available to the
The basic tenet of this emerging area of healthcare centers public on a large scale.
on optimizing nutritional status and correcting underlying
system imbalances by establishing nutritional therapies that
enable the body to function optimally. Because IFMNT 37.2  hat About Their Approach Sets
W
interventions are nutrition-based therapies rooted in dietary Them Apart?
interventions and dietary and herbal  supplements, the
IFMNT-trained nutrition professional is poised to play a In contrast to a conventional, symptom- or disease-cen-
critical role in this medical paradigm. This version of diet tered approach to medicine, Integrative and Functional
therapy is relatively new, and much of the growth and Medicine practitioners offer a different approach; the prac-
momentum of Integrative and Functional Medicine, includ- titioner works in partnership with the patient  to identify
37 ing IFMNT, grew as a result of consumer demand. In response the underlying causes and metabolic  imbalances driving
to this call for a more thoughtful and natural approach to the symptoms and disease state. The integrative and func-
healing, paired with a growing body of evidence lending cre- tional medical model uses evidence-based research to pro-
dence to IFMNT practices, an increasing number of medical vide patient-­ centered care in order to create a unique
professionals are seeking out opportunities to become trained personalized care plan based on each person’s specific envi-
and proficient in IFMNT. ronment, lifestyle, and genes [3]. A major component of
Among dietitians and nutritionists, interest in this spe- environment is a person's diet, and nutrient status is a rec-
cialty area of nutrition and health is high, as demonstrated by ognized  determining factor for health. Thus, the founda-
the exponential growth of DIFM.  Yet the information and tion of any integrative and functional intervention rests
specific training necessary to deliver IFMNT have not yet firmly on dietary habits and optimizing nutritional status.
widely trickled down to the student level in most accredited This is where IFMNT comes in. IFMNT represents the
dietetics programs [1, 2]. In recent years, many more oppor- same kind of patient-centered approach for the nutrition
tunities for learning have become available to nutrition pro- professional. This approach moves away from a one-size-
fessionals, a trend that is sure to continue across disciplines. fits-all methodology to nutrition and wellness, acknowl-
Dietitians and certified nutritionists are not the only edging and harnessing  the body’s innate ability to heal
IFMNT practitioners. IFMNT practices have been employed itself, given the right conditions. An IFMNT practitioner
and embraced by many other healthcare providers, including recognizes  that optimal health is more than simply the
medical doctors, naturopathic doctors, osteopaths, physician absence of disease.
assistants, nurses and nurse practitioners, chiropractors, and To provide patient-centered care, an IFMNT practitioner
licensed acupuncturists. Organizing bodies, such as the gathers information by listening to the patient’s story, look-
Holistic Nurses Association, exist across disciplines and ing for hints and clues about the etiology of the underlying
serve to bring together those practicing under similar phi- imbalances that trigger symptoms. The focus is on the whole
losophies. Because many different types of medical profes- person, who is more than simply a patient with a disease.
sionals are practicing Integrative or Functional Medicine or Establishing a therapeutic relationship between patient and
are interested in offering these services to their patients, the practitioner is important and promotes healing (see
IFMNT provider can function independently in a private 7 Chap. 6). An individual’s beliefs, attitudes, and motivations
 

practice setting or as part of an Integrative/Functional are all considered relevant to physical and emotional well-
Medicine team. In fact, these interdisciplinary teams have being and are typically explored as part of the “story.” The
The IFMNT Practitioner
623 37
­mind-­body-­spirit connection is not only acknowledged but
honored by IFMNT, (see 7 Chap. 36) as well as physical,
  Chronic Insufficiency versus Nutrient Deficiency
social, and lifestyle factors unique to each person. In fact, the Overt nutrient deficiencies resulting in long latency
concept of individuality is at the forefront of IFMNT. deficiency diseases are a public health concern, yet these
Voluntary actions such as decision-making, emotional deficiency diseases (such as rickets, beriberi, and scurvy,
responses, stress responses, and lifestyle habits are taken into the deficiency diseases of vitamin D, thiamin, and vitamin
account, yet so are involuntary actions within the microenvi- C, respectively) are rare in the United States and Canada
ronment of the body, such as nutrient metabolism and [5]. However, established lower limits for what is consid-
absorption, cellular functions, and interactions between ered “within normal limits” for specific nutrients may fall
organ systems, largely influenced by genetic variability and well outside the optimal range for ideal metabolic
epigenetic influences. functioning. In fact, suboptimally low levels of these
Aside from an individual’s dietary and lifestyle choices, same vitamins (vitamin D, thiamin, and vitamin C) are
which influence overall health, people have unique metabolic often seen in clinical practice. Lab values that fall on the
patterns based on genetics and epigenetic influences that high or low edges of normal limits are typically over-
affect nutrient requirements. The interactions between diet, looked in conventional medicine. Practitioners may be
genes, and environment are considered and evaluated as part inadvertently missing opportunities to optimize nutrition
of an IFMNT practitioner’s approach. Even a minor imbal- status, allowing nutrient chronic low-level insufficiencies
ance in the body can trigger a cascade of biological effects to contribute to long-term chronic disease risk [6].
that may eventually lead to presentation of symptoms, com- Because nutrients serve as cofactors for all biochemi-
promised health, or chronic disease. For example, chroni- cal processes in the body, IFMNT acknowledges that
cally low-normal vitamin D may contribute to osteoporosis, chronically low or suboptimal levels of certain nutrients
poor immune function, and other consequences. Chronically may indeed take a toll on human health by inhibiting or
low-normal vitamins B12, B6, and folate can result in hyper- slowing down metabolic processes. While chronic
homocysteinemia, which increases the risk for cardiovascu- nutrient insufficiencies may trigger minor signs and
lar disease and blood clots. Inadequate vitamin B12 status is symptoms of metabolic imbalances – even in the
also linked with fatigue, depression, and anxiety disorders. absence of overt disease states – diminished nutrient
This is why IFMNT practitioners utilize a wide range of status over the long term can trigger progression into
assessment tools and measures, including a nutrition-focused chronic diseases. The integrative and functional medical
physical examination and laboratory data, in an effort to model maintains that there are consequences to
determine nutrient status. These same tools also help to iden- insufficient nutrient status over time, such as mitochon-
tify key system imbalances that may contribute to symptoms drial decay and increased DNA damage [4]. Therefore,
and influence metabolism and health. Rather than suppress a IFMNT practitioners may favor optimal ranges when
metabolic function to mask a symptom, the goal of IFMNT is evaluating nutrient laboratory data, rather than relying
to restore optimal metabolic function to promote health and on conventional laboratory reference ranges, which are
healing. Therefore, the focus is on true healing: the reversal of based on plus or minus two standard deviations of levels
the metabolic disruptions that influence a disease process observed in the general population. In line with recog-
and create symptoms, not just managing or masking symp- nizing genetic individuality and person-centered care,
toms. This focus is at the heart of IFMNT. functional lab testing may be used in addition to
In order to address underlying metabolic disturbances at conventional blood chemistries to provide more specific
play, an IFMNT practitioner is well-versed in biochemical information as to whether nutrient cofactors are present
processes and nutritional biochemistry. These metabolic in levels that are optimal for a specific individual.
pathways are complex and reliant on nutrient cofactors to
operate optimally. Even slight nutrient  deficiencies or
“chronic insufficiencies” left uncorrected over a long period
of time can disrupt metabolic function. According to the tri- Laboratory Data for the IFMNT Practitioner
age theory developed by Bruce N.  Ames, when faced 55 Conventional biomarkers may include:
with  chronic  nutrient deficiency or insufficiency,  the body 55 Complete blood count (CBC)
must prioritize available micronutrients to support the func- 55 Complete metabolic panel (CMP)
tions most critical to survival and reproduction. This priori- 55 Serum nutrient status (e.g., vitamins, minerals)
tization  occurs at the expense of the functions  that protect 55 Red blood cell nutrient status (e.g., magnesium, zinc)
against future cellular damage and aging. [4, 15]. This is how 55 Kidney and liver function tests
chronic insufficiencies can contribute to acceler- 55 Cholesterol panels
ated  aging,  chronic disease, physiological stress, and 55 Homocysteine levels
chronic  inflammation over years. The effects of nutrients, 55 Ammonia levels
and thus nutrient deficiencies and chronic insufficiencies, in 55 Uric acid levels
metabolic pathways are important for an IFMNT practitio- 55 Heavy metals
ner to understand (see 7 Chap. 46).
 
 624 R. L. Foroutan

vidual’s biochemical uniqueness in order to personalize

55 Fatty acids panel medical care.  Functional Medicine practitioners consider
55 Amino acids panel the complex interactions between genetic predispositions,
55 IgE food allergy panels environmental factors, diet, and lifestyle to assess, prevent,
55 Genetic information may include: and treat chronic disease.
55 Single nucleotide polymorphisms (e.g., MTHFR, IFM represents one of the major leaders educating health-
VDR, COMT) care providers in the theories and practices of Integrative and
55 Haplotypes (e.g., celiac disease hap- Functional Medicine. There are several qualified organiza-
lotpes HLA-DQ2 and HLA-DQ8) tions that offer educational programs, certification courses,
55 Functional testing may include: and publications in Functional Medicine (see Resources). As
55 Digestive stool analyses such, IFM developed the first assessment tool, the Functional
55 Microbial stool analyses Medicine Matrix. The Matrix serves as architecture for orga-
55 Organic acids panel nizing the complexity of each case to synthesize information
55 White blood cell micronutrient status and create target interventions for patient care. It offers a
55 Methylmalonic acid (MMA) unique system for homing in on clinically relevant informa-
55 Formiminoglutamic acid (FIGLU) tion that is part of the patient’s “story” and helps the practi-
55 Non-IgE food sensitivity panels tioner organize the information to help clarify the complex
interactions between symptoms that are characteristic of
chronic disorders. It provides a framework to aid the practi-
Once the subjective and laboratory information is gathered, tioner in identifying  and interpreting  the various factors
an IFMNT practitioner may use both conventional and inte- involved in promoting health and preventing disease in each
grative therapies, as appropriate. Integrative and functional individual (. Fig. 37.1).
 

approaches are generally employed to focus on identifying The Functional Medicine Matrix is divided into three
the root causes of symptoms and diseases to focus on pre- main parts: (1) the patient’s story, (2) an assessment of life-
ventive or restorative care. Traditional, non-Western, style factors, and (3) physiological assessments, observations,
approaches may also be used, such as principles of and other signs of clinical imbalances. The patient’s story is
Traditional Chinese Medicine or Ayurveda. The IFMNT further delineated into three subsections: antecedents and
practitioner will make use of any evidence-based approach, predispositions, the “triggering event(s),” and mediators that
whether from conventional or alternative medicine prac- appear to contribute to the patient’s medical condition, health
37 tices. Modalities such as food elimination diets and dietary crisis, or current set of symptoms. Lifestyle assessments,
supplements (e.g.,  vitamins, minerals, herbs, botanicals, referred to as fundamental lifestyle factors, include dietary
probiotics) are commonly used, as are metabolic detoxifica- habits, exercise, sleep, relationships, and life meaning and
tion support  and digestive support programs. Because purpose, with the latter including attitudes and core beliefs.
IFMNT practitioners recognize the value of mind-body Biological and physiological assessments are represented in
interventions, they may also recommend other modalities the largest section, “Clinical Imbalances Found in the
such as yoga, Qigong, meditation, guided imagery, sound Functional Organizing Systems.” This section is where sys-
healing, and healing touch. Whatever the treatment plan, tems data are aggregated and analyzed, including informa-
IFMNT practitioners use their vast  knowledge of tion such as inflammatory biomarkers, body composition,
the  dynamic interaction between biological systems and lab test results, toxicity/detoxification, and physiological
biochemical  pathways, nutrient status, biochemical indi- imbalances. Integrated throughout is the understanding that
viduality, genetics, and epigenetics  to create an effective, the mind-­body-­spirit connection influences each individual
holistic nutrition care plan [7]. patient and must be honored. The Functional Medicine
Matrix represents one of the first assessment tools for
Functional Medicine practitioners.
37.3 The Functional Medicine Matrix

“Functional Medicine,” as a concept, was proposed by 37.4 Opportunities for Education

Jeffrey Bland, PhD, in the early 1980s. Through his vision (Certification, Credentialing,
and leadership, the Institute of Functional Medicine (IFM) and Other Accredited Programs)
emerged. As with Integrative Medicine, Functional
Medicine seeks to address the underlying causes of disease For many years, RDNs and other nutrition professionals were
states and uses a systems biology-oriented approach that primarily self-taught in the concepts and practices of
recognizes the interconnectedness and interplay between Integrative and Functional Medicine, as there had been a lack
the various organ systems, while aiming to foster a thera- of accredited programs that offered comprehensive educa-
peutic relationship between patient and practitioner [3]. tion around IFMNT. With the exception of Bastyr University
Particular attention is paid to acknowledging each indi- in Seattle, WA, the University of Kansas Medical Center in
The IFMNT Practitioner
625 37

FUNCTIONAL MEDICINE MATRIX

Retelling the Physiology and Function: Organizing the Patient’s Clinical Imbalances
Patient’s Story

Antecedents Assimilation Defense & Repair

(e.g., Digestion, (e.g., Immune,
(Predisposing Factors— Absorption, Microbiota/Gl, Inflammation,
Genetic/Environmental) Respiration) Infection/Microbiota)

Mental Emotional
e.g., cognitive e.g., emotional
Structural Energy
function, regulation, grief,
Integrity (e.g., Energy
perceptual sadness, anger,
Triggering Events (e.g., from Subcellular Regulation,
patterns etc.
(Activators) Membranes to Mitochondrial
Musculoskeletal Function)
Structure) Spiritual
e.g., meaning &
purpose,
relationship with
Communication something
Biotransformation
Mediators/Perpetuators (e.g., Endocrine, & Elimination
greater
(Contributors) Neurotransmitters, Immune (e.g., Toxicity,
messengers) Detoxification
Transport
(e.g., Cardiovascular, Lymphatic System)

Modifiable Personal Lifestyle Factors

Sleep & Relaxation Exercise & Movement Nutrition Stress Relationships

Name: Date: CC: © 2015 Institute for Functional Medicine

Version 3

..      Fig. 37.1  Functional Medicine Matrix. (Used with permission from The Institute for Functional Medicine ©2015)

Kansas City, KS, and the Certified Nutrition Specialist (CNS) ­ edical systems, such as Traditional Chinese Medicine and
m
credential, recognized and accredited programs were in short Ayurvedic Medicine. In 2009, the group changed its name to
supply. In the 1990's, other trailblazers developed programs DIFM to better reflect its role in the emerging Integrative and
for healthcare professionals with a focus on nutrition, such as Functional Medicine community. As of 2019, DIFM has
The University of Arizona Andrew Weil Center for Integrative more than 5,500 members consisting of RDNs, dietetic tech-
Medicine and IFM.  Fortunately, the tides have shifted, and nicians (DTRs), dietetic interns, and students interested in
several accredited programs now offer advanced degrees in practicing an integrated and personalized approach to health
IFMNT, as well as a multitude of certifications and other and healing.
training courses (. Table 37.1).
 

Dietitians in Integrative and Functional Medicine

37.5  ajor Advocate for Development
M (DIFM) Mission and Vision [8]
of IFMNT: Dietitians in Integrative 55 Vision: Optimize health and healing with integra-
and Functional Medicine (DIFM) tive and functional nutrition
55 Mission: Empower members to be leaders in
A subgroup of the Academy of Nutrition and Dietetics (for- integrative and functional nutrition
merly the American Dietetic Association), Dietitians in 55 Values: Innovation, integrity, and compassion
Integrative and Functional Medicine (DIFM) had been pre-
viously known as Nutrition in Complementary Care. It was
originally established in 1998 by a group of like-minded DIFM’s contribution to the field of IFMNT has been vast. It
dietitians interested in expanding their skills in topics such as offers members opportunities for continuing education and
functional foods, dietary supplements, and alternative rolled out a certification program in 2017.
 626 R. L. Foroutan

..      Table 37.1  List of IFMNT Training Programs

Organization Educational Opportunities

Academic Programs and Degrees

Bastyr University Bachelors of Science degrees in:

Nutrition
Nutrition & Culinary Arts
Nutrition & Exercise Science
Combined program in Nutrition and Didactic Program in Dietetics
Herbal Sciences
Masters of Science degrees in:
Nutrition Research
Combined program in Nutrition and Didactic Program in Dietetics
Nutrition and Clinical Health Psychology
Non-degree Dietetic Internship

Maryland University of Integrative Health Doctoral Degree in Integrative Nutrition (online)

Masters Degree in Nutrition and Integrative Health

Rutgers University Masters of Science (MS) Degree in Health Science Integrative Health and Wellness

University of Bridgeport Masters of Science in Nutrition (online)

Dual degree, Masters of Science in Nutrition and Doctor of Naturopathic Medicine
Bachelors of Science in Nutrition

University of Kansas School of Health Profes- Non-degree: graduate certificate: Dietetics and Integrative Medicine (DIM) 12 hour
sions, Departments of Integrative Medicine and certificate (online)
Dietetics and Nutrition Degree: Dietetic Internship Fellowship and MS in Dietetics & Nutrition with Integrative
Nutrition emphasis

Certificate, Accreditation and Training Programs

Academy of Nutrition and Dietetics Integrative and Functional Nutrition Certificate of Training Program (online)

Arizona Center for Integrative Medicine iHELP Program

37 Bauman College Nutrition Consultant Training Program (online option)

Certified Nutrition Specialist (CNS) Board for Certification of Nutrition Specialists (BCNS) American College of Nutrition
(CAN)
(MS or PhD eligible)

Certified Clinical Nutritionist (CCN) Clinical Nutrition Certification Board (CNCB)

International and American Association of Clinical Nutritionists (IAACN)

Duke University Integrative Health Coaching Certification

Institute for Functional Medicine Institute for Functional Medicine Certification Program (IFMCP)
Applying Functional Medicine in Clinical Practice (AFMCP)
Introduction to Functional Nutrition Course (online, free)

Integrative and Functional Nutrition Academy Integrative and Functional Nutrition Certified Practitioner (IFNCP) Advanced Practice
(IFNA) Credential (online)
 IFNCP Certificate of Training (online)

Next Level Functional Nutrition IFMNT Integrative and Functional Nutrition Foundations Course (online)
IFMNT Certificate of Training Program (online)
Advanced Studies (online)

Rutgers University Graduate certificates available in Complementary and Alternative Medicine

Graduate certificate in Health Coaching
Graduate Certificate in Integrative Medicine Research

University of Kansas School of Health Profes- Graduate Certificate: Dietetics and Integrative Medicine (DIM) 12 hour certificate
sions, Departments of Integrative Medicine and (online)
Dietetics and Nutrition

University of Miami Integrative and Complementary Academic Medicine: Clinical Nutrition Conference
Series
The IFMNT Practitioner
627 37

Practice Settings
SCREENING & REFERRAL SYSTEM
on
borati Skil
• Identify risk factors Colla ls &C
• Use appropriate tools and methods om
pe
• Involve interdisciplinary collaboration te
nc
01 ies

ge
led
ow
Nutrition Assessment & Re- Nutrition Diagnosis

Kn
Assessment • P - Identify problem
s
tic • Obtain / collect important and • E - Determine etiology / cause
iete

relevant data • S - State signs & symptoms

Com
&D

• Analyze / interpret collected data

munic
n
Nutritio

Health Care Systems

ation
Economics

Individual / Population
04 Interacts with 02
Nutrition Professional

Nutrition Monitoring & Nutrition Intervention

Co d e

ce
Evaluation • Determine intervention and

c ti
• Select or identify quality prescription

Pra
of E

indicators • Formulate goals and determine

sed
t hi

• Monitor & Evaluate resolution action

cs

of diagnosis • Implement action

-ba
ce
iden
Ev
03
Do
cu
me
nta ing
tion Th ink
C r iti c a l
OUTCOMES MANAGEMENT SYSTEM
Social Systems
• Research NCP
• Use aggregated data to conduct research
• Conduct continuous quality improvement
• Calculate and report quality indicators

..      Fig. 37.2  Nutrition Care Process and model. (Reprinted from Swan et al. [13]. With permission from Elsevier)

37.6  tandards of Practice and Professional

S steps are designed to facilitate safe and effective nutrition ser-
Performance vices, promote evidence-based practice, and serve as a frame-
work for critical thinking and decision-making for all RDNs
In 2011, DIFM developed and published core competencies in all settings [7, 9, 14] (. Fig. 37.2). 

as part of their Standards of Process (SOP) and Standards of Also previously described by the Academy of Nutrition
Professional Performance (SOPP), establishing an official and Dietetics are the Standards of Professional Performance
framework to guide the practice and performance of regis- (SOPP), which detail competency levels for credentialed
tered dietitian nutritionists (RDNs) practicing IFMNT. These RDNs and standards of professional behavior. The SOPP are
were updated and revised in  2019. The SOP for IFMNT designed to serve as guides for self-evaluation and to assess
builds upon the previously established four steps of the one’s own individual performance. They also serve as tools to
Nutrition Care Process, which provides a general framework determine additional education and skills necessary to
for the nutrition professional to personalize care and tailor advance one’s individual level of practice [10]. These tools
interventions to each individual. First described by the allow the RDN to continually evaluate his and her own over-
Academy of Nutrition and Dietetics and published as part of all competency by the self-evaluation of skills, learning,
the Nutrition Care Model, the four steps of the Nutrition training, education, and existing knowledge, as well as
Care Process  (NCP) are nutrition assessment, diagnosis, responsibility and accountability in the practice of nutrition
intervention, and, finally, monitoring and evaluation. These and dietetics [11].
 628 R. L. Foroutan

for critical thinking facilitates the shared  decision-making

Steps in the Nutrition Care Process process between patient and practitioner and offers a special-
The Nutrition Care Process includes the following steps [9]: ized version of the NCP for the IFMNT practitioner. Its cir-
55 Nutrition assessment: Collection and documentation cular architecture signifies the multidirectional motion and
of information, including health history, biochemical interrelationships between all aspects of health, imbalances,
data, labs and medical test results, previous medical and disease states.
evaluations, information from a nutrition-focused At the center of the Radial is the NCP, as the focal point of
physical, anthropometric data, and diet record any IFMNT practice is to provide personalized nutrition care.
55 Diagnosis: Information collected from the The steps in providing this care are assessment, diagnosis,
nutrition assessment is synthesized in the intervention, monitoring, and evaluation. The imagery in the
selection of appropriate nutrition diagnoses center circle depicts food as a determining factor in health
55 Intervention: The RDN will determine the appropri- and disease. Surrounding the center circle are five circles rep-
ate nutrition intervention to address the root cause resenting each of the five key  factors to evaluate a per-
of the problem with the goal of alleviating signs and son’s  health:  Diet,  lifestyle and environment; signs and
symptoms of the previously determined diagnoses symptoms; biomarkers; metabolic pathways; and biologi-
55 Monitoring/evaluation: Monitoring and evaluation cal systems to consider. Since IFMNT recognizes that each of
are used to determine if the patient is making these areas is influenced by a person’s biochemical and genetic
progress toward or has achieved established goals uniqueness, the imagery of DNA and microbiota strands link
the five key areas together signifying that each of these areas
is  interconnected, with any imbalance of one potentially
The SOPP are divided into several specific standards, with affecting  the others.  Additional influences to be considered
each standard describing a focus area  or domain meant to include precipitating factors, including stress and belief sys-
serve as a guide for self-evaluation and professional develop- tems, toxic exposure, pathogens and infections, and allergens
ment.  The six domains of professional performance pub- and intolerances.  These potentially  antagonistic  factors all
lished in the 2019 SOPP are as follows: quality in practice, affect metabolism and overall health [7, 14] (. Fig. 37.3).
 

competence and accountability, provision of services, appli-

cation of research, communication and application of knowl-
edge, and utilization and management of resources.  These 37.7.1  ey Area: Food, Lifestyle,
K
standards are to be used by RDNs as a guide for self-­evaluation Environment
37 and demonstrating competence, and as a roadmap to expand
their practice and identify areas for  professional develop- The food, lifestyle and environment area  represents the
ment. Each focus area standard has several indicators or patient’s “story” and a subjective description of overall habits,
quantifiable actions that explain how each standard might be which an IFMNT practitioner must consider as part of the
used. The DIFM-developed SOP/SOPP can help determine NCP.  Since food choices are an important determinant of
whether an RDN is qualified to provide IFMNT and clearly health and disease, food preferences, access to foods, culture,
describes the skills, knowledge, education, and competencies and traditions are major factors to be discussed and under-
required to safely and effectively provide quality IFMNT. It stood by the practitioner. It also includes the health of those
further allows RDNs to categorize themselves as one of three around the patient, how often he or she exercises and moves,
competency levels of practice: competent practitioner, profi- sources and levels of stress, and the coping methods each
cient practitioner, and expert practitioner [14]. person uses. It may include his or her access to nature, fresh
In order to further support IFMNT practitioners, expert air, and the amount of sunlight they are exposed to on a regu-
RDNs Kathie Swift, Diana Noland and Elizabeth Redmond lar basis, as well as the kinds of relationships they have in
developed the IFMNT Radial,which was published as part of their lives. Tools utilized might include a questionnaire or
the 2011 SOP/SOPP and revised in 2018. The Radial custom- nutrition intake survey, food frequency questionnaire, or a
ized the NCP for the IFMNT practitioner and incorporates food record. This is where the practitioner might begin to
the key factors at the core of IFMNT, facilitating the evalua- determine various triggers, antecedents, or precipitating fac-
tion of complex information using the NCP [14]. It repre- tors related to the present health concern [7, 12].
sents the first of such tools developed specifically for the
IFMNT practitioner.
37.7.2  ey Area: Nutrition Physical Signs
K
and Symptoms
37.7 The IFMNT Radial
A major feature of IFMNT is the nutrition-focused physical
Published within the SOP/SOPP in 2011  and updated in exam, which enables the practitioner to assess and evaluate
2018, three  expert IFMNT practitioners established a signs and symptoms. Visual symptoms can be clinically rele-
visual conceptual framework to aid RDNs in implementing vant, such as skin color, texture and moisture, and the appear-
IFMNT in their practice. This patient-/client-centered model ance of the tongue and nails. Other tools employed here
The IFMNT Practitioner
629 37

Allergens Stress
& Intolerances
Food
Lifestyle
Environment

COMMUNITY

Nutrition
Systems IT Physical Signs
Personalized

BOD
& Symptoms
SPIR

Nutrition Care

Y
Assessment
Diagnosis
Intervention
Monitoring
M Evalution
IN H
Pathogens D RT Toxins
EA

Metabolic
Pathways Biomarkers
& Networks

©2010, 2018 Copyright. All Rights Reserved. KM Swift, D. Noland, E.Remond

..      Fig. 37.3  Integrative and Functional Medical Nutrition Therapy (IFMNT) Radial. (Courtesy of Kathie Madonna Swift, Diana Noland, Elizabeth
Redmond)

might include a multi-system questionnaire or other clinical impacting health, as does more advanced functional testing
signs and symptoms as described by the patient. From this for macro- and micronutrient status. These and other labora-
information, the IFMNT practitioner can glean a systems tory measurements  are critical to IFMNT practice because
analysis. In other words, this key area helps to shed light on they seek information on how well metabolic pathways are
body systems that may require support, such as digestive, functioning. Each of these pathways is driven by complex
endocrine, immune, nervous, reproductive, or detoxifica- molecular cascades that are largely reliant on nutrient cofac-
tion/biotransformation systems [7, 12]. tors that can be measured either with conventional or func-
tional testing. Other influencers of these metabolic pathways
include things like accumulated toxins, heavy metal interfer-
37.7.3 Key Area: Biomarkers
ence, digestion and absorption issues, dysbiosis, and single
nucleotide polymorphisms that can be measured using spe-
Biomarkers are of considerable importance to any practitio-
cialty labs and functional diagnostic testing [7, 12].
ner, including those practicing IFMNT. Biological measure-
ments, such as anthropometrics, vital signs, and laboratory
data, are used to help shed light on abnormalities reported by 37.7.3.1  Examples of Conventional Tests
the patient or identified as part of the  nutrition-focused 55 Waist-hip ratio
physical exam. Conventional biomarkers, such as blood and 55 BMI
urine tests, can be used to evaluate nutrient status and look 55 Blood tests (e.g. complete blood count (CBC), compre-
for nutrient insufficiencies and deficiencies that may be hensive metabolic panel (CMP), vitamin and mineral
 630 R. L. Foroutan

levels, immunoglobulin markers, cholesterol panel, way, the “systems” area clarifies the opportunities for inter-
homocysteine, thyroid panel, iron panel, food allergy vention and allows the practitioner to prioritize each inbal-
panels, MTHFR, high-sensitivity C-Reactive Protein ance and intervention.
(CRP), hemoglobin A1C, sedimentation rate) Major system imbalances may include disruption in cel-
55 Urinalysis (e.g. iodine levels, selenium levels, bacteria lular integrity, digestion, detoxification, energy metabolism,
count, white blood cells, red blood cells, glucose, ketones) oxidative stress and inflammation, nutritional status, immune
system, endocrine systems, cardiovascular, and neurological
37.7.3.2  Examples of Functional Tests systems [7].
55 Organic acids testing
55 Genomics (e.g., MTHFR, VDR, GST, COMP, 23andMe,
lipoprotein(a), detoxification panel, apoE) 37.7.6 Precipitating Factors
55 Digestive and microbial stool analyses
55 Provoked urinary heavy metal testing Linking each circle of the Radial are microbial and  DNA
55 Food sensitivity testing strands with examples of precipitating factors that influence
55 Salivary cortisol testing overall health, resilience, and predisposition to illness. In this
55 Salivary hormone testing way, all areas of the Radial are interconnected and influenced
55 Dried urine hormone testing by each person's unique biochemistry and genetics. Each per-
son's individual genome, epigenome and microbiome influ-
ences their health and biology in unique and complicated
37.7.4  ey Area: Metabolic Pathways
K ways. Some  of these factors include stress, toxic exposure,
& Networks infection and pathogens, and allergies and intolerances [14].
Once the IFMNT practitioner has made a comprehensive
Metabolic pathways are the biological machinery of the body, assessment, including all relevant aspects of the Radial, he or
and overall health depends solely on how well these pathways she can develop a treatment plan that prioritizes the areas
run. The metabolic pathways of the body are driven by where the most important system imbalances lie. In terms of
enzymes, the biological catalysts that trigger the conversion the Radial, this will be the circles with the greatest number of
of one molecule to another. These enzymes are dependent on dysfunctions, specifically those that are triggers of the
micronutrient cofactors, which can be measured and assessed patient’s primary symptoms and health concerns [12].
by examining biomarkers. Even a subclinical micronutrient
37 insufficiency can have a disruptive effect on metabolic path-
ways because the body prioritizes available micronutrients 37.7.7 IFMNT Radial Summary
for the most important biological functions. Micronutrient
insufficiencies may be insignificant in the short term but over The IFMNT Radial provides a framework for the IFMNT prac-
time can contribute to the development of chronic condi- titioner to be thorough and organized in prioritizing informa-
tions, poor antioxidant status, increased oxidative stress, pre- tion. It also helps the practitioner identify where further
mature aging, and a compromised ability to heal from injury investigation is warranted. Organizing findings in this way can
or illness. Understanding nutritional biochemistry allows the help the practitioner examine clinical findings into key imbal-
IFMNT practitioner to better understand and recognize ances, further clarifying underlying causes of disease and symp-
micronutrient imbalances, suboptimal metabolic processes, toms from a systems biology approach. In this way, the Radial is
and the potential effects on the present state of health [7, 12]. “a model for critical thinking that embraces both the science
This area focuses attention on assessing the integrity of and the art of personalized nutrition care with considerations of
the metabolic pathways to identify any core imbalances that multiple conventional or complementary care disciplines” [7].
may be present. By reviewing biochemical markers and path-
way intermediaries, the IFMNT practitioner gathers infor-
mation on metabolic pathway functionalities, which can 37.8 Summary
then be interpreted within the context of the patient’s current
health status [12]. An increase in demand for a more natural, holistic approach to
healing, as well as the growing body of evidence supporting the
safety and efficacy of Integrative and Functional Medicine prac-
37.7.5 Key Area: Systems tices, has driven the expansion of Integrative and Functional
Medicine practitioners. Because nutrition and diet modifica-
The systems area serves to summarize and synthesize the tion are the foundation of Integrative and Functional Medicine
findings from the other key areas and clarifies their overall interventions, the growth in IFMNT-­trained practitioners and
effect on health status. By using the Radial, the IFMNT prac- those seeking training has also grown exponentially. Many
titioner can identify the various causes that contribute to a healthcare providers have embraced IFMNT practices across
specific malady, as well as identifying core imbalances that disciplines, bringing nutrition and MNT as a modality for heal-
may be the root cause of several different symptoms. In this ing to the forefront of Integrative and Functional Medicine.
The IFMNT Practitioner
631 37
References 8. Dietitians in integrative and functional medicine: annual report
2015–2016. http://integrativerd.­org/wp-content/uploads/2012/04/
DIFM_DPG_Annual_Report_2015-­2016_FINALIZED.­pdf. Accessed
1. Swift KM. The changing landscape of nutrition and dietetics: a spe-
26 March 2017.
cialty group for integrative and functional medicine. Integr Med.
9. eatrightPRO. Nutrition care process. 2017. http://www.­eatrightpro.­
2012;11(2):19–20.
org/resources/practice/nutrition-care-process. Accessed 20 March
2. Wagner LE, Evans RG, Noland D, Barkley R, Sullivan DK, Drisko J. The
2017.
next generation of dietitians: implementing dietetics education
10. eatrightPRO.  Standards of practice. 2017. http://www.­eatrightpro.­
and practice in integrative medicine. J Am Coll Nutr. 2015;34(5):
org/resources/practice/quality-management/standards-of-­
430–5.
practice. Accessed 20 March 2017.
3. The Institute for Functional Medicine. Functional Medicine deter-
11. Focus area standards for CDR specialist credentials. J Acad Nutr
mines how and why illness occurs and restores health by address-
Diet. 2017. http://www.­andjrnl.­org/content/credentialed. Accessed
ing the root causes of disease for each individual. https://
20 March 2017.
www.­functionalmedicine.­org/Patients/WhatisFM/. Accessed 28
12. Dean S.  Introduction to Integrative and Functional Nutrition, pre-
March 2017.
sented at CDA Annual Conference, 2015. http://www.­dietitian.­
4. Ames BN. Prevention of mutation, cancer, and other age-­associated
org/d_cda/docs/annual_mtg_2015/conference_handouts/
diseases by optimizing micronutrient intake. J Nucleic Acids.
thu4-­9-­15/Dean_IntroductionIFN.­pdf. Assessed 5 Feb 17.
2010;2010:725071. https://doi.org/10.4061/2010/725071.
13. Swan WI, Vivanti A, Hakel-Smith NA.  Nutrition care process and
5. Centers for Disease Control. CDC’s Second Nutrition Report: a
model update: toward realizing people-centered care and out-
comprehensive biochemical assessment of the nutrition status
comes management. J Acad Nut Diet. 2017;117(12):2003–14.
of the U.S. population. https://www.­cdc.­gov/nutritionreport/pdf/
14. Diana Noland, Sudha Raj, (2019) Academy of Nutrition and Dietet-
4page_%202nd%20nutrition%20repor t_508_032912.­p df.
ics: Revised 2019 Standards of Practice and Standards of Profes-
Accessed 28 March 2017.
sional Performance for Registered Dietitian Nutritionists
6. Heaney RP. Long-latency deficiency disease: insights from calcium
(Competent, Proficient, and Expert) in Nutrition in Integrative and
and vitamin D. Am J Clin Nutr. 2003;78(5):912–9.
Functional Medicine. Journal of the Academy of Nutrition and
7. Ford D, Raj S, Batheja RK, et al. American Dietetic Association: stan-
Dietetics 119 (6):1019-1036.e47
dards of practice and standards of professional performance for
15. Bruce N.  Ames, (2018) Prolonging healthy aging: Longevity vita-
registered dietitians (competent, proficient, and expert) in integra-
mins and proteins. Proceedings of the National Academy of Sci-
tive and functional medicine. J Am Diet Assoc. 2011;111(6):902–
ences 115 (43):10836-10844
913.e1–23. ­https://doi.org/10.1016/j.jada.2011.04.017.
 633 38

The Patient Story and

Relationship-Centered Care
Leigh Wagner

38.1  atients, Providers, the Therapeutic Approach,

P
and Relationship-Centered Care [1] – 635
38.1.1 “ PEECE” in Practice – 635
38.1.2 The Patient’s Story and the Institute for Functional
Medicine Matrix – 635
38.1.3 Patient Example – 636

References – 636

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_38
 634 L. Wagner

A defining feature of integrative and functional medicine is can be honed over time. It is also important to keep in mind
the careful collection of the patient’s story. The patient’s that the story will continue to develop as the patient works
story builds on the conventional (acute) medical model of with the practitioner.
gathering a patient’s past medical history, history of present There are several goals of gathering a comprehensive
illness, review of systems, and accounts for the complexity patient story: (1) identifying antecedents, triggers, and
of chronic disease. This information can illustrate to the cli- mediators that impact the patient’s health; (2) establishing a
nician and the patient how the patient’s life events and therapeutic relationship between practitioner and patient
health story have contributed to their health status at the by building trust and rapport with the patient; (3) having a
time of the consultation. starting point and reference for the provider and the patient
The importance of the patient story is emphasized by the to build on during future appointments; (4) identifying any
idea that integrative and functional medicine practitioners barriers or challenges that the patient might have (e.g., poor
treat each patient from the perspective of the “N of 1,” mean- community or family support, physical, psychological, or
ing that the practitioner views the patient as an individual emotional challenges); (5) creating a sense of hopefulness
and takes into account the nuances of the patient’s metabo- in the patient and the provider that there are therapeutic
lism, lifestyle, genetics, stressors, and environment. Thus, options for a patient who may have lost hope in any other
each patient is considered his or her own control when evalu- medical options; and (6) informing the patient of the inter-
ating the effectiveness of a therapy or treatment. vention plan.
Gathering a useful patient story requires a clinician to The Institute for Functional Medicine (IFM) Matrix illus-
ask careful questions that the patient might find culturally trates the complex and comprehensive information gathered
and personally sensitive [1]. The way a practitioner performs from the patient (. Fig. 38.1). The IFM Matrix is a guide for
 

the patient interview can determine whether patients feel learning about the patient’s health story from the standpoint
comfortable enough to share their stories and follow the rec- of mechanism history. This means that the practitioner asks
ommended plan of care. The practitioner’s interviewing skill about the patient’s health from the perspective of chronic

FUNCTIONAL MEDICINE MATRIX

Retelling the Physiology and Function: Organizing the Patient’s Clinical Imbalances
Patient’s Story
Assimilation Defense & Repair
38 Antecedents
(Predisposing Factors—
(e.g., Digestion, (e.g., Immune,
Absorption, Microbiota/Gl, Inflammation,
Genetic/Environmental) Respiration) Infection/Microbiota)

Mental Emotional
e.g., cognitive e.g., emotional
Structural Energy
function, regulation, grief,
Integrity (e.g., Energy
perceptual sadness, anger,
Triggering Events (e.g., from Subcellular Regulation,
patterns etc.
(Activators) Membranes to Mitochondrial
Musculoskeletal Function)
Structure) Spiritual
e.g., meaning &
purpose,
relationship with
Communication something
Biotransformation
Mediators/Perpetuators (e.g., Endocrine, & Elimination
greater
(Contributors) Neurotransmitters, Immune (e.g., Toxicity,
messengers) Detoxification
Transport
(e.g., Cardiovascular, Lymphatic System)

Modifiable Personal Lifestyle Factors

Sleep & Relaxation Exercise & Movement Nutrition Stress Relationships

Name: Date: CC: © 2015 Institute for Functional Medicine

Version 3

..      Fig. 38.1  Functional Medicine Matrix. (Used with permission from The Institute for Functional Medicine ©2015)
The Patient Story and Relationship-Centered Care
635 38
disease mechanisms and core imbalances. In other words, not a cure is possible for a patient’s condition, the provider
the practitioner can fill in the components of the IFM matrix can always give encouragement and help guide the patient
as the patient tells his or her story. toward healing and wellness, if the patient sees that as an
The patient story is both a narrative and a means to note important goal.
patterns that can provide clues to metabolic imbalances. It
also informs the patient’s intervention plan.
38.1.1  “PEECE” in Practice
38.1   atients, Providers, the Therapeutic
P Rakel and Fortney describe the concept of “PEECE” in clini-
Approach, and Relationship-Centered cal practice in their chapter on “The Healing Encounter” in
Care [1] the textbook “Integrative Medicine” [1]. The acronym stands
for Positive prognosis, Empathy, Empowerment, Connection,
There are distinct roles that providers and patients take with and Education. Positive prognosis refers to the concept of
respect to the therapeutic approach to healing. Patients are hope and enhancing positive patient expectations. Empathy
expected to take an active role in their own healing. One of and connection enhance the feeling of being cared for by the
the most important aspects of the provider and patient is the practitioner. Empowerment and education give the patient
therapeutic relationship between the two parties. Relationship-­ motivation to seek health-promoting behaviors.
centered care lowers overall healthcare costs [2, 3].
Providers see themselves as a navigator for the patient,
who is the pilot of their own healthcare. Providers also take 38.1.2   he Patient’s Story and the Institute
T
into account the beliefs and cultural nuances of each patient for Functional Medicine Matrix
and understand the healing journey is unique to each indi-
vidual [1]. Providers help patients overcome barriers to well- One method of organizing and seeing the influence of the
ness and healing. In addition to educating, mentoring, and patient’s story on his or her own health is by using the
coaching patients, providers typically live their own thera- Institute for Functional Medicine’s (IFM) Matrix [5]
peutic, healthy lifestyle; they do this for various reasons: [1] (. Fig. 38.1). The IFM Matrix is a tool that can help the clini-
 

to empathize with the changes the patient is being asked to cian record and visualize the impact of the patient’s story on
make, [2] to live a healthy lifestyle to be able to best care for his or her health. On the left perimeter of the matrix, the cli-
themselves and their patients, and [3] to best guide patients nician is prompted to ask the patient to retell his or her life
on their healing journey. and health story. The clinician can record this in a timeline
The therapeutic approach to healing involves a holistic format or can make notes in each of these categories:
mind-body-spirit view. The mind accounts for the patient’s 55 Antecedents (predisposing factors – genetic/environ-
mental health and knowledge base, especially regarding the mental).
understanding of his or her own lifestyle choices and their 55 Triggering events (activators).
impact on their health outcomes. The body is probably where 55 Mediators/perpetuators (contributors).
conventional healthcare spends most of its focus, checking
anthropometrics (height, weight, body mass index), blood In an IFM presentation, Dr. Dan Lukaczer, ND, [6] describes
pressure, cholesterol levels, and other measurable changes. antecedents as “factors, genetic or acquired, that predispose
Integrative and functional practitioners also incorporate [an] individual to an illness.” He defines triggers as “factors
mind-body and spiritual aspects into the care plan. Spirituality that provoke the symptoms and signs of illness” and media-
can encompass religion, spiritual practices, mindfulness and/ tors/perpetuators as “factors, biochemical or psychosocial,
or meditation, and even the patient’s community support. that contribute to pathological changes and dysfunctional
Each one of these aspects of the mind, body, and spirit is responses.” Examples of antecedents, triggers, and mediators
acknowledged as contributing to the patient’s well-being, include stress, infections (chronic or acute), toxic exposures,
which the provider often conveys to the patient. foods, and allergens, sensitivities, and/or intolerances.
The therapeutic approach to healing also includes The clinician can use the central part of the matrix to
evidence-­based practice that encompasses three facets [4]: record, organize, and visualize the patient’s clinical imbal-
55 The patient’s goals and vision for health. ances: assimilation, structural integrity, communication,
55 Evidence in the scientific literature. transport, biotransformation and elimination, energy,
55 The practitioner’s clinical experience. defense, and repair. In the middle of the matrix, the practitio-
ner is reminded of the importance of the patient’s mental,
Combined, these three aspects of evidence-based healthcare emotional, and spiritual health. Along the bottom border of
can be weighed through gathering the patient’s story and the matrix, the clinician is reminded of the modifiable life-
through the therapeutic relationship. Evidence is also col- style factors that should be reviewed with the patient to find
lected from a variety of sources. out where excesses or deficiencies might appear. These life-
Ultimately, compassion and support are critical to the style factors include sleep, relaxation, exercise, movement,
healing encounter between provider and patient. Whether or nutrition, stress, and relationships. While listening to the
 636 L. Wagner

patient’s story, the clinician can fill in the information on the that she was, in fact, deficient in omega-3 fats and vitamin D
matrix to create a visual to work from and create a personal- was deficient at 17  ng/dl. The patient’s story helped inform
ized plan of care for the patient. what was driving the hives to persist; it led the practitioner to
consider the mechanisms of inflammation and immune dys-
regulation, which can be affected by the eicosanoid cascade
38.1.3  Patient Example (omega fatty acids) and vitamin D’s effect on the immune sys-
tem. The family history of hives in her son following milk
A 30-year-old woman visits with persistent hives. She has seen ingestion advises the practitioner to also check food sensitivi-
her primary care physician, a dermatologist, and an allergist ties in the patient. After successful reintroduction of deficient
and has tried several creams and medications. She has some micronutrients and food elimination, the hives resolved.
relief of her symptoms, but she still has hives. She sought out a
consultation from an integrative and functional dietitian, who
References
asked her about the onset of her symptoms (prior to and dur-
ing her two pregnancies) and her triggers (stress and pressure 1. Rakel D, editor. Integrative medicine. 3rd ed. Philadelphia: Elsevier;
on her skin). She said the hives would persist for weeks, and 2012.
several would develop while others were healing. After getting 2. De Maeseneer JM, De Prins L, Gosset C, Heyerick J. Provider continu-
the patient’s medical background, she shared that she hates ity in family medicine: does it make a difference for total health care
costs? Ann Fam Med. 2003;1(3):144–8.
and avoids all fish and seafood (antecedent/mediator) and
3. Safran DG, Miller W, Beckman H. Organizational dimensions of rela-
that her son has skin rashes when he drinks cow’s milk. She tionship-centered care. J Gen Intern Med. 2006;21 Suppl 1:S9–15.
also says that the symptoms persisted after the birth of her 4. Spring B. Evidence-based practice in clinical psychology: what it is,
second child. A mechanistic understanding of the essential why it matters; what you need to know. J Clin Psychol. 2007;63(7):
fatty acid/eicosanoid pathway helps illustrate how the patient’s 611–31.
5. Jones DS, editor. Textbook of functional medicine. Gig Harbor: The
story may give clues for laboratory testing for the patient and
Institute for Functional Medicine; 2010.
a means to intervene. The dietitian recommended nutritional 6. Lukaczer D, editor. Clinical integration and the Functional Medicine
lab testing: high-sensitivity C-reactive protein (hsCRP), vita- Matrix part 1. Federal Way, WA: Institute for Functional Medicine;
mins D, B12, folate, and an omega-3 index. The labs showed 2015.

38
 637 39

The Nutrition-Focused
Physical Exam
Mary R. Fry

39.1 Background/Introduction – 638

39.2 Conclusion – 691

References – 692

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_39
 638 M. R. Fry

Learning Objectives A prospective Internet-based survey of registered dieti-

55 Recognize the importance of the nutrition physical exam tians in the USA reported the following as factors limiting
for both nutrition professionals (dietitians and nutrition- the incorporation of the NFPE into practice: workload
ists) and medical providers. (70.3%), lack of prior education (42.4%), and training
55 Identify signs of nutritional status and hydration from (43.5%) [9]. Regarding workload or time, 52.3% of US dieti-
physical examination. tians surveyed by Mackle et al. [10] cited time as a limiting
55 Relate pertinent physical examination findings to their factor to using the NFPE, and 25.3% cited confidence in their
nutritional (and medical) causes. ability to competently perform the NFPE.
55 Compare and contrast anthropometric measures and The majority of those surveyed reported that they did not
their clinical utility. receive sufficient training to competently perform the NFPE
on their patients, with the exception of the following assess-
ments: height (96.4% of those surveyed reported feeling
39.1  Background/Introduction competent to measure), weight (97.4% of those surveyed
reported feeling competent to measure), waist circumference
The nutrition-focused physical assessment (NFPA), also (78.0% of those surveyed reported feeling competent to mea-
referred to as the nutrition-focused physical exam (NFPE), is sure), and skinfold measurements with a caliper (65.2% of
a vital part of a nutritional assessment and forms an integral those surveyed reported feeling competent to measure) [9].
part of the nutrition care process (NCP) model, which is To date, similar analyses have not been conducted for
comprised of the following separate and consecutive steps: nutritionists in practice, but similar practice patterns and
assessment, diagnosis, intervention, monitoring, and evalua- competencies in the NFPE are likely, based on a comparison
tion [1]. The nutrition progress note for the NCP model is of the average curriculum across these professions. As it hap-
correspondingly referred to as an “ADIME” note. This model pens, the practice of integrative nutrition may be even more
was devised, in part, to ensure a comprehensive nutrition challenged in the realm of the NFPE, with a wider variety of
assessment. A nutrition-focused physical exam forms an functional tests to learn about and gain competency in, and
integral part of the NCP model assessment step, which itself with fewer opportunities for hospital-based internships
is comprised of five domains: (where a variety of NFPE skills are generally more likely to be
55 Food/nutrition-related history practiced).
55 Medical/psychological or behavioral history On the medical front, physicians’ use of the physical exam
55 Anthropometric measurements is similarly threatened or arguably underutilized. In the
55 Biochemical data/tests/procedures “Physician’s Perspective,” published in The New England
55 Nutrition-related physical findings Journal of Medicine [11], Dr. Jauhar attributes the demise of
the physical exam in medicine to a discomfort with uncer-
Findings from each of these five domains are required to sys- tainty and a fear of subjective observation. Technological
temically analyze and integrate the findings from each por- methods of diagnosis are increasingly seen as more certain
39 tion of the NCP model in order to accurately determine and legally defensible. Rathe’s commentary on the “Complete
nutritional status [1–3]. Physical” [12] concurs, stating that failure to diagnose (accu-
Furthermore, each of the steps listed above (and their rately) commonly results in medical malpractice suits.
domains) informs the subsequent step and actions to be However, proponents of the physical exam emphasize its
taken by the nutrition care professional. For example, dietary importance in supporting the development of trust, empathy,
and medical history should focus on the physical exam and and relationship-building. Verghese and Horwitz [13] con-
subsequent laboratory assessments, which can then result in tend that physicians skilled in physical exams order fewer
a clear and accurate working nutritional diagnosis (or diag- unnecessary tests and make better use of the information
noses). This diagnosis then informs and guides clinical inter- gained from these tests than counterparts who eschew or
vention and the monitoring/evaluation thereof [2–5]. limited their use of the physical exam.
Despite the critical role that the nutrition-focused phys- As to a physician’s knowledge of nutrition (since the
ical exam plays in a comprehensive nutritional assessment, emphasis of this chapter is on the nutrition-focused physical
it did not become a part of a dietitian’s (or nutritionist’s) exam), a recent review of the status of nutrition education in
practice or education until the 1990s, a full decade after the US medical schools reports that “the amount of nutrition
concept for integrating it into the nutritional assessment education medical students receive continues to be inade-
was proposed [6–9]. Despite nearly three decades passing quate” [14]. The survey conducted in this study questioned
since its integration into practice, a vast majority of dieti- nutrition educators at medical schools directly (109 sur-
tians still do not readily incorporate it into a routine patient veyed, with 105 completing the survey) and found that only
assessment [5]. 27% of the schools surveyed provided the minimum 25 hours
The Nutrition-Focused Physical Exam
639 39
of nutrition instruction recommended by the National diac and pulmonary auscultation; and an abdominal exam.
Academy of Sciences. Moreover, medical residents, recent For a more advanced practitioner, competence in performing
graduates, and practicing physicians surveyed in other stud- all of the aforementioned techniques is expected, along with
ies reported feeling ill-prepared to provide nutritional coun- the ability to conduct lymph and cranial nerve exams versus
sel and care [14]. just recognizing their components. Esper [1] describes the
The NFPE is a full head-to-toe exam of a patient in which NFPE as a system-based examination, which is similar to the
their appearance and function are assessed in order to detect physical exam performed by a licensed healthcare provider. It
any signs of malnutrition, nutrient deficiencies, or nutrient is outlined: general inspection, vitals, skin, nails, head/hair,
toxicities [5]. In the realm of integrative and functional nutri- eyes/nose, mouth, neck/chest, abdomen, and musculoskele-
tion, this can be expanded to include signs of suboptimal tal. Examination techniques employed are similar to those
organ system function and imbalances (which will be cov- utilized in a physical exam performed by a licensed health-
ered extensively in the tables associated with this chapter). care provider and include inspection, palpitation, and aus-
The goal of a NFPE is to identify factors that may impede cultation (note that percussion is seldom performed by
normal dietary intake and habits that may impact nutri- dietitians/nutritionists) [17].
tional status and/or that may reflect conditions that are Medical nutrition therapy (MNT) involves the assess-
nutritional in nature [8] or to examine the fat, muscle, fluid, ment of a patient with one or more medical conditions
and micronutrient status of a patient and whether or not it which can place an individual at nutritional risk. MNT has
is outside of normal levels as a result of inflammation, ill- been shown to decrease the duration of hospital stays and
ness, and/or excess or deficient nutrient intake [15]. decrease the need for/use of more costly medical interven-
Dietitians and nutritionists are not qualified/permitted to tions and can, in some cases, obviate the need for hospital-
diagnose medical conditions; however, they are qualified to ization [2]. Integrative and functional medical nutrition
make a nutritional diagnosis, which is defined as a condi- therapy (IFMNT) takes dietetics and medicine to another
tion that can be resolved or improved by nutrition interven- level with the focus on optimizing nutritional status to
tion [16]. The NFPE is designed to assess and diagnose optimize health and, in turn, reduce the risk of nutrition-
nutritional conditions and is to be used to inform other related disease [18].
domains of the nutritional assessment as well as to guide The IFMNT model is an extension of the NCP model.
and inform that monitoring and evaluation of a patient’s The IFMNT approach is encapsulated in the following radial,
case, enabling the nutritionist to gauge the patient’s response with the NCP’s ADIME at its core and an array of factors to
to the intervention [1, 4]. The NFPE can bring medicine, consider radiating out from this. In this chapter, a conven-
nutritional sciences, food science, and technology together tional dietetics approach to the NFPE will be covered as part
to address suspected nutrition-­related health conditions of a more extensive and integrated IFMNT approach. The
and imbalances [4]. NFPE of an integrative nutritionist is more comprehensive
The components of the physical exam were loosely and sensitive (to detect early and subtle changes that reflect
defined originally and ranged from body composition mea- suboptimal nutrient status and health) than that classically
surements (height, weight, percentage body fat, assessment taught to dietitians. Note that in the IFMNT radial below, at
of muscle tissue) to vital signs, visual assessment for clinical least three of the five factors (biomarkers, systems, signs and
signs of nutrient deficiencies, and oral, cardiac, pulmonary, symptoms) influencing nutritional status rely on NFPE find-
abdominal, and dermatological examination [8]. A more ings [19] (. Fig. 39.1).
 

current working definition of the NFPE for dietitians derived To thoroughly perform this exam, each body region is
from Touger-Decker [8] is the measurement of vital signs covered below, along with possible pertinent abnormal find-
and body composition (height, weight, and bioelectrical ings, for reference. Note that the scope and techniques
impedance analysis, among others); inspection for clinical described below extend beyond a typical NFPE performed by
signs of nutrient deficiencies; auscultation of heart, lung, and a dietitian as functional signs and techniques are included (as
abdominal signs; and examination of the head, neck, oral are, in some cases, more medically oriented techniques and
cavity, skin, and cranial nerves. Touger-Decker goes on to findings). These additional examination tools and techniques
differentiate NFPE skills into those expected of an entry-level can aid in detecting early signs of nutrient deficiency or tox-
practitioner: vital signs (pulse, blood pressure); head, neck, icity and functional imbalances that could be caused by or
and oral examination, including extraoral (lips, eyes, nose, contribute to changes in nutritional status.
ears) and intraoral (hard and soft tissue, tongue, teeth, and It is my hope that this chapter revivifies the physical exam
saliva); recognition of the components of lymph node and for dietitians, nutritionists, and other healthcare providers
cranial nerve examination; dermatologic examination for and, in so doing, fosters more comprehensive and qualitative
both nutrient deficiencies and edema; body composition nutritional and nutrition-oriented medical care and enhances
analysis (bioelectrical impedance analysis and calipers); car- the patient-provider relationship (. Table 39.1).
 
 640 M. R. Fry

The Radial: Integrative and Functional Medical Nutrition Therapy

Allergens Stress
& Intolerances Food
Lifestyle
Environment

COMMUNITY
Nutrition
Physical Signs
Systems
& Symptoms

BOD
IT

Personalized
SPIR

Nutrition Care

Y
Assessment
Diagnosis
Intervention
Monitoring
M Evalution
IN H
Pathogens D RT Toxins
EA

Metabolic
Pathways Biomarkers
& Networks

39
©2010, 2018 Copyright. All Rights Reserved. KM Swift, D. Noland, E.Remond

..      Fig. 39.1  Integrative and Functional Medical Nutrition Therapy providers (particularly those practicing functional medicine), thus
(IFMNT) Radial. These factors influence one’s function (physiologic) as facilitating collaboration and coordination of care. (Courtesy of Kathie
well as one’s nutritional status. Further, they provide a common Madonna Swift, Diana Noland, Elizabeth Redmond)
language and bridge between nutritionists/dietitians and medical
The Nutrition-Focused Physical Exam
641 39

..      Table 39.1  Nutrition-focused physical exam reference table

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

General (also This section of the physical exam is devoted to a general survey of the patient for alertness, affect, speech, coordination body
referred to as size (overweight/obese or wasting), and habitus (i.e., build – endo-, meso-, or ectomorphic) and body movements. This is
“Global where your first impressions of the patient/client are formed. You are looking to assess their overall state of health, are they
Examination”) [2] currently ill or frail, or fit or robust? Are they showing signs of mental or physical distress? What is their level of consciousness
and alertness? How are they groomed? Do you detect any unusual odor? [16] This global exam will drive what you focus on
for the remainder of your exam, so pay careful attention to these clinical findings.

Grooming [20] Poorly groomed (unkempt, Dementia

unclean clothing, and personal Psychiatric disorders (psychosis, schizophrenia in
hygiene [grooming/care of the particular)
hair, skin, teeth, mouth, overall Homelessness or poor living conditions
body]) Essential fatty acid (EFA) imbalance
Vitamin B12 status insufficiency

Clothed inappro- Cold intolerance Anemia (iron-deficient)

priately for the Low thyroid function
season [20]

Shoes untied or Pedal edema See “Edema” section below

slippers [20]

Toes of shoes cut Gout or foot ulcers

out [20] Neuropathy with burning feet
“Burning feet syndrome” – thiamine deficiency
(accompanied by peripheral neuropathy)

Body piercings or May be at increased risk of hepatitis C

tattoos [21]

Odor Body Poor hygiene (see “Grooming” above)

Disturbances in skin microflora balance [22]
Diet (spices (cumin), garlic, and onions)
Stress [23]
Steroid hormone imbalances
SNPA ABC11 538G/A or G/G polymorphism associated
with strong axillary odor with perspiration and staining
of clothes (axillary osmidrosis) [24]
Trimethylaminuria (fish malodor syndrome) is a genetic
metabolic disorder that results in an odor of decaying
fish [25]
Liver disease (ammonia)
Kidney disease (uremia)
Chronic genital infections

Breath [21, 26] Alcohol (evaluate for macronutrient status – energy,

protein, and micronutrient status: iron, thiamine,
riboflavin, pyridoxine, niacin, folate)
Fruity/acetone odor – diabetes – due to ketosis [27]
Garlic odor with selenium toxicity
Putrid – may have bacterial overgrowth in GI
Uremia with renal disease

Pain Wincing or painful grimace, Examine/evaluate the painful region or symptoms

increased perspiration, protecting further for the etiology or origins thereof
the affected area [21]

Alertness Evaluate by asking/observing the Allergies or suboptimal liver function/toxicity

patient’s awareness of their Fatigue [28]
environment and their attention Medication [28]
span Narcolepsy [28]
Attention deficit disorder/attention deficit hyperactivity
disorder [28]
Dementia [28]
Schizophrenia [28]

(continued)
 642 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Orientation Oriented to person, time, and Essential fatty acid (EFA) imbalance
place? Vitamin B12 insufficiency
Phosphorus and niacin status for insufficiency

Affect Flat Iron and vitamin B12 insufficiency

Dysthymia/depression
Hypothyroidism/suboptimal thyroid function
Schizophrenia

Speech Dentures click when talking May be related to weight loss

Pressured and/or rapid speech Hypomanic/manic (bipolar disorder)

Rule out hyperthyroidism or thyroid storm as cause

Skin color To evaluate pigmentation, check the conjunctiva, nail beds, palms (loss of crease in severe anemia),
lips, and tongue

Hyperpigmentation Niacin deficiency (with peeling in sun-exposed areas),

folate, and/or B12 deficiency [29], protein energy
malnutrition (when on extremities) [30]
Addison’s disease

Hypopigmentation Vitiligo, pallor, and anemia (iron, folate, or B12

In dark-skinned individuals, deficiency [29], arterial insufficiency)
examination of the palms and B12 deficiency (associated with vitiligo)
soles may be helpful Copper deficiency (hypopigmentation on the neck,
axilla, and/or trunk in Menkes disease) [30]

Pallor Anemia

Erythema (redness) [16, 31] Facial redness, suspect: fever, menopause, rosacea,
hyperthyroidism, niacin supplementation, caffeine,
spicy food intake, or possibly inflammation
Redness in other locations of the body may result from
inflammation, injury, rash or infection, or allergy (red
ears)
Riboflavin, zinc, and EFA deficiency [30]

39 Yellow (jaundice)
To see jaundice in the lips, blanch
Results from excess amounts of bilirubin in circulation
as a result of increased hemolysis, liver disease, or
with a glass slide or small flat glass obstruction of the flow of bile to the intestine [16]
implement If it spares the sclera (white part of the eyes), it is
It is typically first noted in the eyes carotenemia and not jaundice
and then seen in the face, mucous It can occur in pernicious anemia (vitamin B12 defi-
membranes, and eventually all of ciency) [16, 29, 31]
the skin

Orange Carotenemia – look at the palms, soles, and face. Results

from excess consumption of carotenoids

Brown [21] Sun exposure

Melasma (also known as chloasma Melasma can occur in pregnancy (and with sun
or the “mask of pregnancy”) is exposure, use of oral contraceptives)
characterized by dark, discolored Acanthosis nigricans can occur with obesity and
patches on the skin (mainly metabolic syndrome, dyslipidemia, hypertension,
facially) and is generally seen in Addison’s disease, pituitary disorders, hypothyroidism,
women of reproductive age) polycystic ovarian syndrome (PCOS), and administration
Acanthosis nigricans – velvety of growth hormones, oral contraceptives [32], with
brown-to-black markings in areas excess niacin supplementation [30]. Its presence in
of body creases (skin folds, children heralds the development of metabolic
armpits, over joints in the fingers syndrome. It can also be seen in those with lymphoma
and toes) [16] and cancers of the genitourinary or gastrointestinal
tract or from medications and nutrient supplementa-
tion (nicotinic acid) [16]. Excess niacin intake (may be
accompanied by blistering)
Hemochromatosis (iron storage disorder)
The Nutrition-Focused Physical Exam
643 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Gray Iron toxicity [30]

Cyanosis [16, 31] Decreased oxygenation of the blood (note that testing
for oxygen saturation is generally considered a more
accurate of blood oxygenation)
Central cyanosis: cyanotic lips, buccal mucosa,
tongue – see in COPD, heart disease, abnormal
hemoglobins
Peripheral cyanosis: cyanotic nail beds can occur with
exposure to cold, anxiety, CHF, Raynaud’s disease, and
venous obstruction
Hemoglobinopathy

Purpura (bruising) Vitamin C/K insufficiency

If bruising readily with trauma, may be due to essential
fatty acid (EFA) insufficiency [30]
Easy bruising – can be due to platelet disorders (aplastic
anemia), liver failure, hypersplenism (splenomegaly),
autoimmune disorders, alcoholism, and hematologic
malignancies

Use of makeup or cosmetics May affect accuracy of skin assessment (hide skin tone,
lesions, acne)
Tip: inquire about brand of cosmetics (ensure lowest
toxin cosmetics are used) [33]

Edema (peripheral) Positive pitting test: Protein, energy, zinc, and thiamine status for insuffi-
[30, 34] Depressing skin over suspected ciency
edematous area and then Low serum albumin [3]
removing pressure yields a pit that
remains for over 5 seconds

Weight loss, Check temporal lobes and Protein, fat, and energy insufficiency
wasting, or cheeks – well-demarcated bony Malnutrition (a risk factor for infection and poor wound
cachexia [21, 26] prominences and veins [3, 29] healing)
(Sarcopenia is Cancer
referenced later in Dysphagia
this table) Vomiting/diarrhea
Malabsorption
HIV/AIDS (lipodystrophy)

Overweight/ BMI Excess caloric intake/insufficient physical activity/

obesity [20, 21] Waist-hip ratio (WHR) endocrinological imbalance (e.g., low thyroid function)/
Waist-to-height ratio (WHtR) genetics
Skin caliper testing Assess for toxicity (particularly dioxins and heavy
Bioelectric impedance analysis metals)
(See “Aanthropometrics” table Tip: educate the patient about risks of excess weight,
following this table) diabetes, heart disease, stroke, hypertension, osteoar-
thritis, sleep apnea, some types of cancer, inflammation,
and dysbiosis

Central obesity [34] Increased risk of metabolic syndrome (hypertension,

“Apple shape” insulin resistance, inflammation, cardiovascular disease,
Adiposity is concentrated in the dyslipidemia, sleep apnea) with increased visceral
upper half of the body (neck, adiposity
cheeks, shoulder, chest, upper
abdomen)
More common in men

(continued)
 644 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Peripheral obesity [34] Carries health risks of obesity, but lower health risks
“Pear” shape than central obesity
Adiposity is concentrated in the
lower half of the body (lower
abdomen, pelvic girdle, buttocks,
and thighs)
More common in women

Uncoordinated Thiamine or copper deficiency [1]

gait (ataxia) Mitochondrial dysfunction [20]
Essential fatty acid imbalance [20]
Toxin burden [20]

For additional gait disturbances, see the “Neurological” section later in this table

Amputation [26] Possible diabetes complications

Possible history of severe infection
Possible history of traumatic injury/accident
Amputations will affect calculations of weight and
require calculation of an adjusted weight

Body movements Can the individual feed indepen- Lack of ability to independently feed must be
[4] dently (i.e., do they have limited addressed to ensure sufficient nutrient intake
use of hands or inability to sit
upright)?

Posture [20] Dowager’s hump/stooped posture Bone loss (osteomalacia or osteoporosis)

Vitamin A and D, magnesium, or calcium insufficiency
Tip: consider further testing (DEXA and N-telopeptides
cross-links (NTx) to monitor response to interventions)
[35]
Depression
Parkinson’s disease [36]

Preference to sit erect, neck veins Left-sided heart failure [21]

distended

Preference to lean forward, arms Chronic obstructive pulmonary disease (COPD) [21]
39 crossed

Fetal position May be due to pancreatitis [34]

Bend toward the side of the lesion May be due to renal or perirenal abscesses [34]

Still: avoid movement as it May be due to peritonitis [34]

provokes pain

Restless May be due to intestinal obstruction [34]

Tanner stage Evaluate if developmental age is Assess for signs of macronutrient and micronutrient
consistent with chronological age deficiencies that may have delayed growth and
development
Assess for developmental delays that may have affected
food and nutrient intake [16]

Bates – mini Breathing Labored (See “Respiratory” section of table below)

Rapid, shallow
Wheezing
The Nutrition-Focused Physical Exam
645 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Subjective global assessment (SGA) of nutritional status [16, 26, 34]:

Tool to assess malnutrition based on patient’s history and physical exam. It is also a powerful predictor of postoperative complications.
Assesses recent loss of body weight, changes in the usual diet, the presence of significant GI symptoms and the patient’s functional
capacity, and three elements of the physical exam
Assess the following using a scale of normal (0), mild (1+), moderate (2+), and severe (3+)
History assesses:
Recent loss of body weight
Changes in the usual diet
Presence of significant GI symptoms
Functional capacity
Physical exam assesses:
Subcutaneous fat loss – assess the following sites for a lack of fullness (i.e., the skin fits loosely over the tissues): triceps, midaxillary line
(costal margin), palmar areas of the hand, interosseous muscles (between the thumb and forefinger as an example), and deltoid region of
the shoulder
–Assess using a scale of normal (0), mild (1+), moderate (2+), and severe (3+)
Muscle wasting – assess by palpation (and inspection at a distance, as helpful). Examine the quadriceps and deltoids. “Squared off”
shoulders are visible with muscle wasting and subcutaneous fat loss
Loss of fluid from the intravascular space- ankle or sacral edema, ascites. Assess for edema via palpation (pitting test)
Score/classes:
Class A (well-nourished)
Class B (moderately malnourished)
Class C (severely malnourished)

Vital signs The utility of a vital sign is to give the clinician an early indication of ill health or imbalances. They are the signs of life [16] or
“vitality.” They serve to establish a baseline and are a helpful tool for monitoring and evaluation thereafter

Temperature Elevated Confers increased food and fluid requirements [3].

Average normal Can indicate infectious disease, trauma (surgery/injury),
temperature is 97.7 malignancies, immune disorders, blood disorders
degrees Fahrenheit (hemolytic anemia), infarctions, and medications. Fever
(or 36.5 degrees with chills (shaking) – accurate sign of bacteremia [31]
Celsius). (McGee)

Depressed Hypothyroidism or Wilson’s temperature syndrome,

hypoglycemia, insomnia, severe stress/shock, exposure
to cold, anemia, diabetes, Addison’s disease, infection,
liver/kidney failure, paralysis, excess alcohol intake,
starvation, medications [21]
Note that a depressed body temperature can lead to
deleterious consequences metabolically (enzymes do
not function optimally at lower body temperature)
Wide variability of temperature can be seen in adrenal
insufficiency [16, 31]

Pulse Measure radial pulse for at least 15 seconds to obtain (30 seconds is preferred). A number of
different qualities of the pulse are measured/observed in Ayurvedic and Chinese medicine
diagnostics. Normal sinus rate = 50–95 beats per minute (bpm)

Elevated (tachycardia) Anemia, hyperthyroidism, with elevated body

>100 bpm temperature, anxiety, pain, exercise, medications
(antidepressants and others) [3, 31]
Prognostic: can portend increased complications and
poorer survival rate across many clinical disorders
Magnesium, calcium, and/or niacin insufficiency may be
a cause of tachycardia

Depressed (bradycardia) Exercise/training (i.e., improved conditioning), heart

<50 bpm disease, hypothyroidism, medications [3]

Irregular heart rate/rhythm may be due to potassium deficiency (can be seen with diuretics), magnesium deficiency,
dehydration, or allergies
(continued)
 646 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Respiratory rate Measure of the number of breaths per minute

Respiratory rate is the only vital sign under voluntary control (why measuring it without telling
the patient is advised (so take before/after take patient/client’s pulse)
Take for 30–60 seconds to ensure accuracy
Normal respiratory rate = 20 breaths/min (ranges from 16 to 25 breaths/min) [31]

Increased (tachypnea) Dyspnea (difficult or labored breathing) with patient

>25 breaths/min lying down that is relieved while sitting up – can be due
to ascites, pleural effusion, morbid obesity, congestive
heart failure (CHF), or severe pneumonia
Rapid deep breathing (hyperventilation) – can occur
with exercise, anxiety, metabolic acidosis, and brain
stem injury [21]
Can affect calorie and protein requirements as well as
type of food eaten and quantity [3] – as eating may
increase energy expenditure, fatigue, or dyspnea [16]

Decreased (bradypnea) Diabetic coma, medication-induced or due to increased

<8 breaths/min intracranial pressure

Kussmaul respirations – rapid and deep –seen in patients with metabolic acidosis (most other
abnormal respiratory rates see shallow respirations). The rate can be fast, slow, or normal [21]
Cheyne-Stokes breathing/periodic breathing – alternating periods of hyperpnea and apnea.
Occurs when there is enhanced sensitivity to carbon dioxide. Seen in stable congestive heart
failure, neurological disorders, hemorrhage, infarction, tumors, meningitis, and some head
trauma (brain damage), from medications, and at high altitudes or during sleep (considered
normal)
With fluctuations of respiration come fluctuations in mental status
Prognostic: in a patient with heart disease, this respiratory rate is associated with a poor
prognosis

Blood pressure Systolic blood pressure – maximal arterial pressure during systole (the phase of cardiac
When evaluating contraction)
hypertension in Diastolic blood pressure – minimal arterial pressure during diastole (the phase of cardiac
children and relaxation)
adolescents – use Normal blood pressure: 120–129/80–84 mm Hg <120/80 mm Hg
blood pressure for Recommendation to take the mean of at least 2 seated blood pressure readings on 2 or more
39 male/female by age days before deciding on a diagnosis of hypertension [16]
and height Common errors in measuring: wrong cuff size (kids), auscultatory gap, stethoscope pressure
percentiles table(s) too firm, inappropriate level of the arm, feet not firmly on the floor, terminal digit preference
[26] (clinician’s like to round to the nearest 0. 5 or another preferred number) [26, 31, 37]
“White coat hypertension” – temporary increase in blood pressure when in a medical environ-
ment. Consider ABPM (ambulatory blood pressure monitoring) if persists. ABPM periodically
measures and records blood pressure over 24-hour period (or longer)

Elevated (hypertension) “Masked hypertension” – blood pressure readings

> 120/80 mm Hg are normal in a medical visit but elevated in everyday
life [16]
Can be seen with blood loss, myocardial infarction and
cardiac failure, irregular heart rate, medications [3]
May be due to excess sodium intake (in those with a
single nucleotide polymorphism (SNP) that codes for
salt sensitivity) [38]
Potassium, magnesium and calcium [37, 39], and
vitamin D insufficiency [29, 30]

Depressed (hypotension) Medications

Anorexia, electrolyte loss, or dehydration [16]
The Nutrition-Focused Physical Exam
647 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Postural or orthostatic Associated with adrenal insufficiency, dehydration,

hypotension: blood loss, shock, anemia, pregnancy/postpartum,
As a patient stands after lying hypothyroidism, eating disorders, hypokalemia, acute
supine, blood volume shifts to hyperglycemia, AIDS, anxiety or panic disorder, eating
lower body. Normally blood disorders, prolonged bed rest, cardiovascular condi-
pressure can stay stable during tions (congestive heart failure, MI, arrhythmia,
this shift (via compensatory myocarditis, pericarditis, valvular disease, venous
mechanisms to increase cardiac insufficiency), alcohol, medications (antiadrenergics,
output, heart rate, vascular antiarrhythmics, antianginals, antidepressants,
resistance, and circulation of the diuretics, sedatives, neuroleptics, antiparkinsonian
blood to the body (from the agents, narcotics) [40]
heart)), which involves increased Can see more commonly in those >65 y.o. and in those
sympathetic outflow. If compensa- who are frail [40], less physically active at work or who
tory mechanisms fail, (decrease in have multiple comorbidities (such as CHF, stroke,
systolic blood pressure of 20 mm chronic kidney disease [41]
Hg or a decrease in diastolic blood Prognostic: associated with an increased risk of
pressure of 10 mm Hg within dementia [42] and may predict a poor prognosis in
3 minutes of rising from sitting or elderly patients with dementia [43]
supine position), a diagnosis of May be predictive of increased risk of mortality [44]
postural hypotension is made [40]
Note that this may be accompa-
nied by a feeling of dizziness or
lightheadedness on standing,
weakness or fatigue, and syncope
Occasionally orthostatic dyspnea/
chest pain can be seen [16, 40]
Postprandial hypotension (decrease
in systolic blood pressure of at least
20 mm Hg within 75 minutes of a
meal) is related to orthostatic
hypotension [40]

Pulse pressure Pulse pressure = systolic blood pressure (mm Hg) – diastolic blood pressure (mm Hg),
[16, 31] e.g., blood pressure is 120/80  mm Hg; pulse pressure is 40

Elevated Magnesium deficiency

>40 Severe iron-deficient anemia and in hyperthyroidism
The pulse pressure becomes Prognostic: a high pulse pressure may be a strong
elevated as the aorta becomes predictor of heart problems and may indicate heart
more stiff (may be due to high valve incompetence
blood pressure or atherosclerosis) In older adults, a pulse pressure > 60 is a risk factor for
cardiovascular disease, and elevated pulse pressures in
older adults in general are considered a sensitive marker
for carotid artery stenosis (can increase the risk of stroke,
coronary heart disease, and sudden death) [16]

Depressed May indicate poor heart function

<40

Tip: interventions to address hypertension usually also address pulse pressure

Oxygen saturation [16, 31]

Also known as “O2 Sat”
Factors affecting measurement: cold digit, hypotension, excessive ambient light, motion, discoloration of nail bed (if
performing on hand) – can be due to bruising under the nail or darker nail polish
Indicates how well the blood is becoming oxygenated by the lungs – more specifically, the degree of oxygenation of
hemoglobin
Can measure on finger/pinna (earlobe) or toe [measure in patient while supine and then raise the leg (keeping the O2
Sat monitor clipped on the toe) 12–16 inches]. Hold there for 15 seconds. The O2 Sat should not decline more than 2%
Normal: 90–99% O2 Sat (optimal 95–99%)
(continued)
 648 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Increased Not clinically significant

Decreased Anemia, smoking (cigarettes), shock, pneumonia and

<90% other pulmonary diseases, congenital heart disease,
chronic obstructive pulmonary disease (COPD),
emphysema, alpha antitrypsin deficiency [45], obesity,
hyperventilation syndrome, sleep apnea, high altitude,
medications (narcotics, anesthetics)
Clinical significance: negatively impacts wound healing
(95% O2 Sat needed for optimal wound healing)

Decreased toe O2 Sat (i.e., >2% Indicative of compromise in health of blood vessels in
change with raised leg test) legs (peripheral vascular disease, heart failure, stroke,
diabetes, hypertension, hyperlipidemia, atherosclerosis,
cardiac surgery) [37]

Skin The skin is considered an organ of vicarious elimination – skin lesions and pathologies thus often lead us to examine
impaired elimination in the body – due to digestive imbalances (constipation and other dysfunctions), toxicity, and
other causes. Skin changes can also point to impaired absorption of nutrients or alterations in the utilization of
nutrients. The nutrient requirements of the skin are dependent on those nutrients needed for the replacement of its
cells and layers thereof [30]. With the skin turning over fairly rapidly, it is often a marker of fairly recent changes in
nutritional status

Color (see above “General” section of this table)

Temperature (see above “General” section of this table)

Moisture Decreased perspiration (hypohi- Thiamine deficiency [30]

drosis) Medications, skin trauma or disorders, diabetes,
alcoholism, neuropathies, Sjogren’s syndrome [46]

Increased perspiration (hyperhi- Thiamine deficiency [30]

drosis) Medications, tumor, injury, diabetes, gout, menopause
[46]

Lesions Examine for the following:

Location and distribution (generalized or localized) – i.e., extensor or flexor surfaces, all over or
only in specific regions (acne – typically face, upper chest, and back), psoriasis (knees, elbows
39 (and maybe other areas such as scalp), Candida in skin folds
Arrangement (linear/clustered/annular (in a ring)). A ring pattern can be ringworm. A unilateral,
dermatomal pattern is suggestive of herpes zoster or shingles
Type (macule, papule) – a macule is a flat, nonpalpable, circumscribed area of discoloration less
than 1 cm in diameter (a freckle), a papule is a raised, palpable skin lesion <1 cm in diameter –
may be pigmented or nonpigmented (e.g., nevus)
Color
Examine ABCDEs: (asymmetry, border (ragged/irregular vs. smooth), color (more than one
shade), diameter (increased (> 6 mm)), elevation (not as specific a finding so often excluded))

Acne Zinc, vitamin A excess [29, 30], omega-3 fatty acids,

iodine/vitamin B12 insufficiency [30]
May be related to higher glycemic load in diet/
hyperinsulinemia [47]
Correlated with consumption of dairy products [40]
Pubertal hormonal changes, sex hormone imbalances
Food allergy, gastric hydrochloric acid deficiency, blood
sugar dysregulation

Rosacea Vitamin B12 intake [30]

Food allergies and sensitivity to carbohydrates
May be due to decreased gastric acid and pepsin
production [29]
The Nutrition-Focused Physical Exam
649 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Skin tags Can occur due to friction of clothes/jewelry in some

Pedunculated soft lesion (appear cases
like grain of puffed rice cereal Diabetes, insulin resistance, elevated triglycerides, low
attached at one end) LDL (low-density lipoprotein) cholesterol [48]
May be pigmented
Typically found on the eyelid, neck,
or axillae

Actinic keratosis Diet may play a role in the development of AK, with
Actinic keratoses (AK) are moderate intake of oily fish (tuna, salmon, and sardines)
premalignant lesions that result and wine being protective [49]
from long-term exposure to sun Prognostic: AK are strongly predictive of all forms of
(damage therefrom) skin cancer

Urticaria May be due to food allergies

Chronic form associated with autoimmune thyroid
conditions [50]
Approximately 30–50% of those with chronic urticaria
are autoimmune-­mediated [51]

Petechiae Vitamin C, K insufficiency

Texture Rough Hypothyroidism

Keratosis pilaris or follicular hyperkeratosis – thickening
of the outermost layer of the epidermis producing small
red bumps at the base of the hair follicles on the back
of the arms and the anterior thighs
Vitamin A, copper, zinc, and/or EFA insufficiency
Excess vitamin A [29, 30]
Pancreatic enzyme insufficiency (EFA, vitamin A
malabsorption) [29]

Scaling Vitamin A, zinc, EFA insufficiency, or vitamin A excess

Dry (xerosis) Essential fatty acid, vitamin A, biotin, zinc insufficiency

[29]

Wrinkles Protein and/or energy insufficiency [30]

Increased wrinkle score associated with decreased bone
density or fracture risk (suggests that collagen
contributes to both) [32, 52]
(Around the eyes) sleep deprivation

Wounds and ulcers Poorly healing Decreased oxygenation of the blood [16]
Diabetes, steroid use, malignancy, or AIDS [3]
Zinc, copper, vitamin C, protein, and/or EFA, deficiency
[3, 30] vitamin A [29]

Scars (Cue to inquire about surgery/injury)

Keloids Etiology is unknown

Hypertrophic growth of scar More common in individuals with darker skin
(grows larger than the original Preliminary research suggests that keloids may be
scar) associated with insufficiency of EFAs, soluble fiber, and
phytochemicals [53]
Tip: Weigh risks/benefits of surgical procedures as there
could be significant scarring/scar tissue with proce-
dures

Fissuring (dermatomalacia) Vitamin A deficiency [30], niacin, zinc insufficiency [29]

(continued)
 650 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Rashes Dermatitis, eczema Macronutrient (protein and energy) insufficiency

Micronutrient (riboflavin, niacin, zinc) insufficiency [3,
29, 30]
EFA insufficiency [3, 29, 30]
Vitamin B12 toxicity [30]
Seborrheic form related to deficiencies of biotin,
riboflavin, vitamin B6, zinc, and EFAs [29, 30]
Tip: Consider possible imbalances in GI function and/or
the microbiome and evaluate for food allergies [29]

Dermatitis herpetiformis Gluten intolerance/gluten-sensitive enteropathy, celiac

disease

Psoriasis Vitamin A or zinc insufficiency [29, 30]

Clinical significance: considered sign of bowel toxemia
and suboptimal liver health

Hydration/turgor To assess, lightly pinch the back of Decreased turgor with insufficient riboflavin [29]
the patient/client’s hand, over the Insufficient water/electrolytes
sternum or on the inner thigh Decreased turgor can result from the use of diuretic
(using your thumb and forefinger). medication
If the skin does not return to the
normal tension/form within
3 seconds, there is decreased
turgor [16]
Note that this is less reliable in
patients of increased age (the skin
loses elasticity)
Other signs of decreased hydration
include dry mucous membranes,
dry axillae, sunken eyes, and
longitudinal tongue furrows [34]

Edema Due to excess fluid accumulation Nephrotic syndrome, CHF

in the tissues due to ↑venous Protein, energy, zinc, niacin, and thiamine
pressure (CHF), ↑vascular insufficiency [30]
permeability (inflammation), Hypervitaminosis A
39 ↓oncotic pressure (hypoalbumin- Low serum albumin
emia), lymphatic obstruction Evaluate for allergies
(lymphedema), and deposition of
additional tissue (myxedema
(hypothyroidism), lymphedema
(obesity)
Pitting or non-pitting related to
protein content of edema fluid.
Low protein leads to more rapid
pitting and recovery
Pitting test (depressing over
suspected edematous area and
then removing pressure yields
a pit that remains for over
5 seconds)
Non-pitting edema – depression
over 5 seconds leads to only
slightly pitting and resumes to
normal skin tone rapidly (rated as
1 + trace) to pitting edema
(1.3–2.5 mm), 2–5 minutes to
recover from (rated at 4+ severe)
The Nutrition-Focused Physical Exam
651 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Vascularity Capillary fragility If >10 broken capillaries (petechiae) in the circle,

Evaluate with blood pressure cuff: consider vitamin C deficiency [30]
increase the venous pressure in
the forearm with a blood pressure
cuff and inspect the skin for
petechial eruptions (draw a 1 inch
circle 10 cm below the elbow
crease before inflating the cuff to a
pressure midway between the
patient’s systolic and diastolic
pressure). Wait up to 5 minutes for
any petechiae to form

Pruritus Itchiness Parasites, allergies, chlorine exposure (topical), cancer,

iron deficiency or niacin or vitamin A toxicity [29, 30]
Hypothyroidism, liver disease, kidney failure

Dermatographism Writing on the skin (with blunt Associated with hypersensitivities/allergies, heat, stress,
object), the “draw test” – produces cold exposure (exaggerated histamine response)
localized hives that last 15–30 
minutes

Nails [16, 29, 30, Fingernails protect the distal ends of our fingers and toes. They are comprised of keratin (which is derived from the
54, 55, 56] sulfur-rich amino acid cystine). Nails (both fingernails and toenails) can show signs of nutrient insufficiency/toxicity
and exposure to toxins and systemic or localized disease or other conditions. A healthy nail structure requires sufficient
protein and fat in the diet and sufficient hydration (to remain flexible). The nails are a sensitive, early marker of
nutritional imbalances (with changes often preceding other clinical signs or laboratory findings). Clinical significance:
Nail nutrient deficiencies often link to gastrointestinal health
Nail anatomy – the nail plate is what one considers the “nail.” The pinkish color of it is due to a vascular nail bed that is
attached to the lunula (white moon of the nail). The cuticle extends from the nail fold and seals the space between the
fold and plate from excess moisture. The “end” of the nail is referred to as the “free edge”
Fingernails grow ~ 0.1 mm every 6–10 days and are completely renewed in 6 months (toenails grow more slowly) (at
about 1/3 of the rate of fingernails). This timing can help to estimate the onset/exacerbation of medical conditions or
diseases (measure the distance from the nail bed to the lesion/nail pathology and multiply out by 0.1 mm to approxi-
mate the days since the pathology started). With age, nails can lose luster and become more yellow and thickened
(especially the toenails)
Examination – be sure to ask if the patient bites or chews their nails and had an injury to the nails in the last 6 months
or up to a year and if they recently/currently had (or have) polished nails

Shape or growth change

. Figure 39.2
  Clubbing Nail plates have exaggerated Iodine deficiency
upward curve and curl around the Vitamin A excess
fingertips Inflammatory GI disorders (IBD, celiac)
Look for Schamroth’s sign: Dysentery
Disappearance of diamond-shaped Fistulas
window between digits that is Idiopathic pulmonary fibrosis
normally present when paired Pulmonary malignancy
digits are juxtaposed (anteriorly) Hodgkin’s lymphoma
(. Fig. 39.3)
  Tuberculosis
Asbestosis
Chronic obstructive pulmonary disorder (COPD)
Cirrhosis
Congenital heart disease
Endocarditis
(continued)
 652 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

. Figure 39.4
  Koilonychia (spoon Nail plates are depressed and Riboflavin, niacin, vitamin C, zinc, copper, chromium,
nails) appear flat or scooplike. This can selenium, protein (especially methionine and cysteine),
be normal in children and iron insufficiency
Water drop test [16] to evaluate for Iron deficiency anemia
this nail change: Plummer-Vinson syndrome
Place a drop of water on the Malabsorption
nail – if it does not drip off, the nail Hypochlorhydria
is flattened (early koilonychias) Hemochromatosis
Raynaud’s disease
Lupus (SLE)
Nail-patella syndrome
Thyroid disorders
Rheumatic fever
Syphilis
Persistent occupational exposure of hands to petro-
leum-based solvents
Trauma to the nail

. Figure 39.5
  Onycholysis The nail bed becomes separated Iron deficiency anemia, pellagra (niacin deficiency)
from the nail plate Cronkhite-Canada syndrome (low protein in the
blood) – rare
Psoriasis
Eczema
Infection (onychomycosis)
Hyperthyroidism/thyrotoxicosis (referred to as
“Plummer’s nails”)
Sarcoidosis, amyloidosis, and/or connective tissue disor-
ders
Trauma to the nail

. Figure 39.6
  Pitting Few patterns: Patterns correspond to:
  1. Ridges across the nail plate   1. Eczema
  2. Red-brown spots (“oil drop   2. Psoriasis
sign”)   3. Alopecia areata (autoimmune)
  3. Rows

39 . Figure 39.7
  Beau’s lines Depressed horizontal furrows
across (transverse) the nail plate
Malnutrition
Protein, calcium, niacin, zinc, vitamin A, and vitamin C
insufficiency
(May be seen in those with recent history of anorexia)
Carpal tunnel syndrome
Severe illness that disrupts nail growth (mumps,
measles, myocardial infarction)
Hypotension
Hypocalcemia
Uncontrolled diabetes
Surgery
Chemotherapy or immunosuppressive therapy
Exposure to cold temperatures (Raynaud’s disease)
Trauma to the nail

Unusually wide, Hormonal (endocrine) disorders

square nail plates

Unusually long, Pituitary hormone deficiency

narrow nail plates Marfan syndrome

Chronically Nail edge has sawtooth pattern Malnutrition, vitamin deficiencies

chipped, sawtooth from chipping Radiation exposure
nails Chemical exposure/damage
The Nutrition-Focused Physical Exam
653 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

. Figure 39.8
  Ridging of the Often accompanies brittle nails Mineral malabsorption
nails Protein insufficiency
Insufficient fat intake
Iron deficiency (with central ridge(s))
B vitamin insufficiency (thiamine, riboflavin, niacin,
pyridoxine, folate)
Zinc, vitamin A insufficiency

Onychomadesis Spontaneous separation of the nail Hypocalcemia

plate from the nail bed originating Idiopathic
from the proximal end. The nail is After severe systemic illness
then shed as it grows Drug reactions
Infections
Cronkhite-Canada syndrome
Trauma to the nail

Acrodynia Red tips with nail growth Mercury toxicity

abnormalities

Onychorrhexis Irregular, frayed and torn nail Protein, EFA, iron, biotin, boron, folate, zinc, calcium,
(Brittle nails) borders magnesium, silica, sulfur, zinc, vitamin A, carotenoid,
Called “onychoschizia” if the nail vitamin C, vitamin D, and vitamin B12 insufficiency
splits Selenium or vitamin A toxicity
Anorexia
Hyperthyroidism
Hypochlorhydria
Metabolic bone disease
Cronkhite-Canada syndrome
Tip: in postmenopausal women and older men, check
bone density

Absent lunula No visible half-moon on nail Zinc, protein insufficiency

Color change

. Figure 39.9
  Terry’s nails Most of the nail bed is white Niacin, protein insufficiency
except for a pink band near the Copper toxicity
nail tip. Due to decreased Cirrhosis
vascularity and increased Hepatic failure
connective tissue in the nail bed Diabetes mellitus
Generally, the lunula is obliterated Congestive heart failure
Hyperthyroidism

Azure lunula Blue half-moons in the nail bed Copper toxicity

Wilson’s disease (hepatolenticular degeneration)
Silver poisoning (blue-gray)
Quinacrine therapy
Impaired circulation

Yellow lunula Yellow half-moons in the nail bed Tetracycline therapy

Brown/black Brown/black half-moons in the nail Excess fluoride

lunula bed Hyperthyroidism (nail plate brown)

Red lunula Red half-moons in the nail bed Cardiac failure

. Figure 39.10
  Half-and-half nails The proximal half of the nail is Niacin zinc insufficiency
(Lindsay’s nails) white, and the distal half Renal failure (pathognomic)
(horizontally) is pink or brown, and
the lunula is obliterated
(continued)
 654 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

. Figure 39.11
  Muehrcke’s lines Two white lines (arcuate) parallel to Malnutrition (protein deficiency)
the lunula and separated from the Acrodermatitis enteropathica (rare, inherited form of
nail bed with normal nail. Due to zinc deficiency)
abnormality of vascular nail bed – Hypoalbuminemia (pathognomic)
so does not move with nail growth Nephrotic syndrome
Lines disappear transiently with Liver disease
blanch test

. Figure 39.12
  Mees’ lines Longitudinal white streaks from Niacin, calcium, zinc insufficiency (hypocalcemia
(Reynolds/Aldrich the cuticle to the free edge Acrodermatitis enteropathica (zinc deficiency))
lines) Renal failure
Hodgkin’s lymphoma
Myocardial infarction, congestive heart failure
Leprosy
Malaria
Sickle cell anemia
Carbon monoxide poisoning
Arsenic poisoning
Thallium poisoning
Chemotherapy (cancer)

Hapalonychia Nails thin causing the bending and Kwashiorkor

breaking of the free edge and Insufficient intake of protein and/or fat
longitudinal fissures Vitamin A, pyridoxine, and vitamin C and D insufficiency
Calcium, silica, iron, sulfur, and zinc insufficiency

Pallor Iron, vitamin B12 insufficiencies/anemia, selenium and

riboflavin insufficiency

Yellow nail Nails grow more slowly and Rule out smoking and recent nail polish use
develop “heaped up”/thickened Beta carotene excess
appearance and lunula disappear. Vitamin D insufficiency
Thought to be due to abnormal Long-term use of tetracycline
lymph drainage or leakage of Type 2 diabetes [48]
protein as a result of increased Lymphedema
microvascular permeability [16] Pleural effusion
Bronchiectasis
39 Sinusitis
Rheumatoid arthritis
Nephrotic syndrome
Thyroiditis
Tuberculosis
Raynaud’s disease
Immunodeficiency
Cancer (possibly)
Tip: vitamin E may help as an intervention

White nails Selenium, zinc insufficiency

Red nails Malnutrition, lupus, carbon monoxide angioma, or

polycythemia

Brown/gray nails Vitamin B12 insufficiency, diabetes mellitus, hyperthy-

roidism [54], or cardiovascular disease

Blue nails Peripheral cyanosis

Copper toxicity

Longitudinal Protein, calcium, pyridoxine, biotin, and vitamin C

striations insufficiency
(Trachyonychia) Vitamin A excess
Alopecia areata
Vitiligo
Atopic dermatitis
Psoriasis
The Nutrition-Focused Physical Exam
655 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

. Figure 39.13
  Splinter hemor- Longitudinal red streaks from nail Scurvy (vitamin C deficiency)
rhage bed toward proximal margin. Oral contraceptive use
Signify bleeding of the capillaries Pregnancy
Chronic hypertension
SLE
Rheumatoid arthritis
Psoriasis
Peptic ulcer
Subacute bacterial endocarditis
Trichinosis
Trauma to the nail

Telangiectasia Dilated blood vessels in the nail at Rheumatoid arthritis

the margin of the finger nails SLE
Dermatomyositis
Scleroderma

. Figure 39.14
  Punctate White spots or patches between If isolated dots, can be due to trauma to the nail
leukonychia the nail and the nail bed. Due to (including repeated manicures) or zinc, selenium, and
subungual air bubbles niacin insufficiency
If on the entire nail, likely due to a congenital disorder

Longitudinal Brown/black discoloration – Vitamin D, folate, and vitamin B12 insufficiency

melanonychia streaks spread from the nail bed to Malnutrition (protein deficiency)
the surrounding finger GI polyps (discoloration on the nail is in spots)
Benign nevus
Normal variant in darkly pigmented people
Melanoma (large patch or collection of small freckles
most commonly on the thumb and big toes)

Other changes/evaluation

. Figure 39.15
  Paronychia Infection around the fingernail EFA, zinc, and vitamin C insufficiency [29]
Can have redness, pus, swelling,
and tenderness (Acute – Staphylo-
coccus infection
Chronic – fungal)

Hangnails Zinc, vitamin C, folate, and protein insufficiency

Ragged cuticles Boron and iron insufficiency

. Figure 39.16
  Onychophagia Nail biting Stress
Anxiety

Onychotillomania Nail picking Stress

Anxiety

Capillary refill test Technique: Nails must be Blanch time > 2 seconds (i.e., decreased capillary refill):
unpolished. Apply pressure to the Dehydration
nail until it blanches/turns white. Vitamin A and C insufficiency
Remove pressure. Patient is to hold Peripheral vascular disease (arteriosclerosis, hyperten-
the hand above the heart, while sion, diabetes mellitus, smoking, heart disease,
the time it takes for blood to abnormal cholesterol)
return to the tissues (nail turns Shock, hypothermia
pink) is measured
Indicator of tissue perfusion and
hydration

Head Examine the head, scalp, and hair

(continued)
 656 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Hair Examine for quality, quantity, distribution, color, texture, and baldness. Look for hair loss diffusely or in patchy areas on
the scalp. Be sure to inquire about any chemical processing, dying, or bleaching of hair which could affect the color
and/or texture of the hair. Normal hair loss is considered to be 50–100 hairs per day

Hair loss [34, 57, 58] Stress of serious illness or injury, parasites, heavy metal
toxicity, oral contraceptives
Protein, iron, zinc, or biotin insufficiency, anemia
In women, hair loss can occur following (may be up to
2 months after) extreme stress from a major illness,
from following a very low-calorie diet, from rapid
weight loss (post-bariatric surgery), polycystic ovarian
syndrome (PCOS), thyroid disease, or as a result of
medication [16]
Alopecia areata – autoimmune disorder (immune
system attacks hair follicles) – patchy hair loss
Tip: may respond to zinc and biotin supplementation
[16]

Baldness Vertex baldness with hypertension or high cholesterol –

possible marker for increased risk of coronary heart
disease [59]
In women, frontal baldness is associated with PCOS
(usually seen with hirsutism)

Sparse or thin hair Protein, zinc, iron, biotin, linoleic acid, and/or manga-
nese insufficiency [4, 16, 32]
Vitamin A excess
Hyperthyroidism

Hair that is easy to Protein, zinc, and iron insufficiency

pluck

Premature graying PABA (para-aminobenzoic acid) deficiency

Vitiligo
Stress

Dry/brittle EFA and/or manganese insufficiency [29]

39 Hypothyroidism

Dandruff EFA, fat-soluble vitamin insufficiency (due to biliary

dysfunction)
Calcium, pyridoxine, and other B insufficiencies
Antioxidant insufficiency (selenium especially)
Excess refined carbohydrate intake
Hypochlorhydria

Flag sign Bands of depigmented hair can Kwashiorkor, protein deficiencies in ulcerative colitis,
appear horizontally (transverse to and other conditions
the length of hair) during periods
of inadequate protein intake
When protein intake returns to
normal, pigmented hair will grow
again – creating the alternating
band-like appearance

Corkscrew hair At the base of the hair follicle Vitamin C insufficiency

Menkes steely hair Copper insufficiency (due to disordered copper

metabolism) [29]

Scalp Itchiness Calcium insufficiency

Skin rash (psoriasis or other)

Psoriasis Sulfur insufficiency

Imbalanced omega-3 or omega-6 fatty acid ratio
The Nutrition-Focused Physical Exam
657 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Face Affect See above under “General” section

Asymmetry Stroke/neurological issue

Bell’s palsy – paralysis of muscles on one side of the face
(with inability to control facial muscles) generally
idiopathic, though may be due to diabetes, Guillain-­
Barre syndrome, Lyme disease, viral infection (recent
URI), or other causes (tumor)
Facial nerve (CN7) defect

Facial nerve (CN7) examination: Ask patient to make a variety of facial expressions – raise eyebrows bilaterally, close
the eyes, frown, smile, show their teeth, and puff out their cheeks {Bates}

Vertical creases Consider duodenal ulcers

near midline of the
forehead

Seborrheic Biotin, riboflavin, vitamin B6, zinc, and EFA insufficiency

dermatitis Can be seen with diets high in refined sugars
Can be due to food allergies (research supporting this
in children) [60]

Myxedema Characterized by a relatively hard Hypothyroidism

edema of subcutaneous tissue,
with increased content of
proteoglycans in the fluid. May
also see swelling in the neck if
goiter

Loss of lateral 1/3 Hypothyroidism

of eyebrow

Dilated capillaries Excess alcohol, gastric hydrochloric acid deficiency

on cheeks and
nose

Flushing May also be seen with red ears Allergy

Yellow skin Pernicious anemia (vitamin B12 deficiency) [16, 29, 31]

Brown, patchy Especially on cheeks with parotid Protein-calorie deficiency

pigmentation of enlargement and a “moon” facies
the skin

Acne See “Skin” section of table above

Acne rosacea See “Skin” section of table above

Tics/abnormal Evaluate for with smile test Facial nerve (CN7) defect
movements Tourette’s syndrome

Chvostek’s sign To test for this sign, percuss at the Calcium and magnesium deficiency
top of the cheek (just below cheek Tetanus, tetany
bone) with tip of the index or Hyperventilation (induces hypocalcemia)
middle finger. Will see repeated
contractions of the facial muscle if
this sign is present

Trigeminal nerve examination (CN5) examination: Pain and light touch are examined across three zones of this nerve
on the face (ophthalmic, maxillary, and mandibular). Motor function of CN5 is evaluated by feeling for contraction of
temporal and masseter muscles as well as evaluation of the corneal reflexes

Hair growth Excess in women (hirsutism) Hormonal imbalance (excess androgens). Cushing’s,
Frontal baldness and acne may be PCOS, elevated cholesterol, sleep apnea, insulin
present with hirsutism resistance, diabetes, tumors, and medications

(continued)
 658 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Eyes Eye physiology: The eye is a sphere enclosed by three layers – outermost is the sclera/cornea; then there are the
choroid, ciliary body, and iris; and the innermost layer is the retina
The eyeball is largely covered by the sclera (the “white” of the eye). Over the iris is the cornea – this is transparent so
light can pass through the eye
The eye is composed of two chambers of fluid separated by the lens. These carry nutrients and are transparent to allow
light to pass through the eyes. The shape of these chambers changes to allow vision at different distances
The iris is a radial muscle that controls the size of the pupil (allows it to dilate or constrict)
In a nutrition physical exam, the eyes are examined largely with a penlight. Physicians and ophthalmologists typically
use ophthalmoscopes to visualize the retina and can detect retinal hemorrhages and changes in the retinal arteries
that occur with hypertension and diabetes

Eyelids Ptosis Neurological/muscular disease [21]

Retracted lid Neurological/muscular disease, mechanistic (includes

atopic dermatitis and essential hypertension [61]

Exophthalmos Hyperthyroidism (Graves’ disease)

Angular palpebritis or blepharitis Riboflavin, niacin, or pyridoxine insufficiency

Periorbital edema Allergies, local inflammation, myxedema, nephrotic

syndrome/fluid-retaining state

Dark circles under the eyes Allergies (allergic shiners), dysbiosis, liver congestion
with detoxification problems (phase I and II detoxifica-
tion) [20], hypochlorhydria, pancreatic insufficiency,
adrenal hypofunction, and mineral deficiency [57, 58]
Fatigue, sleep deprivation [62]

Dennie’s lines (horizontal creases Food allergies

across the lower eyelids) [60]

Meibomian gland dysfunction May be due to oxidative stress

Tip: may benefit from omega-3 fatty acid supplementa-
tion

Lesions (lumps, Xanthelasma (Slightly raised, May accompany lipid disorders such as hypercholester-
swellings around yellowish, and well-circumscribed olemia [57]
39 the eyes) plaques that appear along the
nasal portion of one or both of the
eyelids)

Conjunctiva Conjunctivitis Allergies, irritation, infection

Inflammation Vitamin A or riboflavin insufficiency

Conjunctival pallor Iron, folate, and B12 insufficiency

Bitot’s spots (foamy, superficial Vitamin A deficiency

patches on the conjunctiva) [1]

Conjunctival xerosis (dryness) Vitamin A or riboflavin deficiency (or environmental/

chemical irritation)
Diabetes [63]

Pupils Dilation Allergy (especially dairy) [29]

Swinging flashlight test Optic nerve (CN2) or retinal lesion

Test of pupillary response to light
Shine penlight first in one eye and
then the other
Normal response:
as light swings from one eye to the
other, each pupil should constrict
briskly
Optic nerve or retinal lesion:
dilates upon exposure to light
The Nutrition-Focused Physical Exam
659 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Nystagmus Thiamine insufficiency [29]

Medication, CNS diseases
Inflammation of inner ear
Albinism
Astigmatism, myopia
Defects in CN3, CN4, and CN6

Lens and cornea Corneal arcus Vitamin A deficiency

Dyslipidemia (middle-aged men) (DN)

Corneal scar, ulcerations Vitamin A deficiency

Corneal xerosis (dull appearance) Vitamin A deficiency

Keratomalacia (cornea is soft) Vitamin A deficiency

Xerophthalmia Vitamin A deficiency

Pterygium Epidemiologic evidence of an association between

obesity and pterygium in women [64]

Cataracts Dysglycemia, vitamin C insufficiency

May be marker of oxidative damage and ultimately
coronary heart disease (CHD)

Glaucoma Hereditary
Chronic subclinical inflammation
May be associated with imbalances in oral microbiome
[65]

Kayser-Fleischer rings Results from inherited accumulation of copper in the

(Greenish-brown deposition of liver due to inherited ceruloplasmin defect
copper in annular ring around Wilson’s disease
periphery of the cornea (where it
meets the sclera/white of the eye))

Iris Iritis Trauma, can also be seen with certain diseases, such as
ankylosing spondylitis, Reiter syndrome, sarcoidosis,
inflammatory bowel disease, and psoriasis. Infectious
causes may include Lyme disease, tuberculosis,
toxoplasmosis, syphilis, and herpes simplex and herpes
zoster viruses

Iris contraction test (A variation on With adrenal insufficiency, the pupil will not remain
the swing flashlight test: upon contracted with exposure to light, but will dilate. This
exposure to light in a darkened dilation will occur within 2 minutes and can last for
room, the pupil should contract 30–45 seconds before another contraction. It is best to
immediately and remain con- time when the dilation occurs and how long it lasts.
tracted) Subsequent retesting can then serve as a monitor for
adrenal status as interventions are employed

Optic (CN2) and oculomotor (CN3) examination: assess extraocular movements (“H” and “X” in space) and evaluation
of pupillary response to light and accommodation

Ophthalmoplegia Thiamine deficiency [29]

Weakness or paralysis of one or
more of the extraocular muscles

Nystagmus Thiamine insufficiency [29]

Medication, CNS diseases
Inflammation of inner ear
Albinism
Astigmatism, myopia
Defects in CN3, CN4, and CN6
(continued)
 660 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Vision changes Reduced visual acuity Essential fatty acid deficiency [29]
Optic nerve defect

Reduced night vision Vitamin A [29], zinc insufficiency

Color blindness Diabetes, glaucoma, macular degeneration, Alzheimer’s

Inherited poor color vision usually disease, Parkinson’s disease, chronic alcoholism,
affects both eyes, and the severity leukemia, and sickle cell anemia
doesn’t change over one’s lifetime Medications can alter color vision, such as some drugs
Examine with Ishihara or that treat heart problems, high blood pressure, erectile
Hardy Rand and Rittler testing dysfunction, infections, nervous disorders, and
psychological problems
Ability to see colors deteriorates slowly as you age
Exposure to some chemicals (carbon disulfide and
fertilizers) may cause loss of color vision [66]

Retinal field defect Vitamin A, vitamin E deficiency [29]

Macular degeneration Tip: lutein, zeaxanthin, and vitamin C may help prevent
Use Amsler grid to examine macular degeneration

Visual contrast Can use to assess loss of visual contrast sensitivity in

macular degeneration, cataracts, and glaucoma and can
help prevent falls in elderly due to loss of contrast sensi-
tivity
A number of factors can affect the ability to perceive
visual contrast: nutritional deficiencies, alcohol
consumption, medication or drugs, exposure to
endogenous or exogenous toxins, including but not
limited to neurotoxins, biotoxins, volatile organic
compounds (VOCs), mycotoxins, mold, microbial, VOCs,
parasites, cyanobacteria, dinoflagellates, heavy metals,
Lyme disease
Visual contrast testing is used to track the progress of
patients undergoing treatment for Lyme disease
Can measure neurotoxicity in those with M.S.
Note: Loss of visual contrast is not diagnostic, but may
39 warrant further evaluation for these conditions [67, 68]

Photophobia Zinc deficiency [29]

Floaters Those with nearsightedness are more prone to floaters

(also those with diabetes and a history of cataract
surgery)
Vitamin C and K and bioflavonoid insufficiency

Ears Diagonal earlobe Highly associated with cardiovascular disease (in men)
crease

Tophi on external Gout

earlobe

Hair in the ear Associated with coronary artery disease

canal

Excess cerumen EFA insufficiency or allergies

(wax) in the canal

Tinnitus Cardiovascular disease, allergies, aspirin toxicity, B12

deficiency [69]

Acoustic nerve (CN8) examination: assess for hearing by rubbing fingers together on either side of the ear at varying
distances and asking the patient to localize as well as evaluating for conductive hearing loss (Weber and Rinne tests
with tuning fork) [21]

Nose External nose Examine for redness, dryness, rashes/skin abnormalities

The Nutrition-Focused Physical Exam
661 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Rhinophyma Related to excess alcohol ingestion

A thickening and reddening of the Hypochlorhydria
skin on the nose. Can see broken May be related to acne rosacea
blood vessels

Malar rash (also referred to as Systemic lupus erythematosus (SLE)

“butterfly rash” for the butterfly Niacin deficiency
shape with the wings of the
butterfly on the cheeks and the
body over the bridge of the nose)
It is a purplish, scaly rash

Salute sign/allergic salute [60] Allergies (especially dairy)

Occurs from rubbing the nose (due
to nasal drip/rhinitis) with an
upward movement of the hand
Allergic crease horizontal lines
across lower portion of the nose
from rubbing the nose with the
hand (saluting)

Nasolabial seborrhea (Seborrheic Pyridoxine, EFA deficiency [29]

rash around the base of the nose
and perioral region)

Nasolabial dyssebacia (a disorder Riboflavin deficiency [29]

of the sebaceous glands character-
ized by excess oil production,
inflammation, exfoliation, and
fissuring of the sebaceous glands
(which appear moist and
reddened) around the base of the
nose and perioral region)

Nasal canal/ Intranasal polyps Allergies (chronic rhinitis)

intranasal [34, 57] Salicylate sensitivity (often seen with asthma) [29]

Epistaxis (nosebleeds) Vitamin C, vitamin K, and flavonoid insufficiency [60]

Allergies
Local trauma
Infection
Dry air
Hypertension or coagulation disorders
Medications
(continued)
 662 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Smell Hyposmia – decreased ability to Zinc deficiency, pernicious anemia

Evaluate sense of smell May be due to nasal polyps, cadmium poisoning,
smell using smell smoking, asthma, allergy, diabetes, hypothyroidism,
identification test fibromyalgia, MS, schizophrenia, sarcoidosis, SLE,
[UPSIT]: Self-­ hepatic or renal failure, tumor
administered Medications: zinc-based intranasal sprays; intranasal
40-item test with medications; antibiotics; antidepressants; antilipidemic;
smell card booklet medications for hypertension, rheumatism, and
Smell discrimina- hyperthyroidism; chemotherapeutic medications; and
tion test: Sniffin’ opioids [71]
Sticks [70] Smell disorders are present in a number of neurodegen-
erative illnesses and part of their early diagnosis
(changes in the sense of smell are the first sign of
idiopathic Parkinson’s disease). Can also be a sign of
early
Alzheimer’s disease [72]
Olfactory (CN1) defect
Prognostic: Decreased olfactory discrimination is a
significant predictor of future cognitive decline [71].
Olfactory dysfunction in old age predicts mortality [73].
Lack of ability to identify smells related to overall health
and one’s life expectancy may be negatively associated
with lowered olfaction [73]

Anosmia – lack of ability to smell Unilateral anosmia may be due to trauma

Chronic infection or inflammation of the nasal passages

Hyperosmia – increased ability to Hyperosmia can occur with Addison’s disease, head
smell injury, multiple chemical sensitivity, before or during
migraine attacks, and following rapid chronic with-
drawal of drugs Depression often accompanies cases of
hyperosmia [74]

Peanut butter test Left nostril impairment of odor detection in patients

Test patient with closed eyes, for with probable Alzheimer’s disease and with mild
their ability to detect the odor of cognitive impairment
39 peanut butter, one nostril at a
time. Hold a container of peanut
This test may also be useful for monitoring disease
progression (the asymmetry was greatest in early stages
butter medially below the nostril of the disease. With disease progression, the right
(ideally it is not a very wide mouth nostril became more impaired – resulting in an overall
(1 oz. is ideal) container) and move decrease of asymmetry [75]
up 1 cm at a time during the
patient’s exhalation. If an odor is
detected, note the distance
between the patient’s nostril and
the top of the container with a
30-cm ruler

Sinuses Examine externally – looking for pain, tenderness, redness, and swelling over the affected sinus(es)

Congestion or (post)nasal drip Chronic allergies

Yellow-green sputum suspicious of infection

Dysbiosis Can be due to hypochlorhydria and pancreatic enzyme

deficiency

Mouth Due to the rapid turnover of cells in the oral mucosa, a number of diseases, disorders, and imbalances have clues, or
definitive diagnoses, which can be made from examining the mouth early in the course of disease (lead poisoning,
eating disorders, nutritional deficiencies, etc.). Prior to starting the exam, it is advised to ask the patient about any
recent changes in taste, burning sensations, pain, or bleeding of the gums or mucosa (Radler and Lister)
The Nutrition-Focused Physical Exam
663 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Lips Cheilosis, angular stomatitis Riboflavin, niacin, pantothenic acid, pyridoxine, folate,
Redness, cracking of one or both B12, iron, and or zinc deficiency [29, 57, 76]
angles of the mouth Infection (Candida in those with dentures, Staph. for
those without)
Poorly fitting dentures (saliva leaks to the mouth
corners – Causing skin irritation)

Cheilitis Early sign of Crohn’s disease

Nutritional deficiencies of cheilosis and/or excess
vitamin A

Actinic cheilitis Excess exposure to sun (loss of pigment in the lips and
Usually on the lower lip may be scaly and thickened)

Lip ulcers or sores Cold sores: selenium deficiency [29]

From herpes labialis (herpes simplex virus I (HSV-1) –
cold sores)
If you see lesions on or around the upper border of the
lip – usually it means it is herpes. Herpes lesions can be
precipitated by stress and adrenal overload and calcium
and EFA deficiency: deficiency of lysine, exposure,
vitamin C, and/or flavonoids [29, 58]
Cancer (squamous cell carcinoma) – usually affects the
lower lip (may be a scaly plaque, ulcer, or nodular). Seen
in those with fair skin and history of prolonged sun
exposure

Enlarged lip Trauma

Angioedema (which can be secondary to food allergies)

Pigmented lip In Peutz-Jeghers syndrome, you will see multiple

pigmented spots on the lips and oral mucosa and
intestinal polyps. There is a slightly higher risk of
gastrointestinal malignancies in this condition

Palate Visualize the roof of the mouth

Assess the pharynx (pillars, tonsils, uvula) for movement, enlargement, or lesions
Use the tongue blade in the middle 1/3 of the tongue. Traction forward and down and have the
patient say “Aah” (elevates the soft palate and allows one to assess cranial nerve function…
more on this later). Don’t touch the back of the tongue or you can elicit the gag reflex
Note that those in a state of parasympathetic stress will have an easy gag reflex (due to
increased alkalinity with too much potassium relative to calcium)

Candida (thrush) May be due to iron and/or vitamin C deficiency

White discharge on palate/ Medications (antibiotics, corticosteroids)
pharynx or mucosa Occurs with reduced immunity and malabsorption
Can result from dry mouth
Diabetes, HIV, cancer, renal failure [76]

Blue-gray Hemochromatosis

Psoriasis May be an indication of the liver and GI imbalances

May cause pain and discomfort (both associated with psoriasis)
and thus affect the types of foods
consumed and quantities
(continued)
 664 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Pharynx Absence of the uvula May be surgically removed (as may be done for
obstructive sleep apnea)

Swollen uvula Pharyngitis

Tonsillitis May be due to allergies

Enlargement of tonsils Vitamin A and/or C and zinc deficiency [29]

Allergies/sensitivities
Chronic infection
Sleep apnea

“Crimson crescents” – bilateral Chronic fatigue syndrome

reddening (a purplish red hue) of
the pillars without any pain or sore
throat

Warts on tonsils/pillars HPV (human papillomavirus)

Glossopharyngeal nerve (CN9) and vagus (CN10) examination: Assess movement of the pharynx while the patient
says “ah” and evaluate for gag reflex (bilaterally). Listen to the voice for hoarseness or a nasal tone and observe for any
difficulty swallowing (CN10 lesion)

Buccal mucosa White spots Oral thrush (Candida) – these can be scraped off –
revealing red, raw (inflamed, bleeding) oral mucosa
underneath. May also see squamous cell carcinoma,
Koplik’s spots (rubeola), or HIV (hairy leukoplakia)
Worry more about hairy leukoplakia (precancerous) in
those who smoke, chew tobacco, abuse alcohol, or have
a history thereof

Pigmented spots Peutz-Jeghers syndrome, smokers’ melanosis, malignant

melanoma, Addison’s disease, hemochromatosis

Red spots: petechiae Vitamin C, K, protein, and/or energy insufficiencies

Thrombocytopenia
Infectious mononucleosis, pyogenic granuloma,
erythema migrans, Kaposi’s sarcoma
39 Xerostomia (dry mouth) Zinc insufficiency

Stomatopyrosis (painful inflamed Iron, B12, folate, and/or magnesium insufficiency

mouth) and dysesthesia (burning
mouth syndrome)

Pallor Iron deficiency

Ulcers/sores (aphthous ulcers Vitamin B12, folate insufficiency

[canker sores]) Allergies (including celiac disease)
(More rarely seen with infection and cancer)
Can recur with use of toothpaste containing sodium
lauryl
sulfate

Gums Gum hypertrophy, bleeding Bioflavonoid and vitamin B12 insufficiency

Poor brushing technique/use of a brush with hard
bristles
Vitamin C and D deficiency (with scurvy see petechiae
(small red or purple spots caused by bleeding into the
skin) on gums)
Puberty, pregnancy
Inflammatory bowel disease (IBD), uveitis, ankylosing
spondylitis, peripheral arthritis, erythema nodosum [77]
Leukemia
Medications (phenytoin, cyclosporin A)
The Nutrition-Focused Physical Exam
665 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Gum recession Silica, calcium, CoQ10, quercetin, antioxidant

Gingivitis insufficiency
Inflammation of the gum tissue Vitamin A and D, riboflavin, and niacin insuffi-
Gingivitis with periodontitis ciency (also see gingival tenderness with niacin
(bacterial infection) is known as deficiency) [78]
periodontal disease. In more Gingival inflammation significant predictor of cognitive
advanced stages, larger gum decline [79]
pockets and teeth loosen and can Oral inflammation and poor oral hygiene associated
fall out with hypertension in individuals <65 years of age [80]
Strong links between chronic oral inflammation and a
number of other health conditions (cardiovascular
disease, stroke, diabetes, Alzheimer’s and other
dementias, and pancreatic cancer) [32, 78]

Lead line Lead or bismuth exposure

A bluish-black line on the gums
(~1 mm from the gum margin)
that may indicate chronic lead
poisoning. The line follows the
contours of the gums and is
absent where there are no teeth (it
is produced by tartar-­forming
bacteria)

Teeth Long teeth Gum recession

Bruxism Excess stress, allergies, parasites

Tooth decay Poor mineral absorption

Vitamin C and B12, fluoride, and phosphorus
deficiency [29]

Tooth discoloration with malposi- Protein calorie malnutrition

tion and hypoplastic line across
upper primary incisors (become
yellow-­brown in color)

Mottled enamel, fluorosis Excess fluoride, calcium insufficiency

Tooth erosion Excess consumption of fresh citrus or sugary sodas

Bulimia (along posterior aspect of the teeth – particu-
larly the incisors)
GERD
Swimming in chlorinated water (chronically)
Frequent wine consumption (acids can erode the teeth)

Dental materials
Nickel and/or other metals used in restoration may lead to allergic reactions in some patients
Mercury amalgams, root canals, implants, mixed noble- and base-metal crowns, partial dentures made of chrome
cobalt, BPA-based resin fillings, night guards, and dentures may create oxidative stress in some patients
Mercury amalgams in young adulthood may lead to increased risk of diabetes mellitus in later life [81]

Taste Nutrients involved in taste [34, 58]

Vitamins: A, E, riboflavin, niacin, pantothenic acid, pyridoxine, folate
Minerals: Copper, iodine, iron, zinc
Taste tests available for individual minerals (potassium, zinc, magnesium, copper, chromium,
manganese, molybdenum, and selenium) may provide some initial information to guide
physical exam and laboratory evaluation (note that these tests are generally considered less
definitive than laboratory assays for these minerals, but are an affordable and rapid in-office
assessment)

(continued)
 666 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Dysgeusia Zinc and vitamin B12 insufficiency

Altered taste perception Diabetes, hypothyroidism, or other metabolic
Differential diagnosis (Ddx): loss of conditions
smell, which can contribute to/ Cancer treatment (chemotherapy and/or radiation),
cause loss of taste postoperatively and/or from certain medications such
as azithyromycin [17], amlodipine, metronidazole,
tetracycline groups, statins, and a number of thyroid
medications [82]

Loss of taste (general) Zinc insufficiency

Be sure to evaluate for loss of smell
(which can contribute to/cause
loss of taste)

Loss of taste for meat Incomplete protein digestion (most likely cause thereof
is hypochlorhydria)
Zinc deficiency
Pepsin and protease insufficiency

Intraoral inflam- Redness of mucosa and/or gums Vitamin C insufficiency [1]

mation

Bitter strips to evaluate supertaster status

Place the control strip on the tongue first and then the bitter strip on the mouth and evaluate for taste
Supertasters are homozygous for the allele that detects this taste. They have more fungiform papillae
Women, Asians, and African Americans are more likely to be supertasters, and about 25% of all Americans are classified
as supertasters. (Being a supertaster may have served an evolutionary advantage in avoiding potentially toxic plant
alkaloids)
Clinical significance: Supertasters tend to have a higher risk of colon cancer, consume more salt, and be leaner than the
average population. They may be more resistant to bacterial sinus infections, and they tend to be pickier eaters
Finally, supertasters may pass the zinc tally taste test, but still be deficient in zinc on later blood analyses
Tasters are more likely to be non-smokers and not in the habit of drinking coffee or tea and more likely to find green
vegetables bitter. Taster status is found more commonly in Native Americans, Inuits, and Australian or New Guinea
aboriginals

Breath odor Disorders of oral cavity Niacin insufficiency [29]

(halitosis) Retained food, stomatitis, glossitis, periodontal disease,
39 poorly cleaned dentures, xerostomia (dry mouth –
decreased saliva)

Disorders of the nose and sinuses Atrophic rhinitis, chronic sinusitis, nasal septal
perforation, ozena (atrophic disease of nose and
turbinates), nasal septal perforation (can be due to
cocaine use), and retained foreign bodies

Disorders of the tonsils and Recurrent tonsillar and adenoid infections, pharyngitis
pharynx

Disorders of the digestive organs Achalasia, GERD, empyema

Dysbiosis, pancreatic enzymes, and/or hydrochloric acid
insufficiency [58]

Disorders of the lungs Abscesses, bronchiectasis, pneumonia, empyema (is the

collection of pus in a body cavity – in this case the lungs
(“pleural empyema”))

Fruity/ammoniacal Systemic causes Diabetic ketoacidosis (fruity smell), fetor hepaticus, and
odor uremia (ammoniacal odor)

Psychiatric conditions Odor of bad breath perceived by the patient but not the
physician/health provider. May be a hallucination.
(Some patients will extend this to overall smells
emanating from their body and will isolate themselves
to avoid others smelling them)
The Nutrition-Focused Physical Exam
667 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Lymph glands Lymphadenopathy (swollen Food allergies

(neck) glands) Infection
Cancer

Parotid gland Enlargement Thiamine deficiency [29]

Protein insufficiency
Bulimia

Tongue [34, 57] The tongue is composed of skeletal muscle covered with mucosa. On the top (dorsum) of the tongue are three
different types of taste buds/papillae:
  Filiform
  Fungiform (which cover the entire surface of the tongue)
  Circumvallate (posterior dorsum of the tongue in semicircular arrangement). In addition to containing the taste
buds, these papillae also increase the surface area of the tongue
Visualization: Have the patient say “Ah” while protruding (and then curling up) the tongue so as to visualize both the
dorsum of the tongue and the sublingual surface. Gauze can be used to examine the far interior and lateral aspects
(place on tip and grasp and pull with the aid of the gauze)

Color Pale Anemia

Red Glossitis: B vitamin insufficiency (thiamine, riboflavin,

Candida (beefy red with white niacin, pyridoxine, folate, B12)
coat); glossitis – various shades of Magenta (riboflavin insufficiency)
coloration Fiery red (niacin insufficiency)
With hyperkeratotic appearance – vitamin A insuffi-
ciency [83]
Note: in folate deficiency, glossitis is accompanied by
normal proprioception, but in glossitis due to vitamin
B12 deficiency/pernicious anemia, abnormal proprio-
ception is seen
Iron deficiency anemia
Severe protein-calorie nutrition and malabsorption
Alcoholism
Oral estrogen – likely due to hormone-­induced
depletion of B vitamins [83]
If Candida is the cause, may co-occur with iron and/or
vitamin C deficiency

Coat Thin The tongue can often be sore (indicates atrophy).

If occurs with atrophied taste buds Vitamin B deficiencies, iron deficiency, alcoholism,
“slick or smooth tongue” or severe protein-­calorie malnutrition, malabsorption
atrophic glossitis May occur with hypochlorhydria and/or small intestinal
bacterial overgrowth (SIBO)

White, cheesy discharge (atop Candidiasis, GI flora imbalance, AIDS

beefy red tongue)

Thin coat with parched appear- Dehydration

ance

Ridges/furrow Fissured tongue (also known as Niacin deficiency and gut-triggered autoimmune issues
“scrotal tongue”) thought to be possible causes as well
May occur with psoriasis (along with geographic
tongue) and Sjogren’s syndrome [83]

Swelling Can often be seen with teeth Poor digestion, allergies, hypothyroidism, dysbiosis,
marks on the lateral border of the amyloidosis, Down syndrome [29]
tongue Can also be seen with thickened speech, snoring, and
sleep apnea
(continued)
 668 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Lesions Geographic tongue B Vitamin and zinc insufficiency

A form of atrophic glossitis that Allergies
has scattered smooth red areas of May occur with psoriasis along with fissuring [83] and
denuded papillae alternating with with chemical sensitivity [32]
normal patches of the tongue – Celiac disorder
lending the map-like appearance
that changes over time (migra-
tory). Considered benign and
self-limited in conventional
medical circles

Hairy black tongue – the “hair” is May follow antibiotic therapy, smoking, and exposure
elongated papillae on the tongue to bismuth exposure
dorsum Use of charcoal at high doses in cases of poisoning/
overdose can also lead to this condition

Hairy leukoplakia – multiple white, Insufficiencies of Vitamin A, riboflavin, niacin, pyridox-

warty, and painless plaques. These ine, folate, B12 precancerous, HIV/AIDS
are usually located on the lateral
aspect of the tongue (and can also
be seen on the inner mucosa of
the cheeks). The plaques each
have hair-like projections.
Ddx – Candida: In Candida, the
white coat can be scraped off,
which is not the case with hairy
leukoplakia

Tongue biting If with history of syncope (fainting), suspect seizures

(generalized tonic-­clonic), especially when biting is on
the sides (lateral portions) of the tongue

Varicose veins on sublingual May be normal variant of age, but in some patients,
(underside of the tongue) veins. may indicate a chronic increase in right-sided pressures
Referred to as “caviar tongue” (e.g., CHF)

Movement Tremors or involuntary movement Hypoglossal (CN12) nerve defect

39 Hypoglossal (CN12) examination: assess the patient’s ability to articulate; inspect the tongue on resting and with
protrusion

Jaw Jaw function – assess for temporomandibular joint (TMJ) dysfunction (it can limit/change food intake)
Palpate the patient’s jaw (also opening of ear canal) as they open and close their mouth. Feel and listen for audible
clicks over the jaw.
Assess for chewing and swallowing

Movement Clicking and misalignment (and TMD/TMJD correlated with increased psychological
often reports of pain) due to TMD/ stress and may be associated with abdominal obesity
TMJ or TMJD (temporomandibular and a lower BMI in women [84]
disorder, temporomandibular joint Headaches, allergies, depression, fatigue, degenerative
disorder) arthritis, fibromyalgia, autoimmune disorders, sleep
apnea, and gastrointestinal complaints were shown to
be more prevalent in those suffering from TMJD [85]
and in those with rheumatoid arthritis, ankylosing
spondylitis, and primary Sjogren’s syndrome [86]
The Nutrition-Focused Physical Exam
669 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Chewing and Important to assess for both Those with chewing and swallowing difficulties had
swallowing chewing and swallowing in elderly significantly lower vitamin A, E, and manganese levels,
3 oz. water swallow test and those with chewing difficulties had significantly
If this test is passed, thin liquids lower magnesium and vitamin E [87]
and other food consistencies can Vagus nerve defect (CN10) could interfere with
be recommended without further swallowing
dysphagia assessment [88]
Dysphagia risk assessment for the
community-dwelling elderly
(DRACE): A valid and reliable tool
for detecting latent risk of chewing
and swallowing disorders in the
elderly community-­dwelling
population [89]

Neck31,34 Lymphatic vessels are located throughout the body in all tissues and organs. Lymphatic vessels accompany blood
vessels – which helps to locate the nodes in some regions of the body. Lymphatic vessels function to collect lymph
(ECF) and carry it to venous circulation. In transit to the venous system, lymph passes through lymph nodes – which
serve to filter lymph fluid. Microbes, malignant cells, and other debris in the lymph nodes can lead to enlargement
and/or hardening of the lymph nodes. If this enlargement or hardening is significant enough, the nodes can be
palpable, and the diagnosis of “peripheral lymphadenopathy” is made. Note that a normal adult has around 400–450
lymph nodes in the body, though only ~100 of these are palpable (in the arm and underarm (axilla), in the leg and in
the head and neck)

Lymphadenopathy Allergies, infection (systemic, may have generalized and

When palpating a lymph node, do chronic LA (lymphadenopathy); acute, may be isolated
so lightly and assess for: node(s) and resolve as the infection resolves), toxin
  Size – >1 cm diameter (usually exposure, Hodgkin’s, lymphoma, leukemia, cancer, HIV,
measured with calipers); CT (connective tissue) disorders. Note that cysts and
considered significant and may lipomas must be considered in the differential
be pathological (may see large Significance by location:
nodes in intravenous (IV) drug   Occipital (kids, childhood infections; adults, rare
users – often benign) (maybe with scalp infection))
  Consistency – Rock hard   Posterior cervical – dandruff
suggestive of malignancy Preauricular – conjunctivitis and lymphoma
(though Hodgkin’s lymphoma   Submandibular, submental – dental or cancer of oral
nodes are usually rubbery). Note or nasal region
that cysts, being fluid filled, are   Supraclavicular node enlargement on the left known
softer, and swollen nodes as “Troisier’s node” signifies spread of intra-abdominal
without malignancy (infection or or intrapelvic malignancies
allergies) will generally be softer   Supraclavicular node enlargement on the right – lung
  Matting – individual nodes swell and breast cancers
together to create larger nodes
that may or may not be stuck to
overlying skin or underlying
tissue
  Tenderness – usually tender in
inflammation, less often with
cancer
In general:
  Benign nodes are usually small,
soft, non-tender, and discrete
(not matted)
Inflammatory nodes, tender, firm,
and often matted.
  Cancerous nodes usually large,
non-tender, matted, and rock
hard. “Sentinel” nodes are nodes
that, when enlarged or abnormal
to palpation, signal a specific
condition
(continued)
 670 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Venous distension Fluid status overload [1, 3] – may be due to heart failure,
along the carotid hypoalbuminemia, retention of salt and water, venous,
artery or lymphatic stasis

Parotid gland Protein deficiency/bulimia (bilateral) [3]

enlargement Thiamine deficiency [29]
Cyst, tumor, or hyperparathyroidism [3]

Range of motion Decreased range of motion can affect ability to properly masticate food [3]

Thyroid [31, 34] With palpation, note size, consistency (soft, firm, rubbery, or hard), texture (diffuse or nodular), tenderness, tracheal
deviation
(seen with asymmetrical goiter), and enlarged lymph nodes [over the thyroid]
Rubbery consistency is palpable with Hashimoto’s thyroiditis, and hardness is noted with cancer
The size of the thyroid varies with the supply of iodine in a diet (less iodine leading to larger glands). Note that
women’s thyroid glands are usually larger and easier to palpate than men’s. And the right lobe of the thyroid is often a
little larger than the left

Goiter Iodine deficiency/excess

Can occur with hypothyroid, euthyroid, or hyperthyroid
status

Nodules Iodine deficiency

Hashimoto’s thyroiditis
Thyroid adenoma, cyst, cancer

Chest Cardiac exam:

Normal: “Lub dub” (S1, S2, or first and second heart sounds produced by the closure of the AV valves (tricuspid and
mitral) and then the pulmonic and aortic valves (S2)). This explains why S1 is heard more in the lower chest and S2 in
the upper
Listen for abnormalities of the sound of S1 and S2 over each of the valves and any additional sounds
Clinical significance: Auscultation can be used to detect a wide range of cardiac conditions using careful techniques of
listening for S1 and S2 over each of the valves, using specific positions or techniques to accentuate suspected
abnormalities and listening for adventitious sounds
Pulmonary exam: Perform both anteriorly (patient lying on back) and posteriorly (patient seated with arms crossed
(spreads scapula to better examine the lungs)). Work from head down – comparing sides as you go (asking them to
take a deep breath in each time you place your stethoscope on a new site)
39 Palpation
Tenderness (can occur with costochondritis – inflammation of the costal cartilage)
Percussion
Determines if the lungs are full of air/fluid/solid masses
Auscultation
Compare sides with patient breathing through the mouth

Cardiac [31, 34, 57] Mitral valve prolapse (MVP) [31, 34, Magnesium, carnitine, potassium, calcium, and niacin
57] insufficiency
Dehydration, allergies, medications

Palpitations, arrhythmia Thiamine, magnesium, coenzyme Q10 (CoQ10), vitamin

K, and calcium deficiency [29]
Potassium or magnesium deficiency/excess, calcium, or
phosphorus deficiency [3]

Cardiomegaly Selenium, thiamine [29]

Tachycardia Thiamine [3], CoQ10 deficiency [29]

Dehydration [3]
Organic heart disease, severe pulmonary disease,
respiratory insufficiency, excessive alcohol consump-
tion, or drug toxicity
The Nutrition-Focused Physical Exam
671 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Pulmonary Barrel chest Thin elderly individuals

inspection Chronic obstructive pulmonary disease (COPD) such as
emphysema

Pigeon chest (bowed chest) Rickets, Marfan syndrome

Familial (normal)

Funnel chest (hollow chest) Can lead to arrhythmias or MVP

Retraction of interspaces Severe asthma, COPD

Use of accessory muscles to Signifies COPD or respiratory muscle fatigue

breathe (sternocleidomastoid
(SCM) and scalene) during
inspiration and abdominal muscles
in expiration. Normally the
diaphragm is the only muscle used
in breathing

Reactive airways Magnesium deficiency

Respiratory rate Increases in respiratory rate lead to increases in caloric, and often fluid, requirements, and
and rhythm changes in respiratory rate can affect acid-base balance [3]

Pursed lip breathing Emphysema (often the result of chronic cigarette

smoking)

Tachypnea (rapid breathing) Physical exertion

Heat stroke, shock, anxiety/panic attack
Metabolic acidosis, diabetic ketoacidosis, pneumonia,
cystic fibrosis, pulmonary embolism, heart failure,
sepsis

Bradypnea Hypothyroidism
Medications: sedatives/narcotics

Apnea (absence of breathing Sleep apnea

20 seconds while awake,
30 seconds while asleep)

Peak expiratory Measurement of air flowing out of Asthma associated with a narrowed airway – using a
flow the lungs peak flow meter gives information about how open the
See . Fig. 39.17. Peak Expiratory
  airways in the lung are (during an attack, the airways in
Flow Rate the lungs slowly begin to narrow)
Green, Yellow Zone and Daily PFM readings for those with asthma are encour-
Red Zone – relative to peak flow aged. This provides valuable information about the
status of the airways and can help to determine triggers
of asthma, how well an asthma management/treatment
program is and when emergency medical care is
needed. With an impending attack, the peak flow rates
start to drop. This allows early changes in one’s
medication or routines to prevent worsening of asthma
symptoms
Decreased peak flow rates may be seen with EFA,
magnesium insufficiency, with food/environmental
allergy and if fewer methyl donors (folate, vitamin B12
insufficiency) available (as these are required for
histamine metabolism)
Prognostic: decreased peak expiratory flow rate
predictive of increased mortality in those with COPD [90]

Auscultation Rales (crackles) Associated with fluid in the alveoli (fluid overload), as
seen in CHF
(continued)
 672 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Rhonchi (high pitched, continuous, Obstruction

clear with cough)

Wheezes (high pitched, musical) Due to narrowing of airways with chronic obstructive
lung disease (including asthma). Hear on expiration

Kussmaul (Deeper and more rapid Diabetic ketoacidosis anion-gap acidosis

breathing) “MAKE UP a List” [34]:
  Methanol poisoning
  Aspirin intoxication
  Ketoacidosis
  Ethylene glycol ingestion
  Uremia
  Paraldehyde administration
  Lactic acidosis

Abdomen [21, Generally, the 4-quadrant method is preferred as the 9-quadrant system often has organs occupying more than one
31, 34] quadrant
Have the patient lie supine (on back) – pillow under the head and with knees bent (or pillow under)
Ask if they need to void their bladder before having them lay down on the exam table
Patient’s arms should be at sides or folded over the chest. Ask the patient to point to any areas of pain and examine
these last. While performing the examination, watch the patient’s face for signs of discomfort. Make sure your hands
and stethoscope are warm and your nails trimmed. If the patient is tense or ticklish, begin the palpation step with their
hand under yours – you can then slip your hand under soon thereafter as they will usually calm quickly. As you carry
out the four steps (inspection, auscultation, percussion, palpation), try to visualize the organs underneath

Inspection Scars, bruising/ecchymosis Sign of abdominal hemorrhage

Distension 6 Fs:
  Fluid (ascites)
  Fat (obesity)
  Flatulence (gas)
  Fetus (pregnancy)
  Feces (constipation)
  Full-sized tumor (abnormal lesion) [16]

Striae (stretch marks) Considerable weight changes

39 Pregnancy
Cushing’s syndrome can see pink-purple striae

Scaphoid (sunken) – occurs with Insufficient caloric intake [3]

loss of subcutaneous fat

Dilated veins Hepatic cirrhosis obstruction inferior vena cava

Rashes, lesions, nodules Keratin and sebum can build up in the umbilicus – lead-
ing to a nodule which can be readily extracted
Prognostic: Sister Mary Joseph Nodule – metastatic
carcinoma of the umbilicus, usually from the stomach,
colon ovary, or pancreas – often means only
10–11 months left of life

Contour (rounded, protuberant, Protein deficiency [29]

bulging flanks) Gas
Obesity
Ascites (often accompanied by edema and hypoalbu-
minemia) [31]

Symmetry Asymmetry with enlarged organ or mass

Caput medusae (abnormal venous Portal hypertension (usually seen in those with
networks on the abdominal wall cirrhosis)

Ascites (accumulation of fluid in Liver disease (severe), cancer, CHF, pancreatitis

the peritoneal cavity) – bulging
flanks, flank dullness
The Nutrition-Focused Physical Exam
673 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Scratch test (Sergent’s white line) If redness is delayed/absent when scratch near the
Take the cap end of a pen and umbilicus, evaluate for decreased adrenal function
stroke it lightly across the abdomen
(make about a 6-inch line)
A normal response is to see a
whitish line, which reddens within
a few seconds. In adrenal
insufficiency, the line remains
white and may grow wider

Auscultation Follows inspection (prior to percussion and palpation) as these can alter the frequency of
bowel sounds. This step of the examination is helpful in determining bowel motility (via the
bowel sounds) and exploring vascular obstructions or abnormalities (such as bruits)
Listen for bowel sounds using your stethoscope over all four quadrants. Bowel sounds usually
occur on the order of 5–34 per minute. You may hear the stomach growling (prolonged gurgle
of hyperperistalsis known as borborygmi). Listen for 2 minutes before deciding if absent
If patient has high blood pressure, listen in epigastric region for bruits∗. (If arterial insufficiency
is suspected in the legs, listen over the aorta, iliac arteries, and femoral arteries. And if the liver
pathology is suspected, listen over the liver for hepatic bruits)
∗A bruit is caused by turbulent blood flow in an artery

Increased borborygmi Diarrhea and in early small bowel obstruction

Decreased borborygmi Post-surgery, later stage bowel obstruction, paralytic

ileus, peritonitis [3]

Percussion Helps to assess the amount and distribution of gas in the abdomen and to identify possible
masses

Hepatomegaly Protein deficiency or vitamin A excess

Hepatitis
Chronic alcohol abuse/cirrhosis, lymphadenopathy [31]

Splenomegaly Lymphadenopathy, infection (tropical diseases (malaria,

typhoid)), HIV, jaundice, hepatocellular disease,
cirrhosis, leukemias, lymphomas [31], hemolytic anemia

Palpation Tenderness to the left of the xiphoid May be due to hiatal hernia syndrome
at the fourth intercostal space

Tender areas in the colon Investigate for yeast overgrowth, dysbiosis, diverticuli-
tis, colitis, cancer (particularly if accompanied by occult
blood), and a variety of functional GI disorders
Testing HCL levels may be indicated [57]

Abdominal wall tenderness test Diabetic neuropathy elicits a positive test and will often
(Carnett’s test) [34, 91] occur with cutaneous hypersensitivity and weakness of
Identify the area of maximal tender- the abdominal organs (producing bulging of the
ness from palpation and apply abdominal wall)
enough pressure to the point to In patients with chronic abdominal pain, a positive
elicit a moderate amount of abdominal wall tenderness test decreases the
tenderness. Continue to apply probability that the pain has a visceral (i.e., organ-
pressure as the patient folds the related) cause
arms on the chest and lifts the head
and shoulders (partial sit-up). If this
elicits increased tenderness at the
site being palpated, it is a positive
test (and thus peritonitis less likely)

Hepatojugular reflex In CHF, will see filling of the neck veins – which
With patient in supine position, characterizes a positive reflex test
exert firm and sustained pressure
on the lower liver edge (in and up
toward the head at the lower right
costal margin)
(continued)
 674 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Musculoskeletal Inspect – for joint swelling, tenderness, and deformity

[21, 26, 31] Palpate – for joint warmth, tenderness, and crepitus
Investigate – range of motion (ROM) of joint
Note that joint pain within the joint (articular disease) often manifests in swelling and tenderness surrounding the
joint and often limits ROM with both passive and active movements, whereas pain outside the joint (extra-articular
disease) causes swelling and tenderness which is localized to specific regions within the joint and does not affect all
aspects of a joint’s ROM
Musculature and skeletal system are related to nutritional status. In developing countries, it can be seen with
marasmus (energy deficiency) and kwashiorkor (protein and energy deficiency) with frank malnutrition, whereas in
developed countries, the presentation is generally subtler, with lower body weight, muscle atrophy and loss of
subcutaneous fat, weakness, and laboratory abnormalities (low albumin, increased creatinine excretion)

Skull Delayed closure of fontanelles in Vitamin D and calcium deficiency [3, 29]
infants or abnormal softening of
bones in the skull (craniotabes),
frontal, or parietal bossing
(swelling or thickening of the front
and sides of the head)

Head/face Muscle wasting (temporal) Protein and calorie insufficiency [1, 3]

Torso Beading of ribs (prominent knobs Rickets, with bowed legs, pain in spine, pelvis and legs,
at the base of the costochondral thickened wrists and ankles, projection of the
joints (also known as Rachitic breastbone, delayed growth, and muscle weakness, due
Rosary). These knobs create to vitamin D deficiency
appearance of beads under the
skin of the rib cage)

Subperiosteal hemorrhages (of the Children with vitamin C deficiency

femur)

Scoliosis Structural (with vertebral rotation or thoracic deformity)

A lateral curvature of the spine or functional (unequal leg length without vertebral
rotation or thoracic deformity)
Some evidence to suggest that scoliosis is associated
with methylation defects (methylenetetrahydrofolate
reductase (MTHFR)) [92]
39 Kyphosis Osteoporosis (adults)
A rounded thoracic convexity If in adolescents, consider Scheuermann’s disease (seen
Dowager’s hump in tall and underweight adolescents). There is a
hereditary component to this disease

Lordosis Can develop in compensation to protuberant abdomen

Accentuation of the normal (pregnancy or marked obesity) or in compensation for
lumbar curve flexion deformities of the hip

Legs Bowing of legs and/or knock knees Rickets (vitamin D deficiency)

Muscle wasting gastrocnemius, Insufficient protein and calorie intake

buttocks Thiamine, vitamin C, phosphorus, and calcium
deficiency [3]

Low skeletal muscle mass lower Independently associated with osteoarthritis of the
leg knee in obese individuals [93]

Weakness, pain in calf muscles Thiamine deficiency

Epiphyseal enlargement Vitamin D deficiency (if painless) or vitamin C deficiency

(if painful)

Arm(s) Arm muscle area – assesses total (See . Fig. 39.18. Anthropometrics Flow Chart)
 

amount of muscle or protein in the

body (uses triceps skinfold measure)

Deltoid muscle wasting Protein and calorie insufficiency [1]

The Nutrition-Focused Physical Exam
675 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Spinal accessory (CN11) examination: Assess patient’s ability to shrug shoulders and strength of sternocleidomastoid
muscles with flexion as head turns against your hand [21]

Wrists and carpal Ganglion (cystic, round, usually Not a known nutritional association. (Though homeo-
joints non-tender swelling along the pathic silica is often used to treat ganglion cysts.)
tendon sheath on the dorsum of
the wrist commonly). They can also
develop elsewhere on hands,
wrists, ankles, and feet

Dupuytren contracture Hereditary (in part), males over 40, dysglycemia,

A fibrous thickening on the palm seizures (for reasons not yet understood)
along the tendon of the fourth History of hand trauma, alcohol, and tobacco use may
finger which keeps the finger also predispose one to the condition
partially flexed

Subluxation of the ulna Chronic rheumatoid arthritis

Epiphyseal enlargement Deficiency of vitamin D (if painless) and of vitamin C (if

painful)

Grip strength Hand grip strength reflects nutrient status and

Measure using a dynamometer accurately predicts postoperative complications
and compare readings obtained to (Lower hand grip strength indicates poorer nutrient
instrument’s normative tables status [particularly protein and vitamin D [29]] and
increased risk of post-op complications) and may be
indicative of presence of sarcopenia
Recommended cut-off values for sarcopenia [94]:
  Caucasian:
    <20 kg in women
    <30 kg in men
  Asian:
    <18 kg in women
    <26 kg in men
Prognostic: There is also evidence to suggest that in
postmenopausal women, grip strength is positively
related to normal bone mineral density and may help to
identify women who could benefit from additional
bone density evaluation [95]
Predictive of risk of cardiovascular disease, cardiovascu-
lar death, and all-cause death (across both genders) [96]
and was a stronger predictor of cardiovascular and
all-cause mortality than systolic blood pressure [97]
Grip strength (post-stroke) of the unaffected side
considered an independent predictor for short-term
functional improvements [98]

Fingers Swan neck deformity, Boutonniere Rheumatoid arthritis

deformity, ulnar deviation

Heberden’s nodes Osteoarthritis (consider allergy to nightshade veg-

Nodules on the distal interphalan- etables) [29]
geal joints (due to bony over-
growth of the joint). They are
usually hard and are painless
Bouchard’s nodes are located on
the proximal interphalangeal
joints and are less common

Callus on the back of the hand Bulimia (from using fingers to stimulate the gag reflex
in order to vomit)
(continued)
 676 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Gout Associated with increased protein (purine-rich foods

such as red meat and sardines), alcohol, medications
(diuretics, low-dose aspirin, cyclosporine, end-stage
renal disease), and metabolic syndrome

Skin cracks/splits Zinc and EFA deficiency [29]

Global symptoms Bone/joint pain Vitamin A, C, and D deficiency [3, 29]

Infection
Degenerative joint changes
Tumor(s)
Multiple myeloma

Muscle spasms Magnesium insufficiency (Carpopedal) calcium,

magnesium insufficiency [29]

Muscle tenderness bilaterally Thiamine insufficiency [3]

Decreased muscle tone (especially Vitamin D insufficiency

of hips and pelvis)

Sarcopenia Defined as the loss of muscle mass Vitamin D insufficiency (and thus likely those with VDR
and strength that occur with polymorphism) and protein (and hence those with
advanced age [99] hypochlorhydria, pancreatic insufficiency, or leaky gut
are at increased risk [32])
Antioxidant insufficiency (vitamins C and E, carotenoids,
and selenium) is linked to increased risk of sarcopenia
in older adults [100]
Considered to be due to chronic low-grade inflamma-
tion driven by decreased physical activity, anabolic
hormone, cytokines, oxidative stress, and adipokines
(with obesity) [101]

Neurological Mental status Confabulation (making up stories) May be due to Korsakoff’s psychosis (deficiency of
[34] and disorientation thiamine resulting from alcoholism) or Wernicke’s
encephalopathy (precipitates the brain damage that
leads to Korsakoff’s psychosis)

39 Acute disorientation Phosphorus and niacin insufficiency [29]

Reflexes Reflexes are involuntary contractions of the muscles which are induced by specific stimuli
We will focus on muscle stretch reflexes, in which a brisk stretch of the muscle induces the
reflex via muscle spindles to the spinal cord (which then sends the signal back to the muscle
and causes the reflexive contraction)
Examining reflexes:
  Have the patient seated on an examination table with their leg dangling and limbs hanging
symmetrically
  Sharply tap (with a reflex hammer) on the point where the muscle inserts distally on the
bone. On tapping the pointed end or blunt end can be used. The pointed end is better in
smaller locations. Hold the hammer between the thumb and index finger so it swings freely
within the hand
  Check reflexes bilaterally and compare. Use only enough force needed to generate a
response. Can reinforce the knee reflex (i.e., accentuate if the reflex response is difficult to
elicit) by asking the patient to clench their jaw and interlace their fingers
  Reflexes typically tested include the biceps, triceps, brachioradialis, abdominal, patellar, ankle,
and plantar [3]
Rate the reflex response according to the following scale:
  0 = absent
  1 = hypoactive (diminished)
  2 = normal
  3 = brisk (increased)
  4 = hyperactive
For the Babinski reflex, stroke the lateral aspect of the foot with the metal end of the reflex
hammer. A normal response is the absence of a reflex response. If dorsiflexion (the toe goes
up), it is a positive sign
Asymmetry of reflexes more suggestive of pathology
The Nutrition-Focused Physical Exam
677 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Hypoactive (Achilles, patellar Hypothyroidism (Achilles)

reflexes) Nutrient deficiencies:
  Potassium [3]
  Thiamine, pyridoxine, vitamin B12, or possibly with
excess B12 (Achilles, patellar reflexes)
  Respiratory alkalosis [3]

Hyperactive CNS disease

Calcium deficiency/hypocalcemia

Positive Babinski sign Parasites, drug/alcohol intoxication, post-seizure (or

upper motor neuron disease – such as amyotrophic
lateral sclerosis (ALS)), vitamin B12 deficiency [102]
(Positive sign is normal to see in infants)

Touch Examine for ability to perceive touch by touching the skin lightly over different dermatomes
with cotton wisp covering as many dermatomes as possible
A dermatome is the area of the skin innervated by the sensory fibers of a single nerve root
If a nerve root is damaged – there will be loss of sensation across the whole dermatome [31]

Monofilament testing If a patient cannot sense this pressure, they have loss of
Apply pressure on the plantar side protective association (seen in diabetes)
of the foot until the monofilament Prognostic: increased risk of foot ulceration and
buckles amputation
Hold for 1 second and release

Paresthesias Thiamine, iodine, vitamin B6, vitamin B12, vitamin E,

Abnormal sensation with “pins and omega- 3 fatty acid, phosphorus insufficiency [29]
needles” (numbness, tingling, Carpal tunnel syndrome, ulnar neuropathy, multiple
pricking sensation) due to damage sclerosis (MS), diabetes, hypothyroidism, alcoholic
to (or pressure on) the peripheral neuropathy, drug toxicity
nerves

Temperature Examine for ability to perceive temperature by touching the skin lightly over different
dermatomes with tubes of warm/cold water or cold tuning fork and warm index finger of
clinician (to discern difference) covering as many dermatomes as possible [31]

Pain Examine for ability to perceive pain by touching the skin lightly over different dermatomes
with sharp and dull object/stimuli (to discern difference) covering as many dermatomes as
possible [31]

Sensation Dermatomal testing discussed previously

Vibration Test with a tuning fork (128 Hz) Decreased vibratory sense seen with exposure to heavy
Strike the tuning fork forcefully metals, neurotoxins [103] decreased antioxidant intake,
against the heel of your palm and methylation defects (riboflavin, B6, folate, B12)
then apply the stem of the fork to Thiamine, riboflavin, niacin, pantothenic acid, and B12
the lateral malleolus (ankle bone) insufficiency
should perceive vibrations for Polyneuropathy of diabetes, Lyme disease, collagen
≥11 seconds (decreases by vascular disease, allergy, and autoimmune conditions
2 seconds for every decade [3]
starting at 40 years)
And ≥15 seconds (decreases by
2 seconds for every decade
starting at 40 years) on the ulnar
styloid

Proprioception/ Grasp the lateral aspect of the toe Loss of proprioception with peripheral neuropathy
position sense [31] or index finger between the Thiamine [29], vitamin B12 deficiency
thumb and forefinger. Have the Diabetes, MS, history of stroke, severe brain disease
patient close his/her eyes and
move the digit up and down –
pausing to ask what orientation
they perceive the digit to be in

(continued)
 678 M. R. Fry

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Neuropathy Peripheral neuropathy EFA, vitamin E, thiamine, pyridoxine, vitamin B12

Characterized by weakness, insufficiency, or excess pyridoxine [3, 29]
paresthesias, ataxia, decreased Alcoholism (polyneuropathy) [36]
tendon reflexes, fine tactile sense,
decreased vibratory sense, and
(position sense)

Tremors [21, 31] Resting (static) Parkinson’s disease

Tremor is most prominent at rest Magnesium and pyridoxine insufficiency [29]
and may decrease or disappear
with voluntary movement

Active tremors Postural: hyperthyroidism, fatigue, anxiety, and also

Postural: Active tremors appear benign (familial) tremor
when actively holding the affected Intention tremor: multiple sclerosis
part. It may worsen with intention.
Essential tremor is the term used
when it is a benign tremor. It is the
most common movement
disorder, and the etiology is
unknown.
Intention: The tremor is absent at
rest, appears with activity, and
worsens as one nears the target
(e.g., picking up a mug)

Balance Romberg test – patient should stand with feet together and eyes open and then close both
eyes for 60 seconds. Note that you will want to have an arm in front of and behind them to
protect them from falling should they lose balance. Only very minimal swaying should occur
unless ataxia (problems with coordination and nervous system function due to neurological
lesion), cerebellar disorders, or an acoustic nerve lesion (CN8) is present

Positive Romberg Diabetic neuropathy, Guillain-Barre, MS

Ataxia
Vascular injuries to the thalamus [36]

Gait [36] Walking is a very complex action that requires integration of many systems (motor, sensory,
39 vestibular, and visual) so most abnormalities in the nervous system are visible in the gait.
Look for symmetry versus asymmetry (muscle, joint, and pain disorders cause asymmetry,
whereas abnormal limb control tends to be more symmetrical and due to central lesions)
Disorders of the gait can be due to pain, joint immobility, muscle weakness, or abnormal
control of the limbs
Note that alcoholism/alcohol intoxication affects gait enormously (can lead to wide gait, poor
tandem gait, and possibly leg ataxia)

Gait speed: ≤0.8 m/s associated with sarcopenia (other measures

Associated with increased survival (of muscle mass and strength) need to be assessed to
in older adults, said to reflect confirm/strengthen diagnosis [100]
health and functional status and to <0.6 increased likelihood of poor health/function
be a potentially useful clinical >1.0 m/s associated with healthy aging [105]
indicator of well-being [104] and
survival [105] in older adults
Measure via measured walk from
standing start (over 8 feet [104] or
4 m [105]
Patient to walk from start to finish
at their usual speed “just as if…
walking down the street to go to
the store” [104]
Time two walks and average
May be less helpful for older adults
who already report dependence in
basic activities of daily living [105]
The Nutrition-Focused Physical Exam
679 39

..      Table 39.1 (continued)

Region Nutrition-associated examination findings Nutritionally related cause/association

examined (and select examination/test techniques)

Slow gait Sarcopenia

Depression
Schizophrenia
Prognostic: predictive of cognitive decline

Rapid gait Mania

Hyperthyroidism

Tandem gait Schizophrenia, alcoholism [36]

Wide gait Thiamine and vitamin B12 insufficiency [29]

Alcoholism

Shorter stride length Schizophrenia

Cortical/basal ganglia disorders

“Parkinsonian gait” Parkinson’s disease

  Short steps (petit pas), reduced Depression (can resolve as depression resolves)
arm swing, stooped posture, Schizophrenia (mild Parkinsonian gait)
anteropulsion/retropulsion, Antipsychotic medications
festination, postural instability

Ataxia Cerebellar, pons or thalamus injury, possible cortical

Increased width of gait, arrhythmic damage
steps, unsteadiness and impaired Alcohol or medications (benzodiazepines, anticonvul-
tandem gait, and loss of position sants) Thiamine, vitamin E, vitamin B12, and copper
sense insufficiency [1, 29]
Mitochondrial dysfunction, EFA imbalance, toxin
burden [20]

Antalgic gait Degenerative joint disease (DJD), orthopedic injury

Spastic gait with scissoring Osteoarthritis, B12 deficiency, trauma, inflammation,

tumor, demyelination disorder

Abrupt onset of gait disturbance, Psychogenic balance disorders

selective disability, gait distur-
bance related to minor trauma

Risk of falling Stops walking when talking Polypharmacy (medications risk factor for falls in at
(difficulty performing both least 30% of elderly exhibiting gait or balance
simultaneously confers increased disorders – especially psychiatric medications)
risk of falling) Hypotension
Timed chair stands: times how Positive get-up-and-go test with sarcopenia
long it takes for a patient to get up
from a chair and sit again three
times in a row (positive is
>10 seconds)
Get-up-and-go test: assesses
mobility and predicts falls – posi-
tive is ≥12 seconds [106]

Coordination Assessed by: Cerebellar disease – clumsy/unsteady movement [21]

  Finger-to-nose test
  R apid alternating movements
  Heel-to-shin tests
 680 M. R. Fry

Anthropometrics

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Stature/height The simplest method to accurately measure height Used relatively (in other measures (such as body mass index and
involves positioning the individual to be measured waist-to-­height ratio)) and for growth chart assessment
with their back against a flat vertical surface upon
which a measuring stick or measuring tape has
been affixed. Then a headboard is positioned at a
right angle to the wall or vertical surface upon
which their back rests and their stature can be
obtained (ideally to the closest 1/8 of an inch)
A stadiometer can also be used to measure height
Some notes on ensuring accuracy with this
measurement:
If a wall is used, the baseboard should be minimal,
and the individual being measured should be
standing on a hard, uniform surface without carpet
For those with difficulty walking or who have
severe spinal curvature, measuring height by this
method would be inaccurate, so their stature is best
estimated from knee height (normative reference
tables are published to interpret this measure)
-Knee height correlates closely with stature
An alternative method is to estimate stature from
upper or lower arm length (though this is used less
often)
The knee and ankle of the left leg are typically
measured (as the left leg was used by researchers in
developing the equations used to determine
normative values)
The knee and ankle should be at a 90-degree angle
to each other (verify this with a right triangle,
square, or other device)
The fixed blade of the sliding caliper is positioned
under the heel of the left foot, and the moveable
blade is placed on the anterior surface of the left
thigh [26]

Length (aka Obtained with subject lying down in face-up Used relatively (in other measures (such as body mass index and
39 recumbent
length)
(supine) position. Usually limited in use for children
≤24 months of age or children who are unable to
waist-to-­height ratio) and for growth chart assessment

Pediatrics stand without assistance. Length forms the basis of

growth charts up to 24 months of age, with height
used in growth charts for children at 2 years and
beyond
To measure recumbent length accurately, a special
measuring device is required, and two people are
needed to accurately obtain the measurement. A
stationary headboard and moveable footboard
must be perpendicular to the backboard
The length is measured from the foot board (“0”
starts at the headboard), with the crown of the
head held securely against the headboard, and a
right angle made between the Frankfort horizontal
plane and the backboard
The soles of the feet are to be held firmly against
the footboard at this time (toes pointing upward),
and the child’s shoulders and buttocks should be
firmly touching the backboard. The length of the
child can then be recorded to the nearest 1/8 of an
inch. Make notes of any challenges or increased
estimation based on the child moving about and
not laying still during this procedure
The rate of gain in length is indicative of nutritional
adequacy [26]
The Nutrition-Focused Physical Exam
681 39

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Head To perform this measurement, with the child seated The measurement of head circumference is very important for
circumference in their caregiver’s lap and the lower edge of a screening in the first year of life, in particular. In the first 12 months of
{Pediatrics} [26] non-stretchable, but flexible, measuring tape life, head circumference increases rapidly and slows by 36 months of
positioned just above the eyebrows and ears age. Pediatric growth charts are used to evaluate head circumference
around the occipital prominence of the head. The for age as a means to monitor growth and development
tape should be tight enough to compress the hair.
The measurement should be read to the nearest 1/8
of an inch
A duplicate reading is best to ensure an accurate
reading

Weight [26] Weight is one of the most important measurements Optimal weight is Overweight Underweight
in nutritional assessment. It is important in 22.5–25 kg/m2. The risk A body weight in Defined as a BMI
predicting caloric expenditure and in determining of death is lowest when excess of some <18.5 kg/m2
body composition the body mass index reference point With a BMI <22.5 kg/m2
Electronic scales are preferred over balance beam (BMI) is approximately The reference (not even under-
scales (for accuracy and they also are generally 22.5–25.0 kg/m2 point is usually weight), the risk of
lighter weight, more portable, and easier to use and For every 5 kg/m2 defined in terms death increases,
have a higher weight capacity (best when weighing increase in BMI, risk of of weight for especially for
obese clients)) death from all causes height smoking-related
Many models of electronic scales can connect into increases by 30%, from Possible for very diseases such as
computer networks, and information on weight, cardiovascular disease muscular person respiratory diseases
body mass, and stature can be directly recorded by 40%, from diabetic to be overweight and lung cancer
into a client’s electronic chart/record renal and hepatic (though not
To weigh a child or adult correctly/accurately, diseases by 60–120%, commonly the
ensure that both feet are firmly planted on the base and from neoplastic case)
of the scale (in the middle of the platform) without diseases by 10% BMI ≥25 kg/m2
touching anything and with weight evenly Usual body weight Obesity
distributed over both feet. Read the weight to (UBW) An excess
within 0.2 lb. Any subsequent reading, if performed Variations from UBW amount of body
correctly, should agree within 0.2 lb. strongly linked to fat relative to
It is best to weigh both children and adults after nutritional risk and lean body mass
voiding (after they have emptied the bladder) and health complications usually expressed
dressed in an item of clothing of known weight, Nutritional risk: as a percentage
such as a gown >5% unexplained of body weight
There are diurnal variations in weight of about 2 weight change in that is adipose
lbs. in children and 5 lbs. in adults, so it is best to <1 month or >10% in tissue
record the time that an individual was weighed and 6 months BMI ≥30 kg/m2
to weigh them subsequently at approximately the Percent usual body Those with a BMI
same time of the day weight [107] in the 30–35 kg/
Non-ambulatory persons require a bed scale or =current body weight m2 range died
wheelchair scale. The individual is positioned into a ×100 2–4 years earlier
weighing sling, which is then raised until the usual body weight Those with a BMI
person is suspended over the bed Percent weight (wt) in the 40–45 kg/
A chair scale can also be used to obtain weight change m2 range died
(which has the person sitting upright in their chair = Present body 8–10 years earlier
while leaning against a backrest). And finally, there weight – usual body (comparable to
are wheelchair scales (upon which the wheelchair is weight ×100 usual body the effect of
rolled) for obtaining a person’s weight weight cigarette
Note: Weight in adolescents more accurately or: smoking on
reflects nutritional adequacy than height [17] % usual body weight – lifespan)
100 = % change
 682 M. R. Fry

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Body mass Because of the difficulty of determining body Child and adolescent: Child and Child and adolescent:
index (BMI) composition and the ease of measuring height and   5th–85th percentile adolescent:   <5th percentile
(Quetelet weight, BMI is used to screen for overweight and on growth chart (BMI   O verweight Adult:
index) obesity in children, adolescents, and adults for age percentile  85th–95th
      Under-
Correlates with underwater weighing and charts) [17] percentile weight<18.5 kg/m2
dual-energy X-ray absorptiometry (DEXA) Adult [17]:   Obese:   BMI <23 in older
BMI = (W/H [2]), which is weight in kilograms   22.5–25 kg/m2  ≥ 95th
    adults (>65 y.o.)
divided by height in meters (squared) percentile confers an increased
Calculations or nomograms available for interpreta- Adult [17]: risk of mortality [17]
tion or classification and online calculators are   O verweight:
available for metric and nonmetric calculation     25–29.9 kg/m2
BMI differs with race/ethnicity, sex, age, and   Obese:
musculature (athletes with increased muscle mass     ≥30 kg/m2
may have elevated BMI measure in the absence of
elevated total body fat). These differences must be
considered in interpreting the BMI
Growth charts Growth charts are used to assess the growth and development of infants, children, and adolescents (up to 20 years of age)
They are based on growth data obtained from large numbers of healthy infants, children, and adolescents and are an
important tool in assessing nutritional status, general well-being and growth, and development of individuals up to 20 years
of age (For infants/young children less than 2 years of age, they are known as the growth standard (as opposed to a growth
reference – which determines what is/exists and is comprised of data from all kids, not just healthy individuals)
Note that growth reference data is all that we have available for the 2–20 years of age growth charts
Growth charts are a helpful tool to monitor nutritional status in those undergoing medical treatment – allowing adjustments
in nutritional intake (enteral or parenteral) to be made in a timely and effective manner
These charts have historically been used to screen for malnutrition but are increasingly being used to screen for overweight/
obesity now
There are two sets of growth charts for both male and female:
  Birth – 24 months of age and 2–20 years of age
There are growth charts that give percentile curves for:
  Weight-for-age
  Length-for-age
  Weight-for-length
Head circumference-for-age
Waist Where fat is distributed in the body may have a greater Increased waist circumference is an independent risk factor for
circumference impact on health than total amount of fat in the body disease [17]
(WC) [107] To measure: Male:
  Have the patient remove any outer clothing   High risk >40 inches
covering the abdomen and waist and place the Female:
39 measuring tape on bare skin   High risk >35 inches
  Obtain the measurement by measuring the May not be a useful measure with height in excess of 60 inches or
distance around the narrowest area of the waist with BMI ≥35
(between the lowest rib and the iliac crest)
  The person being measured should stand erectly with
the abdomen relaxed, arms at side, and feet together
  The tape should be snug against the skin but not
to the point where the skin is compressed
  Take the measurement after the end of a normal
expiration
  Repeat 1–2 times to ensure accuracy and record
to the nearest 0.1 inch
  If the BMI >30, assuming central adiposity, WC is
not necessary to perform [26]
Waist circumference may be used to evaluate
success of weight loss treatment
Little predictive value in people with BMI ≥35 kg/m2
May not apply with height <60 inches (5 ft.)
Ethnic variation (Asian descent – WC > BMI for
predicting disease risk)
Ethnic variation – generally predictive for racial and
ethnic groups in North America – those of Asian
descent – WC > BMI for predicting disease risk
Fat accumulation in the abdomen is linked to
increased risk of type II diabetes and obesity-­
related diseases in general
Recommended to be used as part of routine
physical exam
The Nutrition-Focused Physical Exam
683 39

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Waist-to-­hip =Waist/hip circumference Preferred ratio is to Increased

ratio17 Abdominal fat is comprised of: have the waist abdominal fat is
  Subcutaneous fat circumference less than an independent
Visceral fat – Research that visceral fat (fat around a the hip circumference risk factor for
number of abdominal organs (such as the stomach, (so the ratio <1 (due to morbidity
liver, and spleen)) is most strongly correlated with the increased risk for (sickness) and
morbidity and mortality hypertension with mortality
  Retroperitoneal fat (retroperitoneal fat = outside higher waist circumfer- World Health
of and posterior to peritoneal cavity (which lines ences)) Organization
the surface of the abdominopelvic wall and Optimal/ideal: (WHO):
contains most of the organs))   <0.8 female   >9 in men
  Most accurate measure of abdominal fat is via MRI   <0.9 male   >0.85 in women
or CT – but costly and less practical, so WHR is Benchmark for
used to estimate abdominal adiposity metabolic
  (Hip measurement is taken at the widest part of syndrome
the buttocks (i.e., hip circumference at largest (predicts all cause
point. The anatomic landmark for this is the and CVD
greater trochanter.)) mortality) [17]

Waist-to-­ WHtR = Waist circumference divided by height WHtR = 0.5 (Apple and pear (Chile shape)
height ratio A measure of the distribution of adipose tissue [17] “Keep your waist shapes) Slim:
(WHtR) More sensitive than BMI as early warning of health circumference to less Overweight:   F: 0.35–0.42
risks and also considered to be more sensitive than than half of your   F: 0.49–0.54   M: 0.35–0.43
the waist circumference in several different height” [109]   M: 0.53–0.58 Underweight:
populations (due in part to the fact that it includes General age-related Obese:   F: <0.35
a measure of stature) [108] ranges:   F: 0.54–0.58   M: <0.35
It is easier to measure/calculate than BMI and more   0.43–0.5 adults less   M: 0.58–0.63
affordable (no scale is required, just measuring tape than 40 y.o. Very obese:
for waist circumference and height [108]   0.5–0.6 adults 40–50   F: >0.58
More accurate in adolescents and across different y.o.   M: >0.63
ethnicities   ≤0.6 adults over 50 Higher values of
WHtR > WC > BMI for detecting cardiometabolic y.o [17]. WHtR relate to
risk across both genders [109, 110, 111, 112] increased risk of
The WHtR counteracts differences across ethnicities metabolic
that the waist circumference and WHR cannot (such syndrome and to
as the fact that health risks for Asians are increased obesity-related
with smaller levels of visceral fat than for Cauca- cardiovascular
sians). With the average height of Asians being less conditions
than Caucasians, the WHtR can account for this [17, 108]
WC and WHtR are superior to BMI in predicting
diabetes and CVD risk (BMI does not assess the
accumulation of visceral/abdominal fat) [109]

Body composition analysis – there are several methods for determining body composition [17, 26]
  Densitometry
    Underwater weighing
    Air displacement plethysmography
  Total body water
  Total body potassium
  Neutron activation analysis
  Creatinine excretion
  3-Methylhistidine
  Electrical conductance
    Bioelectrical impedance analysis (BIA)
  Infrared interactance
  Ultrasound
  Computed tomography (CT)
  Magnetic resonance imaging (MRI)
  Dual-energy X-ray absorptiometry
The most accurate and widely used will be discussed in more depth in this table hereafter
 684 M. R. Fry

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Skinfold Most widely used method of estimating percent Normative tables, equations, and nomograms available for
thickness [26, body fat interpretation [26]
107] As these measures assume subcutaneous fat
comprises 50% of the total body fat, and the
measures require considerable skill to perform
correctly, they are not considered the most
accurate method of determining percentage body
fat. However, they do have some advantages:
  Estimates energy reserves (fat and protein) in
subcutaneous tissue
  Measurements can be easily and quickly obtained
  Done accurately, measures can correlate well with
hydrostatic weighing
  Inexpensive and portable equipment (vs.
hydrostatic weighing)
Typical sites measured include:
  Chest
  Triceps
  Subscapular
  M idaxillary
  Suprailiac
  Abdomen
  Thigh
  Medial Calf
Calculations and/or nomograms are used to
determine body fat percentage from one or more
specific skinfold sites (sites chosen for measure-
ment/calculation vary by gender and age)
In hospitalized patients, the sum of:
  Triceps and subscapular skinfold thicknesses
(measured recumbently) are used as indicator of
body’s energy reserves

Arm muscle Arm muscle area is used to assess total amount of Normative tables, equation, and nomograms available for
area (AMA) [26] muscle in the body (uses triceps skinfold (TSF) interpretation
measure and mid-arm circumference (MAC) for
calculation/determination)
Limitations with accurately measuring MAC and TSF
limit use of this measure
39 AMA is correlated with creatinine excretion
(children) and total body muscle mass (adults)
The Nutrition-Focused Physical Exam
685 39

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Bioelectrical Electrical current passed through the body to For more specifics on these measures and their interpretations,
impedance determine fat vs. fat-free mass. This current is consult the guide(s) of the specific machine(s) that you will use for BIA
analysis (BIA) harmless and cannot be felt by the subject testing
[17, 26] Principle: The current is opposed by nonconducting BIA skeletal muscle mass (whole body) measure can be used to screen
tissues (fat and cell membranes) and transmitted by for sarcopenia [94] (in conjunction with handgrip strength and gait
electrolytes in water (in fat-free tissues mainly) speed)
Opposition to alternating current (AC) = “Imped- <8.87–10.76 kg/m2 men
ance” <6.42–6.76 kg/m2 women
Accuracy – comparable to skinfold measurements
(may be better)
Particularly helpful in assessing body composition
in those with edema or in patients who have had an
amputation
Weaknesses: assumes normal hydration
With the weakness of dehydration skewing results,
it is advised to have subjects drink plenty of water
and refrain from exercising heavily for 4–6 hours
and from consuming alcohol and/or taking
diuretics for 24 hours prior to the test
Depending on the device used, a BIA machine may
measure any/all of the following:
  Weight
  Percent total fat
  Fat mass and fat-free mass
  Muscle mass
  Bone mass
  BMR
  Metabolic age
  Visceral fat rating
  BMI
  Physique rating
For more specifics on these measures and their
interpretations, consult the guide(s) of the specific
machine(s) that you will use for BIA testing

Air displace- Body density is measured as a means to estimate body fat and fat-free mass. The BOD-POD device is considered to be an
ment accurate method for determining body composition
plethysmogra- Patient enters a capsule/pod wearing tight-fitting swimsuit and cap to minimize measurement error
phy It is relatively quick, easy, and affordable to test/obtain results and is preferred for children, the elderly, and those with
(BOD-­POD) [17, disabilities over underwater weighing
26] As it does not rely on body water content for determining body density and composition, it has potential utility in those
with hydration imbalances and in adults with end-stage renal disease

Dual-­energy Measures fat, bone mineral, and fat-free soft tissue

X-ray Used in hospital setting
absorptiom- Considered easy to use. Patient needs to remain still for accurate measure so can be a problem for those with chronic pain
etry (DEXA) and the elderly
[17] Affected by hydration status and thickness of tissues
Emits low-level radiation
 686 M. R. Fry

Measure Examination/measurement method Optimal Excess/elevated Deficient/depressed

Measuring Measuring energy expenditure

energy Direct calorimetry
expenditure Indirect calorimetry
[26] Doubly labeled water
Bicarbonate urea
Estimating energy expenditure (REE)
Harris-Benedict equation
World Health Organization (WHO)
NIH
University of Vermont
Mifflin St. Jeor
Estimating energy expenditure – major determinant is fat-free mass (determine 70–80% of variance in REE, with the
remaining 20–30% due to genetics). Note that the WHO equations do not include stature (it was not found to significantly
improve the predictive ability of the equations)
The resting energy expenditure equations must be increased to account for total energy expenditure, and this is achieved
by multiplying the REE by an activity factor. In theory, REE includes the thermic effect of food (TEF) and total energy
expenditure (TEE); however, in most clinical settings, allowance for additional energy needs from the TEF is not given
In cases of disease, injury, and surgery, an additional factor can be included to estimate the 24-hour energy expenditure of
these patients.
The Estimated Energy Requirement (EER) developed by the National Academy of Sciences is defined as “average dietary
intake that is predicted to maintain energy balance in a healthy person of defined age, gender, weight, height and level of
physical activity consistent with good health.” These equations apply only to people with healthy weight. For overweight,
use the TEE equations

Nutrition screening questionnaires

Mini Nutri- Designed to efficiently identify elderly patients at nutritional risk who may then need a more extensive nutritional assess-
tional ment
Assessment The full MNA can be completed in 10–15 minutes
[26] (MNA and The short form (MNA-SF) can be completed in less than 5 minutes
MNA-SF)

Malnutrition Designed to identify adults who are malnourished, at risk of malnutrition, underweight, or obese
Universal It evaluates BMI, history of unintentional weight loss, and the presence of decreased food intake due to illness
Screening Tool Can be completed in 3–5 minutes
(MUST) [26]

39

..      Fig. 39.3  Schamroth’s sign: disappearance of diamond-shaped

window between digits that is normally present when paired digits are
..      Fig. 39.2  Clubbing. (Reprinted from 7 https://commons.­
 
juxtaposed (anteriorly) seen in clubbing. (Reprinted with permission
wikimedia.­org/wiki/File:Acopaquia.­jpg. With permission from Creative from 7 https://www.­flickr.­com/photos/104346167@
 

Commons License 4.0: 7 https://creativecommons.­org/licenses/

 
N06/17001286589)
by-sa/4.­0/)
The Nutrition-Focused Physical Exam
687 39

..      Fig. 39.4  Koilonychia. (Reprinted from 7 https://www.­flickr.­com/

 

photos/coreyheitzmd/15023020192. With permission from Creative

Commons License 2.0: 7 https://creativecommons.­org/licenses/
 

by/2.­0/) ..      Fig. 39.6  Nail pitting. (Reprinted from 7 https://commons.­

 

wikimedia.­org/wiki/File:Luszczyca_paznokcia.­jpg. With permission

from Creative Commons License 3.0: 7 https://creativecommons.­org/
 

licenses/by-sa/3.­0/deed.­en)

..      Fig. 39.7  Beau’s lines. (Reprinted from 7 https://commons.­

 

wikimedia.­org/wiki/File:Beau%27s_lines.­JPG. With permission from

Creative Commons License 4.0: 7 https://creativecommons.­org/
 
..      Fig. 39.5  Onycholysis nail bed becomes separated from the nail
licenses/by-sa/4.­0/)
plate. (Reprinted from 7 https://commons.­wikimedia.­org/wiki/
 

File:Oncymycosis.­JPG. With permission from Creative Commons

License 3.0: 7 https://creativecommons.­org/licenses/by-sa/3.­0/
 

deed.­en)
 688 M. R. Fry

..      Fig. 39.8  Ridging of the nails. (Reprinted from 7 https://

 

commons.­wikimedia.­org/wiki/File:Lunula_07.­jpg. With permission

from Creative Commons License 3.0: 7 https://creativecommons.­org/
 

licenses/by-sa/3.­0/deed.­en)

..      Fig. 39.10  Half-and-half nails (Lindsay’s nails). (Reprinted from

7 https://commons.­wikimedia.­org/wiki/File:Lindsays_Nails_2.­jpg.
 

With permission from Creative Commons License 4.0: 7 https:// 

creativecommons.­org/licenses/by-sa/4.­0/)

39

..      Fig. 39.9  Terry’s nails. (Reprinted from 7 https://commons.­

 
..      Fig. 39.11  Muehrcke’s lines. (Reprinted with permission from
wikimedia.­org/wiki/File:Terry%27s_nails.­jpg. With permission from 7 https://commons.­wikimedia.­org/wiki/File:Muehrcke%27s_lines.­JPG)
 

Creative Commons License 3.0: 7 https://creativecommons.­org/

 

licenses/by-sa/3.­0/deed.­en)
The Nutrition-Focused Physical Exam
689 39

..      Fig. 39.14  Punctate leukonychia. (Reprinted from 7 https://

 

en.­wikipedia.­org/wiki/Leukonychia. With permission from Creative

Commons License 3.0: 7 https://creativecommons.­org/licenses/
 

by-sa/3.­0/deed.­en)

..      Fig. 39.12  Mee’s lines (Reynolds/Aldrich lines). (Reprinted from

7 https://commons.­wikimedia.­org/wiki/File:Mee%27s_lines.­JPG. With
 

permission from Creative Commons License 3.0: 7 https://

 

creativecommons.­org/licenses/by-sa/3.­0/deed.­en)

..      Fig. 39.15  Paronychia. (Reprinted with permission from 7 https://

 

commons.­wikimedia.­org/wiki/File:Paronychia.­jpg)

..      Fig. 39.13  Splinter hemorrhage. (Reprinted with permission from

7 ­https://commons.­wikimedia.­org/wiki/File:Splinter_hemorrhage.­jpg)
 
 690 M. R. Fry

..      Fig. 39.16  Onychotillomania. (Reprinted with permission from

7 https://commons.­wikimedia.­org/wiki/File:Nailbitebad.­jpg)
 

Using a Peak Flow Meter (PFM),

• Set the sliding pointer on the meter to zero
• Hold the PFM by the handle
• Stand erect
• Remove chewing gum or food from mouth
• Take a full deep breath and seal both lips and tongue
around the mouthpiece
• Exhale as quickly and as forcefully as you can
• Note the number where the sliding pointer stopped
• Reset the sliding pointer to zero
• Repeat 3 times
• If any coughing occurs in this process, repeat
• Record the highest reading of the 3 in a graph or log (This is the peak flow.)
• Use daily – ideally around the same time each day
• If a new meter is needed, be sure to determine peak flow for that meter
39 Peak Flow Zone Clinical Meaning Action to take
Green Go Zone – 80-100% of peak flow None
Zone to be in every day
Indication that air is moving freely
through the large airways
Yellow Caution Zone – 50-80% of peak flow Talk to doctor- medication
Clue that large airways are starting to change/increase and/or
narrow other intervention may be
May be symptomatic (coughing, needed
fatigued, short of breath, tightening of
chest
Red STOP Zone – <50% of peak flow Take rescue medication and
Indication of severe narrowing of large call the doctor
airways – MEDICAL EMERGENCY
May have coughing, wheezing, short of
breath. May be difficult to walk & talk

Predicted average peak expiratory flow (L/mins):

Age Height
(yrs) 65” 70” 75”
30 489 617 502 637 513 655
40 483 620 496 641 507 659

..      Fig. 39.17  Peak expiratory flow rate (PEFR) technique

The Nutrition-Focused Physical Exam
691 39

Functional Nutrition Evaluation

Anthropometrics: Body Composition Guide

Increased Increased Increased Increased

YES YES YES
BMI? WC? WHR? Body Fat%?

N N N Y
O O O E
S
Android
Obesity
Increased Increased Increased
WC or WHR? WHR? Body Fat%?

Y N
N Y N E Y O
S Consider
O E O Metabolically E Possible High
S S Metabolic
Obese Muscle Mass or Dysfunction
(OverVAT) Gynoid Large Skeletal
Obesity Frame
(i.e. Metabolic
Increased Increased or OverSAT Syndrome)
Body Fat%? Body Fat%?

N Y N Y
O E O E
S S Consider
Ideal Skinny Fat or Possible High Gynoid Gut/Detox/ Diet and
Metabolically Muscle Mass Obesity or Hormonal Lifestyle
Obese or Athlete OverSAT Dysfunctions Intervention

Version 2

..      Fig. 39.18  Functional Nutrition Evaluation. Anthropometrics: Body Composition Guide. (Used with permission from The Institute for
Functional Medicine ©2015)

39.2  Conclusion The physical exam offers a unique opportunity to truly

relate to a patient in a more intuitive and sensory manner,
In this chapter, we have covered an array of physical signs to connect with them through a kind of ritual that can ini-
and cues that signal nutritional and medical imbalances, dis- tiate a patient-provider bond. Verghese entreats the exam-
orders, and diseases. By integrating this knowledge into iner to perform the exam with skill and consideration so
practice, the dietitian/nutritionist or medical provider may as to not violate the sacredness thereof and the transfor-
benefit from the words of William Osler, a Canadian physi- mation that this ritual can incite [13]. Furthermore, he
cian who emphasized the importance of the history and and his colleagues introduce a conceptual framework for
physical exam in making an accurate diagnosis: the utility of the physical exam organized into seven
themes [116].
»» Learn to see, learn to hear, learn to feel, learn to smell 1. Diagnostic accuracy: Well-performed technique,
and know that by practice alone can you become practiced over time increases diagnostic accuracy.
experts. [113] 2. Ongoing care and prognosis: Physical exam findings can
Indeed, learning the language of the body takes time and guide therapy and prognostic assessments.
presence. The more examinations one performs, the more 3. Patient contact: The physical exam can improve the
the examiner builds a repertoire of knowledge and also an patient-provider relationship through the ritual and
embodied sense of what is normal. This sense then allows touch that it involves.
one’s antennae to more accurately pick up something abnor- 4. Accessibility: Rapid assessment (often with minimal
mal [114]. It is no wonder that Sir Arthur Conan Doyle, the equipment) is possible with the physical exam
creator of iconic fictional detective and astute observer 5. Pedagogic value: Teaches clinical reasoning and bedside
Sherlock Holmes, was a physician [115]! manner and can also be used in patient education.
 692 M. R. Fry

6. Cost: The physical exam may be more cost-effective than 10. Mackle TJ, Touger-Decker R, Maillet JO, Holland BK.  Registered
comparable technological tests. dietitians’ use of physical assessment parameters in professional
practice. J Am Diet Assoc. 2003;103:1632–8.
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They contend that the physical exam may offer healing not 13. Verghese A, Horwitz RI.  In praise of the physical examination. It
provides reason and ritual. BMJ. 2009;339:b5448.
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today, such as misdiagnoses, escalating costs, decline in the medical schools: latest update of a National Survey. Acad Med.
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This chapter provides the knowledge needed to recognize 15. Mordarski B.  Nutrition-focused physical exam hands-on training
and interpret a wide variety of abnormal findings. From what workshop. J Acad Nutr Diet. 2016;116(5):868–9.
16. Litchford MD.  Nutrition focused physical assessment: making
has been covered here, you may notice that a patient who clinical connections. Greensboro: CASE Software and Books; 2013.
presents with keratosis pilaris, fissuring eczema, ridging and 17. Mahan LK, Raymond JL. Krause’s food & the nutrition care process.
missing lunulae of the nails, a tendency toward paronychia, 14th ed. St. Louis: Elsevier; 2017.
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 695 40

Modifiable Lifestyle Factors:

Exercise, Sleep, Stress,
and Relationships
Margaret Christensen

40.1 Introduction – 697

40.2 Gathering Lifestyle Data: The Big Picture – 697

40.2.1 Establishing the Therapeutic Relationship – 697

40.3 Gathering Oneself – 698

40.4 Utilizing Assessment Questionnaire Tools – 698

40.4.1  enefits for Practitioners – 698
B
40.4.2 Benefit for Clients – 699
40.4.3 Insights and Change – 699
40.4.4 Storytelling and Healing – 699

40.5  ow to Ask Questions: Establishing the Therapeutic

H
Relationship – 699

40.6 Assessing Exercise/Movement – 700

40.6.1 E xercise: Assessing the Big Picture – 700
40.6.2 Questions to Ask: Exercise and Movement – 700
40.6.3 Assessing Movement at Home – 701
40.6.4 Assessing Movement at Work – 702
40.6.5 Resources to Motivate and Track Exercise – 703

40.7 Assessing Sleep and Restorative Activities – 703

40.7.1  estorative Activities: The Big Picture – 703
R
40.7.2 Screening Questions for Sleep Apnea – 703
40.7.3 Questions to Assess Sleep Habits – 703
40.7.4 Other Restorative Activities – 704

40.8 Stress and Resilience – 704

40.8.1 S tress and Resilience: Assessing the Big Picture – 704
40.8.2 Tools for Assessment of Stress and Self-Care – 705
40.8.3 Stress: Important Questions to Ask – 705
40.8.4 Abuse and Neglect – 705

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_40
40.8.5  ssessing Anxiety and Depression – 706
A
40.8.6 Basic Questions to Assess Stress Levels – 706
40.8.7 Assessing Resilience – 707
40.8.8 Resources for Assessing and Addressing Stress and Resilience – 707

40.9 Assessing Relationships and Beliefs – 707

40.9.1  elationships and Beliefs: The Big Picture – 707
R
40.9.2 Relationships, Social Networks, and Health Outcomes – 708
40.9.3 Beliefs – 709
40.9.4 Spirituality and Religion – 709
40.9.5 Questions to Ask About Relationships and Beliefs – 710

40.10 Assessing Readiness to Change – 710

40.10.1 T he Nature of Change – 710
40.10.2 Smart Goal-Setting – 711

40.11 Conclusion – 712

References – 712
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
697 40
40.1  Introduction comfortable, nor have the tools, to help a client explore their
deeper belief systems and underlying spiritual values. It is
The skilled IFMNT practitioner understands that developing often that these very important underlying and unspoken
a clear picture of a client’s current life circumstance is imper- codes are the “back story” that unconsciously governs sabo-
ative to helping the client implement desired functional taging behavior. Positive beliefs and spiritual connections
nutritional and lifestyle prescriptions for the long term. can be harnessed to engage not just immediate change but for
Optimizing lifestyle change is the fundamental intervention transformative, inspirational, lifelong benefit.
of the integrative functional medicine approach. Initiating
and sustaining that transformative change is dependent on
many factors, including how the IFMNT practitioner estab- 40.2   athering Lifestyle Data: The Big
G
lishes the therapeutic relationship and maintains knowledge Picture
of critical factors in the social milieu. Knowing how to obtain
a comprehensive assessment of modifiable lifestyle factors in 40.2.1  Establishing the Therapeutic
an insightful, educational, and compassionate manner can Relationship
have lasting impact on the achievement and maintenance of
health goals. For the practitioner, understanding in detail where the patient
The detailed metabolic and physiologic pathways for stands regarding current levels of stress and overwhelm can
nutritional influences on health and disease outcomes have help direct priorities and frame realistic expectations for the
been previously discussed in this textbook. The study of the client’s current capabilities. In addition, interest from the cli-
science behind physiologic mechanisms and biochemical nician can serve to markedly assist in developing trust from
pathways is the science of medicine. Knowing how to engage the patient who feels heard. When the client has been vali-
the patient and how to ask questions is the art of medicine. dated for their obstacles and challenges and sees that the
So, how does the practitioner translate knowledge into action practitioner is interested in finding workable solutions to
for the patient? What tools are available for assessment? For those challenges, they are then more willing to trust the clini-
education and interventions? For ongoing support? What cian’s guidance, want to actively cooperate, and are more
personal interaction skills are necessary for the practitioner? likely to persevere in the face of stumbling blocks. In order to
How do we assess the client’s readiness to change? How do we get optimal outcomes, the client must be mentally, emotion-
support lifelong changes? Each area is discussed in ally, and physically capable of implementing the requested
(7 Chaps. 6 and 9).
  changes to their diet and lifestyle.
We begin by establishing a mutually beneficial dialogue By evaluating each of the subject areas, the practitioner
with the client to understand where they are in their life at can prioritize and provide support tools to help the client
this moment. The bottom of the IFM Matrix tool emphasizes implement change and move beyond limiting beliefs. If the
the role of current lifestyle areas as root factors influencing practitioner doesn’t understand the current circumstances
the complex interconnecting physiologic and biochemical and capabilities of the client, there is likely to be frustration
factors of the Matrix above it. These areas represent the ongo- and disillusionment on both sides, as well as wasted time and
ing modifiable triggers and mediators of biologic function. resources, no matter how brilliant a diagnostician is. There is
As a teaching tool, the practitioner can explain how these five no use telling a client to go on an elimination diet when they
primary “roots” of the Functional Matrix “tree of symptoms” are in the midst of remodeling their kitchen or are drowning
act as major influences on current health. The Matrix pro- in stress from spending their hours in traffic driving kids to
vides an excellent visual to explain complex phenomena in a sports practice with no time for self-care. Meeting the client
simple manner (. Fig. 40.1).
  where they are is imperative.
At the center of these modifiable lifestyle factors is nutri-
tion assessment, the purview of 7 Chap. 9 on IFMNT
 

“Meeting the client where they are is imperative.”

NIBLETS. The four other important areas to assess, in a non-
judgmental and compassionate fashion, are past and current
exercise and movement, sleep and restoration habits, stress Identifying obstacles and opportunities in each area allows
levels and their perception (including resilience levels), as for individualized support tools to be recommended [see
well as relationships and beliefs. Detailed physiological below] and can have profound impact on outcomes. For
impacts of these areas on biochemical pathways have been example, one patient may be a former athlete whose belief
previously discussed (see Part I, Section 2: 7 Chaps. 7 and 8).
  system is easily engaged in focusing on exercise as a leverage
In addition, as part of implementing any kind of program, it point, whereas another may be very committed to their faith
is valuable for the practitioner to know how to assess the cli- practice, whose tenets may be used to support changes in eat-
ent’s readiness to change. ing habits. It’s critical for the practitioner to help clients see
Most practitioners are very comfortable asking about new avenues for change, often from years of entrenched,
exercise and sleep issues and have had training in asking unhealthy patterns. The lifestyle factors section on the Adult
basic stress and relationship questions, but many are not yet Intake Questionnaire [Male or Female] (7 Chap. 46) is an
 
 698 M. Christensen

The Fundamental organizing Systems and Core Clinical Imbalances

Assimilation Energy Transport
7 Clinical Digestion, Absorption, Energy regulation, Mitochondrial function Cardiovascular
Systems Microbiota/GI, Respiration Biotransformation and Elimination Lymphatic systems
Defense and Repair Toxicity, Detoxification Structural Integrity
Immune system, Inflammatory Communication From the subcellular
processes, Infection and microbiota Endocrine, Neurotransmitters, Immune membranes to the
messengers, Cognition musculoskeletal system

Timeline ATMs Antecedents, Triggers, and Mediators

Individual Mental, Emotional, Experiences,

Spiritual Influences Genetic Predisposition
Predispositions Attitudes, Beliefs

Sleep & Relationships

Lifestyle Relaxation
Factors Exercise & Stress
Movement
Nutrition

..      Fig. 40.1  Modified IFM tree. (Used with permission from The Institute for Functional Medicine ©2015)

excellent starting tool for basic assessments, pointing the the client [3]. 7 Chapter 46 has an assessment questionnaire,
 

practitioner to areas that may require more in-depth “Walk the Talk,” specifically designed for practitioners to look
­assessment with other questionnaires. at themselves. In this arena, the ancient wisdom teaching of
“know thyself ” connected to the biblical command of “physi-
cian heal thyself.” (7 Chap. 6) Both speak volumes!
 

40.3  Gathering Oneself Since studies have shown that 60–80% of office visits for
physical complaints are, in reality, related to personal psy-
The IFM acronym “GOTOIT” [1] is an organizational frame- chosocial stressors [4], the clinician must cultivate both
work pneumonic that refers not only to gathering informa- internal personal resources and external network of resources
tion and data on the client but to gathering one’s self as a for referral to the appropriate support mechanisms, such as
practitioner. psychotherapists, social workers, support groups, domestic
40 abuse shelters, trainers, nutritionists, bodyworkers, lifestyle
coaches, acupuncturists, chiropractors, biologic dentists, cri-
“GOTOIT”
sis centers, as well as clinical subspecialists. It takes a village,
55 Gather
and creating health is a team sport!
55 Organize
55 Tell
55 Order
55 Initiate
40.4   tilizing Assessment Questionnaire
U
55 Track
Tools

40.4.1  Benefits for Practitioners

We must ask ourselves, “How well do I do as a practitioner
regarding daily meditation or mindfulness-prayer practices, Collecting lifestyle data can be done both with direct ques-
movement, rest, and restoration?” Does the clinician have a tioning and indirectly by using any of several different ques-
support system? What kind of personal growth and ongoing tionnaires and assessment tools. As direct questioning in all
psychotherapeutic work has been done? Burnout is extremely these different areas at one sitting is a daunting task, the use
common among today’s physicians and nurses [2], affecting of questionnaire materials ahead of time can allow for the
the clinician’s ability to be present. The practitioner’s energetic gathering of much data with minimal time. Many useful
state can markedly influence the patient’s receptivity. Calm, questionnaires are available through organizations (such as
present, mindful clinicians, following their own advice, are the IFM Toolkit, available on the IFM website, and referred
much more likely to inspire confidence and participation by to henceforth as “Toolkit”) [5] as well as online resources.
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
699 40
Practitioners can initially utilize the answers on a modifiable hol they consume, or they may realize just how much their
intake form, such as the comprehensive Adult Medical Intake job is impacting their health and begin contemplating a
Questionnaire [male or female] found in the IFM Toolkit. change. Filling out the exercise questionnaire often gets them
Each lifestyle area is addressed with basic questions to help moving a little more before they come in for their visit.
begin a dialogue. While reviewing the questionnaires with Answering questions about stress factors from the past, such
the client on intake, the opportunity often arises to segue as the Adverse Childhood Events (ACE) score can be illumi-
directly into brainstorming of ideas for improvement or nating. These questions can help a client to see and realize
changes that can be made. Multiple examples are listed just how important current strategies and tools to help mod-
throughout this chapter and provide an opportunity to have ulate the lifelong impact of those events become. An oppor-
a back-and-­forth dialogue about what is possible. tunity arises for discussing resiliency tools and strategies. The
For more in-depth and illuminative information, areas of ACE questionnaire tool and resources can be found at the
concern can be investigated with additional self-­administered Centers for Disease Control and Prevention website (7 cdc.­  

questionnaires such as the sleep questionnaire, the DASS gov) or for the layperson at 7 ACEsTooHigh.­com.
 

[Depression Anxiety Stress Scale] questionnaire or an exer- It is particularly valuable to focus on whatever a patient is
cise assessment, or self-care questionnaire (Appendix A2). doing right and build on the positives rather than focusing
The practitioner can easily uncover areas of concern while on the negatives. The use of the word “why” as in “Why aren’t
noticing opportunities for leveraging behaviors and beliefs to you exercising?” should be avoided as it creates defensive-
expand on what is already working. The questionnaires can ness. Instead, when exploring obstacles and challenges, use a
additionally help triage the client’s ongoing needs to the phrase such as, “Tell me about….” For example, “Tell me
appropriate practitioner. For example, a busy physician may about what gets in the way of exercising or movement for
not have the time or expertise to counsel a client on an exer- you.”
cise prescription, but they recognize the need to refer to the
lifestyle coach or to refer another client for counseling
because of abuse issues. 40.4.4  Storytelling and Healing

Just the act of telling their story to an attentive listener and

40.4.2  Benefit for Clients being witnessed has therapeutic value for the patient and has
been documented as a healing tool in and of itself [6].
The benefit for the client from filling out these detailed ques- Unfortunately, because of the time limitations within the
tionnaires is that the process itself can have educational and conventional medical model, few clients have had an oppor-
therapeutic value. They may wonder why they’re being asked tunity to tell their histories in a comprehensive way and to
about how they were born or whether they had ear infections discuss their current lifestyle challenges in-depth. As the cli-
while growing up. They may ask how answering that ques- ent is watching, the practitioner can draw arrows from the
tion will help them now. A question regarding whether a cli- lower half of the Matrix, illustrating connections from life-
ent was breastfed helps them to begin to understand the style factors to the functional metabolic disturbances above –
connection between early life nutrition and later outcomes an excellent, concrete teaching strategy.
such as autoimmune and gut function. It is often an eye- Once the client’s information is gathered, the attentive
opening experience for the client to begin to see just how and compassionate practitioner tells the patient’s story back
many layers of stress they have been dealing with, or how to them, organized in such a way that a path to healing can be
little time they have for self-care, or how having lots of anti- illuminated through the modifiable factors, inspiring hope
biotics as a child may be impacting their health now. We may and confidence. Reiterating the client’s history in this way lets
often be the first to ask about histories of childhood abuse, them know they have been heard and often elicits astonished
and they will be relieved and grateful. Many have new insights appreciation and a willingness to eagerly move forward. Not
into what is really underlying their health issues and begin uncommonly, a sense of great relief and well-being happens
connecting dots from the past to be able to make the neces- for the client without the practitioner actually “doing” any-
sary changes moving forward. The questions themselves pre- thing. Thus, with a thorough and caring intake assessment,
pare the client to be more receptive to solutions the done well, a therapeutic relationship begins.
practitioner can provide.

40.5   ow to Ask Questions: Establishing

H
40.4.3  Insights and Change the Therapeutic Relationship
Questionnaire-induced insights may bring about shifts even
before the practitioner meets with them. For example, after »» The consciousness in which you gather your information
filling out a DASS, the client may purposefully seek to cut is just as significant as the information you gather.
down on watching stressful television or the amount of alco- – Monique Class, RN, MSN, IFMCP
 700 M. Christensen

When gathering lifestyle information, it is important to ask ing, standing, walking, or moderate physical activity has
questions with empathy in a nonjudgmental and neutral been shown to reduce morbidity and mortality [12].
way, as many of these areas are sensitive or may elicit guilt So, what are the challenges faced by so many of us in
or shame response from the client’s perceived lack of con- implementing a regular exercise program? This is where the
trol or failure to have previously implemented changes. compassionate inquiry skills of the IFMNT practitioner are
Focusing on what is already working and expanding those beneficial. For example, for many women in particular, “exer-
areas can often be more useful than just focusing on what a cise” is a dirty word, something else added to the “should” list
client is not doing “right.” Again, one of the most important of too many things to do already, when they are exhausted,
things a clinician can do to improve their credibility with not well or don’t enjoy it. Having tools to help assess and
clients is to assess and address each of these areas in them- reframe their beliefs from the idea of more “work” or a “have-
selves [7–9]. to” into one of compassionate self-care can be valuable.
The following are eight practices that are found to pro- Identifying and engaging in opportunities to increase move-
mote healing relationships, outlined in an excellent article by ment throughout the day, no matter if formal exercise or not,
psychologists Churchill and Schenck on “Healing Skills in can be useful.
Medical Practice” [10]. They are well worth printing out for
clinicians to remind themselves how to create the most posi-
tive interactions. 40.6.2   uestions to Ask: Exercise
Q
1. Do the little things: Introduce yourself and your team, and Movement
greet everyone, shake hands, smile, sit down, make eye
contact, give your undivided attention, be human, and Beyond the questions on the Adult Intake Questionnaire, the
be personable. IFM Exercise History and Activities of Daily Living ques-
2. Take time and listen: Be still, be quiet, be interested, and tionnaires are excellent tools to help develop a comprehen-
be present. sive assessment of overall daily movement, including formal
3. Be open: Be vulnerable, be brave, face the pain, and look exercise and general activity levels, enjoyability, and per-
for the unspoken. ceived roadblocks. Yet for some, filling out the extended
4. Find something to like, to love: Take the risk, stretch Exercise History Questionnaire can sometimes feel over-
yourself and your world, and think of your family. whelming and shaming when inadequacies in this area are
5. Remove barriers: Practice humility, pay attention to revealed.
power and its differentials, create bridges, be safe, and It is always best to initially frame these questions in terms
make welcoming spaces. of “what are the motivations for and perceived benefits of the
6. Let the patient explain: Listen for what and how they client’s long-term health goals?” For example, start with:
understand, listen for fear and anger, and listen for “Would you like better sleep, mood, weight loss, brain func-
expectations and hopes. tion, cardiovascular health, cancer prevention?” Beginning
7. Share authority: Offer guidance, get permission to take with the end in mind helps create a bridge for incremental
the lead, support patients’ efforts to heal themselves, and change (see . Fig. 40.2).
 

be confident. A comprehensive exercise intake assessment includes

40 8. Be committed and trustworthy: Do not abandon, invest “FITT” questions about frequency, intensity level, type of
in trust, be faithful, and be thankful. exercise, and time done and covers cardiovascular activities,
strengthening, stretching, and balance. Other pertinent areas
to assess are:
40.6  Assessing Exercise/Movement 55 What types of activities do they prefer? Formal or
informal?
40.6.1  Exercise: Assessing the Big Picture 55 What do they like most about exercising?
55 What do they like least?
It is well established that adequate and regular exercise has a 55 Do they prefer solo, partner, or group activities?
great number of health benefits impacting every area of 55 Do they have a membership at any facility that includes
metabolism and physiology, as elucidated in earlier chapters. movement?
A person need not be familiar with intricate beneficial bio- 55 Do they have any of their own equipment?
chemical cellular impacts to intuitively understand that they 55 What obstacles do they have? Time constraints?
feel better when moving. There are those clients who are Financial? Transport?
already engaged in an excellent exercise regime and may not 55 What are some possible solutions?
require much motivation, but unfortunately, the majority of 55 Best time of day?
clients present struggling to incorporate “exercise” into their 55 When do they have the most energy and time?
lives. Currently 70% of the average American adult’s time is 55 What are their goals regarding balance, flexibility,
sedentary, while the remaining 30% is only light activity [11]. fitness, and body composition?
The data is clear that chronic sitting is as deadly as smoking. 55 What kind of injuries or physical limitations with joint
Encouraging clients to replace any sedentary time with sleep- or musculoskeletal pain do they have?
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
701 40

What are your motivators for exercise? (Check all that apply)
Prevent cardiac disease and stroke Decrease stress
Reduce blood pressure Improve sleep
Control blood glucose Weight reduction
Prevent bone loss Increase mental alertness
Increase energy Better endurance
Increase self esteem Increase interest in sex
Improve mood Other

..      Fig. 40.2  Motivators for exercise. (Used with permission from The Institute for Functional Medicine ©2015)

55 What kind of medical conditions such as neurologic to day. For example, chores can be arranged so a person can
issues, breathing issues, balance, congestive heart failure, alternate downstairs and upstairs tasks, purposefully making
or angina limit their activities? as many round trips as able. Using breath and mindfulness
techniques at the same time can help keep the person present
It is often helpful to walk a client through their day from to the miracle of movement.
morning to bedtime to help reveal where the obstacles and For those with severe fibromyalgia, chronic fatigue syn-
opportunities lie. Encouraging the patient to substitute any drome, or other debilitating illness, an excellent functional
movement for screen time can be beneficial for every aspect impact questionnaire that includes activity can be found
of health [13, 14]. online at 7 Myalgia.­com or 7 FIQR.­info. These questionnaires
   

Explain at a metaphorical level that movement is about can be downloaded, or better yet, online electronic calcula-
“taking the next right step” and “moving forward” in life. tors used, to make it very fast and easy to assess and follow a
Literal movement is a concrete external manifestation of the client’s progress over time. The Toolkit handout of Lifestyle
internal changes the client wants to make. Movement can be Modification for Chronic Pain and Fibromyalgia Syndromes
reframed as a form of prayer or meditation, e.g. taking time can be supportive.
to be mindful of each step, of the neighbor’s gardens, and of Inquire about the patient’s experience with tai chi, Pilates,
the changing seasons or while mentally rehearsing a favorite and yoga (which can be done at all intensity levels from
spiritual verse or poem, dedicating themselves to a higher restorative to intense) as all are good choices for core
good. “My body is my temple and the home to my soul” is a strengthening, flexibility, and balance. Many people can’t
wonderful mantra to repeat while walking. stand the thought of a gym, whereas others find it energizing
If a client is feeling “stuck” in old patterns and hates the and improving of their self-esteem, but transportation and
concept of “exercise,” this attitude can be reframed into an membership cost can be an obstacle [15]. Dancing, hiking,
opportunity to literally “create more movement” in their life. gardening, and yard work are all ways to move aerobically
A simple strategy to encourage moving beyond inertia is to without a gym. Of course, running, cycling, weights, swim-
suggest putting tennis shoes and sweats right by the bed, get- ming, martial arts, and aerobics classes are excellent modali-
ting up first thing without thinking, putting them on, and ties. A balance ball is a very inexpensive tool to utilize for
walking 10  minutes in one direction out the door and sitting both at home and work. Help clients look for lower
10 minutes back. No gym required. cost resources such as a YMCA or recreation center and
Additional strategies include asking, “Do you feel safe classes such as senior “SilverSneakers” or chair yoga classes
walking in your neighborhood? Do you have a friend you can for the over-65 crowd. “Pickleball” is the new rage for all ages,
go with?” For some, the opportunity to have “walk and talk” especially found in senior communities, combining tennis,
therapy time with a good friend or buddies cycling together badminton, and table tennis, all elements for multigenera-
can provide the motivation to get out and going. Having a tional fun. Dance is an excellent form of exercise, from
client setting a goal of only watching their favorite rerun Zumba to ballroom dancing, country and western to
while on the treadmill, balance ball, or mini trampoline can Argentine tango, ballet to barre, involving balance and flexi-
provide incentive. Make it fun by encouraging the use of bility as well as aerobic activity. Dance classes can provide a
favorite dance music from the time a person was in his/her social milieu as well. Encourage at least one activity a week in
teens and 20s as a way to engage the joyful, high energy spirit community for the importance of social connection.
that naturally makes the body want to move.
For the more sedentary or ill client who is having diffi-
culty moving, utilizing the Activities of Daily Living 40.6.3  Assessing Movement at Home
Questionnaire is a gentler introduction. It provides not only
a realistic assessment of physical capability but also an oppor- Unfortunately, given all the “convenience” appliances and
tunity to suggest simple measures that can be incorporated to foods of this day and age, people are moving far less and sit-
enhance what movement is already naturally occurring day ting more both at home and at work. They work in order to
 702 M. Christensen

Household Management
Energy Expenditure (HMEE)
7,000

Employment
6,000 6,004
Status
Employed
Not Employed
5,000 All Women
**
MEAN: kcal/week

4,663
4,504 *
4,095
4,000 *
** *
* 3,671 3,592
3,553 3,486
3,324
3,000 3,105 ** *
2,877 Decade-to-Decade
** 2,769 2,806 *p<0.05
2,436 2,517 **p<0.001
**
2,132 2,206 2,182
2,000

1,000
1960s 1970s 1980s 1990s 2005+ 2010++ + 2003-2005
++2006-2010
1965-2010
US Women 19-64 years

..      Fig. 40.3  Household energy expenditure. Depicts the decade to decade change in household management energy expenditure per week
(HMEE/week) for all women and by employment status. (Reprinted from Archer et al. [16]. With permission from Creative Commons License)

pay for those conveniences and then pay more to go to the Encouraging singing along loudly and dancing while
gym to workout. Yet, too often the thought of going to the sweeping, vacuuming, going up and down the stairs multi-
gym or standing and preparing a real meal becomes exhaust- ple times to carry laundry, making the bed, and bending
ing for a burned-out working individual, especially with chil- and moving while cleaning can turn mundane “have to’s”
dren. Commonly, many are recuperating from stressful days into fun and playful opportunities to burn calories. Putting
through sedentary time involved with watching television, the kids in a stroller and going out for a walk after dinner is
40 sitting at a computer, or using handheld devices while eating a time-honored way to substitute TV time for moving fam-
a prepackaged microwaved meal. Unfortunately, these activi- ily time (. Fig. 40.3).
 

ties have become the sole source of “restorative” activities for Additionally, we are burning less calories from maintain-
a vast majority of the American population. Yet, for each ing temperature regulation compared to even 40  years ago
additional hour of television watched per day, there is an 11% because of HVAC systems keeping the temperature at steady
increase in all-cause mortality [14]. states so our bodies don’t have to. Keeping indoor tempera-
For those who are already quite sedentary, examine tures cooler has been shown to expend more calories from
their written exercise intake or use the verbal interview to thermogenesis as well as exercising in the cold [17–20].
discover how much movement they are already engaged in Shivering and sweating are simple ways to increase caloric
with housework or yard work. Expanding on those areas expenditure whether moving bodies indoors or out. Have
can be useful ways to begin to increase caloric expenditure. everyone turn thermostats down in winter and up in sum-
Everyday chores can be a source of burning extra calories. mer.
The average 1950s housewife was burning 1000–3000 more
calories a week with sweeping, doing laundry and walking
to the local market, chopping and preparing daily meals, 40.6.4  Assessing Movement at Work
etc. [16]. Suggest listening to good music or podcasts while
engaging the whole family in chopping vegetables, making One can assess if the client’s job is stationary/sitting or if it
meals and hand-washing dishes or while mindfully stand- naturally involves movement, such as being a nurse or retail
ing and ironing, turning those humdrum chores into activi- worker required to spend most of their shifts on their feet.
ties of pleasure rather than boring repetitive tasks. A number of wearable devices are now available, such as the
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
703 40
Fitbit, and many smartphones can track movements and Recent data on all causes of mortality in the United States
provide positive feedback to the client to encourage incre- show sleep apnea to be a major cofactor for many chronic
mentally increasing their goals [see Toolkit for a list of per- diseases. Although sleep apnea affects more than 22 million
sonal device options]. Engaging their competitive spirit with Americans, 80% of cases are undiagnosed. Sleep deprivation
co-­workers can also be motivating. contributes to many health challenges including metabolic
Portable standing desktop stations and chairs that raise syndrome, cardiovascular disease, inflammation, neuropsy-
from sitting to standing are available that can encourage the chiatric disorders, and type 2 diabetes, along with impaired
client to frequently change positions. Balance-ball chairs memory [23–25]. Sleep disorders may also trigger immune
actively engage core muscles while sitting. Devices, such as a system abnormalities, inducing autoantibody production
stationary pedal for underneath the desk, are engaging and and autoimmune disease: SLE, RA, etc. [26] (7 Chap. 35).
 

easy. Utilizing simple at-work stretching exercises for desk Thus, screening for insomnia, narcolepsy symptoms,
sitting and setting a timer to remind to stand every snoring/sleep apnea, and restless leg syndrome is paramount.
15–20 minutes can be useful. Getting up frequently to go to Appropriate strategies to improve sleep quality can be imple-
the water cooler or taking stairs instead of an elevator can mented, and the need for further diagnostic testing such as a
easily add to a daily step count. Helping the patient to think sleep study at an overnight sleep center can be recommended.
creatively can assist them in their goals. Fortunately, home sleep study equipment is now available
through a number of different vendors which may be less
expensive, less disruptive, and more amenable to encourag-
40.6.5   esources to Motivate and Track
R ing a client to be proactive in addressing their issues than
Exercise going to a sleep center. For many with mild-to-moderate
obstructive sleep apnea, a special dental appliance, created by
Once an assessment is made of the current activity level and a dentist trained in this area, can be an economical option in
the challenges and opportunities outlined, it is much easier lieu of a CPAP machine, improving compliance.
to utilize a tool such as the IFM Exercise Prescription, which
reiterates the FITT model of desired frequency, intensity,
type, and time. High-intensity interval training [HIIT] such 40.7.2  Screening Questions for Sleep Apnea
as the “7-minute workout” (many versions available online)
has become a popular, efficient, and effective use of time for Important screening questions to identify sleep disturbance
cardiovascular fitness. Again, the client is much more likely pathology include:
to have interest and be compliant if the practitioner is also 55 On average, how many hours of sleep do you get in a
practicing what they are preaching [12]. Tracking over time 24-hour period?
can be done with a form such as the IFM Exercise Goals and 55 Do you snore?
Tracking Journal, both found in the Toolkit. 55 During the past 30 days, for about how many days did
Two excellent handouts for motivation which also can you find yourself unintentionally falling asleep during
be found in the Toolkit include “The Power of Movement: the day?
Living an Active Lifestyle” and “Tips to Incorporate 55 During the past 30 days, have you ever nodded off or
Mindful Daily Movement.” Suggest a TV moratorium for fallen asleep, for even just a brief moment, while
4 weeks and see how much time is freed up for all forms of driving?
self-care!

40.7.3  Questions to Assess Sleep Habits

40.7   ssessing Sleep and Restorative
A
Activities A more extensive sleep questionnaire can include questions
about sleep environment, including light, sound, temperature,
40.7.1  Restorative Activities: The Big Picture pets etc., including the use of electronic devices and sources of
EMFs that may interfere with sleep. Physiologic changes in
More than a third of US adults don’t get enough quality sleep. the brain have been documented from electromagnetic fields
According to recent data from the CDC, 50–70 million adults generated by cell phones, electronic appliances, and house-
in the United States have chronic sleep and wakefulness dis- hold electrical meters positioned near bedrooms. These have
orders [21]. Sleep difficulties are associated with all chronic been shown to either produce or exacerbate a wide spectrum
diseases, mental disorders, health-risk behaviors, and the of neuropsychiatric effects including depression [27].
underlying limitations of daily functioning, injury, and mor- Questions include:
tality. Insomnia is a known independent risk factor for 55 What time do you go to bed? What time to you wake
depression and other psychiatric disorders. Most patients up?
with mood disorders experience insomnia. Conversely, one-­ 55 Are you watching the news or stimulating TV before
third to one-half of patients with chronic sleep problems bed?
have mood disorders leading to a vicious cycle [22]. 55 Are you on your laptop or electronic device before bed?
 704 M. Christensen

55 On average how long does it take you to fall asleep? mindful concentration is brought to the moment, no matter
55 How many times do you wake up? Why? Going to the activity, it has the capacity to rest the mind, body, and
bathroom? Hot flashes? Mind racing? spirit, shifting physiology. Bringing mindfulness and breath
55 Are you able to fall back asleep? focus, to whatever pursuit engaged in, can significantly
55 Are you refreshed when you wake up? reduce levels of distress for clinician and client alike.
55 Are there pets in the bedroom? Laughter is truly the best medicine and yet is something
55 Does your spouse snore? that is frequently lacking. We know it raises endorphins, low-
55 Is there a TV in the bedroom? ers stress hormones, and modulates immune function, help-
55 Do sounds and/or lights wake you easily? ing to mitigate the impact of stress [32, 33]. Ask, “what makes
55 How much alcohol and caffeine do you typically drink you laugh, and how often?” One suggestion could be that if
per day? they are going to watch TV, choose only something benign,
like a cooking or auto show, or something funny that will
It can be useful to help the client to take time for a bedtime make them laugh. Pets can also be a great resource in this
routine, beginning an hour prior to bed, as a form of enjoy- area. Seeking out humor on purpose, especially during times
able deep self-care, rather than another “have to.” Consider of stress, can help alleviate its intensity.
putting on calming music and taking time for a hot Epsom Questions for Restorative Activities:
salt bath with essential oils such as lavender and frankincense 55 What is your favorite way to relax?
(known to have calming effects on the nervous system). 55 What do you do that is fun? Joyful? Playful?
Everyone needs time for good oral hygiene, and women in 55 What makes you laugh? And how often?
particular often need extra time to mindfully take care of 55 How do you express yourself creatively?
their skin, face, and hair with nontoxic cleansers. Reading a 55 What did you do for fun as a kid?
good book, stretching, journaling, and utilizing meditation,
prayer, and gratitude can be very simple mindful ways to
peacefully wind down, bringing a sense of contentment and 40.8  Stress and Resilience
closure to an otherwise very hectic day. Counsel patients that
bedtime begins an hour before sleep with routine prepara- 40.8.1   tress and Resilience: Assessing
S
tions that may include bathing and story time for themselves, the Big Picture
no different than the parent has a routine with their children!
We live in a highly stressed culture, rapidly moving from one
activity to the next, focused on maximum productivity, min-
40.7.4  Other Restorative Activities imal downtime with much hidden as well as overt violence.
Our society doesn’t value space, emptiness, silence, and
Leading-edge science on neuroplasticity has shown many nature, unfortunately to the detriment of our long-term
benefits of tools like mindfulness meditation, gentle yoga, tai health. Stress is a word that can have many different connota-
chi, gratitude, and journaling practices in rewiring the cir- tions for the client along with many different sources. Patients
cuitry leading to chronic activation of the hypothalamus-­ are usually focused on the external sources of stress such as
40 pituitary-­adrenal (HPA) axis. It is important to ask, “Besides work, finances, family life, and poor health, which may be
sleep, what other type of restorative activity do you engage both acute and chronic. Many people utilize sugar, alcohol,
in? How do you express yourself creatively? What brings you or TV and excessive electronics to manage their stress level,
joy? Makes you laugh?” Many clients will get blank looks or which inputs often only further exacerbate the total stressful
even well up with tears when asked these questions, as they load. Adequate sleep and restorative activities as discussed
realize they have no answers. Particularly women, who are above can contribute significantly to building resilience from
wrapped up in meeting their families and children’s needs, stress, as can other activities, which are outlined below.
find themselves last on their list. For the clinician, it is imperative to understand the
As discussed in previous chapters, meditation and sources of the patient’s stress, the current perceptions of their
mindfulness-­based stress reduction techniques are ancient impact, and their level of resilience and coping strategies in
practices revealed by modern-day technologies to signifi- order to target appropriate interventions. Does the patient
cantly impact learning and memory, emotional regulation, have a strong internal locus of control with established resil-
perspective, cognitive restructuring and learning, immune iency factors such as optimism, perseverance, and a social
function, and HPA axis regulation. It is known to increase support system, or are they focused on an external locus,
brain-derived neurotrophic factor (BDNF), stimulate the blaming others, having chronic negative self-thoughts and
prefrontal cortex, and facilitate neurogenesis. It has been feelings of hopelessness? How an individual responds to
shown to be one of the most cost-effective intervention tech- stress is extremely variable and has genetic, learned and envi-
niques for improving quality of life, particularly in chronic ronmental components whose internal physiologic and met-
health conditions [28–31]. Other meditative and restorative abolic consequences are extensively discussed in Parts II and
practices can be knitting or other needlework, fishing, hik- IV of this textbook. From a functional medicine standpoint,
ing, gardening, tinkering with tools, and cooking. When the practitioner aims to support the client by alleviating the
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
705 40
total body burden of external stressors impacting the internal ors, and health are all important to get an overall picture of
sources, offering them tools to help ameliorate both sides of challenges and strengths.
the equation. What about their work life? What kind of work do they
Unfortunately for many seeking functional medicine eval- do? Are they satisfied with it? How are their relationships
uations, the largest sources of stress are their chronic health with co-workers or bosses? How much pressure do they feel
issues, unresolved or worsened, often after years of seeking and is there adequate time and support to get the work done
help from many different specialists with little improvement. they need? What kind of commute do they have? Driving in
They may be disillusioned, angry, and skeptical. Failure to traffic can often be one of the biggest sources of chronic low-­
resolve root causes of health issues has impacted their finances, grade stress. Using tools such as listening to interesting pod-
relationships, self-esteem, level of anxiety, and depression and casts, fun or inspirational music and books on tape while
kept them in a downward spiral of hopelessness. Channeling commuting, rather than cacophonous talk radio or stressful
anger and hopelessness into community and action can be news, can be helpful.
important ways to transform those stressors. Ask about their social life. Friends. Their significant other.
Assessing how much stress a person feels on a daily/ Who takes care of the children if both parents work? What
weekly/yearly basis can also be useful in understanding what other health issues are other family members dealing with?
testing to order and interventions to recommend. Every sin- Teenagers? Elderly parents? Are there major financial or legal
gle physiologic node of the Matrix is impacted: hormones stressors? For many working women, childcare issues and
and neurotransmitters, inflammation, microbiome, etc. For lack of time for self-care contribute to feelings of being
example, depending on the presentation, the clinician may majorly overwhelmed. For stay-at-home moms, acknowledge
want to run a diurnal salivary cortisol test to see the impact that raising children and caring for a home is a full-time job
on the HPA axis, or in another with severe IBS, a stool test to with its own set of stressors, not to be devalued. Men often
assess effect on the microbiome and intestinal permeability. shoulder their burdens internally and in isolation. In a culture
Focusing on implementing simple external coping strategies that frowns upon asking for help, they tend to be minimizers
can be one of the most effective interventions. Often the least on questionnaires and may require subtler questioning.
expensive and time-honored prescriptions are ones of commu- It may be helpful to ask whether there are ongoing issues
nity, laughter, downtime, adequate sleep, or mindful breathwork such as alcoholism, addiction, or abuse. Does the person feel
and meditation – all shown to benefit the internal physiology. safe in their home? With their partner? In their neighbor-
Physically writing a prescription for self-care on a prescription hood? One in every three women and one in every four men
pad and telling the client to put it on their bathroom mirror or have been victim of violence in their lifetime, most often from
refrigerator where they can see it every day can be an effective an intimate partner [34]. These questions cannot be ignored.
measure to engage their self-­compassion and compliance.

40.8.4  Abuse and Neglect

40.8.2   ools for Assessment of Stress
T
and Self-Care Unfortunately, far too many of us, practitioners and patients
alike, did not grow up in optimum circumstances, and some
Excellent preliminary intake questions encompassing the traumas can have lifelong health impacts if not acknowl-
common stress sources are found in the IFM Adult Intake edged and addressed. Ask what things were like growing up.
Questionnaire and the Self-Care Assessment Questionnaire, How stressed were their parents? What behaviors and coping
both found in the Toolkit. These questions gently raise aware- skills were modeled? Were they allowed to speak their voice
ness in a nonjudgmental way and give the client insight into and offered comfort and appropriate support, or did dys-
possibilities for change. Emphasize that there are no wrong function, verbal and physical abuse, neglect, and other forms
or right answers. For more in-depth and insightful assess- of violence predominate? Did they grow up in an alcoholic
ments, the DASS and ACE questionnaires (discussed below) family system? All practitioners should be familiar with
can be essential tools for evaluating dimensions of emotional administering the CDC’s Adverse Childhood Events [ACEs]
distress and root causes of chronic illness. All practitioners Study and scale, which looks at ten different types of child-
should be familiar with them. hood trauma, to understand the sobering long-term implica-
tions for personal and public health.
The ACE is an extremely useful tool for helping patients
40.8.3  Stress: Important Questions to Ask to understand how early childhood trauma can have long-­
term health impacts and can help to dissipate some of the
A simple way to begin a conversation is: “On a scale of 1–10, shame and silence often associated with these events.
with 10 being the highest amount of stress, where do you feel Unfortunately, shame and guilt are extremely toxic emotions
you are running on average today? For the last month? For to the nervous and immune systems. Silence often leads to
the last year? What are your major sources of stress and can the perpetuation of violence and abuse from one generation
you tell me more?” Asking about work, family, social rela- to the next, no matter the socioeconomic status. Findings of
tionships, intimate relationships, children, financial stress- the ACE study show:
 706 M. Christensen

Consequences of Lifetime Exposure to

12-step recovery groups, and licensed social workers famil-
Violence and Abuse iar with how to support the client, who may be revealing
this information for the first time to a healthcare practitio-
ENT
Neurological ner.
Infectious
Dental disease
40.8.5  Assessing Anxiety and Depression
Surgery General/Other
Categories Anxiety and depression are some of the most common symp-
Rheumatology toms presented by clients as ongoing sources of chronic dis-
COLEVA
Cardiovascular tress. While there are many different depression and anxiety
Dermatology assessment tools, including the Beck Depression Inventory,
Gastrointestinal
Hamilton Anxiety Depression Scale, and GAD-7, the use of
Mental the Depression Anxiety Stress Scale [DASS] developed by
Health Opthalmology
Lovington and Lovington in Australia adds sensing of the
third axis of physiologic stress separated from anxiety and
Behavioral Ob-Gyn
issues depression symptoms (see 7 Chap. 29).
 

Orthopedics
Allergies »» The DASS is a 42-item questionnaire which includes
three self-report scales designed to measure the
Genito-Urological negative emotional states of depression, anxiety and
Respiratory/
pulmonary
stress. Each of the three scales contains 14 items, divided
Endocrine into subscales of two to five items with similar content.
Oncology The Depression scale assesses dysphoria, hopelessness,
devaluation of life, self-­deprecation, lack of interest/
..      Fig. 40.4  Consequences of lifetime exposure to violence and
involvement, anhedonia, and inertia. The Anxiety scale
abuse. (Based on data from Academy on Violence & Abuse assesses autonomic arousal, skeletal muscle effects,
(7 AVAHealth.­org). Exposure to Violence and Abuse (COLEVA).
  situational anxiety, and subjective experience of anxious
(Retrieved from: 7 https://www.­avahealth.­org/resources/ava_publica-
 
affect. The Stress scale (items) is sensitive to levels of
tions/ava_publications_new.­html) chronic non-specific arousal. It assesses difficulty
relaxing, nervous arousal, and being easily upset/
agitated, irritable/over-reactive and impatient.
Childhood trauma is very common, even in employed
Respondents are asked to use four-point severity/
white middle-class, college-educated people. There is a direct
frequency scales to rate the extent to which they have
link between childhood trauma and adult onset of chronic
experienced each state over the past week [35]. The
disease, including heart disease, lung cancer, diabetes, and
questionnaire, along with its interpretive guide, can be
many autoimmune diseases, as well as depression, violence,
accessed through the Psychology Foundation of
40 being a victim of violence, suicide, and a host of other mental
health issues. People usually experience more than one type
Australia website or can be found in the IFM Toolkit.
of violence, rarely is it only sexual or verbal abuse. More
types of trauma increased the risk of health, social, and emo-
tional problems [34]. 40.8.6   asic Questions to Assess Stress
B
Another excellent interactive resource for understanding Levels
the documented impacts of violence and chronic childhood
stress on all organ systems is from the COLEVA project: 55 How stressed do you feel on a scale of 1–10?
Consequences of Lifetime Exposure to Violence and Abuse, a 55 What are the major sources of your stress?
project of the Academy on Violence and Abuse (7 avahealth.­
  55 How are things going for you at home? With work? With
org) shown in . Fig. 40.4.   relationships? With finances?
Whichever stressors are uncovered, the clinician can 55 How much is your health contributing to your stress
impart the positive, hopeful findings of neuroplasticity, levels?
including the possibility of rewiring the brain, to change 55 Did you feel safe growing up?
PTSD and stress responses by cultivating resiliency tools 55 Do you feel safe at home now?
such as mindfulness-based stress reduction (MBSR), mind-­ 55 Physical, emotional, and sexual abuse are unfortunately
body breathwork, EMDR, HeartMath, and other therapeu- very common – is this an area for us to discuss?
tic modalities. All clinicians should be familiar with the 55 What “courageous conversation” are you not having
attributes of resiliency detailed below for themselves as about an issue that’s bothering you?
well as patients and must have a network of resources to 55 Is the level of anxiety or depression, grief, or sadness you
which they can refer, such as crisis hotlines, psychologists, feel impacting your quality of life?
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
707 40
40.8.7  Assessing Resilience ask these questions when they recognize they don’t have an
answer.
Studies show that recovery is possible from even extreme Twelve-step programs, such as AA and Al-Anon,
trauma and stressors, both past and future [36, 37]. The fol- Overeaters Anonymous, etc., offer inexpensive and incredi-
lowing list, adapted from the work of psychotherapist bly valuable support tools that provide a day-to-day plan for
Elizabeth Scott, MS, explains how qualities found in resilient getting through the most difficult of circumstances. All prac-
individuals can be purposefully cultivated and include [38]: titioners should be familiar with them and are encouraged to
1. Developing a positive attitude – learning to view life’s attend open meetings to learn more. Remembering that joy,
difficulties as challenges to overcome, rather than fears fun, humor, and creativity even in the midst of severe exter-
to be avoided, moving from self-pity and blame to nal circumstances can be what carry people through. They
positive self-talk and taking responsibility. are potent healing modalities. Build on whatever they are
2. Developing emotional awareness – asking “Why are you doing well, look for positives, and expand them.
upset?” “What needs to change?” Journal to express
feelings.
3. Developing an internal locus of control – even if we can’t 40.8.8  Resources for Assessing
control an external situation, we can control how we and Addressing Stress and Resilience
respond.
4. Cultivate optimism by maximizing strengths and The Toolkit offers resources to share with clients on an array
minimizing weaknesses. of topics, including:
5. Rally social support and tap into community resources. 55 Relaxation response
6. Maintain a sense of humor. 55 Strategies for transforming stress
7. Exercise and get adequate rest. 55 Mindfulness for sleep disorders and anxiety
8. Get in touch with spiritual side, in whatever form is 55 Integrated guide to visualization and imagery
meaningful. 55 Meditation-getting started
9. Perseverance and determination not to give up. 55 IFM gratitude journal
55 Breathing techniques to soothe the soul, restoration
Many resources from books, DVDs, personal devices, and prescription
apps are available to help clients cultivate resiliency and 55 Cultivating self-awareness and mindfulness
learn techniques to retrain emotional and physiologic reac- 55 Restoration activities
tivity. Perhaps some of the best-studied tools include those 55 Health benefits of napping
from the HeartMath Institute (7 HeartMath.­org), which have
 
55 Tips to incorporate mindful movement daily
created many biofeedback programs focusing on heart rate
variability and coherence for both personal and professional Other modalities to raise sympathetic tone may include
use. The Monroe Institute (7 MonroeInstitute.­org) offers
 
bodywork such as massage, lymphatic therapy, craniosacral
many modalities focusing on using Hemi-Sync binaural work, acupuncture, and laughter.
sound technology to entrain brain waves into relaxed states.
QEEG neurofeedback harnesses the power of the brain’s
electromagnetic fields to restore calm; both personal devices 40.9  Assessing Relationships and Beliefs
such as Muse and professional devices are available. Many
apps can be downloaded to help learn mindfulness and 40.9.1  Relationships and Beliefs: The Big
mediation including Headspace, Calm, Insight Timer, and Picture
others. Well-known investigators and research pioneers in
the fields of meditation, mindfulness, and trauma recovery Of critical importance for the practitioner to assess is the cli-
have audio. A number of spiritual leaders, from all tradi- ent’s current state of relationships, whether at home, with
tions, have online broadcasts that are easily downloaded to a extended family and friends, pets, work, and community, and
portable device. including their support systems and beliefs. These factors are
Ask your clients “How do you manage your stressors?” the “back story” which underlie and can either completely
and explore what are their resources for support: Family? undermine or be the lynchpin for positive change. Those
Friends? Community? Church? Pets? Nature? Exercise? wishing to make significant lifestyle changes that deviate
Meditation? Prayer? Silence? Have they sought counseling? from the norm of their friends and family may encounter
Support groups? When is the last time they had a vacation or major obstacles in obtaining support or be directly under-
long weekend? How are they sleeping? Do they get some exer- mined. At the same time, many feel isolated from a commu-
cise? How often do they laugh? What tools do they use to nity or are far from family or perhaps they are purposely
relax and have fun or express themselves? As discussed above, disengaged from a dysfunctional family system and need a
some of the most powerful and insightful question you can source of community to support their goals. Unlike small
ask is: “What do you do that is fun, joyful, creative, or play- communities and extended generations, where skills were
ful?” It is amazing how many clients will get tearful when you passed from one generation to another, today’s highly mobile
 708 M. Christensen

and distant lifestyle can make many feel isolated and alone. Weight Watchers, smoking cessation, Alcoholics Anonymous,
Pets and animals can be an important source of comfort, and other similar 12-step programs, and have shown the power
relaxation, affection, and attachment for many. They may of a collective consciousness in creating positive outcomes.
often be an incredibly important primary relationship in a The IFMNT practitioner can harness this phenomenon
person’s life, whose well-being is tied to their own (7 Chap. 6).
  to great advantage with the opportunity to do learning and
Beliefs encompass not only belief in themselves and their group visits, also known as shared medical appointments
ability to make the required lifestyle changes but also the per- (SMAs), which have been shown to enhance individual
son’s belief in whether they feel connected to something larger patient experience, improve population health, and reduce
than themselves – a religious or spiritual source of sustenance, the cost of healthcare, three cofactors upon which some
no matter the particulars. Developing knowledge of the cli- models of reimbursement are now based [43–46]. Coined the
ent’s stage of readiness to change, from pre-­contemplative to “Triple Aim” of improved “care, health, and cost,” stakehold-
ready to take action, can focus the efforts of clinician and cli- ers have recently acknowledged the necessity of upgrading to
ent alike. By having an understanding of these forms of con- the “Quadruple Aim,” adding the fourth component of “pro-
nectivity, along with the obstacles and opportunities vider satisfaction,” as rates of physician, nursing, and clinical
presented, the clinician can help inform and guide the utiliza- staff burnout are significantly high. Healthcare clinicians and
tion of positive forces and known benefits of social networks staff, appropriately trained in the necessary group facilitation
in supporting the health goals of their patients. skills based on a team model of shared responsibilities, can
significantly benefit from this group model, with overall
improved personal and professional satisfaction [47, 48].
40.9.2   elationships, Social Networks,
R The SMA/group care model has been successfully imple-
and Health Outcomes mented in many primary care settings and includes improved
outcomes in diabetic and cardiovascular care, prenatal care,
Many studies have shown that a person’s habits and state of cancer, autoimmune, asthma, diabetes, ulcerative colitis,
health are closely tied to their relationships with family and multiple sclerosis, HIV, pain management, menopause,
community of friends. Family ties and social networks can insomnia, and stress [49–51]. An excellent review, published
markedly impact longevity and quality of life [39]. The famous by Massachusetts General Hospital in 2012 for the hospital
Roseto study of an Italian-American community, published in and outpatient clinic setting, outlines a practical framework
the early 1960s, showed rates of death from heart disease were for implementing the three basic goals of SMAs:
unexpectedly lower than surrounding neighborhoods, even 1. Access to medical care visits
though the theoretical cardiovascular risks from smoking and 2. Education for patients on their medical condition or
poor diets were the same. The factors that seemed to play the disease
important role in longevity were close intergenerational fam- 3. Enhancement of self-management skills for lifestyle and
ily ties with a strong social network of like-minded values behavioral change, to promote self-­management at home
[40]. A recent study concluded that family aids most in lon- and consistency in follow-through on medical recom-
gevity, as marriage bonds were found to be more important mendations [51] (see . Fig. 40.5)
 

than friends in terms of survival [41]. However, what about

40 overall health, weight, obesity, and nutritional and lifestyle An additional excellent resource for implementing group vis-
choices? How do family and friends impact these factors? its, focused specifically on the practitioner of functional med-
A pivotal longitudinal study by Christakis, published in icine, has been developed by family practice physician Shilpa
2007, looked at the spread of obesity between friends and Saxena, MD, IFMCP and can be found through her website.
family and revealed that it is the network of friends, particu- Ideally, impacting population health for the better begins
larly the ones with the closest and strongest ties, which had with impacting prenatal and postnatal health. An excellent
the most powerful influence on gaining weight or not. example of how relationships developed in early prenatal
Christakis concludes, “The spread of obesity in social net- care, utilizing a group visit model, can be used to great advan-
works appears to be a factor in the obesity epidemic. Yet the tage to achieve the Quadruple Aim, is reviewed in Strickland’s
relevance of social influence also suggests that it may be pos- 2016 article, “Centering Pregnancy: Meeting the Quadruple
sible to harness this same force to slow the spread of obesity. Aim in Prenatal Care” [52]. Originally developed in the early
Network phenomena might be exploited to spread positive 1990s by certified nurse-midwife Sharon Rising and champi-
health behaviors, in part because people’s perceptions of their oned by the Centering Pregnancy Health Institute [CHI] to
own risk of illness may depend on the people around them… great advantage, “Centering Pregnancy is a group prenatal
People are connected, and so their health is connected” [42]. care model that engages pregnant women in their care,
It is the social support, advocacy, accountability, and sup- [resulting] in promising health and system outcomes…this
portive influences found in groups, not necessarily the direc- innovative care model deliver[s] the Quadruple Aim of
tives of what a person is actually being told to do, that create the improved patient experience, quality of care, cost contain-
anticipated behavioral change. These factors have been utilized ment, and provider satisfaction” [53]. Strickland’s article out-
for a number of years in the layperson setting of peer support lines how women involved in supporting one another
groups, ranging from divorce and grief support groups to through pregnancy and postnatal care had significantly
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
709 40

Types of Groups

ACCESS EDUCATION BEHAVIORAL CHANGE

Main Focus of To improve access to To improve health education To promote and enhance
medical care and address and teaching skills for self strategies for lifestyle and
the Group
direct medical needs management behavioral change

• Shared medical • Diabetes self- • Medical group visits

appointments management education
• Group medical clinics, groups by CDE • Group psychotherapy
Examples of veterans administration diabetes nurse
Groups by hospital educators • Patient peer-to-peer
Focus support groups
• Health coaching

..      Fig. 40.5  Types of group visits or shared medical appointments. Group Visits at Massachusetts General Hospital, Jan 2012. Retrieved
(Reprinted from with permission from Putting Group Visits into from: 7 http://www.­massgeneral.­org/stoecklecenter/assets/pdf/
 

Practice- A Practical Guide to Implementation and Maintenance of group_visit_guide.­pdf )

reduced episodes of preterm birth, increased healthy birth ing levels of spirituality correlate with decreasing levels of
weights, and markedly improved rates of breastfeeding, all medical utilization, healthcare costs, and death” [54].
known factors in long-term cost and health outcomes for In 2012, Dr. Harold Koenig of Duke University’s
later life. In addition, markedly improved clinician personal Department of Spirituality and Medicine published an exhaus-
and professional satisfaction was a measured outcome in sev- tive review of more than 1200 papers on prayer, health out-
eral studies referenced, bringing back a sense of hope, mean- comes, and longevity [54]. Other studies have shown even that
ing, and rededication to their vocations [54]. most physicians believe in medical miracles [55]. The data is
clear that a regular spiritual or meditation practice is associ-
ated with improved well-being and outcomes and that all
40.9.3  Beliefs practitioners should ask their patients about spiritual needs.
Indeed, the Joint Commission on Accreditation and the
Beliefs encompass everything from a person’s thoughts about Association of American Medical Colleges have directed all
themselves and their capabilities, to their place in the world, health institutions and medical schools to implement a short
to their connection to a spiritual source greater than them- spiritual assessment as part of the medical history, to help
selves. Belief systems can be powerfully engaged to help the caregivers deliver compassionate and appropriate care [56].
client make needed changes toward their health goals. Although religious beliefs and practices play a large role
Determining if a client has a sense of an internal locus of con- in many people’s lives, those who find themselves a-religious
trol in which they believe in themselves, versus an external may feel a strong sense of spiritual connection through ani-
locus, feeling chronically buffeted by outside forces over mals or nature or feel drawn to the embodied spirituality of
which they feel helpless, can direct the clinician in the lan- yoga or tai chi practices or martial arts.
guage and resources necessary to engage and inspire that cli- Engaging larger values in serving a greater cause can help
ent. Ask what are they passionate about? What moves them? motivate new behaviors. For various reasons, a client may
Is there an area they feel strongly about? How do they feel have a hard time believing they can make changes for them-
about their ability to implement and sustain necessary selves, yet they would be willing to take steps to be of benefit
changes? What can help or hinder them? others such as animals or planet or family or their children or
grandchildren. For example, many people are aware of large
issues such as terrorism or wars but feel powerless or hopeless
40.9.4  Spirituality and Religion to do anything about it. Helping them see how day-to-day
choices, e.g., by becoming mindful of their spending habits
Spirituality is the point of connection for the entire Patient’s and which foods they choose, are personal ways of impacting
Story. Asking in a nonjudgmental, non-directed way whether forces much greater than themselves. Some can be motivated
or not a client has a regular spiritual or meditative practice to engage in frequenting a local community garden or farm-
can open a dialogue to engage God, truth, or a higher power er’s market as a way to get exercise and healthy food, to spend
as a personal resource for positive behavioral change. As dis- quality time with family and community, and to know they
cussed by Saguil et  al., “The medical literature has become are contributing to supporting local and organic economies.
replete with articles purporting positive links between spiri- Engaging their “inner child” can be a tool to use to help
tuality and such diverse conditions as cardiovascular disease, motivate. “If your adult-self were watching your child-self
COPD, cancer, cirrhosis, rheumatoid arthritis, leukemia, stay up late, not eat, punish yourself with negative words and
AIDS, depression, adolescent risk behaviors, anxiety, and thoughts, how would you re-parent yourself?” Supporting a
pain. In addition, multiple studies have reported that increas- client in awakening compassion, not blame toward their pre-
 710 M. Christensen

vious choices, helps to overcome shame and guilt and creates 55 Do you have a sense of belonging?
a hopeful path forward. 55 Is there any activity you are engaged in that makes you
The Rev. Rick Warren, along with functional medicine leader feel part of a community?
Mark Hyman, MD, showed exactly the benefit of engaging small 55 Do you have silence in your life?
groups and beliefs utilizing “Food + Fitness + Faith + Focus + 55 What wishes do you have for yourself, what do you value
Friends” in their combined effort called “The Daniel Plan.” Small most about yourself and your work?
prayer groups already found at the church were engaged in life- 55 What makes you feel most alive?
style changes grounded in biblical principles to help the entire 55 Do you believe there is a higher purpose in the health
congregation get on board. Regarding positive outcomes, as Dr. challenges you have suffered?
Hyman likes to joke, “A New England Jew meets a born-again
Christian and an entire church loses 10 tons along the way!” The IFM Adult Intake Questionnaire [male/female] includes
Jewish Community Centers have utilized this concept to help a section in which similar questions are easily covered,
create centers of service and community that include everything including stress assessments and relationships together and
from childcare resources to mental health and counseling to can be an initial resource to investigate areas of concern.
exercise and religious study, as has the YMCA. Whether in Hare Finding a higher purpose and meaning in their health
Krishna, Buddhist temples, or Muslim mosques, faith, fitness, journey may be one of the key factors that can help inspire
and fellowship can go together. Some churches are educating hope and enable clients to become willing to move through the
their communities about the detrimental environmental and necessary steps of readiness to change. Particularly for those
health consequences of genetically modified foods by using the who have been very sick and isolated for a long time, finding
adage that GMO stands for “God Move Over”! meaning in their suffering can be a source of hope for healing.
As outlined in detail above, no matter what faith, or none, Viktor Frankl, the famed psychotherapist, Nazi concentration
mindfulness meditation is a powerful tool that has shown camp survivor, and author of the classic, “Man’s Search for
extraordinary ability to create new neural pathways and can Meaning,” began a powerful psychotherapeutic approach,
be combined with any daily activity, faith or healing practice. logotherapy, which arose out of his horrific experience [57].
For example, the Christian concept of centering prayer uses He realized that those prisoners who were able to find a higher
mindfulness techniques and a repeated sacred word as points purpose or meaning in their suffering were much more likely
of focus. Fishing or knitting both use active forms of mind- to survive the bleak and dangerous hopelessness of the con-
fulness. Respectfully exploring the importance of a patient’s centration camp than those who felt there was nothing to live
spiritual beliefs gives permission to actively engage this most for. For himself, it was imperative to do everything he could to
powerful resource of healing. survive, so he could be a witness to the horrors he experienced.
Can you help your client to be able to share his or her own
process of healing? To take the tools and information they
40.9.5   uestions to Ask About Relationships
Q
will be learning and turn around their experience to reach
and Beliefs
out and to help others out of their suffering? For all people,
young or old, with devastating anxiety and/or depression,
The practitioner should approach relationship and beliefs
cancer or CFS, gastrointestinal and autoimmune issues, or
assessments in a nonjudgmental, non-threatening manner
40 (without injecting their own beliefs unless asked) and using
neurologic disorders, all conditions being suffered by hun-
dreds of thousands of their peers – what if they can become a
open-ended questions such as:
voice for greater change as their challenges are turned around
55 How are things going at home with your spouse/
to be a beacon of light for so many others on similar paths?
partner?
No matter who, telling their story through the lens of the
55 With your co-workers and boss?
hero’s/heroine’s journey can be a powerful tool for inspira-
55 With your children/parents?
tion, enabling long-lasting health and well-being.
55 With extended family?
55 Do you have pets to whom you are connected?
55 Do you feel safe and supported at home?
55 Do you have close friends who know what is going on 40.10  Assessing Readiness to Change
with you?
55 Do you feel you have someone to talk to in times of need 40.10.1  The Nature of Change
and to share triumphs?
55 How supportive are your close friends and family of
your health goals? »» Change is not just about integrating new ideas.... It’s
about transforming old ones! –Monique Class, MSN,
55 Do you feel like your life has purpose and meaning?
IFMCP [58]
55 Do you have a regular spiritual or faith practice that is
meaningful to you? Change and transformation are the underlying mechanisms
55 What kind of extended support system do you have? for improving lifestyle. So, what is change and how is it differ-
55 Do you see a counselor or therapist? ent from transformation? What can we do to foster change in
55 Any support groups to which you belong? patients (and ourselves)? Why is change difficult? What are
Modifiable Lifestyle Factors: Exercise, Sleep, Stress, and Relationships
711 40
stages that we should recognize? Where do patients get stuck? willing and ready a person is to make changes in their diet,
Where do practitioners get stuck? Why is it important to talk nutrients, fitness, tracking, sleep, etc. utilizing a scale of 1–5.
about spirituality with our patients to foster change, transfor- If a patient is still in the pre-contemplative stage, they may
mation, and healing? These are all important questions for require further education or questioning about their beliefs,
practitioners to grasp when engaging their clients to make values, social support, and perceived benefits to help move
changes for optimal health outcomes. them forward, versus someone who is seeking out a practitio-
We want to be able to encourage “change,” which is a goal-­ ner purposefully because they are ready to take action.
oriented, past or future action and is measurable. At the same Ongoing maintenance is often a more difficult area and one
time, we would like to inspire “transformation,” which can be that is influenced by all of the factors discussed above, includ-
defined as a significant alteration in behaviors due to insight ing relationships, beliefs, social support, and barriers such as
from the subconscious mind and which is more likely to help transport and cost.
sustain change for the long run.
Understanding the stages of change and where the patient
is on their journey can be helpful to direct the appropriate 40.10.2  Smart Goal-Setting
education, inspiration, and interventions, to help a person
meet their health goals. Prochaska, in his seminal work Once opportunities for change have been identified in each
“Changing for Good,” outlines the stages that occur not neces- area, encouraging the client to set attainable goals in each
sarily in a linear fashion, but more akin to moving up and area of lifestyle factors can be very helpful. Start with one
down a spiral: the five stages include [59]: simple goal in each area and add incrementally. Having the
1. Pre-contemplation: I don’t even know or don’t want to client write down their goals, using the SMART technique of
know that I need to do something. naming a specific goal, that is measurable, action-oriented,
2. Contemplation: I need to do something in the next realistic and timely can markedly improve engagement. A
6 months. specific goal answers the questions who when, what, where
3. Preparation: I am going to do something in the next and why. For example, “I will ride my bike three times a week
month. for 15 minutes in the neighborhood, to help with stress relief
4. Action: I am actively pursuing changes. and improve my metabolism.” A measurable goal answers the
5. Maintenance: I am continuing to have new behaviors question of “how?” As in, “I can keep track of my mediation
ongoing. time with my Headspace or Calm app, and work on adding
an additional minute each week, until I’ve reached 30 min-
The IFM Adult Questionnaire has an abbreviated version utes per day.” Or, “I can write three gratitudes in my journal
addressing these stages as part of the intake, assessing how for what I have done well that day” (. Fig. 40.6)
 

SMART Goal Component Example

Specific I will walk at least five days per week in the evenings to help
State the desired outcome as explicitly as possible, and target me reduce my waist size (in inches).
a specific area for improvement. This is the “who, what, where,
when, which, and why” of your goal.

Measurable I will meditate for 30 minutes a day five times a week in order
Identify the ways in which you will track your progress, and be as to lower my stress levels and blood pressure.
specific as possible. This is the “how” of your goal.

Action-oriented I will make an effort to move my body for at least 15 minutes

Start with small, achievable goals that are easily outlined into three days a week, increasing my time each week by five
specific steps that will enable you to complete the goal. Then, minutes until I reach 30 minutes per day. I will add an extra
as you meet those smaller goals, work up to intermediate goals day every two to four weeks until I reach 30-60 minutes for
and goals that are more difficult to achieve. five days a week.

Realistic I will begin my bedtime ritual one hour before bedtime,

Create a goal that you are both willing and able to accomplish. which will help me fall asleep faster each night.

Timely Over the next month, I will start eating breakfast every day.
Set a deadline or time for achieving your goal to help keep For the first week, I will make breakfast (or prepare it ahead
you motivated. the night before) twice per week. In the second week,
I will make breakfast three times per week. In the third week,
I will make breakfast five times per week. In the fourth week,
I will make breakfast every day.

..      Fig. 40.6  Smart goal-setting. (Used with permission from The Institute for Functional Medicine ©2015)
 712 M. Christensen

40.11  Conclusion 10. Churchill LR, Schenck D.  Healing skills for medical practice. Ann
Intern Med. 2008;149:720–4.
11. Owen N, Sparling PB, Healy GN, Dunstan DW, Matthews CE.

As practitioners, by doing an in-depth, compassionate, and Sedentary behavior: emerging evidence for a new health risk. Mayo
insightful assessment of all lifestyle factors, we can help Clin Proc. 2010;85(12):1138–41. https://doi.org/10.4065/
inspire transformative change in the five fundamental modi- mcp.2010.0444.
fiable lifestyle areas: nutrition, exercise and movement, stress 12. Berra K, Rippe J, Manson JE. Making physical activity counseling a
priority in clinical practice, the time for action is now. JAMA.
and resilience, sleep and restoration, and relationships and 2015;314(24):2617–8.
beliefs. Gathering oneself as a practitioner, being present and 13. Stamatakis E, Rogers K, Ding D, et al. All-cause mortality effects of
mindful, and knowing how and what questions to ask, replacing sedentary time with physical activity and sleeping using
including the use of targeted questionnaires, can efficiently an isotemporal substitution model: a prospective study of 201,129
and compassionately engage the client in a therapeutic rela- mid-aged and older adults. Int J Behav Nutr Phys Act. 2015;12:121.
14. Dunstan DW, Barr EL, Healy GN, et al. Television viewing time and
tionship. mortality: the Australian Diabetes, Obesity and Lifestyle Study
Supporting transformative change by utilizing nonjudg- (AusDiab). Circulation. 2010;121(3):384–91.
mental questioning techniques and encouraging statements, 15. Murray J, Fenton G, Honey S, Bara AC, Hill KM, House A. A qualitative
such as “Your body has a remarkable ability to heal itself from synthesis of factors influencing maintenance of lifestyle behaviour
the cellular to the spiritual levels. Everything we consume at change in individuals with high cardiovascular risk. BMC Cardiovasc
Disord. 2013;13:48.
all levels of body, mind and spirit become us, so changing
16. Archer E, Shook RP, Thomas DM, Church TS, Katzmarzyk PT, Hébert
and transforming what you are consuming, at all levels, helps JR, et al. 45-year trends in women’s use of time and household man-
to change and transform the body and your health,” can be agement energy expenditure. PLoS One. 2013;8(2):e56620.
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suffering, their challenges, their learning, and their opportu- tissue as an antiobesity agent in humans. J Clin Invest. 2013;
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18. Johnson F, Mavrogianni A, Ucci M, Marmot A, Batterham R, Vidal-­
Acknowledging the client by retelling their story with Puig A. Could increased time spent in a thermal comfort zone con-
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72, 74–6 the patient requires care of the provider. Ann Fam Med. 2014;
34. Centers for Disease Control and Prevention (CDC). National inti- 12(6):573–6.
mate partner and sexual violence survey: 2010 summary report. 49. Housden L, Wong ST, Dawes M. Effectiveness of group medical visits
Retrieved from: https://www.­cdc.­gov/violenceprevention/pdf/ for improving diabetes care: a systematic review and meta-­analysis.
nisvs_report2010-a.­pdf. Accessed Jan 2017. CMAJ. 2013;185(13):E635–44.
35. Aces Too High News. Got Your ACE Score? Retrieved from: https:// 50. Bartley KB, Haney R.  Shared medical appointments: improving

acestoohigh.­com/got-your-ace-score/. Accessed Jan 2017. access, outcomes, and satisfaction for patients with chronic cardiac
36. Bonanno GA, Galea S, Bucciarelli A, Vlahov D. What predicts psycho- diseases. J Cardiovasc Nurs. 2010;25(1):13–9.
logical resilience after disaster? The role of demographics, resources 51. Putting group visits into practice: a practical overview to prepara-
and life stress. J Consult Clin Psychol. 2007;75(5):671–82. tion, implementation, and maintenance of group visits at
37. Southwick SM, Vythilingam M, Charney DS.  The psychology of Massachusetts General Hospital January 2012. http://www.­
depression and resilience to stress. Annu Rev Clin Psychol. massgeneral.­org/stoecklecenter/assets/pdf/group_visit_guide.­pdf.
2005;1:255–91. Accessed Jan 2016.
38. verywell mind. Cope with stress and become more resilient.
52. Strickland C. Centering pregnancy: meeting the quadruple aim in
Retrieved from: https://www.­verywell.­com/cope-with-stress-and- prenatal care. N C Med J. 2016;77(6):394–7.
become-­more-resilient-3144889. Accessed 17 Jan 2017. 53. McNeil DA, Vekved M, Dolan SM, Siever J, Horn S, Tough SC. A quali-
39. Compare A, Zarbo C, Manzoni GM, et al. Social support, depression, tative study of the experience of CenteringPregnancy group prena-
and heart disease: a ten year literature review. Front Psychol. tal care for physicians. BMC Pregnancy Childbirth. 2013;13(Suppl
2013;4:384. 1):S6.
40. Stout C, Morrow J, Brandt EN Jr, Wolf S. Unusually low incidence of 54. Koenig H. Religion, spirituality, and health: the research and clinical
death from myocardial infarction: Study of an Italian American implications. ISRN Psychiatry. 2012;2012:278730, 33 pages.
Community in Pennsylvania. JAMA. 1964;188(10):845–9. 55. Dossey L. Survey of physicians’ views on miracles. The Louis

41. American Sociological Association. Relationships with family mem- Finkelstein Institute for Religious and Social Studies of the Jewish
bers, but not friends, decrease likelihood of death. Retrieved from: Theological Seminary, New York, December 2004.
http://www.­asanet.­org/press-center/press-releases/relationships-­ 56. Hodge D.  A template for spiritual assessment: a review of the
family-members-not-friends-decrease-likelihood-­death. Accessed JCAHO requirements and guidelines for implementation. Soc Work.
Jan 2017. 2006;51(4):317–26.
42. Christakis N, et al. The spread of obesity in a large social network 57. Maria Marshall, Edward Marshall. Logotherapy revisited: review of
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43. Wynn JD. The value of exceptional patient experience. N C Med J. Logotherapy. 2012.
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 715 41

Developing Interventions
to Address Priorities: Food,
Dietary Supplements,
Lifestyle, and Referrals
Aarti Batavia

41.1 Introduction – 716

41.2 Initial Interventions – 717

41.2.1 F ood – 717
41.2.2 Whole Food Versus Specific Dietary Nutrient – 719
41.2.3 Meal Timings and Intervals – 720
41.2.4 Increased Intake of Vegetables with Moderate Fruit Intake – 721
41.2.5 Consumption of Organically Raised and Locally Grown Foods
whenever Possible, with Low-Fat Animal Products
(Low-Fat Dairy and Poultry) in Moderation – 722
41.2.6 Increased Intake of Fiber – 723
41.2.7 Removal of Potential or Documented Allergens
and Excessive Alcohol – 724
41.2.8 Adequate Intake of Fatty Acids – 727
41.2.9 Adequate Water Intake – 730
41.2.10 Inclusion of Prebiotic and Probiotic Foods – 731
41.2.11 Lifestyle – 736
41.2.12 Referrals – 739

41.3 Monitoring and Evaluating Interventions – 739

References – 739

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_41
 716 A. Batavia

41.1  Introduction imbalances of the particular patient. Evaluating interven-

tions that are available at each of these five levels can help to
Integrative and functional medical nutrition therapy is done identify a reasonably thorough set of strategies from which to
within the context of therapeutic and healing partnerships. choose. The following list incorporates only a few examples
The purpose of such a relationship is to help the patient heal of various types of interventions within these five different
by identifying the influences and underlying mechanisms levels.
that initiated and continue to mediate the patient’s illness. It 1. Whole-body interventions: The human organism is a
is an equal investment of focus by both the dietitian/nutri- complex adaptive system with countless points of access.
tionist and the patient to work together to identify where to Therefore, interventions at one level will affect points of
apply the leverage of change – may it be nutritional or related activity in other areas as well. For example, improving
to sleep, relationships, or stress management. Connection, the patient’s sleep will beneficially influence the immune
rapport building, deep listening, reflection, presence, humil- response and melatonin levels, along with decreasing
ity, vulnerability, compassion trust, and gratitude are all oxidative stress. Exercise reduces stress, improves insulin
essential for healing to occur [1]. sensitivity, and improves detoxification. Reducing stress
There are four essential components in integrative and can reduce cortisol levels, improve sleep, improve
functional medicine nutrition therapy (IFMNT), and they emotional well-being, and reduce the risk of heart
can be used by all healthcare professionals applying the func- disease. Changing an individual’s nutrition plan can have
tional medicine approach: myriad effects on health, from reducing inflammation to
1. Listening to the patient story on the initial intake reversing coronary artery disease or insulin resistance to
2. Evaluating, prioritizing, and focusing on the patient’s even impacting cognitive decline.
modifiable lifestyle factors 2. Organ system interventions: These interventions are used
3. Organizing the patient’s clinical imbalances by underly- more frequently in the acute presentation of illness and,
ing causes into a systems biology matrix framework in most cases, would require a referral to a non-nutrition
4. Creating a therapeutic and healing partnership between professional. Examples include draining lesions;
the dietitian/nutritionist and patient to provide practical repairing lacerations; reducing fractures, pneumothora-
evidence-based interventions with timely monitoring ces, hernias, or obstructions; or removing a stone to
and evaluation [2] reestablish whole-organ function. There are many
interventions that improve organ function. For example,
After gathering and working through the patient’s history continuous positive airway pressure (CPAP) machines
and laboratory findings; organizing the subjective and objec- improve inspiratory flow rate sleep quality and decrease
tive data on the functional medicine timeline and matrix; daytime sleepiness and oxidative stress in individuals
retelling the story back to the patient and acknowledging with obstructive sleep apnea syndrome (OSAS), thereby
their goals, antecedents, triggers, and mediators; and identi- improving metabolic functions and cognition [4]. There
fying the clinical imbalances in the organization of physio- is also evidence that effective management of OSAS not
logical systems of the matrix, the dietitian/nutritionist comes only has positive impacts on the individual but also
to the most critical aspect of the encounter: intervention. infers positive benefits to their partners’ sleep and
A completed matrix facilitates the review of common daytime functioning [5].
pathways, mechanisms, and mediators of disease and helps 3. Metabolic or cellular interventions: Cellular health can be
the nutrition expert select points of leverage for nutritional addressed by ensuring the adequacy of MAPDOM
41 and lifestyle interventions. The nutrition practitioner may status – minerals and fiber, antioxidants/phytonutrients,
also find an opportunity to refer the patient to another proteins, vitamins, fatty acids, and methylation factors in
healthcare practitioner for their medical expertise. For exam- the diet or, if necessary, from supplementation. An
ple, one might send a patient for vision evaluation if one individual’s metabolic enzyme polymorphisms can
complains of strained eye/poor vision or send a male patient profoundly affect his or her nutrient requirements. For
to a physician specializing in bioidentical hormones if he has example, adding conjugated linoleic acid (CLA) to the
very low testosterone and cardiovascular or cognitive decline. diet can affect body weight, alter the peroxisome
However, even with the matrix as an aid to synthesizing and proliferator-activated receptor (PPAR) system, and
prioritizing information, it can be very useful to consider the modulate the inflammatory response. However, in a
impact of each variable at five different levels: person who is insulin resistant and/or has diabetes,
1. Whole body (the “macro” level) adding CLA may induce hyperinsulinemia, which is
2. Organ system detrimental. Altering the types and proportions of
3. Metabolic or cellular carbohydrates in the diet may reduce insulin secretion,
4. Subcellular/mitochondrial increase insulin sensitivity, and essentially alter metabo-
5. Subcellular/gene expression [3] lism in the insulin-resistant patient.
4. Subcellular/mitochondrial interventions: There are several
It is important for the nutrition practitioner to identify thera- examples of mitochondrial nutrient-­support interven-
pies based on their potential impact on the most central tions. Inadequate iron intake causes oxidants to leak
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
717 41
from the mitochondria, damaging mitochondrial 41.2  Initial Interventions
function and mitochondrial DNA. Making sure there is
­sufficient iron helps to mitigate this concern. Ensuring 41.2.1  Food
sufficient antioxidants and cofactors for the at-risk
individual must be considered in each part of the matrix. Food is not only nutrition; it also plays a significant role in
Carnitine, for example, is required as a carrier for the cultural and personal identity, along with shaping and
transport of fatty acids from the cytosol into the expressing social relations. The nutrition professional should
mitochondria and in improving the efficiency of beta consider these factors while personalizing a nutrition plan
oxidation of fatty acids and resultant ATP production. In for the patient. It is also crucial to consider family history,
patients who have lost significant weight, carnitine history of diseases and chronic conditions, physical activity,
undernutrition can result in fatty acids undergoing allergies and food intolerances, access to food, epigenetic
omega oxidation, a far less efficient form of metabolism. markers, and food preferences.
Patients with low carnitine may also respond to ribofla- This is an era when diets can be a lot like religion, and
vin supplementation. there are proponents of each food culture – from paleo to
5. Subcellular/gene expression interventions: Many com- vegan or vegetarian. It is crucial that the nutrition practi-
pounds interact at the gene level to alter cellular tioner has insights into the latest “diet trends,” along with
response, thereby affecting health and healing. Any critically differentiating between an effective therapeutic
intervention that alters NF-κB entering the nucleus, food plan tailored for the patient utilizing evidence-based
binding to DNA, and activating genes that encode research and whatever diets are popular at the moment. In
inflammatory modulators such as IL-6 (and thus CRP), current times, the dietitian/nutritionist has a plethora of
cyclooxygenase 2, IL-1, lipoxygenase, inducible nitric therapeutic diets to work with based on the patient’s needs.
oxide synthase, TNF-alpha, or a number of adhesion Examples of therapeutic diets are Specific Carbohydrate
molecules will impact many disease conditions. There Diet (SCD); fasting; the ketogenic plan; intermittent fast-
are several ways to alter the environmental triggers or ing; time-restricted feeding, low-glycemic plan; elimina-
NF-κB, including altering emotional stress, exercising, tion food plans; low-histamine diet; the Dietary Approaches
lowering oxidative stress, and consuming adequate to Stop Hypertension (DASH) diet; gluten-free or casein-
phytonutrients, antioxidants, alpha-lipoic acid, EPA, free diets; the Gut and Psychology Syndrome (GAPS) diet;
DHA, and GLA. Vitamin D has key roles in controlling fermentable oligosaccharide, disaccharide, monosaccha-
gene expression, inflammation, bone metabolism, ride, and polyol (FODMAPs) diet; a Mediterranean food
calcium homeostasis, endocrine and cardiovascular plan; and the Zone diet. The nutritionist/dietitian also
physiology, and healing [3]. needs to be aware of the different effects of nutrients
Once the nutritional professional has ample experience according to our genetic constitution (nutrigenetics) and
using this model along with improved pattern-recognition how nutrients may affect gene expression (nutrigenomics).
skills, it will often lessen the need for extensive laboratory Dietary advice that is specific to individuals with a particu-
assessments. However, there will always be certain lar genotype is more effective at preventing chronic dis-
clinically perplexing cases that simply cannot be assessed eases than general recommendations about diet. The next
without objective data, and, for most patients, there may chapter will go into the details about each of these thera-
be an irreducible minimum of laboratory assessments peutic diets.
required to accumulate information. For example, in the Personalized and precision medicine and nutrition can
clinical workup of patients with Alzheimer’s disease, be considered as occurring at three levels: (1) conventional
heavy metal toxicity, infection, or mold exposure may play nutrition based on general guidelines for population groups
an important role [6, 7]. Heavy metal body burden or by age, gender, and social determinants; (2) individualized
mold toxicity cannot be sensibly assessed without nutrition that adds phenotypic information about the per-
laboratory studies. In such cases, it becomes critical for son’s current nutritional status (e.g., anthropometry, bio-
the nutrition practitioner to develop a network of capable, chemical and metabolic analysis, physical activity); and (3)
collaborative healthcare practitioners with whom to genotype-directed nutrition based on rare or common gene
co-manage challenging patients and to whom referrals variation. Research and appropriate translation into medical
can be made for therapies outside the nutritional profes- practice and dietary recommendations must be based on a
sional’s own expertise. This will enrich patient care and solid foundation of scientific knowledge and practical solu-
strengthen the nutritionist/dietitian-patient relationship. tions that the patient is able to follow and comply [8].
1. Removal of processed foods: high-glycemic-­index foods,
No two patients are treated identically in functional medi- high-fructose corn syrup, and trans or partially hydroge-
cine, but some advice is applicable to nearly every patient. nated fats
The following lifestyle recommendations also meet the crite- The Western-style diet, also known as the meat-sweet diet
rion of helping to normalize and have a large impact on mul- or standard American diet, is characterized by an over-­
tiple systems, working as whole-body interventions and thus availability and overconsumption of food, along with
providing a foundation of health. high intakes of high-sugar desserts, sweetened drinks,
 718 A. Batavia

high-fat foods, refined grains, red meat, and high-fat

dairy products. The heat processing of these foods 55 Emphasize whole grains such as oatmeal, brown
involves high levels of dietary advanced glycation end rice, beans, quinoa, and whole grain or bean/lentil
products (dAGEs). The National Health and Nutrition pasta over meat when making meal choices.
Examination Survey (NHANES) showed that 68.3% of 55 Limit your intake of processed foods, which are
those studied were considered overweight (BMI ≥25) often pasteurized at high temperatures.
and 33.9% were obese (BMI ≥30) [9]. Chronically
increased intake of these foods correlates with higher
concentration of fasting insulin, C-peptide, leptin, tissue- Phytochemicals are a large group of chemical compounds
type plasminogen activator antigen (tPA), C-reactive pro- naturally occurring in plants, fruits, vegetables, legumes,
tein (CRP), E-selectin (sSELE), intercellular adhesion whole grains, nuts, seeds, fungi, herbs, and spices, conferring
molecule 1 (sICAM-1), vascular cell adhesion molecule 1 aroma, flavor, texture, and color. These compounds have
(sVCAM-1), and interleukin 6 (IL-6). This affects multi- been developed over thousands of years of evolution to
ple metabolic functions, causing oxidative stress, a higher defend organisms from the effects of free radicals, fungi, bac-
osteoporosis risk, and chronic kidney disease [10–12]. In teria, and viruses. One would wonder as to why these phyto-
general, processed foods impact each and every clinical chemicals have beneficial effects on humans if they are
imbalance in the matrix, causing changes in digestion produced to protect plants. Humans have been ingesting
and absorption, impairing insulin regulation, leading to plants as part of their diet throughout their evolutionary his-
immune system activation and vasculature to causing tory, and our neurons have conserved many of the same sig-
hormone biotransformation. naling pathways that first evolved in insects and other
2. Consumption of whole-food meals at regular intervals herbivores that preceded humans in evolution. Examples
Epidemiological studies have shown that regular con- include pathways that signal via SIRT1, AMPK, and Nrf2.
sumption of whole foods is associated with health pro- Activation of one or more of these signaling pathways that
motion and reduced risks of developing several chronic evolved to defend cells against potentially toxic phytochemi-
diseases, as well as all-cause mortality. The underlying cals appears to be a major reason why ingestion of phyto-
physiological mechanisms behind the protective effects chemicals can protect us against injury and disease [15].
of whole foods can most likely be ascribed to a concerted Phytochemicals can be classified into several major
action of a wide variety of phytochemicals, phenolic com- groups based on their chemical structure: alkaloids, sulfur-­
pounds, carotenoids, vitamin E, sterols, and dietary fiber containing phytochemicals, terpenoids, and polyphenols
[13]. Plants are the only source of these nutrients, whereas [16]. Apart from imparting flavor, color, and texture, these
animals are essentially devoid of them [14]. phytochemicals perform a slew of functions – they decrease
oxidative stress and neutralize free radicals, act as anti-­
inflammatory and antibacterial agents, reduce carcinogenic
What Can You Do to Reduce High-AGE Foods in activity via inhibiting tumor growth, detoxify carcinogens,
Your Diet? and slow down the progression of such degenerative diseases
55 Eat more raw or steamed fruits and vegetables as osteoporosis, macular degeneration, and cataracts [14].
and eat meat less often for damage control. Fruits Phytochemicals have beneficial or stimulatory effects on
and vegetables are high in antioxidants and have animal cells, though they can be toxic when consumed in
anti-aging properties. high amounts. The beneficial effects are an example of “hor-
41 55 Limit the amount of grilled, fried, or broiled foods mesis.” When cells and organisms are challenged with mild
in your diet. stress by some of the noxious phytochemicals present in the
55 Lower the flame to low on a gas grill. plants, they respond adaptively in ways that help them with-
55 Use “wet” cooking methods, such as stewing,
stand more severe stress. Hormetic phytochemicals such as
boiling, braising, slow-cooking, or steaming, often
resveratrol, sulforaphane, curcumin, catechins, allicin, and
because dry-heat cooking methods create more
hypericin are reported to activate adaptive stress response
AGEs than moist ones. For example, a chicken breast
signaling pathways that increase cellular resistance to injury
broiled for 15 minutes contains more than five times
and disease [15].
as many AGEs as the same food boiled for 1 hour.
Alkaloids from Piper nigrum (black pepper) exhibit anti-­
55 Trim visible fat from meat before cooking at high
inflammatory activity via activating the Nrf pathway. The
temperatures. Cook with less fat.
activation of Nrf2 has been shown to be a key step in the
55 When you do grill, use acidic marinades including
cellular response against several common diseases, including
lemon juice and vinegar, which are thought to
inflammation, aging, diabetes, cardiovascular disease, acute
help to fight AGEs.
pulmonary injury, neurodegenerative diseases, and cancer
55 Don’t eat the browned or charred portions of
[17]. Glycoalkaloids produced by eggplants (α-solamargine
cooked meats and cheeses.
and α-solasonine), potatoes (α-chaconine and α-solanine),
55 After cooking, cut off any portions of food that
and tomatoes (α-tomatine) or their hydrolysis products
were charred.
(mono-, di-, and trisaccharide derivatives and the aglycones
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
719 41
solasodine, solanidine, and tomatidine) have been shown to classified as flavonoids and non-flavonoids, based on their
inhibit the growth of cancer cells in culture (in vitro), as well chemical structure. Flavonoid-type polyphenols are divided
as tumor growth in vivo. In experimental studies, α-tomatine into different subclasses: anthocyanins, anthocyanidins, fla-
also contributed to protective immunity elicited by a malaria vones, flavanols, catechins, isoflavones, flavanones, and fla-
vaccine candidate [18]. vonols. Non-flavonoids are comprised of stilbenes, phenolic
Organosulfur compounds such as allicin, ajoene, and iso- acids, lignans, and hydroxycinnamic acids [21].
thiocyanates have shown antibacterial activity against both Polyphenols have been studied for their potential involve-
gram-negative and gram-positive bacteria. Allicin is an ment in many areas, including cardiovascular, diabetes, can-
organosulfur compound obtained from garlic when it is cer, neurodegenerative conditions, inflammation, and
crushed, which causes the enzyme alliinase to convert alliin microbial diseases. Their protective activity was firstly attrib-
into allicin. This transformation occurs only in crushed uted to their free radical scavenger, antioxidant, and metal
plants; in intact plants, alliin and alliinase are kept in differ- chelator properties and later on to their ability to inhibit or
ent cell compartments, coming into contact only when the reduce different enzymes. The best studied stilbene is resve-
cloves are broken. Allicin has also shown antibacterial activ- ratrol, found in grapes and grape products, for its role in acti-
ity against P. aeruginosa, S. epidermidis, Burkholderia cepacia, vation of sirtuin enzymes that increase longevity, reduction
S. agalactiae, MRSA, and oral pathogens causing periodonti- of TNF-α and TGF-β, and induction of neurotrophic factors
tis and caries [16]. such as brain-derived neurotrophic factor (BDNF) [22, 23].
Terpenoids are a group of substances that occur in nearly The richest sources of lignans are flaxseed and sesame seeds,
every natural food. Their main subclasses discussed as bene- while minor sources are cereals, lentils, fruits (pears, prunes),
ficial to maintain and improve health are monoterpenes (like and vegetables (garlic, asparagus, carrots) [22]. Sesamin, a
limonene, carvone, or carveol), diterpenes (including the lipid-soluble lignin, has shown to potentiate TNF-α-induced
retinoids), tetraterpenes (which include all different carot- apoptosis, inhibit proliferation of a wide variety of tumor
enoids like α- and β-carotene, lutein, lycopene, zeaxanthin, cells, and downregulate NF-κB activation induced by various
and cryptoxanthin), and terpenoid chromanols [19]. inflammatory stimuli and carcinogens [24].
Tocotrienols and tocopherols (vitamin E) are terpenoid Fibers found in whole plant foods powerfully support the
chromanols and tocotrienols that possess the ability to stim- gastrointestinal, cardiovascular, and immune systems
ulate the killing of cancer cells selectively through apoptosis through multiple mechanisms and will be discussed further
in order to reduce cancer cell proliferation, while leaving in this chapter. Yet more than 90% of adults and children in
normal cells unaffected. One of the mechanisms by which the United States do not get the minimum recommended
tocotrienols are thought to suppress cancer is related to the amount of dietary fiber [14].
isoprenoid side chain. Isoprenoids, along with selenium,
have been shown to suppress the initiation, growth, and pro-
gression of prostate and other cancers. They are commonly 41.2.2   hole Food Versus Specific
W
found in almonds, peanuts, and walnuts, which may explain Dietary Nutrient
why diets rich in these foods such as the Mediterranean diet
have consistently been shown to reduce the incidence of can- Consumption of whole foods is strongly associated with
cer. Much of the broad involvement of vitamin E in human reduced risk of chronic diseases. It is therefore reasonable
metabolism is due to its role as the body’s primary lipid-­ for scientists to identify the bioactive compounds responsi-
soluble antioxidant. Tocopherols and tocotrienols are part of ble and hope to find the “magic pill” to prevent chronic dis-
the body’s highly effective defense system, without which life eases. The critical question then is whether a purified
could not exist. This defense system consists of a network of phytochemical has the same health benefit as the phyto-
antioxidants, interacting with and supporting each other. chemical present in whole food or a combination of foods
Antioxidants such as vitamin C, coenzyme Q10, and gluta- [25]. Summaries, which mostly represent meta-analyses,
thione are needed for effective recycling of tocopherols and show no long-term benefit for vitamin supplements (Collin
tocotrienols. The unique power of both tocopherols and C) if no dietary and interventional changes are made.
tocotrienols is their ability to break the chain reaction of lipid Dietary supplements do not have the same health benefits as
peroxidation by neutralizing peroxyl radicals to prevent the a diet rich in whole grains, legumes, nuts, seeds, fruits and
spread of free radical damage in cell membranes. Vitamin E vegetables, because, taken alone, the individual antioxidants
is a generic term for at least eight structurally related mole- studied in clinical trials do not appear to have consistent
cules: α-tocopherol (αT), β-tocopherol, γ-tocotrienol (γTE), preventive effects. Constituents delivered by foods taken
and δ-tocotrienol. Among them, αT is the predominant form directly from their biological environment have different
of vitamin E in plasma and tissues and is the form that has effects from those formulated through technologic process-
drawn most attention in the past. Combinations of different ing. The isolated pure compound either loses its bioactivity
forms of vitamin E may be superior to each alone [20]. or may not behave the same way as the compound in whole
Polyphenols are one of the largest secondary plant metab- foods [25, 26].
olites ubiquitously present in fruits and vegetables consid- For example, numerous studies have shown that the risk
ered an integral part of the human diet. Polyphenols are of cancer is inversely related to the consumption of green and
 720 A. Batavia

yellow vegetables and fruits. As beta-carotene is present in more common in children and may have contributed to both
abundance in these vegetables and fruits, it has been exten- the increasing prevalence of obesity in children as well as
sively investigated as a possible cancer-preventive agent. dyslipidemia in adolescents during the past few decades.
However, the role of carotenoids as anticancer supplements In a study conducted at Queen’s Medical Centre in the
has recently been questioned as a result of several clinical United Kingdom, irregular meal frequency disturbed energy
studies. In one study, the incidence of non-melanoma skin metabolism in healthy lean women, leading to a lower post-
cancer was unchanged in patients receiving a beta-carotene prandial energy expenditure, higher degree of insulin resis-
supplement. In other studies, smokers gained no benefit from tance, or lower postprandial insulin sensitivity and higher
supplemental beta-carotene with respect to lung cancer [25]. fasting lipid profiles, thereby indicating a deleterious effect
Vitamin C supplementation also has been shown to lower on these cardiovascular disease risk factors [30]. A more
the incidence of cancer and heart disease. A Cornell University evenly spaced pattern of three meals per day with no snacks
study reported that phytochemical extracts from fruit have was more strongly associated with a lower prevalence of
strong antioxidant and antiproliferative effects and proposed overweight and obesity and a nutritionally higher-quality
that the combination of phytochemicals in fruits and vegeta- diet [31]. Meanwhile, prolonged intervals between meals and
bles is critical to powerful antioxidant and anticancer activity. skipping meals may trigger migraines and hypoglycemia in
For example, the total antioxidant activity of phytochemicals some individuals.
in 1 g of apples with skin is equivalent to 83.3 mol vitamin C Physiological responses to what and how much we eat
equivalents – that is, the antioxidant value of 100 g of apples is represent the foundation for translational as well as basic sci-
equivalent to 1500 mg of vitamin C. This is much higher than ence aimed at preventing and treating metabolic diseases,
the total antioxidant activity of 0.057  mg of vitamin C (the including obesity and diabetes. However, the timing of food
amount of vitamin C in 1 g of apples with skin). In other consumption independent of total caloric intake and macro-
words, vitamin C in apples contributed only <0.4% of total nutrient quality has emerged as a critical factor in maintain-
antioxidant activity. Thus, most of the antioxidant activity ing metabolic health. Panda states that when healthy adults
came from phytochemicals, not from the vitamin C. The nat- eat identical and isocaloric meals at breakfast, lunch, or din-
ural combination of phytochemicals in fruit and vegetables is ner, the postprandial glucose rise is lowest after breakfast and
responsible for their potent antioxidant activity [27]. highest after dinner, as if the dinner were twice the size of the
In another study, researchers compared the efficacy of breakfast. In addition, when healthy adults are given a con-
lycopene supplementation with consumption of tomato stant glucose infusion over 24 hours, blood glucose rises at
products on intermediate cardiovascular risk factors, includ- night and falls around dawn. This is likely because melatonin
ing oxidative stress, inflammation, endothelial function, inhibits insulin release from pancreatic islets through the
blood pressure, and lipid metabolism. Tomato intake pro- melatonin receptor and the evening rise in melatonin likely
vided more favorable results on cardiovascular risk endpoints causes hyperglycemia. This indicates that in addition to what
than did lycopene supplementation [28]. and how much we eat, when we eat helps determine the phys-
In short, the effect of the whole food is more powerful iological response to nutrient availability [32, 33].
than the effect of a specific dietary nutrient. However, public Almost every cell in the body has a circadian clock
confusion proliferates on this issue, incurring huge monetary machinery, each with an approximately 24-hour period.
and social costs [29]. It is important that the nutrition practi- Circadian rhythms are an integral part of physiology that
tioner emphatically relays this message to their patients. seems to be essential for health. The circadian system is a
Practitioners have often seen new patients coming to their master integrator of both the internal state of the organism
41 first visit with a bagful of supplements. With all the informa- and the organism’s interaction with nutrition and ambient
tion available on the Internet and individuals and companies light. The suprachiasmatic nucleus (SCN) in the hypothala-
claiming benefits of these supplements, a desperate patient mus acts as a master clock to coordinate independent oscilla-
might buy these supplements without correct guidance. tors throughout the body and determine the period of the
Helping patients to understand the importance of whole organism. Unlike peripheral oscillators, the SCN is com-
foods then becomes one of the important objectives of nutri- posed of a network of neurons with intricate intercellular
tion education during that visit or subsequent visits, which- communication to produce robust outputs through both
ever seems apt for the practitioner. neural and humoral cues. In addition to this internal regula-
tion, the SCN also receives external input, such as light, to
help an organism coordinate with their environment.
41.2.3  Meal Timings and Intervals Nutrient consumption also has a large influence on biological
rhythms, but it has a more direct effect on peripheral oscilla-
We are increasingly moving away from regular meals as more tors than the SCN. Together, light and nutrients coordinate
meals are being eaten outside the home and family meals internal biological rhythms with the environment.
have been eroded by hectic schedules. The prevalence of The erratic lifestyle associated with modern society  –
irregular meal patterns is greater among adolescents than it aberrant eating and sleep patterns, inappropriate light expo-
was during previous decades. Irregular snacking has become sure, jet lag, and shift work – contributes to circadian rhythm
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
721 41
disruption. This disruption compromises multiple levels of catalyze oxidation, reduction, and hydroxylation reactions
physiology, metabolism, and inflammation and increases the and convert hydrophobic compounds to reactive interme-
risk for noninfectious chronic diseases such as metabolic dis- diate metabolites in preparation for their reaction with
order, diabetes, cardiovascular disease, dental caries, and water-­soluble moieties to improve excretion. Phase II
cancer [34]. Light at night suppresses sleep and promotes enzymes – such as glucuronosyltransferases, sulfotransfer-
extended wakefulness, thereby allowing ingestive behavior to ases, and glutathione transferases – catalyze these conjuga-
continue late into the night. Therefore, room lighting (or tion reactions.
darkness) is critical during sleep. It is important to keep bed- Numerous constituents of plant foods, including isothio-
rooms as dark as possible and avoid blue light before sleep. cyanates, flavonoids, and allyl sulfides, are potent modulators
Conversely, maintaining a consistent daily eating and fasting of the CYP monooxygenases. However, the effects of some of
rhythm and sleeping in a dark room maintains normal circa- these phytochemicals on CYPs are complex. They have the
dian physiology and can prevent or mitigate several of these capacity to inhibit certain enzymes at high concentrations of
chronic diseases [35, 36]. the compound or to activate moderately the same enzyme at
lower concentrations, while others may be competitive
inhibitors of CYPs. Even when present at low concentrations
41.2.4  I ncreased Intake of Vegetables and in combination with other compounds, their actions can
with Moderate Fruit Intake be significant.
The capacity to conjugate metabolically activated inter-
Fruits and vegetables are rich sources of a variety of nutri- mediates and excrete them from the body is critical in pro-
ents, including trace minerals, vitamins, and dietary fibers, tecting against many potential mutagens, and efforts have
along with other classes of biologically active compounds. focused on determining how vegetable and fruit constituents
These phytochemicals can have complementary and overlap- can influence the phase II conjugating enzymes. In a series of
ping mechanisms of action, including modulation of choles- small studies where individuals were supplemented with
terol synthesis, reduction of platelet aggregation, 300 g of brussels sprouts, the results showed the capacity of
detoxification enzymes, stimulation of the immune system this cruciferous vegetable to affect specific glutathione trans-
and hormone metabolism, reduction of blood pressure, pro- ferase isoenzymes and increase plasma concentrations of
mote brain health and antibacterial, antioxidant, and antivi- glutathione transferase. Induction of these enzyme systems is
ral effects [37]. rapid, and enzymatic activity rises and plateaus within 5 days
of continued daily ingestion of a food with inducing capacity.
41.2.4.1  Antioxidant Activity Similarly, the enzyme activities drop rapidly when the food is
The antioxidant defense system has both enzymatic and non- removed from the diet.
enzymatic components that prevent radical formation, elimi- Xenobiotics share many of the same metabolic pathways
nate damaged molecules, repair oxidative damage, remove with drugs, relying on the same enzyme systems for their
radicals before damage can occur, and prevent mutations. biotransformation. For example, compounds in cruciferous
Phytochemicals from fruit and vegetables can induce the vegetables can alter drug metabolism by both inhibiting and
expression of endogenous antioxidant enzymes along with inducing certain CYPs and possibly by inducing select con-
metalloenzymes. For example, mitochondrial superoxide jugating enzymes. Lampe mentions a study in which feed-
dismutase is a manganese-containing enzyme, and adequate ing individuals a diet of cruciferous vegetables enhanced
consumption of vegetables and fruit can provide the neces- their ability to metabolize phenacetin and antipyrine (a
sary manganese [15]. Nonenzymatic components of the anti- pain-­relieving drug) oxidatively. Consuming a diet contain-
oxidant defense system interrupt the free radical-initiated ing brussels sprouts and cabbage for 1 week could also influ-
chain reaction of oxidation or scavenge and disable free radi- ence select conjugating enzyme systems, stimulating the
cals before they react with cellular components. Typically, the conjugation of acetaminophen with glucuronide but not
antioxidants vitamins C and E and beta-carotene have with sulfate.
received the most attention. Two-week administration of
carrot and tomato juices (330 mL/d) and spinach powder (10 41.2.4.3  Stimulation of the Immune System
g/d), added separately to a low-carotenoid diet, decreased Nutrients and other constituents of fruit and vegetables have
endogenous lymphocyte DNA strand breaks and reduced the potential to affect almost all aspects of the immune sys-
DNA-based oxidation in 23 healthy men [38]. tem. Several of the vitamins associated with diets high in
fruit and vegetables have been shown to improve immune
41.2.4.2  Modulation of Detoxification status. Del Corno and his colleagues demonstrated the
Enzymes immune-protective role of polyphenol metabolites to human
Detoxification, or drug-metabolizing, enzymes are essen- dendritic cells in markedly impairing the production of pro-
tial for the biotransformation of many important endoge- inflammatory cytokines and chemokines in response to bac-
nous compounds and xenobiotics. Phase I enzymes, such terial application and its role in the prevention of acute and
as cytochrome P450 (CYP)-dependent monooxygenase, chronic inflammatory diseases [39, 40].
 722 A. Batavia

41.2.4.4  Decreased Platelet Aggregation lent to 300–500 g of cabbage) for 7 days increased estrone
Blood platelet aggregation is fundamental to a wide range of 2-hydroxylation from 29% to 46%. A randomized clinical
physiologic processes  – e.g., normal blood coagulation, trial compared the effects of 400 mg I3C, 20 g of cellulose,
thrombosis, atherosclerosis, and tumor formation and and placebo daily on 2-hydroxylation of estrogen in women.
metastasis. Activated platelets adhere to altered blood vessel The mean ratio of 2-hydroxyestrone to estriol, a measure of
walls, where they aggregate and promote the release of 2-hydroxylation, increased 1.6-fold in the first month and
­mitogenic factors that stimulate endothelial cell prolifera- remained at that level for the 3 months of the study, while no
tion. A subsequent cascade of events leads ultimately to change from baseline was observed in the cellulose or pla-
occluded vessels. cebo group [38].
Lampe’s article mentions two studies showing reductions It has been hypothesized that shifting the metabolism of
in platelet aggregation of 16.4% and 58% with 9 g and 10 g of 17β-estradiol toward 2OHE1, and away from 16OHE1,
fresh garlic cloves, respectively. The antiplatelet effects are could decrease the risk of estrogen-sensitive cancers, such as
attributed to the allyl propyl disulfide, diallyl disulfide, and breast cancer. Reding and her colleagues demonstrated that
other sulfur compounds contained in the essential oil. fruit consumption, specifically banana and citrus fruits, was
Mitogenic factors released by platelets, such as platelet-­ positively associated with 2- OHE 1 concentrations and not
derived growth factor (PDGF), are thought to be important associated with 16α-OHE 1 , thereby suggesting that breast
in the initiation and progression of atherosclerotic lesions tissue exposure to estrogen metabolites may be influenced
and to respond to alterations in diet. High consumption of by diet [42].
carotenoid-rich vegetables (carrots and spinach) and soy
foods (tofu and textured soy protein) increased concentra- 41.2.4.7  Antibacterial and Antiviral Activity
tions of serum PDGF in study participants, thereby demon- Plants have developed sophisticated active defense systems
strating the anti-atherogenic role of carotenoids [38, 41]. against pathogens, one being the production of antibiotic
compounds. Cranberry juice has long been advocated as a
41.2.4.5  Alterations of Cholesterol treatment for urinary tract infections in women. In a double-­
Metabolism blind, randomized, placebo-controlled trial, Avorn et  al.
Isolated dietary fibers from vegetable and fruit sources, par- showed that 300 mL of cranberry juice per day for 6 months
ticularly pectins, have hypocholesterolemic action. The addi- can influence bacterial flora in the urinary tract.
tion of pectin and fiber-containing foods in experimental The protective effects of vegetables and fruit observed in
diets lowered plasma cholesterol to varying degrees – a vari- epidemiologic studies are not observed with pharmacologic
ety of vegetables (570 g/d) and fresh apples (600 g/d) by 4%, doses of plant foods or their constituents, but with intakes
fresh carrots (200 g/d) by 11%, apples (350–400 g/d) by constituting part of a usual diet. Research on the effects of
8–11%, and prunes (100 g/d) by 5%. The reductions in cho- pharmacologic doses of individual plant food constituents
lesterol are probably due to different mechanisms specific to may identify particular uses for selected compounds.
the type of fiber source and to different dietary fiber intake However, it is unlikely that any one compound will be a
amounts. On the basis of the physiologic effects observed in magic bullet preventing a whole range of chronic diseases,
humans, possible mechanisms include (1) increased excre- and humans will still continue to eat food to nourish body
tion of fecal bile acids and neutral steroids; (2) altered ratios and soul, so we must remain committed to consuming a vari-
of primary to secondary bile acids; (3) increased fecal choles- ety of vegetables and fruit as part of a whole-food diet [38].
terol and fatty acid excretion; (4) and indirect effects, such as
41 high-fiber foods replacing fat- and cholesterol-containing
foods in the diet [38]. 41.2.5  Consumption of Organically Raised
and Locally Grown Foods whenever
41.2.4.6   odulation of Steroid Hormone
M Possible, with Low-Fat Animal
Concentrations and Hormone Products (Low-Fat Dairy and Poultry)
Metabolism in Moderation
A vegetarian diet is associated with lower circulating concen-
trations of sex steroid hormones, increased fecal excretion of Numerous studies have compared organic and conventional
estrogens, and different hormonal profiles than those food production, in relation to both their nutritional value
observed with consumption of an omnivorous diet. In the and their content of chemical residues. Reganold looked at 15
past, much of the response to such a diet has been attributed reviews or meta-analyses of the scientific literature compar-
to the physiologic effects of dietary fiber. However, other ing the nutrition of organic and conventional foods that were
constituents of vegetables and fruit also may influence published in the preceding 15 years. Twelve of these studies
metabolism of endogenous steroid hormones. found some evidence of organic food being more nutritious
Effects of indole-3-carbinol (I3C), a constituent of cruci- (for instance, having higher concentrations of vitamin C,
ferous vegetables, on estrogen metabolism have been total antioxidants and total omega-3 fatty acids, and omega-3
observed in men and women. In men, 500 mg I3C/d (equiva- to omega-6 ratios). Whether or not these are nutritionally
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
723 41
meaningful differences continues to be debated. The rest of polysaccharide with 10 or more monomeric units which is
the three studies concluded that there were no consistent not hydrolyzed by endogenous hormones in the small intes-
nutritional differences between organic and conventional tine. Dietary fiber and whole grains contain a unique blend
foods. of bioactive components including resistant starches, vita-
Organic farming systems produce lower yields compared mins, minerals, phytochemicals, and antioxidants. Dietary
with conventional agriculture. However, they are more prof- fiber is indigestible in the human small intestine but digested
itable and environmentally friendly, and they deliver equally completely or partially fermented in the large intestine. It is
or more nutritious foods that contain less (or no) pesticide examined in two groups: water-soluble and water-insoluble
residues, compared with conventional farming. organic compounds.
Studies have found that children who eat conventionally Based upon their digestibility in the gastrointestinal (GI)
produced foods have significantly higher levels of organo- tract, they are divided into two basic groups: nonstructural,
phosphate pesticide metabolites in their urine than children nonfibrous polysaccharides or simple carbohydrates (starch,
who eat organically produced foods [43]. In 2012, the simple sugars, and fructans) and structural, non-starch poly-
American Academy of Pediatrics reported that an organic saccharides (NSP) or complex carbohydrates that are resis-
diet reduces children’s exposure to pesticides and provided tant to digestion in the small intestine and require bacterial
resources for parents seeking guidance on which foods tend fermentation located in the large intestine (cellulose, hemi-
to have the highest pesticide residues [44]. cellulose, lignin, pectin, and beta-glucans). NSP can be fur-
Organic livestock are fed with organically produced feed ther subdivided into the two general groups of soluble and
that is free of pesticides and animal byproducts, and therefore insoluble.
it is supposed that there should be lower accumulation of Soluble fiber (pectins, gums, inulin-type fructans, and
chemical residues. An intriguing study by Hernandez and his some hemicelluloses) dissolves in water, forming viscous
colleagues found pollutants in both conventional and organic gels, bypasses the digestion of the small intestine, and is eas-
meat. This group examined 76 samples of organic and con- ily fermented by the microflora of the large intestine.
ventional beef, chicken, and lamb for 33 carcinogenic pollut- Insoluble fibers (lignin, cellulose, and some hemicelluloses)
ants that are commonly found in nonorganic meat. They are not water-soluble and do not form gels, so their fermenta-
found pollutants not only in the conventional samples but tion is severely limited [48, 49].
also in the organic samples. In fact, the difference in the level
of pollutants between both was minimal. Of the samples, they Health Benefits of Fiber
41.2.6.1 
found that lamb  – both nonorganic and organic  – had the Cardiovascular
highest level of pesticides, with the organic samples actually High levels of dietary fiber intake are associated with lower
containing more pollutants than the nonorganic. Both kinds rates of coronary heart disease, stroke, and peripheral vascu-
of chicken had the lowest levels [45]. Another study found lar disease, as well as lowering such major risk factors as
that conventional chicken and pork had a 33% higher risk for hypertension, diabetes, obesity, and dyslipidemia.
contamination with antibiotic-resistant bacteria compared to The probable mechanisms behind dietary fiber and car-
organic alternatives [43]. In short, the organic meat was far diovascular disease prevention may be as follows: First, solu-
from being devoid of persistent organic pollutants. ble fibers have been shown to increase the rate of bile
A large meta-analysis by Dominika and colleagues iter- excretion, therefore reducing serum total and LDL choles-
ated that there was a difference in the composition and qual- terol. Second, dietary fiber affects the ability to regulate
ity of fat between conventional and organic meat, with energy intake, thus enhancing weight loss or maintenance of
organic meat having more unsaturated fat, including anti-­ a healthier body weight. Third, short-chain fatty acid produc-
inflammatory omega-3 s [46]. tion, especially propionate, has been shown to inhibit choles-
These studies demonstrate that environmental contami- terol synthesis. Fourth, dietary fiber has been shown to lower
nation by POPs is ubiquitous and human exposure is difficult risk of type 2 diabetes, either through glycemic control or
to avoid. Even consumers who choose to consume organic reduced energy intake. Fifth, fiber has been shown to decrease
food, which is theoretically healthier with better composition proinflammatory cytokines such as interleukin-18, which
of fatty acids, have exposure rates to fat-soluble pollutants may have an effect on plaque stability. Sixth, increased con-
that can become even higher than those of consumers who sumption of dietary fiber has been shown to decrease circu-
eat conventional food. There needs to be a consistent effort to lating levels of C-reactive protein (CRP), a marker of
minimize environmental toxic pollutants and consume ani- inflammation and a predictor for coronary heart disease.
mal products in moderation [45, 47].
Obesity
Dietary fiber’s ability to decrease body weight or mitigate
41.2.6  Increased Intake of Fiber weight gain could be attributed due to several factors. First,
fiber may significantly decrease energy intake. Second, solu-
The World Health Organization (WHO) and Food and ble fiber, when fermented in the large intestine, produces
Agriculture Organization (FAO) state that dietary fiber is a glucagon-­like peptide (GLP-1) and peptide YY (PYY). Both
 724 A. Batavia

these gut hormones play a role in inducing satiety. Third, Salmonella, and Listeria. This could be beneficial in such dis-
dietary fiber may decrease diet metabolizable energy, which orders as ulcerative colitis and C. difficile infections. In one
is gross energy minus the energy lost in the feces, urine, and study, inulin decreased the risk of colon cancer by reducing
combustible gases. Also, as dietary fiber intake increases, the colorectal cell proliferation, decreasing interleukin-2 release,
intake of simple carbohydrates tends to decrease. Both solu- and decreasing exposure to genotoxins.
ble and insoluble fiber may lead to weight loss.
Cancer
Diabetes Cancer continues to be one of the top health concerns of
Although other risk factors such as obesity, lack of physical populations worldwide. Insoluble fiber found in whole grains
activity, and smoking are precursors for type two diabetes, has direct effects in the colon by promoting laxation, decreas-
dietary factors also seem to play a significant role. Type 2 dia- ing transit time, and binding substances such as bile acids
betes results from decreased insulin sensitivity and hypergly- and carcinogens. Soluble fiber is acted upon by the gut
cemia. Several explanations have been proposed to microbiota, and the utilization results in changes to the num-
understand the physiology behind the relationship between bers and types of bacteria and, more importantly, changes to
glycemic index and diabetes. First, simple carbohydrates are their metabolic activities in terms of the formation of tumor
high in glycemic index and produce higher blood glucose promoters, genotoxins, and carcinogens.
levels. This chronic hyperglycemia may lead to the dysfunc- Selective prebiotic fiber sources  – such as resistant
tion of beta cells in the pancreas, thus decreasing insulin starches, inulin, and some oligosaccharides – act as a selec-
release. Second, because of the high glycemic load, tissues tive substrate for bacteria that produce specific short-chain
such as skeletal muscle, liver, and adipose become resistant to fatty acids and can lower the intestinal pH and prevent the
insulin. growth of pathogenic bacteria. They increase the number of
There is an inverse relationship between dietary fiber and bifidobacteria in the colon, and this and the reduced intesti-
diabetes, independent of age and body weight. The mecha- nal pH have a direct impact on carcinogenesis in the large
nisms behind insoluble fiber are more peripheral and not intestine. The SCFA butyrate has shown to increase apoptosis
limited to nutrient absorption. First, an accelerated secretion of colonic tumor cell lines.
of glucose-dependent insulinotropic polypeptide (GIP) is
observed directly after the ingestion of an insoluble fiber. GIP Immune System
is an incretin hormone that stimulates postprandial insulin Soluble fibers such as inulin and other oligofructoses stimu-
release. Second, insoluble fiber can result in a reduced appe- late growth of bifidobacteria and lactobacilli in the colon.
tite and food intake, and this may lead to a decreased caloric These bacteria generate short-chain fatty acids and stimulate
intake and BMI. Third, short-chain fatty acids, via fermenta- the immune system. Some of the other health benefits of
tion, have been shown to reduce postprandial glucose these bacteria include protection from intestinal infection;
response in insulin-sensitive tissues. activation of intestinal function; assistance in digestion and
absorption, especially of calcium; lowering of intestinal pH
Gastrointestinal Conditions for formation of acids after assimilation of carbohydrates;
Dietary fibers affect the entire gastrointestinal tract from the reduction of the number of potentially harmful bacteria; pro-
mouth to the anus. Soluble fibers usually delay gastric empty- duction of vitamins and antioxidants; bulking activity and
ing, while insoluble fibers tend to decrease gastric transit production of fecal matter; and potential reduction in the
time. In the small intestine, fibers can reveal responses of a risk for colorectal cancer [48].
41 wide variety of gastrointestinal hormones that serve as incre-
tins to stimulate insulin release and affect appetite. They can
bind bile acids, impede micelle formation, and thereby 41.2.7   emoval of Potential or Documented
R
increase fecal excretion of cholesterol and bile acids. They are Allergens and Excessive Alcohol
also effective in increasing total fecal volume and promoting
regular bowel movements. In the colon, soluble fibers increase One of the most powerful tools for a whole-body interven-
microbiota mass, with some acting as prebiotics to promote tion is identifying food triggers, food allergens, and intoler-
health-promoting bacteria bifidobacterium and lactobacilli. ances. This becomes an integral part of a nutritionist/
Guar gum and other soluble fibers are associated with low dietitian’s 5-R approach (see . Table 41.1). Identification of
 

levels of gastric acid production, which may protect from food allergies is done through IgE testing for foods, whereas
GERD. Evidence strongly indicates that high fiber intake is to identify non-IgE-related food sensitivities, there are a
associated with lower prevalence of duodenal ulcer disease plethora of tests in the market. If the patient has monetary
than lower fiber intake. Judicious use of soluble fibers may restrictions, a well-structured elimination plan focusing on
offer benefits to individuals who are in remission from ulcer- MAPDOMs offers the patient the opportunity to experience
ative colitis. Inulin as a prebiotic has the ability to stimulate a much healthier approach to eating. Many common ail-
the growth of bifidobacterium while restricting the growth of ments tend to resolve once the individual focuses on more
potential pathogenic bacterial species such as E. coli, plant-based and organic foods.
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
725 41

..      Table 41.1  Integrative 5-R approach

Inter- Definition Food Dietary supplements Lifestyle Referrals

ventions

Remove Remove stressors Remove foods and Antimicrobial Eliminate toxic DC/DO/NUCA-
Remove what harms beverages that are Anti-parasites elements and C1/C2/
This step focuses on likely to contain Oil of oregano, chemicals from Correct
eliminating pathogenic toxins, food allergens, olive leaf extract, food and environ- structural stress
bacteria, viruses, fungi, or antigenic chal- garlic extract, ment Medical
parasites, and other lenges berberine, undecyle- Mold remediation specialties – gas-
environmentally derived toxic Elimination diets nic acid, grapefruit HEPA filters troenterology
substances from the Top 10 antigens seed extract, Toxic relationships Reduction of
gastrointestinal tract FODMAP monolaurin, EMF hiatal hernia –
Eliminate or reduce ongoing Remove processed mastic gum, Fix irregular sleep osteopathic,
toxic exposures in the home foods containing dyes caprylic acid, patterns: regularize chiropractic, or
and/or workplace or chemicals wormwood extract, sleep as per visceral
Avoid highly clove extract, black circadian rhythms manipulation
processed foods walnut hull, Eliminate Teflon Allergy and
Avoid foods cooked at artemisinin, pans, plastic immunology,
high temperatures – cinnamon bark, pau containers infectious
these are high in d’arco inner bark Smoking cessation disease,
advanced glycated extract, ILADS, Lyme- lit-
end products (AGEs) rosemary leaf extract, erate practitio-
Eliminate refined thyme oil, ner
flours apple cider vinegar Functional
Eliminate soda and Chelating agents: medicine
sugary beverages modified citrus psychiatrist
Limit/ eliminate pectin, chlorella, Referral for IV
alcohol activated charcoal chelation
Energetics: bioener-
getic therapies
(cancer – Rad-Tox
from Apex)

Replace The second clinical site: Optimize nutrition Digestive enzymes, Mindful eating Meyer’s cocktail,
Replace factors that may be through whole foods betaine HCl, zinc for Chewing food Vitamin C
lacking or limited Correct nutritional HCl production, Eating meals at Acupuncture
deficiencies lipotropic factors, regular timings
Apple cider vinegar pancreatic enzymes, Clean filtered water
Papaya, pineapple diamine oxidase, Sleep hygiene
DPP IV proteases helps with
Swedish bitters melatonin
Gentian production –
Prokinetics such as important for
D-limonene digestive support
ginger HEPA/ULPA filters
iberogast, to reduce dust,
Chinese herbs (TJ 43) molds, volatile
organic com-
pounds
Indoor plants
(continued)
 726 A. Batavia

..      Table 41.1 (continued)

Inter- Definition Food Dietary supplements Lifestyle Referrals

ventions

Reinocu- Reintroduction of desirable Butyrate in food: Butyrate Sleep Medical

late bacteria, or “probiotics,” into pasture butter/ inulin, Emotional specialist for
the intestine to reestablish buttermilk/SCFA larch- arabinogalac- resilience prescribing
microfloral balance Prebiotic foods: tans, Anger manage- butyrate enemas,
Asparagus psyllium ment fecal transplanta-
Bananas modified citrus pectin Avoid negative tion
Burdock root Probiotics self-talk
Chicory Saccharomyces Meditation,
Chia seeds boulardii practicing loving
Fruit Lactobacillus kindness
Garlic species – reuteri, casei,
Leeks rhamnosus, acidophi-
Onions lus
Peas Streptococcus species
Sunchokes Bifidobacterium
Probiotic foods: species: infantis, lactis,
Buttermilk longum, bifidum
Jeruk
Khimchi
Kombucha
Miso
Nato
Olives
Raw pickles
Sauerkraut
Antibiotic-free animal
produce

Repair Provide nutritional support Whole-food nutrition Glutamine Prayer/grace before Medical
for regeneration and healing Raw spinach, cabbage, N-acetyl glucosamine meals specialist for IV
of the gastrointestinal okra, Fiber for SCFA (both Quiet environment glutathione
mucosa aloe vera soluble and insoluble) Avoid microwave Psychotherapist
Avoid highly butyrate Forgiveness in Chiropractor
processed foods colostrum relationships Physical therapy
Avoid high-­ aloe,
temperature cooking artemisia, boswellia,
processes – high curcumin,
advanced glycated geranium, licorice/
end products DG,
marshmallow,
quercetin,
41 rutin,
slippery elm
Essential fatty acids
Antioxidants: Vitamins
C, A, and E,
CoQ10
Liposomal glutathi-
one
Pro-resolvins
Alpha lipoic acid
Zinc picolinate/
carnosine
Gamma oryzanol
N-acetyl cysteine
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
727 41

..      Table 41.1 (continued)

Inter- Definition Food Dietary supplements Lifestyle Referrals

ventions

Rebal- Modify attitude, diet, and Whole clean foods As needed for Healthy mind/ Yoga therapy
ance lifestyle to promote healthier appropriate for the maintenance healthy body/ Chiropractor
living individual Melatonin mindful eating Craniosacral
Eat no later than 2–3 5HTP Practice gratitude practitioner
hours before bedtime GABA Movement Music therapy
Meal spacing Adrenal support Purpose Water therapy
Eating at regular Magnesium Dinacharya: Art
intervals Fiber practice of daily Chakra balancing
Pro-resolvins routine as per Guided imagery
Fatty acids Ayurveda Hypnosis
Phosphatidylserine HeartMath
Ashwagandha Acupuncture
Massage
Prayer
Meditation
Regular exercise
Laughter: What
makes you laugh?
Steam/sauna
Hydrotherapy
Dry skin brushing

The elimination diet excludes saturated and trans fats, 41.2.8  Adequate Intake of Fatty Acids
empty calories, sugars, additives, hormones, and antibiotics
in food along with toxic chemicals and xenobiotics. Alcohol Fatty acids are constituents of cell membranes, act as an
needs to be eliminated, as ethanol depletes intestinal integ- energy source, and have biological activities that act to influ-
rity and causes gut dysbiosis. Butyrate, a fermentation by-­ ence tissue, metabolism, and function, along with respon-
product of gut microbiota, is also negatively altered following siveness to hormonal and other signals. The biological
chronic alcohol consumption [50]. activities may be grouped as regulation of membrane struc-
With this one therapeutic modality, the dietitian/nutrition- ture and function; transcription factor activity; regulation of
ist can reduce food antigenicity and inflammatory reactions, intracellular signaling pathways and gene expression; and
improve gut permeability, rebalance Th1 and Th2 cytokines, regulation of the production of bioactive lipid mediators.
rebuild the brush border, and improve digestion and absorp- Fatty acids influence health and well-being, and aberrations
tion. Implementation is simple but may not be easy for patients in their profiles influence metabolic conditions such as car-
and their families. Some improvements stem from the reduc- diovascular diseases, neurovascular diseases, type 2 diabetes,
tion of the antigenic load at the level of the gut and the resultant inflammatory diseases, and cancer.
T-helper cell Th1 vs. Th2 immune shifting. While the simple Different foods contain different amounts of fat and dif-
sensitivities may take hours to days to improve, immune system ferent types of fatty acids, and these may be affected by pro-
rebalancing may take weeks to decrease and eliminate antigens cessing, storage, and cooking methods. Humans eating a
from the gut and show improved symptoms on a clinical scale. varied diet will consume many different types of fatty acid
No one likes to change dietary habits, but it is an essential each day. The pattern of fatty acid consumption varies from
part of the management of chronically ill patients. It is meal to meal, from day to day, and from season to season.
important to emphasize the importance of complete adher- Aging, geographical location, and cultural and religious
ence to the plan. When patients are prescribed an elimina- practices also impact fatty acid intake. Fatty acids can be syn-
tion diet, they will typically start “negotiating” the terms, thesized in the human body, either from non-lipid precur-
including alcohol. It is here where motivational interviewing sors such as glucose or from other fatty acids; exceptions to
skills will serve both the practitioner and the patient. this are the so-called essential fatty acids, which must come
Elimination of dietary triggers helps with most chronic from the diet.
conditions, including mental health issues. A paper published
by Karakula et al. reviews the relationship between gut micro- 41.2.8.1  Effects of Saturated Fatty Acids
biota, intestinal permeability, and dietary antigens in the etio- Palm oil, coconut oil, cocoa butter, and animal-derived fats
pathology of schizophrenia [51]. Studies on the role of such as lard, tallow, and butter are rich sources of saturated
ketogenic diet in mental health have been on a rise [52, 53]. fatty acids. The amounts of individual saturated fatty acids
 728 A. Batavia

present vary among these sources. Many plant oils contain a Cell membrane phospholipids contain some palmitoleic
significant amount of saturated fatty acids, particularly pal- acid and significant proportions of oleic acid. Replacing satu-
mitic acid, as do fish and fish oils. Dairy fats contain some rated fatty acids with oleic acid has a small cholesterol- and
odd-chain saturated fatty acids. Saturated fatty acids are also LDL cholesterol-lowering effect with an inconsistent effect
synthesized de novo in humans, the precursor being acetyl-­ on HDL cholesterol. Oleic acid also renders LDL fairly resis-
CoA, produced from carbohydrate or amino acid metabo- tant to oxidation and limits the formation of pro-atherogenic
lism. Processed and refined carbohydrates, when consumed oxidized LDL.  Although oleic acid is often called “anti-­
in excess, are also converted to fatty acids. inflammatory,” its effects on inflammatory processes are
Saturated fatty acids influence cell signaling in many cell modest, and it seems likely that any anti-inflammatory effects
types through their roles in phospholipid, sphingolipid, gan- of olive oil are due to polyphenolic substances rather than
glioside, and lipid raft structure and in covalent modification oleic acid. Oleic acid seems to improve glucose control and
of proteins. Through effects on regulation of transcription insulin sensitivity along with a small lowering effect on blood
factors involved in lipid metabolism and in inflammation pressure.
(NF-κB), saturated fatty acids influence cholesterol, fatty Effects of oleic acid are observed when it is used to replace
acid, and triacylglycerol biosynthesis; lipoprotein assembly, saturated fatty acids in the diet, and it is likely that these
secretion and clearance, and metabolism; and inflammatory effects are due to partial removal of the deleterious biological
processes. Hence, they play important roles in normal cellu- effect of saturated fatty acids rather than to any specific
lar and tissue metabolism and function but also influence molecular or cellular action of oleic acid. However, some
factors involved in determining risk of cardiometabolic and studies show effects of oleic acid on transcription factors
other inflammatory diseases [54]. involved in lipid homeostasis. The effects seen when satu-
Based on the recent controversy with saturated fats, one rated fatty acids are replaced with oleic acid would be
could easily assume that the “butter/bacon is back” move- expected to lower risk of cardiovascular disease [54].
ment has won and that reducing saturated fat is no longer In terms of preventing cardiovascular events, the
important for heart health. A few recently published stud- Prevención con Dieta Mediterránea (PREDIMED) study
ies conclude that there is no association between intake of reported that a 4.8-year intervention with a Mediterranean
­saturated fats and cardiovascular risk [55, 56]. One of these diet that included extra-virgin olive oil  – a source of oleic
studies was a meta-analysis of observational studies report- acid – reduced myocardial infarction, stroke, and cardiovas-
ing associations of saturated fat with all-cause mortality, cular death by 30% compared with the control diet [59].
cardiovascular mortality, and stroke (de Souza). The Over the past decade, palmitoleic acid – found in maca-
researchers concluded that saturated fats are not associated damia nuts, avocado, and sea buckthorn – has received sig-
with those outcomes. The other popular study was the nificant interest due to its description as a “lipokine.” A
Minnesota Coronary Experiment (MCE), a randomized lipokine is a lipid messenger released from adipose tissue
control trial conducted with 9423 men and women [56]. having effects on other tissues such as the skeletal muscle, by
The researchers concluded that replacing saturated fat in increasing insulin sensitivity, and in the liver, where it reduces
the diet with polyunsaturated fats had no impact on mor- fat accumulation.
tality, even though it reduced cholesterol. While these stud- In conclusion, the two major dietary MUFAs appear to
ies and arguments seem compelling, the vast majority of have a cardioprotective and anti-inflammatory role, espe-
the research still links saturated fat intake with increased cially when substituted for saturated fatty acids [54].
risk for cardiovascular risk. Critiques of the above meta-
41 analysis show that the researchers based their conclusions 41.2.8.3  Effects of Omega-6 PUFAs
on selective data and ignored the data that showed replac- Linoleic acid is the most prevalent omega-6 (n-6) polyun-
ing saturated fat with high-quality carbohydrates  – fruits, saturated fatty acids (PUFAs) in the human diet. Many nuts,
vegetables, and whole grains – reduced the risk of cardio- seeds, and oils contain high proportions of linoleic acid. For
vascular disease [57, 58]. example, linoleic acid comprises 75% of fatty acids in saf-
flower oil and around 50–55% in corn oil, soybean oil, sun-
41.2.8.2  Effects of MUFAs flower oil, and cottonseed oil. It also makes a significant
Oleic acid is the most prevalent monounsaturated fatty acid contribution to vegetable oils that are rich in oleic acid (rape-
(MUFA) in the human diet. Plant oils and animal-derived seed, peanut, and olive oils) or palmitic acid (palm oil). Some
fats such as lard, tallow, and butter are good sources of oleic seeds and seed oils contain metabolic products of linoleic
acid. Olive oil is an especially rich source, with oleic acid acid such as γ-linolenic acid and are found in evening prim-
typically contributing about 70% of fatty acids present. In rose oil, but these are not important dietary constituents.
low-erucic acid rapeseed oil (aka canola oil), which is geneti- The second most common dietary n-6 PUFA is arachi-
cally engineered, oleic acid typically makes up about 60% of donic acid, which is found in foods of animal origin, such as
fatty acids. Palmitoleic acid is found in low amounts in many meat and eggs. Linoleic acid is the metabolic precursor of
plants oils and animal fats, and it is quite abundant in maca- γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic
damia oil and in fatty fish and fish oils. Both palmitoleic and acid. Membrane phospholipids of human cells contain sig-
oleic acids can be synthesized de novo in humans. nificant proportions of both linoleic and arachidonic acids
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
729 41
and often contain some dihomo-γ-linolenic acid. Linoleic acid in Western diets is 7–20. This may be one reason why
acid is an important constituent of ceramides, especially metabolism of α-linoleic acid to EPA is poor in humans and
those found in the skin, and essential fatty acid deficiency that to DHA is extremely limited.
results in breakdown of skin integrity and inability to prevent EPA, DPA, and DHA are found in seafood, especially in
transdermal water loss. However, only a fairly low intake of fatty fish, and in fish oil supplements. Unless a person is regu-
linoleic acid is required to prevent essential fatty acid defi- larly consuming fatty fish or taking a fish oil supplement daily,
ciency (1% of energy), and most diets provide intakes greatly α-linolenic acid will be the most common n-3 PUFA in the
in excess of this. diet. Cell membranes contain very little α-linolenic acid, but
Linoleic acid lowers blood cholesterol and LDL choles- most contain modest amounts of EPA and greater amounts of
terol concentrations, particularly when it replaces the com- DPA and DHA.  Membranes of the brain (gray matter) and
mon saturated fatty acids. It has an effect in hepatic cholesterol eye (rod outer segments) contain high amounts of DHA. The
metabolism by inducing the gene encoding cholesterol structure of n-3 PUFAs, especially DHA, has a strong influ-
7α-hydroxylase, which is the rate-limiting enzyme in the ence on the physical properties of membranes into which
synthesis of bile acids from cholesterol. This upregulation they are incorporated and on membrane protein function. As
increases the production of bile acids that are exported from the result of effects on membrane-generated intracellular sig-
the liver to the gallbladder, thereby lowering hepatic choles- nals, EPA and DHA can modulate transcription factor activa-
terol and LDL.  Linoleic acid was found to increase insulin tion and thereby expression of genes. The transcription factors
sensitivity and activate NF-κB, but is not associated with affected by EPA and DHA include NF-κB, Ki-67, SREBPs, and
increasing CRP, IL-6, or soluble TNF receptor and may thus PPAR-α and PPAR-γ. These effects are central to their role in
have only a limited effect on inflammation in humans. controlling inflammation, fatty acid and triacylglycerol
Arachidonic acid has a structural role in the brain. Studies metabolism, and adipocyte differentiation.
of infants receiving formulas that combine arachidonic acid The replacement of cell membrane arachidonic acid by
with the long-chain n-3 PUFA docosahexaenoic acid have EPA and DHA influences the pattern of lipid mediators pro-
found improvements in cognitive development. Free arachi- duced. There is decreased production of eicosanoids from
donic acid has roles in cell signaling and can directly pro- arachidonic acid and increased production of eicosanoids
mote inflammation by acting via the NF-κB pathway. A from EPA, especially of the selective proresolving mediators
major role of cell membrane arachidonic acid is as a substrate (SPM), which play an anti-inflammatory role and also influ-
for the synthesis of eicosanoids, which include series 2 pros- ence the immune system. Therefore, EPA and DHA can
taglandins, thromboxanes, and leukotrienes. These are influence inflammation, immune function, blood clotting,
formed by metabolism of arachidonic acid by cyclooxygen- vasoconstriction, and bone turnover, along with several
ase or lipoxygenase pathways. The resulting metabolites have other processes. An adequate supply of DHA is essential for
many roles in platelet aggregation and blood clotting, inflam- optimal neural, behavioral, and visual development of the
mation and pain, regulation of the immune response and infant. EPA and DHA have important roles in brain function
bone turnover, smooth muscle contraction, tumor cell prolif- throughout the life course.
eration, renal function, and cancer progression. Eicosanoid These n-3 PUFAs are effective at lowering blood triglycer-
mediators are formed in a cell-specific manner and often ide concentrations. DHA can influence the concentrations of
have opposing effects to one another, thereby acting to ensure cholesterol-carrying lipoproteins and can cause a small
a controlled biological response [54]. It is well-known that increase in both LDL and HDL cholesterol. EPA and DHA
n-6 and n-3 fatty acids share metabolic pathways and can also increase LDL particle size, rendering LDL less athero-
potentially compete with each other, causing n-6 to interfere genic. They also exert an effect on blood pressure, aldoste-
with potential cardiovascular benefits of the n-3. Studies have rone secretion, generation of nitric oxide by the endothelium,
found that the combination of both types of fatty acids is vascular reactivity, and cardiac hemodynamics. EPA and
associated with the lowest levels of inflammation and lowest DHA also reduce inflammation.
risk for metabolic diseases [60]. Evidence from prospective and case-control studies indi-
cate that consumption of EPA and DHA reduces the risk of
41.2.8.4  Effects of n-3 PUFAs CVD outcomes. Three key mechanisms have been suggested
The essential n-3 PUFA α-linolenic acid is synthesized in to contribute to the therapeutic effect of EPA + DHA: first,
plants. Flaxseeds and flaxseed oil, walnuts, and chia seeds are altered cardiac electrophysiology, seen as lower heart rate,
rich sources of α-linolenic acid. Soybean oil and rapeseed oil fewer arrhythmia, and increased heart rate; second, an anti-
contain about 7–10% α-linolenic acid. There is a metabolic thrombotic action resulting from the altered pattern of pro-
pathway by which α-linolenic acid can be converted to eicos- duction of eicosanoid mediators that control platelet
apentaenoic acid (EPA) and then on to docosapentaenoic aggregation; and lastly, due to the anti-inflammatory effect of
acid (DPA) and docosahexaenoic acid (DHA). However, the EPA and DHA, which serve to stabilize atherosclerotic
conversion of α-linolenic acid to DHA is poor. There is direct plaques, preventing their rupture. EPA and DHA may directly
competition for metabolism of n-6 and n-3 PUFAs as this influence cancer cells and the tumor environment by inhibit-
pathway shares the same enzymes as the metabolism of lin- ing or slowing tumor initiation, invasion, and cell prolifera-
oleic acid. A typical dietary ratio of linoleic to α-linolenic tion and by promoting tumor cell apoptosis [54].
 730 A. Batavia

Most human studies of the functional effects of EPA and and is the primary means for dissipating excess body heat.
DHA have used supplemental forms with differing ratios and When a person is dehydrated, the structure of critical cellular
dosages, where the fatty acids have been provided without any biomolecules is adversely affected, reducing their function.
dietary change and without removal of other fatty acids from All systems are influenced by dehydration, resulting in
the diet [54]. While this has undoubtedly contributed to con- reduced energy production, neurotoxicity, alteration in the
fusion among medical professionals, the current scientific lit- function of concentration of substances within cells, pH
erature provides a strong evidence that n-3 fatty acids reduce changes, and altered enzyme function. Muscle cramping,
the risk of metabolic diseases, including cardiovascular risks muscle soreness, constipation, fatigue, and sensitivity to toxic
and brain health [61]. This has encouraged national and inter- substances all increase during states of dehydration, while
national guidelines to collectively recommend that healthy mental clarity is reduced. In these cases, water becomes the
adults consume at least 250 mg per day of long-chain omega-3 limiting nutrient for support of functional physiology [65].
fatty acids to maintain cardiovascular health, with many orga- In a functional medicine assessment, the adequacy of
nizations recommending higher amounts for those at greater water to maintain functional organ reserve should be a first-­
risk of CVD and other inflammatory conditions [62, 63]. stage priority. Body composition measurements using bio-
impedance analysis can provide information about both
41.2.8.5  Role of Trans Fats intra- and intercellular water status. Three simple indicators
Industrially produced trans fats resulting from the hydroge- of hydration status include thirst, body weight, and urine
nation of vegetable oils are generally found in snack foods osmolality. Thirst typically lags behind an acute change in
and baked goods, such as cakes, muffins, and pies. These are hydration, developing after humans incur a 1% to 2% acute
identified as partially or fully hydrogenated vegetable oils on reduction in body mass. It is observed that endurance and
the label. A 2% increase in trans fat consumption is associ- cognitive performance decline at slightly less than 2% acute
ated with a 23% increase in the incidence of cardiovascular loss of body mass. The signal to initiate drinking behavior
disease. The presence of a trans double bond causes the phys- does not appear to be synchronized to prevent deterioration
ical properties of the fatty acid to be more like a saturated of function, and therefore thirst is commonly viewed as a
fatty acid than an unsaturated one. Therefore, incorporation less-than-ideal method of tracking hydration. Therefore,
of trans fatty acids into cell membranes causes the mem- thirst should be used in combination with acute change in
branes to become less fluid, which then influences membrane body weight and urine color to develop fluid intake strate-
protein function and interactions, in turn affecting cell-­ gies. Body weight and acute change in body weight following
signaling processes. The trans fats adversely affect LDL par- exercise and/or heat exposure are a relatively accurate and
ticle number and inflammation markers such as CRP and reliable measures of hydration status. Specific gravity or
IL-6. Because of these biological effects, trans fatty acids as a urine osmolality is also a predictor of hydration status, and
class appear likely to confer greater health risk than other elevations in osmolality or specific gravity of a urine sample
fatty acid classes. The current dietary guidelines recommend suggest the onset of dehydration. For specific gravity, a value
that trans fats should be limited to less than 1% of energy or of greater than 1.020 (equivalent to an osmolality of approxi-
as low as possible [54, 64]. mately 900 mOsm/kg) categorizes an individual as dehy-
The functional medicine use of fatty acids, especially drated, and a value of 1.035 is considered frank dehydration.
essential fatty acids, in nutrition intervention is an important Hydration has shown to impact various aspects of human
therapeutic tool. Understanding the pathophysiology health. Poor hydration status may be associated with com-
involved in inflammation and metabolic dysfunction allows promised oral health, such as dental caries and erosion of
41 the nutrition professional to manage patients in a vigilant dental enamel. Adequate fluid consumption has a positive
and systematic manner. effect on intestinal and hormonal health. Consumption of
water has shown to increase stool weight and volume along
with decreasing bowel transit time in some individuals. It has
41.2.9  Adequate Water Intake also been associated inversely with certain types of cancers.
This is because water consumption results in accelerated
Hydration is integral to health, and water trails only air transit of potential carcinogens through the intestinal tract
among the most important substances in maintaining hemo- and decreased time for exposure and dilution of carcinogens
dynamics and functional reserve. The human body survives in the water phase (phase 2 detoxification  – sulfation and
for only a few days without meeting essential water require- glucuronidation) of the stool. It may also be because of
ments but could sustain itself for several weeks without greater intestinal excretion of hormones such as estrogen
ingesting macronutrients or micronutrients. Water is that are associated with cancer, because weak evidence of a
involved in critical anatomical and physiological functions, relationship was seen between bowel motility and breast can-
such as in providing mass and structure to the cells, function- cer. Enhanced hydration also leads to a reduced sympathova-
ing as the medium and reagent for metabolic reactions. gal ratio, decreases the sympathetic nervous system drive to
Intercellular water binds to proteins, carbohydrates, and retain fluids, and increases the parasympathetic activation to
nucleic acids to maintain their proper function, lubricates excrete fluids, all of which could, in a state of dehydration,
adjoining tissues, transports substrate and metabolic waste, facilitate responses leading to hypertension. In individuals
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
731 41
who are susceptible to nephrolithiasis, increased water inges- programs to ensure drinking water safety. Even with the law
tion reduces the risk of subsequent kidney stones, specifically in place, more action needs to be taken with regard to the
calcium nephrolithiasis with stones composed primarily of water quality. The EPA in January of 2017 initiated a peer
calcium oxalate. The mechanism is thought to be a result of review of draft scientific modeling approaches to inform the
the dilution in concentration of materials that would precipi- agency’s evaluation of potential health-based benchmarks for
tate stones on saturation. Continuous ingestion of water lead in drinking water [72].
stimulates urine production and contributes to the dilution Pure water on this planet has become a diminished
and excretion [66]. resource. All of these problems have significant health impli-
The WHO has declared that “all people, whatever their cations, ranging from neurological damage to respiratory
stage of development and their social and economic condi- problems to gastrointestinal ailments. Access to safe water
tions, have the right to have access to an adequate supply of for drinking, bathing, and normal household use is a very
safe drinking water.” Although presence of a public water dis- important part of a healthy life – one of which we are most
tribution network is often an indicator of a suitable water sup- aware when it no longer exists.
ply, it should not be expected that the piped water quality is One of the smarter options is to recommend patients fil-
always adequate for human consumption [67]. Like the fish we ter their own water and carry it with them in a stainless steel
eat – which are now significant sources of toxins such as mer- bottle. There are many filtering options. A few options would
cury, cocaine, and antidepressants  – our water can contain be to use simple carbon filters or a reverse-osmosis filter sys-
everything from pesticides to substances we add to water as a tem, which puts the water through a multistep process to
function of general public use (chlorine, fluoride, lead, and remove the toxins. There is an initial installation cost, but it is
iron leaking from lead pipes, softening agents), to residues cheaper over the long run. Filtering bathing and washing
from farming practices, to bacterial or parasitic agents result- water is also recommended. A practitioner may recommend
ing from contamination or overuse. People are also exposed to a whole-house water filter with an additional drinking water
disinfected drinking, shower, or bathing water containing at filter as the best option.
least 600 identified disinfectant by-products [68].
Citizens of a small town in Colombia had a significant
prevalence of autoimmune thyroiditis, which was traced Hydration Tips
back to the contamination of drinking water with phenolic 55 On a sedentary day, try to drink around 2 liters of
chemicals. Those chemicals adversely influenced the immune water.
system, resulting in production of anti-thyroid antibodies. 55 Start by drinking a glass of fresh water when you
When the water supply was purified, the prevalence of auto- get up in the morning.
immune thyroiditis was significantly reduced in the commu- 55 If you are not used to drinking water regularly, try
nity [69, 70]. initially replacing just one of your other drinks a
In April 2014, the city of Flint, Michigan, switched to the day with fresh water, increasing your consump-
Flint River as a temporary drinking water source – without tion as the weeks go by.
implementing corrosion control  – discontinuing the pur- 55 Drink a glass of water before and during each meal.
chase of treated water from the Detroit Water and Sewer 55 Hot water with fresh mint, lemon balm, or a piece
Department (DWSD). Ten months later, water samples col- of fruit in it – like lime, lemon, and orange – often
lected from a Flint residence revealed progressively rising helps those who want a hot drink.
water lead levels – 104, 397, and 707 μg/L – coinciding with 55 Carry a bottle filled with water with you whenever
increasing water discoloration. An intensive follow-up moni- you leave the house.
toring event at this home investigated patterns of lead release 55 During exercise, drink at 10- to 15-minute
by flow rate. All water samples contained lead above 15 μg/L, intervals, or think of it as a full glass every 30
and several exceeded hazardous waste levels (>5000 μg/L). minutes. Drink slowly and drink early, as it’s
After analysis of blood lead data revealed spiking lead in the physically easier to do this when you are still
blood of Flint children in September 2015, a state of emer- feeling fresh.
gency was declared, and public health interventions (distri- 55 Keep a check on your urine. As a general guide to
bution of filters and bottled water) likely averted an even hydration, it should be plentiful, pale in color, and
worse exposure event due to rising water lead levels. This odorless.
incidence will have long-term health consequences in infants
as well as in adults, including developmental delays, learning
difficulties, mood disorders, miscarriages, joint pains, hyper-
tension, and cognitive decline in adults [71]. 41.2.10  Inclusion of Prebiotic
The Safe Drinking Water Act (SDWA) is the federal law and Probiotic Foods
that protects public drinking water supplies throughout the
nation. Under the SDWA, the Environmental Protection Nutrition plays a key role in the modulation of gut microbi-
Agency (EPA) sets standards for drinking water quality and, ota composition, and, in turn, the gut microbiota plays a
with its partners, implements various technical and financial critical role within the body. The gut microbiota is mainly
 732 A. Batavia

involved in the development and growth of immunity; the with high consumption of carbohydrates and simple sugars,
promotion of barrier integrity; the prevention of antigens indicating a correlation with a carbohydrate-based diet more
and pathogens from entering the mucosal tissues; the regula- typical of agrarian societies and vegetarians [74].
tion of several fundamental metabolic pathways such as syn-
thesizing vitamin K; the promotion of angiogenesis and 41.2.10.1  Probiotics
enteric nerve function; and reductive reactions such as meth- Probiotics are live microorganisms that, when administered
anogenesis, acetogenesis, nitrate reduction, and sulfate in adequate amounts, confer a health benefit on the host [75].
reduction, to name a few. There exists a long history of human consumption of probi-
Dysbiosis, on the other hand (quantitative and/or quali- otics (particularly lactic acid bacteria and bifidobacteria) and
tative alterations of gut microbiota), impairs homeostasis in prebiotics, either as natural components of food or as fer-
the immune system as well as metabolic pathways, leading mented foods.
to the development of several gut microbiota-related dis- The colonic microbiota is able to metabolize complex car-
eases. These include functional gastrointestinal diseases, bohydrates and oligosaccharides into short-chain fatty acids
inflammatory bowel disease, gastrointestinal malignancies, (SCFAs) such as butyrate, acetate, and propionate. These
allergic diseases, intestinal infectious diseases, liver diseases, metabolites play a role in regulating intestinal pH.  A small
obesity and metabolic syndrome, diabetes mellitus, autism, variation of acid concentrations may exert important conse-
and others. quences. A one-unit decrease in pH from 6.5 to 5.5 has been
The four major microbial phyla that represent over 90% shown to have a profound selective effect on the colonic
of the bacterial component of the gut microbiota are microbial population, with a prevalent decrease of Bacteroides
Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria. spp. and a growth of butyrate-producing gram-positive bac-
The majority of “good” bacteria harboring the human gut teria. The decrease of pH caused by high concentration of
microbiota are represented by Firmicutes and Bacteroides. SCFAs prevents the growth of potentially pathogenic bacte-
Firmicutes are subgrouped in Clostridium, whereas ria, such as E. coli and other members of the Enterobacteriaceae
Bacteroides phyla are subgrouped with a great number of family.
Prevotella and Porphyromonas. The human gut microbiota The most common sources of probiotics are yogurt, but-
also includes viruses, especially phages, Eukarya as fungi, termilk, cheese, and kefir. Traditionally, yogurt has only one
Blastocystis, Amoebozoa, and Archaea. Lactic acid bacteria or two bacteria, whereas kefir tends to have several probiotic
(LAB) and bifidobacteria (Actinobacteria) are two important bacteria. Other foods produced by bacterial fermentation are
types of gut bacteria, which are present from birth or acquired Japanese miso, natto, tempeh, sauerkraut, sourdough, kim-
from digested food. Lactobacillus and Leuconostoc spp. are chi, kombucha, olives, and pickled vegetables.
the main lactic acid bacteria found in the human intestine.
Bifidobacterium spp. are the predominant bacteria found 41.2.10.2  Prebiotics
among the first colonizers of newborns and persist at a low Different types of dietary fibers, complex carbohydrates
level in adults. Infants fed with breast milk had higher levels (digestible and nondigestible) and oligosaccharides, act as
of Bifidobacteria spp., while infants fed with formula had prebiotics and exert a different influence on the composition
higher levels of Bacteroides spp., Clostridium coccoides, and of the gut microbiota and, consequently, on its fermentative
Lactobacillus spp. [73]. metabolism. Prebiotics are nondigestible food ingredients
Diet has been known to have a strong influence on the that beneficially affect the host by selectively stimulating the
composition of intestinal microbiota, and to confirm this growth and/or activity of one or a limited number of bacteria
41 hypothesis, researchers sequenced oral microbiota from skel- in the colon that can improve the host health. Prebiotics can-
eton teeth of people who lived over the various eras. The not be digested by pathogenic bacteria. They stimulate the
most significant changes in human gut microbiota occurred growth of probiotic bacteria and allow them to grow pre-
during two socio-dietary breakthroughs over the human his- dominantly. Prebiotics are usually polysaccharides or oligo-
tory: the first one around 10,000 years ago, during the pas- saccharides. They are naturally found in such fruits and
sage from the hunter-gatherer Paleolithic era to the farming vegetables as asparagus, bananas, dandelion greens, eggplant,
Neolithic era, with a diet rich in carbohydrates, and the sec- endives, garlic, honey, Jerusalem artichokes, jicama, leeks,
ond one at the beginning of the industrialized period approx- legumes, onions, radishes, tomatoes, and whole grains. The
imately two centuries ago, characterized by a processed flour commonly known prebiotics are inulin, fructo-­
and sugar diet. Studies show that there are differences oligosaccharides (FOS), galacto-oligosaccharides (GOS),
between the intestinal microbiota of subjects fed with a stan- soya-oligosaccharides, xylooligosaccharides, pyrodextrins,
dard American diet and that of subjects with a diet rich in isomalto-oligosaccharides, and lactulose [76].
fibers. Literature shows an increased prevalence of Bacteroides The Western diet is considered to cause intestinal dysbio-
and Actinobacteria is positively associated with animal pro- sis and trigger local inflammation, leading to an increase of
tein and a high-fat diet (more prevalent in Western coun- intestinal permeability. Studies show that a high-fat diet
tries), but is negatively associated with fiber intake, whereas induces the proliferation of certain gram-negative bacteria
Firmicutes and Proteobacteria show the opposite association. which can ultimately result in increased intestinal lipopoly-
In contrast, the Prevotella-prevailing enterotype is associated saccharide (LPS) and increased gut permeability. Increased
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
733 41
gut permeability is associated with a decrease in Bifidobacteria the problem – for example, weight gain or high blood glu-
spp., bacteria that are known to reduce LPS levels and also cose due to increased energy intake.
improve gut barrier function. Interestingly, prebiotic treat- During the planning phase of intervention, the nutrition
ment with nondigestible carbohydrates increases bifidobac- practitioner uses evidence-based guidelines along with
teria and reduces intestinal permeability, LPS concentrations, institutional policies and procedures to reach medical nutri-
and metabolic endotoxemia [74]. tion therapy goals, desired behavior changes, and/or
The healthful effects of probiotics and prebiotics factor in expected outcomes. The nutrition prescription identifies the
their potential impact on the balance of the body’s microflora specific nutritional interventional strategies and establishes
and directly or indirectly in their enhancement of the func- the patient-focused goals to be accomplished. The goals
tion of the gut and systemic immune system. Tailoring the should be measurable, achievable, and time-defined. The
diet to include probiotic foods that the patient enjoys can functional medicine nutrition professional must make sure
have a significant positive impact in improving the patient’s that they are jointly set with the patient, keeping in mind not
nutritional intake [77]. just the clinical indicators and biomarkers but also the
socioeconomic, cultural, spiritual, and emotional aspects of
healing.
41.2.10.3   ranslating Expertise into
T Implementation of nutrition intervention should also be
Intervention accompanied by data collection initiated during nutrition
Diet has an enormous impact on many aspects of our health, assessment, and practitioners should revise the intervention
even beyond providing energy and essential nutrients. The based on the patient’s response. In most cases, the initial
circulating substrates derived from food have both direct and nutrition intervention consists of nutrition education, where
indirect actions to activate receptors and signaling pathways, the nutritional practitioner imparts knowledge and shares
in addition to providing fuel and essential micronutrients. skills to help the patient manage and modify food choices
Ultimately one can consider food as a cocktail of “hormones.” and eating behaviors. Nutritional counseling, a supportive
A hormone is a regulatory compound produced in one organ process, organically follows, either during the first visit or
that is transported in blood to either inhibit or stimulate spe- during follow-ups. This is a collaborative relationship to set
cific cells in another part of the body. They exert their effects priorities, evaluate goals, and fine-tune a nutrition plan to
on target tissues by acting on cellular receptors to alter activ- foster self-care and treat or manage an existing condition and
ity through intracellular signaling cascades or via nuclear promote health.
receptors to regulate gene transcription. Although food is not It is important to note that initiating multiple changes
produced in the body, its components travel through the during one single visit may overwhelm indiviudals seeking
blood, and nutrient substrates can act as signaling molecules help. Some patients are able to make many changes at a time,
by activating cell-surface or nuclear receptors [78]. If the but most patients with long-term chronic issues need time.
body does not receive appropriate materials or if there is They might need to make just a few changes at a time. The
inappropriate signaling due to nutritional deficiencies – for key to successful nutrition intervention in the nutrition care
example, B12 and homocysteine or excessive amounts of process is helping patients understand the rationale behind
omega-6 foods  – metabolic processes suffer and health prescribing an individualized food plan; keeping health goals
decline. and objectives at the forefront; and fostering self-efficacy by
As nutritional practitioners, we hold a valuable position sharing recipes, menu-planning, and providing resources
in helping patients through one of the most critical modify- that will enable them to translate the nutrition consultation
ing lifestyle factors, and that is food and nutrition. Planning into practical application and behavioral change. This helps
and implementation are two components of nutrition inter- with compliance, builds trust, and fosters a healthy practitio-
vention. The practitioner has to prioritize nutritional diag- ner-patient relationship.
nosis, based on the severity of the problem, safety, patient/
client need, the likelihood that the nutrition intervention
will impact the problem, and the patient’s perception of Recipe: Carrot Beet Probiotic Beverage
importance. The nutrition intervention is directed when- (Carrot-Beet Kanji)
ever possible at the etiology or the cause of the problem 55 Ingredients:
identified. If it is not possible to direct the nutrition inter- ȤȤ Water – 8 cups
vention, the nutrition intervention is aimed at reducing the ȤȤ Carrots (orange or purple) – 2 medium, peeled
impact of the signs and symptoms of the problem. For and julienned
example, if the etiology is related to food allergies or sensi- ȤȤ Beet – 1, peeled and julienned
tivities, nutrition intervention is based on the elimination of ȤȤ Green chilies – to taste, slit on one side
trigger or offending foods. If excessive energy intake is (1 small, optional)
caused by depression and initiation of a psychiatric pre- ȤȤ Powdered mustard seeds – 1 1/2 tbsp
scription (changing or withholding prescription drugs is out ȤȤ Salt – 1 1/2 tsp (or to taste)
of RDNs’ scope of practice), the nutrition intervention is ȤȤ Red chili powder (optional) – 1 tsp
aimed at reducing the impact of the signs and symptoms of
 734 A. Batavia

supplements to help ensure their identity, purity, strength,

55 Method and composition. These GMPs are designed to prevent the
1. In a clean pitcher or bottle with a lid, preferably inclusion of the wrong ingredient, the addition of too much
glass or ceramic, add all of the ingredients and or too little of an ingredient, the possibility of contamination,
mix well. Do not use plastic bottles or pitchers. and the improper packaging and labeling of a product. The
2. Cover and keep the pitcher in the sun for 3–4 days, FDA periodically inspects facilities that manufacture dietary
stirring at least once daily with a clean spoon. supplements.
3. Once fermented, taste the kanji. When it’s ready, it In addition, several independent organizations such as
has a tangy and fermented taste. Taste it daily just to US Pharmacopeia and NSF International offer quality testing
understand the change in flavor, its food chemistry in for dietary supplement manufacturers and allow products
action! Store the kanji in the refrigerator. that pass these tests to display their seals of approval. These
4. Serve chilled. Mix before serving. Carrots, beets, seals of approval provide assurance that the product was
and green chilies can be eaten. properly manufactured, contains the ingredients listed on the
label, and does not contain harmful levels of contaminants.
In North India, deep purple-colored carrot is These seals of approval do not guarantee that a product is safe
fermented along with crushed mustard seed, hot or effective. NSF International also offers an NSF Certified
chili powder, and salt for a few days to get a popular for Sport Program so that athletes can be sure that their
drink called kanji, which is considered to have high dietary supplements do not contain banned substances.
nutritional value and cooling and soothing proper- Several companies provide unsolicited post-market sur-
ties. According to the Indian Journal of Microbiology, veillance of dietary supplements to ensure quality and integ-
lactic acid bacteria (LAB) play an important role in rity in the supplement industry. Consumer Labs and the
the fermentation of vegetables, improving nutritive nonprofit Center for Science in the Public Interest are two
value, palatability, acceptability, microbial quality, such prominent entities.
and shelf life. Under the Dietary Supplement Health and Education Act
of 1994 (DSHEA), supplement manufacturers are solely
responsible for ensuring that their products are safe. There is
no approval of claims, no product registration, and no for-
41.2.10.4  Dietary Supplements mula standards. The FDA does pre-market review of new
The majority of adults in the United States take one or more dietary ingredients (NDI). The term “new dietary ingredient”
dietary supplements either every day or occasionally (ODS. NIH). means a dietary ingredient that was not marketed in the
According to the Academy of Nutrition and Dietetics position United States in a dietary supplement before October 15,
paper on nutrition supplementation, “dietetics practitioners 1994. There is no authoritative list of dietary ingredients that
should position themselves as the first source of information on were marketed in dietary supplements before October 15,
nutrient supplementation.” In order to accomplish this, the reg- 1994. Even if the NDI is reviewed by the FDA, there is no
istered dietitian/clinical nutritionist must keep up to date on the guarantee of safety. If a dietary supplement causes harm, it is
issues associated with regulation, safety, and efficacy, along with up to the FDA to prove the supplement is unsafe and remove
identifying supplements available in the market. it from the market. Under the current legislation, it is a
According to the Food and Drug Administration (FDA), a daunting task for the government to regulate the dietary
dietary supplement is a product intended for ingestion that supplement industry.
41 contains a “dietary ingredient” intended to add further nutri- Very few supplements have been banned by the FDA in
tional value to (supplement) the diet. A “dietary ingredient” recent times. Ephedra sinica, aristolochic acid, and dimethyl-
may be one, or any combination, of the following substances: amylamine (DMAA) are on the list of banned supplements.
55 A vitamin Herbal products may pose a significant risk in some cases as
55 A mineral they have multiple chemical constituents that have not been
55 An herb or other botanical adequately characterized. Hypericum perforatum, also called
55 An amino acid St. John’s wort, is one of the most problematic herbs as far as
55 A dietary substance for use by people to supplement the pharmacokinetics and safety go, along with Schisandra chi-
diet by increasing the total dietary intake nensis and black pepper. It is important that a nutritional
55 A concentrate, metabolite, constituent, or extract professional recommending herbal products therapeutically
seek additional herbal training.
Dietary supplements may be found in such forms as tablets,
capsules, softgels, gelcaps, liquids, or powders. Some dietary 41.2.10.5  Rationale for Recommending
supplements can help ensure that you get an adequate dietary Supplements
intake of essential nutrients; others may help you reduce your Before recommending supplements, the functional medi-
risk of disease. cine/nutrition practitioner must determine the clinical indi-
Dietary supplements are complex products. The FDA has cators for the use. Some of the factors that can help in the
established good manufacturing practices (GMPs) for dietary decision making are:
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
735 41
55 Filling nutritional gaps: Does the patient have nutritional Some of the responsibilities of the practitioner initiating
deficiencies evident from dietary analysis, signs and the use of dietary supplements are as follows: to assess nutri-
symptoms, or laboratory evaluations? tional status of the patient to determine the likelihood of
55 Increased nutritional needs: Does the patient have an inadequate or excessive intake of minerals and vitamins; to
increased need for nutrients as a result of inborn errors evaluate for the potential benefit or harm of nutrient supple-
of metabolism, absorption or transport defects, abnor- mentation; to evaluate safety with regard to dosage and
mal enzyme production, or excessive renal losses? The potential drug-nutrient interaction; to educate patients about
patient may have elevated needs of additional nutrients the potential benefits and rationale behind using dietary
or enzymes secondary to acute or chronic illness, such as supplements; to be informed of the research on the supple-
burns, traumatic brain injury, hypochlorhydria, small ments suggested; and to be aware of the regulatory, legal, and
intestinal bacterial overgrowth, IBD, and pancreatic ethical issues of recommending and selling supplements.
enzyme deficiency. Whenever possible, it is advisable to validate the need for
55 Maintenance: Does the patient need supplements to supplementation with laboratory testing and therefore col-
maintain balance of nutrients? For instance, patients laboration of care. Referrals, and building a community of
who are on calcium supplements for bone health often healthcare providers, become important in a functional
require magnesium to maintain an appropriate calcium- medicine practice. Specific nutrient levels can be obtained
to-­magnesium ratio. through standard labs and specialty functional medicine
55 Drug-nutrient interactions: Is the patient on prescription testing such as organic acid tests, stool analysis, fatty acid
drugs such as statins, antacids, or corticosteroids? If so, profiles, hormone metabolites, and nutrigenomic testing.
they might benefit from supplementation of CoQ10, The functional nutrition practitioner should be aware of
B12, and calcium, respectively. potential adverse effects of dietary supplements and should
55 Genetic factors: Does the patient have single-nucleotide monitor patients appropriately. While the use of dietary sup-
polymorphisms and therefore increased needs of certain plements usually has an excellent safety profile, side effects
nutrients? For example, MTHFR hyperhomocysteinemia can occur, and high doses of certain nutrients such as B3, B6,
might require adequate folate and B12 intervention. B12, zinc, and vitamin D can have serious toxic effects.
55 The recommended daily allowances (RDAs) and Sensitive individuals may have allergic reactions not only
adequate intakes establish nutrient intake levels for from the excipients, additives, colorings, and flavorings
healthy individuals and may not address the specific added but also from food-based ingredients and products
needs of every individual. Individuals who are very containing herbs. Patients with advanced renal or hepatic
active or participate in sports, or who have chronic insufficiency may develop toxicity from some nutrients. In
inflammatory conditions, may benefit from dietary such patients, supplements may be contraindicated, and they
supplementation. There might be a need for supplemen- should be used only under the direction of practitioners who
tation even in women of childbearing age, pregnant are proficient in management of serious cases.
women, and older adults to meet optimal nutrient needs. The functional nutrition practitioner must update his/her
knowledge on dietary supplements on a regular basis.

41.2.10.6  Roles and Responsibilities

It is important to use an evidence-based approach when rec- Supplement Education Resources
ommending supplements and screen for drug-nutrient inter- 55 Websites:
actions and over-supplementation to ensure safety. ȤȤ Office of Dietary Supplements: 7 https://
 

It is the responsibility of the nutrition practitioner to ods.­od.­nih.­gov/

make sure any products dispensed from the office are high-­ ȤȤ National Center for Complementary and
quality products and that the manufacturers comply with Integrative Health: 7 https://nccih.­nih.­gov/
 

Good Manufacturing Practices to ensure safety and efficacy. ȤȤ Linus Pauling Institute Micronutrient
Look for quality ingredients such as chelated minerals that Information Center: 7 http://lpi.­oregonstate.­
 

can be more easily absorbed than mineral salts; active B vita- edu/mic
mins, especially for patients with single nucleotide polymor- ȤȤ 7 Drugs.­com Drug Interactions Checker:
 

phisms, for example, pyridoxal 5-phosphate instead of 7 https://www.­drugs.­com/drug_interactions.­

 

pyridoxine hydrochloride; and D-alpha tocopherol with html

mixed tocopherols versus the synthetic counterpart DL-­ ȤȤ Medscape Drug Interaction Checker: 7 http:// 

alpha tocopherol. Just as the functional medicine nutrition reference.­medscape.­com/drug-interaction-

practitioner encourages patients to choose clean eating and checker
minimally processed foods, the practitioner should also rec- ȤȤ Natural Medicines Comprehensive Database:
ommend dietary supplements with minimal processing and 7 https://naturalmedicines.­
 

excipients: binders, flavorings, colorings, high-fructose corn therapeuticresearch.­com/

syrup, and so on. For patients with food allergies or sensitivi- ȤȤ Consumer Lab: 7 https://www.­consumerlab.­com/
 

ties, ensuring allergenic-free supplements is critical.

 736 A. Batavia

consoles throughout the day, many individuals use such

55 Books: devices at night. This results in circadian phase delay and is
ȤȤ Mosby’s Handbook of Herbs and Natural associated with a lack of sleep and is thought to underlie
Supplements, 4th edition by Linda Skidmore- clock desynchronization disorders. This amounts to a type of
Roth, RN, MSN, NP chronic jet lag, also referred to as social jet lag – that is, a mis-
ȤȤ The Health Professional’s Guide to Dietary alignment between the clock and social time – and can jeop-
Supplements by Shawn M. Talbot and Kerry ardize health. Desynchronization manifests through atypical
Hughes clinical symptoms, such as persistent fatigue, sleep disorders
ȤȤ The Health Professional’s Guide to Popular leading to chronic insomnia, poor appetite, and mood disor-
Dietary Supplements, 3rd edition, by Allison ders that can cause depression, though some desynchronized
Sarubin Fragakis, MS, RD with Cynthia people do not experience any of these clinical signs.
A. Thomson, PhD, RD Chronic sleep deprivation results in drowsiness, decreased
ȤȤ Nutritional Medicine by Alan Gaby levels of attention and alertness that underlie a doubling in
the risk of traffic accidents, cardiovascular risk (elevated
blood pressure and lipids), GERD, dysregulation in glucose
41.2.11  Lifestyle metabolism, insulin resistance (diabetes and obesity), macu-
lar degeneration, and cognitive and mental health disorders.
Lifestyle is way of living. It is a set of habits and attitudes – Educating and creating awareness in patients about the
physical, mental, social, and spiritual – that together consti- importance of sleep and encouraging them to have good
tute a mode of living for an individual or group. sleep hygiene may help bring metabolic and physical changes
At the base of the functional medicine matrix are modifi- and improve health and well-being along wih preventing
able personalized lifestyle factors such as sleep and relax- societal harm [79, 80].
ation, exercise and movement, nutrition and hydration, stress
and resilience, and, last but not least, relationships and net-
Strategies for Restful Sleep
works. Earlier in this chapter, we reviewed the nutrition and
55 Avoid exposure to light up to 30 min prior to
hydration aspects. This section will be an overview of the
going to sleep.
other lifestyle factors.
55 Opt for a morning shift that starts before 7 a.m.
41.2.11.1  Sleep 55 Keep the same sleep timing most days.
55 Avoid stimulants such as alcoholic, caffeinated, or
Circadian rhythms are endogenous rhythms with a periodic-
sugary beverages.
ity of approximately 24 hours, plus or minus 4 hours. These
55 Complete aerobic exercise 3 hours before
rhythms are dependent on an internal clock located in the
bedtime.
suprachiasmatic nucleus (SCN) of the anterior hypothala-
55 Avoid reading stimulating materials at night.
mus. Each of the paired suprachiasmatic nuclei is composed
55 Avoid arguments and difficult conversations
of a group of about 10,000 interconnected neurons that give
before bedtime.
rise to circadian rhythms through specific neuronal gene
55 Avoid large meals before bedtime.
expression patterns and by the rate at which they fire action
55 Take hot Epsom salt aromatherapy baths.
potentials. In addition to the SCN, peripheral clocks have
55 Sleep in a dark room.
been identified in numerous tissues such as the liver, kidney,
41 heart, skin, and retina, and these are capable of acting in an
55 Use HEPA or air purifiers/filters to clean air in your
bedroom.
autonomous manner. The SCN subsequently synchronizes
55 Use humidifiers if needed.
peripheral clocks with each other and thus aligns the entire
55 Avoid shift work or night work when pregnant.
circadian system to the external light-dark cycle.
The circadian system in human beings is a complex entity
that starts in the eye and terminates in the pineal gland,
which produces melatonin and is essential for functioning of 41.2.11.2  Exercise and Movement
the clock. In humans, melatonin is secreted during the dark Exercise and movement may alter and therapeutically impact
phase of the light-dark cycle. Daytime melatonin levels are mental (improve memory, increase hippocampal size, and
very low. Light is considered to be the most potent circadian increase BDNF), emotional (increase mood, decrease depres-
synchronizer for humans, although non-photic time cues – sion, mood, and anxiety), and spiritual aspects (experience
such as meal times, physical activity, and social interaction – sense of purpose; enhance social network, peer support, and
also play a part in synchronization of the circadian system. sense of community; nature-based exercises aka “dose of
Even low-intensity light, as emitted by recent technolo- nature”) in an individual  – the very core of the functional
gies such as LEDs, computer screens or televisions, mobile medicine matrix [81–83].
phones, and tablets, is capable of acting on the clock, thus Exercise and movement also have a therapeutic impact
leading to a phase delay and a slowing of melatonin secretion. on each of the clinical imbalances in the function medicine
In addition to being exposed to light from a range of LED matrix.
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
737 41
zz Assimilation: Many individuals may feel daunted by the thought of
55 Exercise initiated early in life increases gut bacteria changing their lives and starting new, more active routine. A
species which promotes psychological and metabolic functional medicine practitioner/nutritionist can help pro-
health. vide motivation and support during this transition by help-
55 Exercise improves the Bacteroidetes-Firmicutes ratio ing patients to remember a few key tips:
and stimulates proliferation of bacteria which can 1. Emphasize fun: Focus on what the patient enjoys and
modulate mucosal immunity and improve barrier loves to do rather than exercise being a punishment.
function. 2. Attach activity to habits: Taking a walk after dinner is a
55 Exercise may also stimulate bacteria capable of time-honored way to get moving. Any routine behavior
producing substances such as SCFAs that protect can have a small activity bonus built in.
against gastrointestinal disorders and colon cancer 3. Involve others: Chances are that the patient’s friends,
along with providing psychological health family, and co-workers want to be more active too. It
­benefits [84]. then becomes a community and peer-shared experience.
Swap sitting at a coffee shop for walks; swap dinners for
zz Structural integrity: bowling or after-dinner walks.
55 Increases muscle mass 4. Be inventive: Challenge your patient with more active
55 Helps in the reduction of body fat living. Suggest ideas such as an extra lap around the
55 Increases peak oxygen intake grocery store perimeter, standing while watching
55 Decreases blood viscosity and fibrinogen television, getting off a bus earlier, using a standing desk
at work, and stretching one part of the body when your
zz Communication: patient texts someone.
55 Increases insulin sensitivity, AMPK, adiponectin, 5. Be forgiving: If the patient had one sedentary day,
NO, semen quality, and vagal tone [85, 86] suggest them to not overwork the next day or punish
55 Reduces HbA1c, adrenergic activity, and estradiol themselves.
[85, 87] 6. Track progress: Consider suggesting a pedometer app/
device and having fun with it.
zz Transport:
55 Increases maximal oxygen consumption, heart rate It is very important for functional medicine practitioners to
variability, flow-mediated dilatation, angiogenesis, walk the talk. Modeling healthy habits not only provides the
endothelial function, HDL, and aerobic threshold functional medicine practitioner the deep knowledge of what
55 Decreases resting heart rate, blood pressure, LDL, is required of the patient but also increases the likelihood
and triglycerides [88] that you will counsel patients successfully – may it be provid-
ing recipes, healthy eating, exercising, or creating a work-life
zz Biotransformation and elimination: balance. Improving one’s own health practices increases effi-
55 Improves bowel function cacy at lifestyle counseling. Practicing one’s own preventative
55 Increases skeletal muscle glucose uptake and healthy behaviors increases patient adherence to recom-
mendations.
zz Energy:
55 Increases mitochondrial biogenesis and ATP 41.2.11.3  Stress and Resilience
production Walter Cannon, professor and chairman of the Department
55 Decreases fatigue of Physiology at Harvard Medical School, wrote extensively
about stress, and his work during World War I helped to
zz Defense and repair: establish the groundwork for understanding the physiology
55 Improved immune system of mind-body interactions [90]. Later, Hans Seyle reintro-
55 Decreased inflammation duced the term and he is now considered the “father of
55 Increase natural killer cell activity stress.” Per Seyle, “stress is the nonspecific response of the
body to any demand, and a stressor is any agent that pro-
The intensity and duration of exercise also determine energy duces stress at any time.” Stressors can be loosely classified as
consumption. Exercise performed for the same duration at direct physical systemic threats, e.g., starvation, cold, pain,
different intensities results in more energy consumption dur- hemorrhage, or “progressive threats,” e.g., psychosocial
ing the higher-intensity segments. Exercise intensity also threats such as defeat, separation, helplessness, and social
affects the secretion of hormones associated with energy sub- isolation.
strate oxidation. Studies report that carbohydrates are the Allostasis is the ability to achieve homeostasis when a
main energy substrate in high-intensity exercise, compared stress is applied to the system. Homeostasis is achieved via
with lipids being utilized more in low-to-moderate intensity acute and chronic changes through the neuroendocrine axis
exercise. In recent times, high-intensity interval training (primarily the hypothalamic-pituitary-adrenal, or HPA,
(HIIT) has gained attention [89]. axis), the immune system, the autonomic nervous system,
 738 A. Batavia

and the cardiovascular system. The HPA axis responds to coid receptor and heightened stress responses. Early stressed
input by involving the immune, cardiovascular, and meta- offspring must learn to adapt to environmental challenges
bolic systems. Acute stress induces changes that are generally and maintain stability through change, a characteristic
thought to be adaptive and essential, whereas chronic stress referred to as “resilience.” In addition to epigenetic effects, a
is thought to induce a higher physiological price by creating number of genetic variants have been identified to cause
an allostatic load, defined as a long-term effect of physiologic altered response to stress and mood disorders. For example,
response to stress. polymorphisms in catechol-O-methyltransferase enzyme
While acute stress heightens cognition, these same have been implicated in mental illness with the presence of
responses when activated chronically are highly deleterious. certain SNPs resulting in susceptibility to posttraumatic
It may injure hippocampal cells via cortisol release in stress disorder.
response to CRF and ACTH. Such injury could lead to dys- In summary, a functional medicine practitioner/nutri-
function and atrophy of critically important memory and tionist needs to not only understand the nutrition interven-
emotional brain structure [91]. tion aspect but also have insight into psychosocial and
Chronic or cumulative stress, representative of lifetime genetic aspect of an individual in order to better help the
exposure to adversity, is also thought to exert its influence patient. Functional medicine can be integral throughout a
through a “chain of risk,” wherein early adverse life events patient’s life, from prevention to preclinical symptoms to dis-
increase the risk for later exposures. The cumulative stress, in ease manifestation and progression [95].
turn, impacts physical, behavioral, and mental outcomes
such as hypertension, pain, physical disability, psychiatric
disorders, drug and alcohol abuse, and other chronic illness. Relaxation Response
Such chronic stress may impact the autonomic nervous sys- Herbert Benson, MD, elucidated the physiological
tem (ANS) and can be noninvasively measured by methods underpinnings of the trophotropic center – a combina-
such as heart rate variability (HRV). Lower indices of HRV tion of the parasympathetic nervous system, somatic
and altered ANS function may contribute to cardiac mortal- muscle relaxation, and cortical beta rhythm synchroniza-
ity, decrease vagal tone, and increase cardiac workload and tion. First, he described what he called “the four states”:
endothelial dysfunction [92]. awake, sleep, dream, and the fourth state. The difference
Simply asking a patient “What are the main stressors in between the first three states and the fourth state is that
your life?” can be very useful. Together the functional medi- the first three happen spontaneously, while specific
cine practitioner and patient can generate a list of all the actions are required to enter into the fourth state or
stressors, so that they can be tracked and addressed. what Benson initially called “eliciting the relaxation
Like nutrition and exercise, there is a role for personaliza- response (RR).”
tion in one’s approach to stress, which can be encompassed in 55 Comfort: Sit easily in a chair or on the floor.
the diversity of modalities from which an individual can choose 55 Quiet: Be alone in a spot where you will not be
to modify their behavior to cope with it. This may include such disturbed, i.e., no texts, emails, cell phones, etc.,
mind-body practices as relaxation response developed by while eliciting the relaxation response.
Herbert Benson, mindfulness-based stress reduction (MBSR) 55 Tool: Focus on a word, thought, breathing, sound, or
from Jon Kabat-Zinn, vipassana meditation [93], yoga, Kirtan short prayer.
Kriya, squared breathing, and diaphragmatic breathing. 55 Attitude: When other thoughts enter your mind,
Studies in the area of mind-body medicine are now
41 becoming more molecular-focused. For instance,
refocus on your tool to the exclusion of everything
else for 10–20 minutes twice a day.
Balasubramanian et  al. compared salivary expression of 22
differentially expressed proteins in subjects after 20 minutes
of yogic breathing and those who chose to read a text of their
choice. The subjects who practiced the 20-minute yogic
breathing technique had increased salivary secretion which What Is Squared Breathing?
regulates digestive, nervous, immune, and respiratory sys- Squared breathing is just four simple breath segments
tems. The researchers also elucidated that yogic breathing done to a count of four.
could potentially stimulate salivary expression of the nerve 55 Inhale 2 3 4
growth factor, a trophic factor involved in the development, 55 Hold 2 3 4
maintenance, and survival of the peripheral nervous system 55 Exhale 2 3 4
and cholinergic neurons of the CNS that are significantly 55 Hold 2 3 4
reduced in Alzheimer’s disease patients [94].
Certain individuals may be epigenetically and genetically Focus on the breath and the count of four; repeat the
more inclined to respond to stress. Children subjected to same process until you reach a relaxed state.
abuse have decreased hippocampal expression of glucocorti-
Developing Interventions to Address Priorities: Food, Dietary Supplements, Lifestyle, and Referrals
739 41
41.2.12  Referrals related outcomes (intake of food and dietary supplements,
knowledge and beliefs, food availability, physical activity,
There might be cases in practice when nutritional therapies, nutrition, and quality of life); biochemical data, medical tests,
use of supplements, and lifestyle modifications show no and procedure outcomes; anthropometric measurement; and
improvement or benefit or only slight improvements. For a nutrition-focused physical findings.
functional medicine practitioner, it is imperative to get to the Follow-up visits give the patient and practitioner the time
root cause of the problem. In such cases, look for toxicity and and space to monitor and evaluate for compliance of nutri-
underlying infections such as molds and their toxins, silicone tion intervention and laboratory biomarkers; clarify patients’
breast implants and other implants, parasites, viruses, or questions or concerns and provide support; identify positive
Lyme disease and its co-infections. In such cases, refer the and negative outcomes; change nutrition behaviors with
patient to a practitioner proficient in those areas. foods and supplements; implement other new behaviors,
No single practitioner  – and no single discipline  – can including sleep, exercise, relaxation, relationships, and hydra-
cover all the viable therapeutic options. Interventions differ tion; and reinforce motivation and a sense of well-being for
by training, specialty focus, licensure, and even by beliefs and the patient until the patient reaches his or her goal. The
ethnic heritage. Practitioners in any specialty can, to the follow-­ups can be spaced out for longer duration at regular
degree allowed by their training and licensure, utilize a func- intervals during the maintenance phase until the patient is
tional medicine approach, including integrating the matrix discharged.
as a basic template for organizing and coupling knowledge
and data. So it is important to seek out other providers who
have also acquired some functional medicine training, build- References
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whether in-office or virtual. Treatment success can be affected 1. Churchill LR, Schenck D.  Healing skills for medical practice. Ann
Intern Med. 2008;149(10):720–4.
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know your colleagues in other fields. Perm J. 2016;20(4):16–109.
Educate yourself about what other disciplines have to 3. Jones D Hoffman L Quinn S 21st century medicine: a new model for
offer. As a nutritional practitioner, you may want to build up medical education and practice [Internet]. Institute of Functional
a team that includes physicians, a chiropractor, a naturo- Medicine; 2010 [Cited 2017 Feb 2]. Available from: https://www.
functionalmedicine.org/files/library/21st-century-medicine_001.
pathic or osteopathic physician, an acupuncture specialist, pdf.
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trist, and so on. It is beyond the mission of this chapter to 5. Luyster FS. Impact of obstructive sleep apnea and its treatments on
partners: a literature review. J Clin Sleep Med. 2017;13(3):467–77.
discuss the training, scope of practice, or therapeutics of the 6. Killian L, Starr J, Shiue I, Russ T.  Environmental risk factors for
many different healthcare approaches available today, but dementia: a systematic review. BMC Geriatr. 2016;16:175. https://
many publications and websites do provide such informa- doi.org/10.1186/s12877-016-0342-y.
tion. Developing a network of capable, collaborative health- 7. Harris S, Harris E. Herpes simplex virus type 1 and other pathogens
care practitioners with whom you can co-manage are key causative factors in sporadic Alzheimer’s disease. J Alzheim-
ers Dis. 2015;48(2):319–53. https://doi.org/10.3233/JAD-142853.
challenging patients and to whom you can refer for thera- 8. Ferguson L, De Caterina R, Görman U, et al. Guide and position of
pies outside your own expertise will enrich the care your the International Society of Nutrigenetics/Nutrigenomics on per-
patients receive and will strengthen the clinician-patient sonalised nutrition: Part 1 – fields of precision nutrition. J Nutrige-
relationship. Many patients do not tell one practitioner netics Nutrigenomics. 2016;9:12–27. https://doi.
about care they are receiving from other practitioners. Keep org/10.1159/00445350.
9. Sampey B, Vanhoose A, Winfield H, et al. Cafeteria diet is a Robust
those lines of communication open and alive. All referral Model of human metabolic syndrome with liver and adipose
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41
 743 42

Therapeutic Diets
Tracey Long and Leigh Wagner

42.1 Introduction – 744

42.2 Defining “Therapeutic Diets” – 744
42.3 Traditional/Historical Perspective on Therapeutic Diets – 744
42.4  onventional Approaches to Therapeutic Diets (and the
C
Nutrition Care Process) – 744
42.5 I ntegrative and Functional Approaches to Therapeutic Diets
(and the Nutrition Care Process) – 744
42.6 IFMNT Assessment Tools – 744
42.7 Commonly Used IFMNT Therapeutic Diets – 745
42.7.1 E limination Diets – 745
42.7.2 Low-Histamine Diet – 746

42.8 Where to Find Histamine – 747

42.9 How Can We Support Histamine Overload? – 748
42.9.1 Low-Carbohydrate High-Fat Diet – 748

42.10 H
 ow Do Diabetic Ketoacidosis and Nutritional Ketosis
Differ? – 748
42.11 What Is LCHF? – 749
42.12 What Are the Benefits of LCHF? – 749
42.12.1 Carbohydrate Restriction in Cancer Therapy – 749

42.13 Who Should Avoid LCHF? – 749

42.14 Intermittent Fasting – 750
42.15 Benefits of Intermittent Fasting – 750
42.16 C
 oncerns and Special Considerations for Intermittent
Fasting – 751
42.17 Different Methods of Intermittent Fasting – 751
42.18 Summary and Conclusion – 752
References – 752

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_42
 744 T. Long and L. Wagner

42.1  Introduction modifications, and additional feedings (snacks and oral sup-
plements). Each of these is recommended based on assess-
We so often hear the saying by Hippocrates, “Let food be thy ment of the patient and recommendation by the doctor,
medicine and medicine be thy food,” but do we really pause to another healthcare provider, and/or a registered dietitian.
consider the meaning and relevance of his words? “Food as
medicine” is using the functional characteristics of foods that 42.5  Integrative and Functional Approaches
allow the body to heal and function optimally. Medicine as
to Therapeutic Diets (and the Nutrition
our food is the idea that how we eat can be used on a daily
basis, as a lifestyle or preventive medicine-type approach that
Care Process)
will keep us well or prevent disease. This chapter will sum-
IFMNT is a specific approach to medical nutrition therapy
marize and examine therapeutic diets from an integrative and
(MNT) that expands on the assessment portion of the nutri-
functional perspective. We will describe dietary approaches
tion care process (NCP). The NCP involves assessment, diag-
used therapeutically by practitioners, the evidence for their
nosis (nutritional diagnosis), intervention, monitoring, and
use, the application, and any caveats or cautions for their use.
evaluation. An expanded assessment requires specific tools
(including time) as a means to investigate core nutritional
42.2  Defining “Therapeutic Diets” imbalances in patients. The IFMNT practitioner has the ben-
efit of additional time with the patient, often spending
The term “therapeutic diets” is defined by the Academy of 60–90  minutes for an initial consultation and close (often
Nutrition and Dietetics as “a diet intervention ordered by a frequent) monitoring of interventions.
healthcare practitioner as part of the treatment for a disease
or clinical condition manifesting an altered nutritional sta- 42.6  IFMNT Assessment Tools
tus, to eliminate, decrease, or increase certain substances in
the diet [1].” We will use this working definition of therapeu- Prior to an initial appointment, a patient completes paperwork
tic diets within the context of nutrition approaches for inte- that includes prompts about their goals, lifestyle barriers and
grative and functional medical nutrition therapy (IFMNT). challenges, health history, family history, social history, nutri-
tion and diet histories, environmental exposures history, phys-
42.3  Traditional/Historical Perspective ical activity, dental history, symptoms, dietary supplementation
on Therapeutic Diets and medication histories, and other backgrounds. During the
initial consultation (often 60–90 minutes), the IFMNT practi-
In early civilizations, particularly of India and China, ancient tioner will ask about any questions identified from the patient’s
traditions included dietary approaches to healing. These were initial intake forms. Through the interview, the IFMNT practi-
some of the earliest documented accounts of using food as tioner collects the patient’s story (see 7 Chap. 38 for more on
 

medicine. India’s ancient healing paradigm, Ayurveda, is one of the patient’s story) and fills in any gaps left in the paperwork.
the oldest medical systems in the world. Its name is derived During the initial appointment, the IFMNT practitioner
from Sanskrit words “life science” or “life knowledge.” Ayurveda assesses more than just the patient’s nutritional status and
takes the approach to health with the belief that all aspects of an metabolism; she also assesses their readiness to change, self-­
individual’s lives are interconnected (humans, health, and the efficacy, and level of feasibility to make necessary changes.
universe) [2]. Ayurveda also uses individual constitutions or The IFMNT practitioner will be able to help troubleshoot any
“doshas” that characterize an individual’s tendencies to disease of the patient’s challenges to ensure that if the patient would
and specific remedies, especially dietary recommendations. like to make changes, they will be able to access the support
42 Similarly, and slightly more recently, traditional Chinese they need to make them. Sometimes this involves family,
medicine (TCM) is an ancient medical system that also uses friends, and their community to serve as caregivers or sup-
therapeutic diets as part of its foundation to health. TCM is port systems (7 Box. 42.1).
 

similar to Ayurveda in viewing human health as connected

to the larger environment and universe as a whole [3].
Box 42.1  IFMNT Tools
55 Time
42.4  Conventional Approaches 55 The client’s story and health timeline
to Therapeutic Diets (and the Nutrition 55 IFM Matrix
55 IDU assessment tool
Care Process) 55 Intake assessment form
55 Health symptoms questionnaire
Conventional nutritional approaches to therapeutic diets 55 Fats and oils questionnaire
have included several categories of diet modifications, 55 Nutrition physical exam
including nutrient modifications (i.e., macronutrients, 55 Body composition measurement
55 Laboratory testing (conventional and functional)
micronutrients, fiber), texture or consistency modifications 55 Motivational interviewing and stages of change model
(mechanical soft, puree, etc.), food allergies and intolerance
Therapeutic Diets
745 42
42.7  Commonly Used IFMNT Therapeutic (mediated by immunoglobulin E (IgE)). Food intolerances
Diets involve an adverse reaction to food due to a lack of adequate
amounts of an enzyme to digest the food (e.g., lactose intol-
There are countless “diets” widely promoted on the Internet erance is a deficiency of the enzyme lactase) [45]. Food sen-
and social media that may or may not be based on evidence sitivities are a non-IgE, immune-mediated reaction to a
and many that are conventionally accepted and used: carbo- food when ingested. These are often less severe reactions
hydrate counting for diabetic patients (often matching carbo- like adverse digestive symptoms (stomach pain, bloating,
hydrate intake to insulin dosage) [4]; a “cardiac diet,” which nausea, breathing problems, eczema, brain fog, etc.). Non-
includes lowering total and saturated fat intake [5], sodium celiac gluten sensitivity is a condition characterized by
levels, and egg yolks; calorie counting for weight loss; and a adverse symptoms (fatigue, digestive problems, brain fog,
general Mediterranean diet for heart health. These are gener- etc.) caused by ingestion of gluten without having classic
ally well accepted in the conventional medical world but in a characteristics of celiac disease [10]. Although the mecha-
broad sense lack the nuance of each individual patient. The nism is not fully understood, some hypothesize that the
IFMNT approach to therapeutic diets is based on the founda- adverse reaction may be due to histamine intolerance [46].
tional concept of evaluating the patient’s nutrition status and Further, evidence suggests that the pathophysiology of
implementing an intervention that is personalized to that celiac disease is related to a response by the adaptive
individual. immune system, while non-celiac gluten sensitivity is a
reaction by the innate immune system [47]. This phenome-
non has been measured via fecal assays suggesting an
42.7.1  Elimination Diets immune reaction to gluten/dairy [48].
People with IBS often try to eliminate certain foods (e.g.,
Elimination diets (also called “exclusion diets”) [6] are both a gluten and dairy) in an attempt to alleviate symptoms [40]. A
diagnostic tool to identify food adverse food reactions and a low FODMAP diet is another version of an elimination diet
broad term for a systematic dietary approach to mitigate with compelling evidence that it contributes to amelioration
symptoms of adverse food reactions or to alter disease pro- of IBS symptoms [49].
gression. At the extreme end, celiac disease and food allergies
are conditions that necessitate the avoidance of certain foods 42.7.1.1  Implementation of an Elimination
to protect the patient from life-threatening illness. Less Diet
severe, but also on the spectrum of adverse food reactions, Elimination diets are often followed for 4–12  weeks (the
are food sensitivities and intolerances, which also warrant time period foods are withdrawn) with additional time to
the elimination of certain foods (e.g., lactose or fructose systematically reintroduce foods back into the diet. To
intolerance or non-celiac gluten sensitivity); these have a less begin, a person avoids one or several foods for the specified
severe but still detrimental impact on one’s health and often time period. During that time, the individual keeps a diary
quality of life. Another category of conditions that may war- of their dietary intake and symptoms (see . Fig  42.1) to
 

rant an elimination diet are autoimmune diseases like rheu- ensure that suspected foods are completely removed and
matoid arthritis [7] or Crohn’s disease [8]. there aren’t any hidden sources of the food(s) remaining in
Although there has been skepticism of sensitivities to the diet. Symptoms are recorded, along with the time and
foods like wheat and gluten outside of overt celiac disease, food eaten, to note any patterns in food ingestion with elic-
evidence is emerging that there can be measurable physi- ited symptoms. At the end of the period of elimination, each
cal changes in immune activation and cellular damage in of the eliminated foods is reintroduced (“challenged”) back
people with wheat sensitivity without celiac disease [9]. into the diet, one-by-one, to determine which (if any) foods
Alessio Fasano [10] has contributed significantly to the elicit symptoms. If the person has an adverse response to
evidence around characterization of non-celiac gluten the food, they are to eliminate it again, wait for the
sensitivity. symptom(s) to subside, and try another new food to assess
A PubMed search for “elimination diet” shows that most tolerance. After all foods are reintroduced or “challenged”
recent publications were specifically related to therapeutic back into the diet, then the person can wait another period
use for eosinophilic esophagitis (EoE) [11–31]. When search- of time before trying to reintroduce any remaining foods
ing for “exclusion diet,” one may find that most publications again.
refer to inflammatory bowel diseases [6, 32–38]. Terminology
of elimination diets seems to vary by diagnosis or area of 42.7.1.2  Types of Elimination Diets
research. Other conditions studied for the therapeutic use of There are many dietary approaches that aren’t necessarily
elimination diets include irritable bowel syndrome (IBS) [39, referred to as “elimination diets” but may fall within the
40], autism spectrum disorder [41–43], migraine headache general umbrella of the term: foods are eliminated with the
[44], and others. expectation that symptoms or signs of disease or illness
The elimination diet is often used by individuals who may improve. Examples of elimination diets include (1) the
suspect they have food intolerances. Food intolerances are Paleolithic or ancestral diet (Paleo diet) [50], (2) a low
adverse food reactions that are not overt food allergies FODMAP diet (fermentable oligo-di-monosaccharides
 746 T. Long and L. Wagner

..      Fig 42.1  Diet and symptom

diary Date/ Location/ Food or beverage Amount Mood and symptoms
time activity consumed (cup, etc)

Reviewed by Date/Time

..      Table 42.1  Potential vulnerabilities

Eliminated food Macronutrient vulnerabilities Micronutrient and phytonutrient vulnerabilities

Gluten [54] Fiber, carbohydrate Iron, folate, calcium, selenium, magnesium, zinc, niacin, thiamin,
riboflavin, vitamins A and D

Dairy Protein, fat Calcium, potassium, phosphorus, vitamin A, vitamin D, vitamin

B12, riboflavin, niacin

Soy [55] Fiber, protein Calcium, B-vitamins, iron, zinc

Egg [56] Protein, fat/cholesterol Choline, retinol (vitamin A), vitamin E, thiamin (B1), riboflavin
(B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), folate (B9)

Nuts [57] Mono- and polyunsaturated fatty Vitamins E and K, folate, magnesium, copper, potassium,
acids, protein, fiber selenium, carotenoids, antioxidants, phytosterols

Grains [58] Fiber, carbohydrate Folate, thiamin, iron, niacin, riboflavin, vitamin B6, zinc, sodium

Paleo Fiber, carbohydrate Folate, thiamin, iron, niacin, riboflavin, vitamin B6, vitamin B12,
(Free of grains, dairy, legumes) [50] zinc, sodium, calcium, potassium, phosphorus, vitamins A and D

Low FODMAP [51] Fiber, fat Iodine, selenium

Specific carbohydrate diet [32] Fiber (due to rationale for the Vitamin D, calcium [32] (limited data and study in pediatric
(study in pediatric population) diet) population)

42
and polyols): eliminating all categories of highly ferment- 42.7.1.3  Cautions for Elimination Diets
able carbohydrates and reintroducing them back into the A major concern for the implementation of an elimination
diet one FODMAP category at a time) [51], and (3) the diet is the risk for nutritional deficiencies or insufficiencies,
specific carbohydrate diet [32]. Other approaches involve especially if followed for a long period of time. . Table 42.1 

individualized elimination diets based on food sensitivity summarizes the potential macro- and micronutrients that
testing (IgG blood testing) to determine which foods to may be insufficient in someone following an elimination diet.
eliminate [52]. Even a low-histamine diet and a ketogenic
diet (high fat, low carbohydrate) could be considered elim-
ination diets, and they will be covered later in this chapter. 42.7.2  Low-Histamine Diet
Although there have been clinical trials on the implemen-
tation of elimination diets [53], there is still a lot to be A low-histamine diet is one of several specialized food pat-
learned about elimination diets and their indication and terns to assist patients with food sensitivities, food intoler-
safe implementation. ances, and/or food allergies. Focusing on this specific diet is
Therapeutic Diets
747 42
warranted, as this is a therapeutic diet that is seemingly more is a phenomenon known as mast cell activation disorder
and more common. Many integrative and functional nutri- (MCAD) [62]. Because mast cells live in the mucosal lining
tion practitioners are noticing an increase in patients need- of the gut, if the gut lining is inflamed for any reason, mast
ing support for histamine intolerance. cells may become activated and/or have the opportunity to
Histamine belongs to a family of biogenic amines that are migrate from the mucosa system-wide due to leaky mucosal
classified into monoamines and polyamines. Monoamines tight junctions [63].
are derived from one ammonia molecule, NH3, where one of Histamine load may also come from food, especially food
the hydrogen molecules is dropped and replaced with subject to spoiling or degradation as microbes degrade the
another chemical structure. Polyamines have more than one amino acid histidine in food with the HDC enzyme and
NH3 starter group. Five commonly known monoamines are make histamine. Foods rich in protein are culprits, but so are
histamine, serotonin, dopamine, norepinephrine, and epi- foods and beverages allowed to ferment, such as wine, sauer-
nephrine [59]. Another trace monoamine is tyramine, which kraut, and kombucha. Foods high in protein will be degraded
can be yet another cause of biogenic amine-related food by microbes after cooking, raising histamine content. While
intolerance. To understand histamine, it is helpful to under- refrigeration will slow histamine production, only freezing
stand genetic and biochemical possibilities. Several boxed will stop histamine content from increasing [64].
genetic notes are provided for more in-depth understanding. Allergies to food and the environment are the more obvi-
ous sources of histamine production. IgE-type allergy testing
may be warranted to reduce load [64]. Elimination of anti-
Genetics Note 1: the enzyme histidine decarboxylase gens and/or treatment for allergic-type hyper-response may
(HDC) is made from the HDC gene. Its purpose is to be needed.
convert the amino acid histidine into histamine. In some The stress response may increase histamine production
individuals, genetic variants may cause an increase or [65]. Assisting patients with stress management is key in
decrease in the enzyme function possibly resulting in regulating histamine load.
too much or too little histamine. Active Vit B6 or P-5-P Estrogens (both naturally occurring and estrogen-­
is a required cofactor of HDC [60]. Some fish are high in mimicking “xenoestrogens”) also contribute to the hista-
microbes that are capable of producing HDC that, when mine load [66]. Assessing patients for estrogen dominance
consumed by some individuals who do not clear hista- and genetic risk for estrogen dominance may be helpful.
mine well, can contribute to histamine overload [61]. Lifestyle and dietary interventions to reduce estrogen involve
avoiding exposure to plastics or heating food in plastics.
Increasing cruciferous food intake is also supportive to
Histamine is most recognized for its role in symptoms asso- decrease estrogen.
ciated with classic allergy in IgE-mediated immune system Emerging evidence suggests that specific species of gas-
activation: hives, tissue swelling, nasal congestion, asthma, trointestinal microbes produce histamine. Examples are
headaches, oral allergy symptoms, and gastrointestinal com- Lactobacillus casei, Lactobacillus delbrueckii, and Lactobacillus
plaints. However, histamine has many beneficial roles in bulgaricus. Testing for small intestine bacterial overgrowth
human function including neurotransmission, gastric acid may be a diagnostic tool in determining if dysbiosis may be
secretion, inflammation and immune system ­support, and an underlying contributor. Certain microbes are known to
smooth muscle tone [60]. assist with histamine degradation such as spore-based probi-
Those with histamine intolerance may be affected by a otics, Lactobacillus plantarum, Lactobacillus rhamnosus, and
variety of sudden onset and seemingly unexplainable symp- Bifidobacterium longum [63].
toms such as flushing, hives, rapid heartbeat, profuse sweat-
ing, nosebleeds, car sickness, migraines, itchiness, and more.
For a comprehensive lists of symptoms of histamine over- Genetics Note 2: the enzyme catechol-O-methyltrans-
load, see references listed below, especially the books by ferase (COMT) made by the gene of same name is
Jarisch and Lynch. important for estrogen degradation. Individuals who are
homozygous positive for variants may have estrogen
dominance and benefit from estrogen clearing support.
42.8  Where to Find Histamine SAMe (methylation ability), magnesium, and vitamin C
are cofactors for COMT [67].
Histamine intolerance may actually be an imbalance between
histamine production and accumulation and the ability to
degrade histamine. The body is capable of making histamine Based on the above-described reasons that histamine may
and storing it in specialized immune cells called mast cells. accumulate and individual sensitivity to histamine, it is best
Mast cells are sentinel cells found primarily in mucosal tis- to describe histamine intolerance as “histamine overload.”
sue that help initiate an inflammatory response when a When the body is unable to handle the load, histamine can
threat is detected. Releasing histamine is important for build up and eventually “spill over” the tolerable limit for the
immune function, unless the mast cells are overactive. This individual and create a histamine response.
 748 T. Long and L. Wagner

42.9  How Can We Support Histamine

Overload? N-methylhistamine, which then is further degraded by
MAOB so the body can finally get rid of the histamine. If
1. Decrease the dietary load. Limit very high histamine MAOB is not working well due to lack of cofactor and/or
foods: red wine, champagne, aged cheeses, cured meat presence of genetic variants through feedback inhibi-
and fish, bone broth and fish stock, vinegar and fer- tion, HNMT slows down making histamine buildup. The
mented foods such as sauerkraut, and chocolate. A more easy fix is a trial of the cofactor vitamin B2 (riboflavin) as
comprehensive list of high and moderately high hista- about 400 mg taken 2–5 times a week [68, 69].
mine foods is available in the references. Patients may
benefit from suggested meals and meal plans based on
lower histamine foods.
2. Avoid fish high in histamine unless very fresh or fresh 42.9.1  Low-Carbohydrate High-Fat Diet
and flash frozen.
3. Avoid or limit eating leftovers. Freeze leftovers for future “There has been a dramatic resurgence of interest in the keto-
reheating and consumption. genic diet during the past several years,” as stated in a 1997
4. Assess genes that may influence the ability to degrade review article by Swink et al. [70]. This original study empha-
histamine. See boxed notes for DAO and HNMT sized the utility of the KD in treating children with epilepsy
genetics. starting in the 1920s, which then fell out of favor in the 1970s
5. Support with probiotics (mentioned above) that are due to the invention of antiepileptic medications. The 1997
known to degrade histamine. paper mentioned the return of interest in the KD in severe
6. Identify possible allergens and eliminate and/or refer for cases of pediatric epilepsy when medications did not work.
treatment. The same research team published a follow-up review in
7. Assess for gut inflammation and/or SIBO and support as 2007, The ketogenic diet: one decade later, where they acknowl-
needed edged that this diet, with evidence of use as far back as
8. Support with nutrients and/or supplements known to 500 B.C., was maintaining its momentum after 10 years [71].
support degradation of histamine such as selenium, This food trend continues to thrive as numerous research
quercetin, vitamin C, stinging nettle, EGCG (primary teams are diving into its many health applications [70–78].
catechin in green tea), and the DAO enzyme [68, 69]. This summary of the KD will be referred to from this
9. Collaborate with other healthcare providers who may be point on as the low-carb high-fat or low-carb healthy fat
able to offer support with prescription antihistamines. (LCHF) food pattern. Many health professionals are making
Be aware that many antihistamines decrease stomach the transition to using the term LCHF due to the negative
acid secretion that may result in low vitamin B12. and often misunderstood confusion between nutritional
Consider assessing for B12 deficiency. ketosis and diabetic ketoacidosis.
10. Assist with stress management techniques.
42.10  How Do Diabetic Ketoacidosis
Genetics Note 3: the enzyme diamine oxidase (DAO) is and Nutritional Ketosis Differ?
produced by the cells that line the gastrointestinal tract.
DAO is a key enzyme that degrades dietary histamine in Diabetic ketoacidosis is an acute life-threatening condition
the extracellular space (especially the gastrointestinal usually only seen in type 1 diabetes and rarely in type 2 dia-
tract). Individuals with significant genetic variants might betes [79]. In diabetic ketoacidosis, there is too little insulin
42 be impaired at making adequate DAO. Even without to control a sharp rise in glucose and ketones, a result of an
genetic variants, a damaged gut lining may impair DAO acute (usually within 2–4  hours) onset of a catabolic state
production. DAO is available as a supplement that is [80]. Other biomarkers include a pH less than 7.0, a bicarbon-
recommended for use as 15 minutes prior to consuming ate less than 10 mEq/L, and an anion gap >15 mEq/L. Blood
high histamine foods. Vitamin B6 is a cofactor for DAO ketones are measured as beta-­hydroxybutyrate with serum
[68, 69]. levels >8  mmol/L [80] or 15–25  mmol/L [72]. Notice that
Genetics Note 4: the enzyme histamine researchers do not agree on a standard level for beta-
N-­methyltransferase (HNMT) degrades histamine hydroxybutyrate, but the combination of the above mark-
inside the cell. It is primarily concentrated in the liver. ers is what is significant. This combined “perfect storm”
Individuals with significant genetic variations may can result in a critical threat warranting immediate medical
benefit from additional cofactor support to help speed treatment.
up HNMT which is SAMe [68, 69]. Nutritional ketosis is a mild form of ketosis where blood
Genetics Note 5: the enzyme monoamine oxidase glucose is relatively low, blood pH remains within normal
B (MAOB) provides an important step in the histamine reference ranges, and blood ketone values usually are between
degradation pathway. HNMT degrades histamine to 0.5 and 5  mmol/L [74]. Medically therapeutic ketosis for
treating epilepsy ranges from 2.0 to 7.0 [81].
Therapeutic Diets
749 42

..      Table 42.2  Macronutrient percentages

Macronutrients as Standard Paleo Mild LCHF Moderate LCHF Medically therapeutic LCHF (epilepsy
percent of total kcals American Diet [82] diet [83] diet [72, 73] diet [72, 73] and Alzheimer’s disease [70, 73]

Carbohydrate 50 22–40 20 10–15 7–8

Protein 15 19–35 20 15–20 12–13

Fat 35 28–47 65 70 79–80

42.11  What Is LCHF? from the large WHEL (Women’s Healthy Eating and Lifestyle)
and WINS (Women’s Interventional Nutrition Study) trials
A LCHF food pattern is high in (healthy) fat, adequate or mod- [87, 88]. A LCHF food pattern may also increase lifespan of
erate in protein, and low in carbohydrates. Healthy fats are those with glioblastoma and metastatic glioblastoma [77, 78].
considered, in the context, to be fats derived from whole food In addition to insulin, other biomarkers may be consid-
sources (grass-fed meat and poultry, avocados, olives, cold- ered. An observational study of 269,391 participants in Korea
pressed oils, butter, etc.) versus fats derived from chemical and over 2 years between 2002 and 2005 found that all-­cause mor-
heat processing (seed and soy-based oils). This pattern is able tality, including cancer, was lower in those with higher blood
to assist the human body in making ketone bodies for energy. lipids [89]. Certainly clinical trials are needed to verify this,
The formation of ketones for energy occurs with fasting, pro- but studies such as this support possible benefits to higher lip-
longed exercise, and very low carb intake. Comparing the mac- ids which can occur in some people following LCHF.
ronutrient percentages of LCHF variations with the standard The LCHF food pattern may support starving cancer cells
American intake may be helpful as listed in . Table 42.2. The
 
of glucose. The energy demand of cancer cells dependent on
Paleo diet was included for additional reference as this food glucose for energy is about twenty times greater than normal
pattern, which emphasizes a whole food approach to food cells. This altered energy utilization and increased demand is
intake, is often used as a reference template for LCHF. known as the Warburg effect [76].
When should LCHF be avoided in cancer? Genetic muta-
tions such as the BRAF V600E mutation result in dietary fat-­
42.12  What Are the Benefits of LCHF? fueled tumor growth [90]. Note that some cancers are
learning to use other sources of fuel such as protein, amino
Scientists are rapidly studying many possible benefits of a acids, and fats instead of glucose [91–93].
LCHF food pattern. Research covers a wide range of hypoth-
eses from effects on exercise performance to metabolic zz Rationale for benefits of a LCHF dietary pattern
derangement to chronic disease. Here is a summary of some 1. Alzheimer’s disease: LCHF resulting in mild to metaboli-
of the current findings. cally therapeutic level of ketone production is recom-
mended by The Bredesen Protocol to End Alzheimer’s for
three reasons: (1) to provide an alternative energy source
42.12.1  Carbohydrate Restriction in Cancer to brain cells, (2) to decrease neural inflammation, and
Therapy (3) to increase brain-derived neurotrophic factor [73].
2. Cardiometabolic disease: LCHF may support reversing
First, note that not all cancers are related to diet, such as chronic diseases such as type 2 DM, blood lipid dysregu-
those associated with virus, environmental exposures, age, lation, hypertension, obesity and overweight, and
and genetic mutations [74]. However, when these types of chronic inflammation and decrease the need for insulin
cancer are diagnosed and treated, diet can be an important in type 1 DM [72, 94].
factor in outcomes. 3. LCHF has been shown to enhance athletic performance,
Some common cancers have been linked to dietary influ- especially in endurance athletes [95].
ences. These cancers include breast, colon, some lung, pros- 4. LCHF may simplify food intake as many find this food
tate, and gallbladder/biliary cancers and endometrial pattern more satiating with a reduction in cravings for
adenocarcinoma. These cancers are linked to hyperinsu- carbohydrates and the need to eat frequently [72, 94].
linemia based on data from people with diabetes mellitus
(DM) [84–86]. A therapeutic diet could be one that promotes
lower insulin and may be helpful in cancer prevention. 42.13  Who Should Avoid LCHF?
Dr. Dawn Lemanne is recommending a moderate carbohy-
drate restriction of about 100 grams of net carbohydrates per Many people are finding benefit from increasing healthy fats
day in breast cancer and in stage III colon cancer in those with while lowering carbohydrates. As more adopt this food pat-
BMI >25 [74, 75]. The breast cancer recommendations come tern and research data accumulates, we may find additional
 750 T. Long and L. Wagner

reasons to avoid LCHF, but at this time the only recommended et al., in a 2018 review, summarized findings in animal models
avoidance is for starting this food pattern during pregnancy showing that IF may reduce oxidative stress, improve cogni-
[72, 94]. The most important consideration when adopting tion, and slow down the aging process [102]. This same review
LCHF is a slow acclimation and progression to LCHF to assist found that while the human clinical trials are small (many
the body to adapt to using fat for fuel over carbohydrates to with fewer than 300 participants), they are showing evidence
avoid possible flu-like symptoms and muscle cramps [96]. of sustainable weight loss and improved insulin sensitivity.
IF between meals and overnight is a newer dietary ther-
apy for digestive problems such as inflammatory bowel dis-
42.14  Intermittent Fasting ease (IBD), irritable bowel syndrome (IBS), and small
intestine bacterial overgrowth (SIBO). The author (TL) uses
Intermittent fasting (IF) is the conscious choice to abstain IF for 12 hours overnight and 4–5 hours between meals for
from food for health-promoting reasons such as spiritual, bowel rest with good clinical and anecdotal success for these
cleansing, or detoxing or as a method to ameliorate a disease. gastrointestinal (GI) conditions. This concept is based on the
IF is also referred to as time-restricted feeding or periodic work of Mark Pimentel, MD, the director of the GI Motility
fasting. This section will refer to IF but could mean any of the Program and Laboratory at Cedars-Sinai. He has authored
three above titles. Intermittent fasting is not starvation. many papers, and his book, A New IBS Solution, describes the
Starvation is a state of forcefully being deprived of food such migrating motor complex (MMC) function in the gastroin-
as lack of availability (war or famine) or withholding food. testinal tract [103]. The MMC is a wavelike pulse that has
Note: anorexia nervosa is considered a form of purposeful been shown to sweep microbes and food debris out of the
food refusal involving complex emotional, social, mental, small intestine helping to prevent SIBO.  He describes the
and nutrition-related factors. Appropriately, this discussion MMC as pulsing naturally about every 90 minutes when food
does not include anorexia nervosa. is not present. He has found that when the MMC runs 10–12
Fasting has no set duration. It is a cycle of consuming food times every 24 hours, IBS/SIBO treatment is optimized. This
followed by an abstinence period from food. The concept of IF can only occur during intermittent fasting states instead of
represents cyclical and pre-planned periods of fasting followed the conventional ideal of eating three meals and two to three
by appropriate food intake. This could be simply avoiding food snacks each day. Additionally, bowel rest has traditionally
intake between meals, i.e., avoiding snacking between a stan- been used for IBD conditions for the past 40  years as a
dard breakfast and lunch. Other examples of fasting cycles are method to decrease inflammation. IF is a method to provide
overnight, alternate-day, or extended-day fasts. The modified, rest intermittently with nutritious food intake [104, 105].
shorter versions of fasting are showing promise with many Prominent clinicians are using varying methods of IF to
health benefits and are more appealing to the general popula- support treatment of some chronic diseases. One example is
tion over extended fasts. IF can be eucaloric or hypocaloric Dr. Jason Fung, MD, Canadian nephrologist and head of the
and still result in positive outcomes. The variability in fasting Intensive Dietary Management program to support weight
regimens allows the healthcare professional to individualize loss and type 2 diabetes reversal. He teaches both low-­
the needs of patients. Many patients benefit from individual- carbohydrate diets and IF to patients. Dr. Fung has written
ized guidance on how to implement a fasting protocol based two books on his methods noted in the references. He is col-
on health goals and reason(s) for fasting. Understanding the lecting data in his clinic and shares many clinical and anec-
basics of fasting will provide guidance for patient support. dotal stories about his success using his protocols to reverse
diabetes, a disease that conventional wisdom has touted as
being progressive, insidious, and irreversible [94, 106].
42.15  Benefits of Intermittent Fasting Because Dr. Fung’s IF methods are individualized to each
42 patient, such as 12-hour overnight fasting, between-meal
A 2017 review by Patterson et al. [97] found that IF supports fasting, and/or alternate-day or extended-day fasting, refer to
weight loss, improves metabolic health markers, and may his books for further examples and application. He shares
influence other aspects of health, such as improved sleep cir- clinical assessments to ensure safe implementation of IF.
cadian rhythm and microbiome biology. Some of the meta- Dale Bredesen, MD, neurologist and founder of MPI
bolic health markers include lipids, such as lower total Cognition, studies Alzheimer’s and other neurodegenerative
cholesterol, lower LDL cholesterol, improved HDL choles- diseases. A key dietary aspect of his protocol is IF.  Dr.
terol, lower triglycerides, and improved blood glucose and Bredesen recommends a 12-hour overnight fast on a daily
insulin. A more recent review found that most evidence basis, but those with increased genetic risk are instructed to
related to IF and weight loss and improved lipid profiles are extend their fast more. Those with the ApoE 3/4 genetics for
observational and suggested the need for more clinical stud- Alzheimer’s risk use a minimum 14-hour overnight fast, and
ies to confirm these initial findings [98]. those with the ApoE 4/4 genetic variants for Alzheimer’s risk
Regarding weight loss, IF is supportive as a manageable are instructed to use a minimum overnight fast of 16 hours.
method for caloric restriction, promoting adipose thermo- The goal is to produce a state of mild nutritional ketosis to
genesis, and altering the gut microbiome to increase metabo- help fuel the brain, optimize brain mitochondrial function,
lism via influences on adipose tissue [99–101]. Stockman and reduce neural inflammation [73].
Therapeutic Diets
751 42
Also noteworthy is the research by Valter Longo, PhD, cramps. Patients should be carefully monitored and
Professor in Gerontology and Professor in Biological Science, provided with electrolyte replacement if warranted,
University of Southern California. His clinical animal trials along with plenty of water during any fast [106]. Be
have yielded the following findings [107, 108]: aware for extended fast, usually beyond 3 days, risk of
55 IF is chemo protective because it protects normal cells refeeding syndrome is possible [111].
from treatment side effects. When starved, normal cells 55 Coach patients about managing feelings of hunger.
slow division, which is protective during cancer treatment. Hunger tends to come in waves so strategies to assist
However, when cancer cells are starved, they continue through these sporadic periods are important. Some
dividing because their growth switch is broken in the “on” strategies include drinking a glass of water or a cup of
position making them more vulnerable to treatment. green tea, taking a walk, or engaging in an activity that
55 IF sensitizes tumor cells to chemotherapy treatment. requires concentration; staying busy during the fasting
55 IF slows tumor growth even without chemotherapy. period can be helpful.
55 Many overeat when breaking a fast, especially longer
In 2010, a group of ten volunteer patients requested that Dr. fasts. Patients need to be guided in breaking a fast, such
Longo use them in a human trial with a model used in his as planning a small snack to start with or pretend he/she
rodent trials. At the time, he refused, citing many concerns never fasted and eat a normal meal.
that included unlikely IRB approval. The group of patients 55 Advise patients that they should not make an announce-
said they would attempt his animal model fasting techniques ment about their fast. Many people will think fasting is
on their own, and he was invited to take notes. The results of extreme and may not be supportive. Suggest that
this volunteer study were published in 2012 with the follow- patients only share this with a few supportive people.
ing findings [109, 110]: 55 Heartburn can be a problem when breaking a fast. This
55 Fasting was well tolerated with some mild lightheaded- can be avoided by consuming smaller meals after fasting.
ness and weakness (temporary). 55 Some patients may need to take medication during a fast.
55 Fasting reduced fatigue. Dr. Fung suggests that while fasting patients can eat a few
55 Fasting reduced overall weakness. pieces of lettuce before swallowing medications [106].
55 Fasting resulted in fewer gastrointestinal side effects. 55 Patients on blood sugar-lowering medication need to
55 No adverse effects on tumor volume or serum tumor carefully monitor blood glucose levels and seek assis-
markers were identified. tance on altering medication doses during fasting, if
55 The proposed mechanism is that fasting enhances leptin needed.
sensitivity and lowers insulin (a growth hormone). 55 Patients with diagnosed eating disorders should not fast.
Each situation needs to be assessed. For example, a
Note: this study included ten volunteers with various malig- mother of teenage girls may want to avoid fasting due to
nancies. They fasted 48–140  hours prior to chemotherapy risk of influencing possible disordered eating in her
and for 5–56 hours following. children.

42.16  Concerns and Special Considerations 42.17  Different Methods of Intermittent

for Intermittent Fasting Fasting

Concerns and considerations for IF vary depending on the The studies of IF have been difficult to review due to varying
model. These are summarized below based on Dr. Jason models. . Table 42.3 below summarizes the most commonly
 

Fung’s book and on the clinical experience and application of used fasting models. Some fasts encourage water-only fasting
IF by the author (TL) [106]. A literature review did not reveal with electrolytes, as needed. Other models, especially when
any specific scientific studies on possible harm with IF, combined with a low-carb high-fat protocol, allow for con-
although basic understanding of physiology, psychology, and sumption of fat such as MCT oil or cream and/or bone broth
biochemistry provides background to address concerns and during the fast. Beverages such as coffee or tea with added
considerations. cinnamon and/or added fat are acceptable according to some
55 Making drastic, significant changes: Many patients get providers [106]. Another type of fast called the 5:2 fast sug-
enthusiastic about fasting, which can lead to discourage- gests continuing normal dietary intake for 5 days out of the
ment and failure. Proper assessment for readiness and week; the other 2 days are fasting days that allow for intake of
appropriate stage is important. Starting small, like 0–600 kcals from protein, fat, and non-starchy vegetables. A
fasting overnight for 12 hours and/or helping patients primary goal of many fasting models is a compressed eating
restructure meals to feel satiated (often with higher window (CEW). Because eating food (some foods more than
healthy fat and higher fiber options), will help with a others) creates an inflammatory response, a CEW is often
between-meal fast. recommended as a method to decrease inflammation [104,
55 Electrolyte imbalances: Some patients may experience 105]. A CEW may also support gastrointestinal conditions
symptoms such as dizziness, headaches, and muscle mentioned above like IBD, IBS, and SIBO.
 752 T. Long and L. Wagner

..      Table 42.3  Types of intermittent fasting

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 755 43

Dietary Supplements:
Understanding the Complexity
of Use and Applications
to Health
Eric R. Secor

43.1 Trends in Dietary Supplement Use – 756

43.2 A Growing Marketplace – 756

43.3 Nomenclature and Formulations – 756

43.4 Dietary Supplement Labels – 758

43.5 Nutrition Facts Panel Selection and Dose – 758

43.6 The Role of Government Regulations – 759

43.7 Supplement Selection and Education – 760

43.8 Quality Control and Safety – 760

43.9 Engaging Manufacturers – 761

43.10 Clinical Relevance and Controversies – 762

43.11 Summary – 764

References – 764

© Springer Nature Switzerland AG 2020

D. Noland et al. (eds.), Integrative and Functional Medical Nutrition Therapy,
https://doi.org/10.1007/978-3-030-30730-1_43
 756 E. R. Secor

43.1  Trends in Dietary Supplement Use

..      Table 43.1  Change in sales of top selling herbal supple-
ments in 2016
Complementary and integrative healthcare includes a selec-
tion of modalities, products, and dietary approaches that Ingredient Latin binomial Total sales Change
usually begin outside the biomedical or modern healthcare from 2015
system. This may include chiropractic, naturopathic medi- Ashwa- Withania $8,732,489 55%
cine, functional medicine, massage therapy, acupuncture gandha somnifera
and traditional Oriental medicine, nutritional medicine, and
Cranberry Vaccinium $7,513,172 36%
mind-body therapies [1, 2]. When evaluating the use of inte-
macrocarpon
grative healthcare in the population, published reports con-
sistently place the frequency from 32% to 62% [3, 4]. In an Turmeric Curcuma longa $47,654,008 32%
analysis of the 2012 National Health Interview Survey, it was Horsetail Equisetum spp. $5,334,706 16%
determined that 59 million Americans had at least 1 payment
Dandelion Taraxacum $2,520,049 15%
dedicated to complementary health with $30.2 billion in total officinale
out-of-pocket expenditures, which included $14.7 billion for
visits to practitioners and $12.8 billion for purchases of natu- Mushrooms Order Agaricales $4,527,372 14%
ral products [5]. The total out-of-pocket expenditures for Cherry fruit Prunus spp. $3,507,680 13%
purchases of natural supplements increased significantly as
Kava Piper methysticum $3,232,327 10%
family income increased and the total spent ($12.8 billion)
represented approximately 24% of out-of-pocket expendi- Ginger Zingiber officinale $2,454,767 9%
tures ($54.1 billion) for prescription drugs.
From a sample of 89,000 Americans, it was determined
that nonvitamin, nonmineral dietary supplements remained
the most prevalent complementary health approach in use PricewaterhouseCoopers Global (Global PwC), nutraceutical
when examining trends from 2002, 2007, and 2012 [3]. sales were estimated at $142 billion in 2011 and were expected
Investigators determined that participants reported taking at to grow to $180 billion into 2017 [19]. BCC Research pro-
least one of the following supplements within the prior jected that the market would grow to $199 billion in 2016
30  days: fish oil, glucosamine or chondroitin, probiotics or while adding growth of functional beverages and functional
prebiotics, melatonin, Coenzyme Q–10 (CoQ10), Echinacea, foods upward of $71.5 and $64.6 billion, respectively [20].
cranberry (pills or capsules), garlic supplements, ginseng, According to a recent report by Zion Market Research [21],
Ginkgo biloba, green tea pills (not brewed tea), or EGCG pills the global, nonvitamin, nonmineral dietary supplement mar-
[4], “combination” herb pills, MSM (methylsulfonylmeth- ket was valued at $133 billion in 2016, increasing to well over
ane), milk thistle (Silybum), Saw palmetto, and Valerian [3, $220 billion (US) by 2022. These analyses suggest dietary
6]. Supplement use was also found to be associated with supplements are a very large and expanding market. The use
female gender, older age, more education, any physical activ- of the Internet for patient-directed purchasing and expanding
ity, and being of normal weight or slightly underweight [4]. markets in Eastern Europe, India, and China [22] will ensure
The top-selling herbal supplements in 2016 included steady growth in all of these sectors for decades to come.
Ashwagandha (Withania somnifera), cranberry, and turmeric
(Curcuma longa) [7], which are summarized in . Table 43.1.
 

Ashwagandha sales were found to increase approximately 43.3  Nomenclature and Formulations

55% from 2015 to 2016, and sales of turmeric alone topped
$47 million. In individual populations, supplement use was One of the first legally acceptable definitions of dietary sup-
found to be common in cardiac patients [8], cancer patients plements was put forth in the federal Dietary Supplement
Health and Education Act (DSHEA) of 1994. The his-
43 [9], hospitalized patients [10, 11], the military [12], those
torical underpinnings of DSHEA are rooted in the Food
with sickle cell disease [13], and among athletes [14, 15].
Although supplement use continues to be widespread, there Supplement Amendment or the Proxmire Amendment,
remains considerable confusion about how best to navigate also known as “the Vitamin Bill,” S.2801, introduced in the
the marketplace, wade through the myriad of products and 93rd Congress between 1973 and 1974 [23]. The Proxmire
their formulations, and arrive at the most appropriate prod- Amendment was proposed to set forth the potency of ingre-
uct choice for an individual’s healthcare needs [16–18]. dients of vitamin and mineral products that are not inher-
ently dangerous. When introduced in 1973, its language
included, “shall not limit the potency, number, combina-
43.2  A Growing Marketplace tion, amount, or variety of any synthetic or natural vita-
min, mineral, or other nutritional substance, or ingredient
Analysts have been assessing the ebb and flow of the dietary of any food for special dietary uses if the amount recom-
supplements mentioned above as well as the broader mended to be consumed does not ordinarily render it inju-
nutraceutical marketplace for decades. According to rious to health.” Two decades later, DSHEA amended the
Dietary Supplements: Understanding the Complexity of Use and Applications to Health
757 43
Federal Food, Drug, and Cosmetic Act [23–25] and defined
a dietary supplement as: Box 43.1  Common Forms and Delivery of Dietary
Supplements
»» ...a product other than tobacco, intended to supple- 55 Bulk herbs – Minimally processed herbal material (sort, cut,
ment the diet, that contains a vitamin, mineral, herb and dry)
or botanical, dietary substance, or a concentrate, 55 Capsules – Encapsulating a defined amount of liquid or
metabolite, constituent, extract, or combination of the powder into a gelatin capsule
55 Essential oil – Distilled aromatic oils, applied orally, via
above ingredients; that is intended for ingestion, is not
inhalation, or topically within a fixed oil
represented as food or as a sole item of a meal or diet, 55 Extracts – Process of concentrating an herb with a specific
and is labeled as a dietary supplement; that includes an solvent
article approved as a new drug, certified as an antibi- 55 Extract, decoction – Raw herbal material (stems, roots,
otic, or licensed as a biologic and that was, prior to such leaves) boiled in water to concentrate
55 Extract, fluid – Herbal mixtures (alcohol, glycerine, vinegar,
approval, certification or licensure, marketed as a dietary
water) concentrated via evaporation
supplement or food, unless the conditions of use and 55 Extract, solid – Fluid extracts concentrated via evaporation
dosages are found to be unlawful; and excludes such to form a solid (soft or crystalline)
articles which were not so marketed prior to approval 55 Extract, tea – Steeping fine herbal material in water to
unless found to be lawful. Deems a dietary supplement concentrate water-soluble material
55 Extract, tincture – Soaking herb in alcohol and water to
to be a food.
concentrate alcohol-soluble components
This definition lays the groundwork for the regulatory 55 Glandulars – Animal gland extracts (thyroid, adrenal)
55 Homeopathics – Ultradilution of a variety of materials
aspects of DSHEA, which will be discussed below, but it does
(animal, vegetable, or minerals)
little to provide practical education to healthcare providers, 55 Lozenges – Candied, gummy, tableted, sublingual
practitioners, and patients. For example, the common term 55 Spa therapy – Baths, colonics, steam, wraps, sauna
“dietary supplement” may refer to a large range of ingredients 55 Suppositories – Material combined and delivered in a
including vitamins, minerals, botanical and/or herbal prod- vehicle (glycerine)
55 Tablets/pill – Compressing a defined amount of active
ucts (concentrates, metabolites, constituents, and extracts),
material under force
fish oils, amino acids, glucosamine, creatine, and essential 55 Topicals – Balm, creams, gels, slaves, poultice, clay, and lotion
fatty acids [6]. These products can be found sold and mar-
keted as single ingredients or in a multitude of combina-
tions [26], as well as added as ingredients to medical foods
[27], functional foods [28], and/or beverages. In contrast These combinations may include vitamins; minerals; glandu-
to dietary supplements, the Food and Drug Administration lars; fatty acids; probiotics; bulk botanicals parts (fruit, leaf,
(FDA) distinguishes prepared tube feedings as medical food or root); botanicals in the form of dried, crystallized solid
in the use and dietary management of a specific disease or extracts; and essential oils [4, 30, 35–37].
health-­related condition that causes distinctive nutritional In addition to the delivery form and/or route, it is critical
requirements different from healthy people and “formulated to consider that different forms may be easier to absorb or
to be consumed or administered enterally under the supervi- deliver a higher dose as compared to another. For example,
sion of a physician [28].” However, “functional” foods and although not set in stone, a good rule of thumb to follow is
beverages do not have a formal FDA designation and are that as the form of (a botanical) product becomes more con-
commonly defined based on ingredients, formulations, and centrated, the strength and dose may increase. So the bulk
label or health claims. herb may be less potent when compared to its solid extract,
In addition to taking into account the broad definition of i.e., potency of bulk herb < tea < decoction < tincture < fluid
dietary supplements put forth under DSHEA, when selecting extract < solid extract [38]. In addition, scientific advances in
or advising patients on the most appropriate choice for them, the formulation of plant extracts have led to changes in how
it is critical to understand the common forms by which healthcare practitioners approach drug delivery. These new
dietary supplements are delivered and find their way into systems, which include nanoparticles, nanocapsules, lipo-
foods, beverages, and the multitude of products in the mar- somes, phytosomes, nanoemulsions, and microspheres, are
ketplace [25, 29]. An overview of some of the most common transforming product solubility, bioavailability, and stability,
forms that product ingredients are available is provided in which ultimately will lead to enhanced biological activity and
7 Box 43.1. From bulk herbs (which can be purchased by the
  novel clinical applications [39]. Therefore, the forms, dosage,
pound) to essential oils (by the ounce) to common lozenges, and standardization information should be clearly presented
tablets, and topicals (creams, gels, salves, poultices, clay, and on all dietary supplement bottles and delivery devices to help
lotion), most individual products limit themselves to one guide the consumer, patient, and healthcare team. Caution
“form,” such as in a Calendula cream, a cranberry (fruit) or should be exercised as the same product formulated differ-
turmeric (root /rhizome) extract [25, 30–34]. Other manu- ently may impart a variety of biological effects. For example,
facturers may combine numerous forms into complex com- consider green tea and its L-theanine (γ-glutamylethylamide)
bination products with 15 to 25 or more individual extract, which is now widely used as a mild anxiolytic as
components, not including binders, fillers, and additives. opposed to a low-dose caffeine stimulant [40].
 758 E. R. Secor

43.4  Dietary Supplement Labels

..      Table 43.2  Common forms of dietary supplement
ingredients
The Department of Health and Human Services’ Office of
Inspector General (OIG) outlined several key aspects of Vitamin/mineral Common forms
dietary supplement labels that are required to ensure that ingredient
consumers make the best possible choices to increase safety Vitamin A Acetate, beta carotene, mixed carotenoids,
and lower risk when selecting products [41]. In the report palmitate
“Adverse Event Reporting for Dietary Supplements, an
Vitamin B12 Methylcobalamin, cyanocobalamin
Inadequate Safety Valve,” the OIG presents a template com-
posed of two main elements: [1] label content (ingredients, Calcium Carbonate, citrate, dibasic calcium
intended use, safety information, directions for use, and phosphate, malate, pantothenate
product information) and [2] label presentation (standard- Vitamin D Cholecalciferol-D3, ergocalciferol-D2
ized format, distinct product features, readability, balance,
Vitamin E Tocopherols – alpha, beta, delta and/or
and constructive use of space). Ingredients should be listed gamma
fully and clearly and reflect the accurate amount per serving
Folate Folic acid, L-5-MTHF- Metafolin®
and per bottle as much as possible. Intended use would distin-
guish “support to health” from health claims, which require Iron Ferric (citrate, sulfate), ferrous (aspartate,
scientific validation. Information on safety should include fumarate, sulfate, gluconate)
potential interactions or contraindications, such as whether Magnesium Glycinate, malate, oxide, stearate, sulfate
it is safe in pregnancy. Directions for use may include sug-
Selenium Sodium selenite, selenomethionine
gested dosage, if known. Product information would identify
the manufacturer, lot, and possibly gross and net amounts of Zinc Citrate, gluconate, oxide, sulfate
the ingredients listed. The label presentation template pro- Botanical Form, part, and standardization
vides details on consistency, similar types of information in ingredient
a similar order, design, and format, made easy to understand
Camellia sinensis Green tea: leaf extract – 30–50%, polyphe-
by a wide range of consumers and provides information in nols, EGCG, picatechin, epicatechin gallate,
a balanced manner (benefits, risks, claims, and facts) while epigallocatechin, catechin, gallic acid
using product packaging to provide additional sources of
Echinacea Herbal: stem, leaf, and/or flower extract,
information beyond the nutrition facts panel.
purpurea 3–4% phenolics

Curcuma longa Turmeric: rhizome or root extract. 70–95%

43.5  Nutrition Facts Panel Selection curcuminoids

and Dose Allium sativum Garlic: bulb and/or oil extract. % Alliin,

allicin, diallyl sulfide, or ajoene
In addition to being able to identify the list of key components Ginkgo biloba Ginkgo: leaf extract (1:4–50:1). 6–24%
on dietary supplement labels, a more pressing issue is select- heterosides, terpene lactones
ing and distinguishing a product based on the individual Hypericum Hypericum: aerial/herb. 0.3% hypericins
ingredient(s), their forms or parts used, as well as additional perforatum
additives such as dyes, binders, and fillers. In . Table  43.2,
 

Polygonum Resveratrol: root extract. 5–50% trans resve-

examples of some of the most common forms of vitamin,
cuspidatum ratrol
mineral, and botanical ingredients are highlighted. Vitamin
A can be found as acetate, beta carotene, mixed carotenoids, Rhodiola rosea Rhodiola: root extract. 0–30% rosavins
(rosarin, rosavin, rosin)
palmitate [42], and vitamin B12, in either the cyanocobala-
43 min or methylcobalamin form [43]. Calcium carbonate is Serenoa repens Saw palmetto: fruit extract. 45% fatty acids
said to be cheaper and harder to absorb than citrate, but a Tanacetum Feverfew: aerial, leaf extract. 0.4% to 0.7%
clinical determination must be made when choosing citrate parthenium parthenolide
over malate or pantothenate [44]. When choosing iron for a
patient with gastrointestinal upset [45], would the best choice
be ferric (citrate, sulfate) or ferrous (aspartate, fumarate, sul-
fate, gluconate) conjugates, and are these best delivered in rect part and therapeutic strength of the extract [36, 37, 48].
liquid, tablet, or fortified in food [46]? For example, with Camellia sinensis or green tea, identifying
To many, interpreting botanicals within dietary supple- that material as a leaf extract is very straightforward, since tea
ments is even more overwhelming when compared to vitamin is derived from or is the leaf product. Next is the therapeutic
and mineral ingredients [6, 36, 47]. Once the botanical thera- determination of a dose and delivery provided by a wide range
peutic is chosen based on the health indication, the genus and (10–50%) of total polyphenols or the individual green tea
species should be verified, and then a determination must be polyphenols, such as catechin, epicatechin gallate, epigallocat-
made to validate that the dietary supplement contains the cor- echin, gallic acid, and/or epicatechin [49]. Both the ranges (%)
Dietary Supplements: Understanding the Complexity of Use and Applications to Health
759 43
and content of polyphenols may vary widely. With Allium
..      Table 43.3  Common additives found in dietary supplements
sativum, or garlic, the consumer must distinguish between the
garlic bulb and oil, if it was extracted, and what percentage of Common additives Function Avoid or
common sulfur-­containing compounds (alliin, allicin, diallyl consider
sulfide, or ajoene) is represented in the product [50]. For all
botanical ingredients, high-quality products should clearly Butylated hydroxy- Preservative – pre- Avoid
toluene (BHT) vents oil oxidation
distinguish the part (aerial, bulb, fruit, leaf, herb, rhizome, or
root), as well as if there is a particular marker compound to Corn Starch, Binder/filler – absorbs Avoid
which the botanical ingredient has been standardized. Most modified moisture
should be clearly defined, such as Boswellia serrata gum FD&C Blue 1, Colorant Avoid
extract (standardized to alpha and beta boswellic acids), Yellow 6, Red 40
Curcuma longa rhizome extract (standardized to total cur- Gelatin Collagen containing Consider
cuminoids), Crataegus oxyacantha leaf and flower extract gelatin capsule
(standardized to total flavonoids), Coleus forskohlii root
Gellan gum Stabilizer-bacterial Consider
extract (standardized to forskolin), and Tanacetum parthe- fermentation
nium feverfew leaf extract (standardized parthenolide). It is
also important to consider that marker compounds [51] may Lactose Milk sugars – Consider; avoid
thickener, filler if intolerant
be different from the active compounds, if they are known,
and the product should be dosed accordingly. Magnesium Excipient, binder Avoid
Also as part of the manufacturing process, additives are stearate
commonly used to preserve, bind, absorb moisture, add Maltodextrin Thickener, filler – pre- Consider
color, smooth or distribute flavor, and provide a coating and vents crystallization
moisture barrier. See . Table 43.3. When selecting a product,
 
Microcrystalline Bulking agent and Consider
the educated consumer should question whether additives cellulose filler
are necessary, cause harm, or should be avoided if sensitive or
Parabens Preservative and Avoid
intolerant [52]. For example, gelatin, gellan gum, and micro-
anti-microbial agent
crystalline cellulose are naturally derived additives, whereas
butylated hydroxytoluene or BHT [53], polyethylene glycol, Polyethylene glycol Flavor distribution Avoid
(GRAS)
polyvinyl alcohol, and FD&C colorants are not [54]. Consider
if the effectiveness and quality of the dietary supplement are Polyvinyl alcohol Coating agent-­ Avoid
altered when individual additives are removed or remain in moisture barrier
the product. Additionally, as the dietary supplement market Silicon dioxide Anti-caking agent Avoid >2% by
continues to expand, manufacturers are constantly adding product weight
new products and formulations. This requires that healthcare
Talc Absorbs moisture, Avoid
providers and patients continually educate themselves and be debulking agent
aware of the benefits and risks of the individual ingredients
as well as therapeutic goal of the combined product.

genotoxicity testing be carried out on botanicals and herbal

43.6  The Role of Government Regulations supplements in initial clinical trials under an IND applica-
tion as an added layer of regulation and mechanistic testing.
Since DSHEA, government agency oversight of dietary sup- As products become more and more concentrated (pine-
plements and their regulation is complex and still evolving. apple vs bromelain or green tea vs L-theanine) and their bio-
The Congress of the United States granted authority to the logical activity enhanced through specialty delivery
FDA and FTC to provide oversight of manufacturing and mechanisms, the historical divide between drugs and foods
health claims on food labels as well as false advertising [29, and drugs become blurred. DSHEA allows manufacturers to
55, 56]. The FDA regulates foods, drugs, and cosmetics in distribute dietary supplements without having to prove safety
interstate commerce, and new drugs are not allowed to be and efficacy, so long as the manufacturers use good produc-
introduced into interstate commerce until they are proven tion practices and make no specific claims linking the supple-
safe and effective for their intended use. Foods have different ments to treating a specific disease state [55–57]. State laws
regulatory requirements and commonly bypass safety and also play a small role in the regulation use and ­distribution of
efficacy trials. Currently dietary supplements and botani- supplements through scope of practice, professional licen-
cal new drugs in the United States are entitled to a waiver sure, and malpractice coverage of prescribing healthcare pro-
when conducting preclinical and pharmacology/toxicology viders. Regarding licensure, each state has enacted unique
studies. As with new pharmaceutical drugs in development, medical licensing that prohibits the unlicensed practice of
genotoxicity testing is required. Due to the lack of metabolic medicine and thereby criminalizes activity by unlicensed pro-
safety data, the FDA and NIH are considering mandating that viders who offer healthcare services to patients. Similarly,
 760 E. R. Secor

scope of practice defines how these nutritional interventions patients. By asking straightforward commonsense questions
may be applied. Discussions of liability have arisen when pro- within the patient intake or via discussion, providers can
viders prescribe biologically active dietary supplements, engage patients, gain their trust, and learn about their home
which have drug-like activity (with potential side effects) but health habits and the degree to which they may be self-­
are regulated as food. The definitions of liability are no differ- prescribing appropriate or inappropriate dietary supplements.
ent in integrative medicine practice as compared general In investigating the attitudes and beliefs providers and
medicine; however, its application for use as a tool to provide patients have toward supplements, Tarn and colleagues [59]
legal protection and fill the regulatory gap produced by discovered that there were several topics that were identified
DSHEA raises novel questions that require consideration. as important to all parties. Summarized in 7 Box 43.3, all
 

The Food and Drug Administration’s Center for Food supplements should be discussed and the potential for
Safety and Applied Nutrition Adverse Event Reporting supplement-­ supplement or supplement-drug interactions
System, or CAERS [29], is one of the only mechanisms in outlined, and providers need to advise and provide an
which surveillance is carried out and reports on safety are evidenced-­ based opinion about the supplements their
generated. According to Schmitz, the CAERS reports were patients take. Patients have numerous concerns about dose
relatively small in number, had incomplete validation, and ranges, what is therapeutically optimal, and what, if any, risk
had inconsistencies within and are currently inadequate. He is there in overdosing. Physicians and the healthcare team
concluded that the concept and application of Nutravigilance ought to provide additional options or alternatives to pre-
or “the science and activities relating to the detection, assess- scription medications and discuss the accuracy of informa-
ment, understanding, and prevention of adverse effects tion acquired from outside sources. Lastly, there is an
related to the use of a food, dietary supplement, or medical increasing interest for consumers to understand more details
food” require the entire industry to be proactive, systematic, about such supplement characteristics as their composition,
and risk-based and must apply a scientific approach to all if they should be natural or synthetic, and their purity and
product safety. Only then can the public have full confidence quality.
that the products they choose are safe.

Box 43.3  Common Supplement-Related Topics

43.7  Supplement Selection and Education
Important to Providers and Patients
55 All supplements taken by a patient should be mentioned
In addition to suggestions from family and friends, patients during medical visits
who use dietary supplements are largely dependent on advice 55 Supplement-drug interactions and potential effects or
from online websites and manufacturer’s label claims, both adverse events should be discussed
of which tend to diminish useful information on potential 55 Importance of providers advising or providing an opinion
about supplements
prescription-­supplement interaction, which can be observed 55 Potential benefits and risks of overdosing on supplements
in the clinic [17, 58]. As outlined in 7 Box 43.2, ask patients
 
should be discussed
open-ended questions without judgment: Why are you tak- 55 Patients believed that doctors should talk about alterna-
ing this? Who suggested you take it? How did you arrive at tives to prescription medications
the product, dose, and form? Do you have clear expectations 55 Providers discuss accuracy of information (friends,
iInternet, television, other providers)
of health outcomes to be evaluated, and do you understand 55 Supplement characteristics, composition, purity, quality,
interactions or potential side effects? It is critical that patients natural or synthetic
discuss their intended or current use with their entire health-
care team and practitioners must be proactive in querying

43.8  Quality Control and Safety

43 Box 43.2  Questions to Ask When Taking Dietary One of the most concerning aspects of dietary supplements is
Supplements fully understanding quality control and being able to guaran-
1. Why am I taking this? tee product safety [32, 60–62]. There is an urgency to acquire
2. Who suggested I take this? reputable information assuring both that the individual is
3. What are the health or medical indications for use?
4. What dose and duration are appropriate?
selecting the best product for their health interest and that
5. What is the optimal form to take? manufacturers provide premium product formulated with
6. What other ingredients contribute or detract from the highest quality, safety, and stability. As an overview of
effectiveness? this process, consider the life cycle of a dietary supplement
7. Are there any safety concerns or interactions? or an individual ingredient as it goes into making single
8. Are laboratory tests required?
9. Do I have clear expectations of outcomes and need to
or combination products (. Fig.  43.1). In this example, we
 

reevaluate? will use Ananas comosus, the common pineapple. During

10. Do I understand signs of any potential side effects? every step of the process, the source product and extracted
material (bromelain, the enzymatically active pineapple
Dietary Supplements: Understanding the Complexity of Use and Applications to Health
761 43
..      Fig. 43.1  Life cycle of a
dietary supplement Lifecycle of a Dietary Supplement

DSHEA informs process 1. Grow

Harvest Verification of raw materials,
Manufacturers self-govern & follow good
Process marker compounds & quality
manufacturing practices,
by grower and/or broker
FDA & FTC inspect & review label claims
DSHEA
4.Blend 2. Export/
GMP
Bottle Import
FDA
Buy COA
FTC
QC passes manufacturer blends Grower/broker provides
& bottles, then sends out for 3. Quarantine Certificate of Analysis (COA)
product finish QC testing Q/C to importer or manufacturer
Testing

Manufacturer accepts COA or places

material in quarantine and sends out for
independent quality control (QC) testing

extract) require verification [63, 64]. Beginning with step One of the best series in understanding the complex
#1, the pineapple is grown and harvested and bromelain process of dietary manufacturing and quality control was
processed. Pineapple is verified through organoleptic tech- published in “Integrative Medicine: A Clinician’s Journal”
niques (inspection via sense organs such as sight, taste, odor from 2007 to 2009 [31, 65–68]. In this brief series, the issues
color, texture) to determine maturity and ripeness. To obtain of quality control and quality assurance are clarified.
bromelain, the primary raw material, mature stems are then “Simply put, quality control is conducting testing and per-
processed via maceration, centrifugation, extraction, and forming the procedures to ensure that established quality
drying. The marker compounds (bromelain) are verified specifications for raw material and finished products are
via high-­performance liquid chromatography (HPLC) and met. Whereas quality assurance is the strict regulation of all
Fourier-­transform infrared spectroscopy (FTIR) after which of the processes used to create the final product.” It is very
product activity or potency (strength of enzymatic activity) important to consider that a manufacturer may have a
is assessed. In step #2, this information, as well as basic qual- robust quality assurance program while actually conduct-
ity control testing (for heavy metals and microbial profile), ing very little quality controls testing. A dietary supplement
is summarized in a certificate of analysis (COA) by grower manufacturer can have established raw material, and fin-
and/or broker, and the product is available for import to the ished product specifications as part of a GMP certification
manufacturer. Upon acquiring the raw material, step #3, process have assurance processes in place, but some or all
the dietary supplement manufacturer decides to accept the its products may not meet standards of acceptable quality
COA and may begin product formulation, or the material control. Such products can be low or high potency, con-
is placed into quarantine and independent quality control taminated, and adulterated (contain unwanted ingredients
(QC) testing begun. This is one of the key differentiators such as pharmaceutical drugs) and have poor stability and
of what determines the quality of finished products on the lose potency over the duration of their shelf life. Consider
shelf. Since many of the raw materials, such as bromelain, that the FDA cGMPs do not mandate that manufacturers
are supplied by the same companies, it is the verification and establish high-quality specifications; they just must meet
validation of the COA and by testing each lot that makes specifications, which may unfortunately turn out to be low
the difference. Once the product passes this secondary QC quality.
testing, the manufacturer can, in step #4, blend, formulate,
bottle, and send out the finished product for one final round
of authentication testing. Those companies that pay for test- 43.9  Engaging Manufacturers
ing of each lot of every ingredient that they use are generally
very willing to share this information. Lastly, this life cycle One of the best ways to ensure that dietary supplements are
of a dietary supplement, albeit complex, is similar for almost of highest quality is to ask the salesperson to differentiate
all ingredients described under DSHEA. The manufacturers between products or directly ask the manufacturer to
largely self-­govern and are required to follow good manu- answer your questions. As practitioners, patients, or provid-
facturing practices. The FDA can inspect facilities and hold ers who use dietary supplements, the goal is to ensure that
manufacturers accountable for documenting and maintain- products exceed all regulatory requirements and are clini-
ing strict oversight of the life cycle, whereas the Federal Trade cally effective and safe for use. It is difficult to improve
Commission reviews label claims and issues surrounding health and succeed without reputable, high-quality materi-
advertising. als and services. Therefore, we want to work with outstand-
 762 E. R. Secor

ing dietary supplement manufacturers and their products 43.10  Clinical Relevance and Controversies
that meet and exceed national standards set forth by
DSHEA, FDA and USP, and GMP and published in the Fed- The health outcomes and clinical benefits attributed to
eral Register. It is good to recognize suppliers who provide dietary supplements remain highly controversial and debated
legitimate proof through documentation that their products topics. It is important to note that the field is regulated (see
consistently meet label claims, are authentic, and lack con- 7 Box 43.5). In terms of the general benefit to society and
 

tamination or adulteration and assure raw material and fin- individual populations, there are numerous studies which
ished product authenticity and stability. When trying to suggest that dietary supplements may improve overall health
ensure that the supplements you are taking are safe, here are and specific aspects of quality of life. A report by the US
ten questions to consider asking dietary supplement manu- Centers for Disease Control and Prevention suggests that
facturers (7 Box 43.4). This list is a summary from Dr. Liva’s
 
three in ten people experience selected nutritional deficien-
quality control and quality assurance series, which provides cies [69]. Blumberg et  al. reviewed nutrient intake data in
a more comprehensive and detailed list in the Supplier Cer- more than 10,000 adults recorded in the National Health and
tification Questionnaire, which he created and is accessible Nutrition Examination Surveys and determined that, as
online [65, 67, 68]. compared to food alone, the added use of dietary supple-
ments significantly increased an average of 15 out of 18 nutri-
ents assessed and reduced nutrient inadequacy rates [69].
Box 43.4  Ensuring Supplement Quality via Elia and colleagues examined the cost-effectiveness of using
Manufacturer-­Directed Questions nutritional supplements (energy-/protein-enriched func-
1. Does your quality control department have the authority to tional foods, vitamins, and/or minerals) in community and
approve and reject procedures, specifications, test methods home care environments [70]. Their group conducted a sys-
and results, raw ingredients and components, finished tematic review of high-quality publications and found that
ingredients, packaging materials, and labels?
both short-term and long-term use produced significant cost
2. Do you have a cGMP system? Which do you follow: Ffood
cGMPs or FDA cGMPs for dietary supplements? savings. In addition to cost benefits, the authors noted clini-
3. Have you been independently certified for cGMP compli- cally relevant benefits such as improved quality of life, lower
ance via USP, NSF, and/or NPA? infections, and postoperative complications.
4. Do you use an in-house lab or contract lab? How are they
audited?
5. When conducting testing of raw materials, are they checked
for microbiology profile (bacteria, yeast, and mold), identity Box 43.5  Government, Regulatory, and Association
(authenticate material or botanical genus and species), Resources
potency (if potency claim exists), heavy metals (lead, 55 National Institutes of Health Office of Dietary Supplements:
mercury, cadmium, arsenic), chemical solvent residue, 7 https://ods.­od.­nih.­gov/HealthInformation/makingdeci-
 

aflatoxins, and herbicide and pesticide residue? sions.sec.­aspx NIH ODS provides a variety of information
6. Do you accept a certificate of analysis (COA) in lieu of for consumers, researchers, and professionals including
independent testing of raw materials? dietary supplements fact sheets, consumer safety updates,
7. Are your finished products tested for label claim potency and a dictionary of terms used throughout healthcare and
prior to release for sale? supplement industry
8. Do you put expiration dates or a use-by date on your 55 The National Center for Complementary and Integrative
products? Health (NCCIH): 7 https://nccih.­nih.­gov/ NIH center
 

9. Do you conduct label claim stability testing, verifying focused on scientific research into diverse medical and
product through its expiration date? healthcare systems, practices, and products
55 The National Cancer Institute Office of Cancer
Complementary and Alternative Medicine (OCCAM):
7 https://cam.­cancer.­gov/ NCI’s office focused on research
 

Reputable manufacturers should be able to provide written in CAM relating to cancer prevention, diagnosis, treat-
ment, and symptom management
examples of #2, #3, #5, #8, #9, and #10 (7 Box 43.4) above
43  

by providing the testing information for two or three lots of

55 The US Food and Drug Administration: 7 https://www.­fda.­
 

gov/Food/DietarySupplements/ Information for consum-

a random product you select from their catalog. The manu- ers and industry on dietary supplement products,
facturers may need assurance that this is for patient safety ingredients, recalls, and adverse event reporting
and educational purposes only and, if reputable, should 55 The Herbal Medicine Institute and the American Botanical
Council: 7 http://abc.­herbalgram.­org/site/PageServer
respond quickly. It has been the experience of the author
 

Council provides reliable information on botanicals and

that if companies readily conduct these tests, PDFs can be natural products and advocates for consumers and industry.
emailed within 2–24 hours. If companies choose to exclude 55 Consumer Healthcare Products Association (CHPA):
product details that may reveal intellectual property on a 7 https://www.­chpa.­org/ CHPA advocates for consumers
 

research or patent basis, then select another basic product and industry and provides educational tools to ensure safe
use of dietary supplements and OTC medicines
from their catalog, such as a multivitamin, B complex, or a 55 Dietary Supplement Label Database: 7 http://dsld.­nlm.­nih.­
 

1–5 botanical combination, to determine the degree to which gov/dsld/ Searchable database of ingredients, products,
the manufacturer is adhering to or exceeding quality control and ~2500 manufacturers
testing standards.
Dietary Supplements: Understanding the Complexity of Use and Applications to Health
763 43
There is also growing clinical evidence for the use of select
categories of supplements in well-defined clinical popula- Box 43.6  Peer-Reviewed Journals
tions. For example, the effect of dietary prebiotics on gut 55 Journal of Natural Products: 7 http://pubs.­acs.­org/journal/
 

jnprdf
microflora and metabolism in human subjects was reviewed
55 Journal of Dietary Supplements: 7 http://www.­tandfonline.­
by Kellow and Reid [71, 72]. In 26 trials with more than 830
 

com/toc/ijds20/current
subjects, prebiotics were found to significantly reduce post- 55 The American Journal of Clinical Nutrition: 7 http://  

prandial glucose and insulin, whereas effectiveness against ajcn.­nutrition.­org/

lipids, inflammatory markers, and immune function was 55 Journal of Nutrition: 7 http://jn.­nutrition.­org/
 

55 Advances in Nutrition: 7 http://advances.­nutrition.­org/

inconsistent. Green tea and its polyphenols have been deter-  

55 Journal of the American College of Nutrition: 7 http://

mined to have numerous beneficial health effects [49]. Tea
 

www.­americancollegeofnutrition.­org/content/the-journal
and its extracts act as antioxidants, reduce oxidative stress, 55 Journal of Medicinal Food: 7 http://www.­liebertpub.­com/
 

provide defense against inflammation in cardiovascular dis- overview/journal-of-medicinal-food/38/

ease, and modulate key metabolic pathways such as NF-kB 55 The Chemistry of Natural Compounds: 7 https://link.­  

springer.­com/journal/10600
and cyclooxygenase. Mechanistic studies have implicated a
55 Natural Product Reports: 7 http://www.­rsc.­org/journals-
role for green tea in inflammatory bowel disease, apoptosis,
 

books-­databases/about-journals/npr/
neurodegeneration, fatty liver disease, cognitive function, 55 Natural Product Research: 7 http://www.­tandfonline.­com/
 

and metabolic weight loss. toc/gnpl20/current

Turmeric, or Curcuma longa, has a long history of thera- 55 Journal of Nutrition and Diet Supplements: 7 http://  

www.­scienceinquest.­com/journal-of-nutrition-and-diet-­
peutic use as a natural botanical in the Indian healing system
supplements/journal-home.­php
of Ayurveda. In modern times, turmeric and its concentrated 55 Evidence-Based Complementary and Alternative Medicine:
extracts are being investigated for its ability to act as an anti-­ 7 https://www.­hindawi.­com/journals/ecam/
 

inflammatory agent and improve dermatologic diseases [73], 55 BMC Complementary and Alternative Medicine: 7 https://  

radiation-induced dermatitis [74], and arthritis [75]. Due to bmccomplementalternmed.­biomedcentral.­com/

55 Journal of Pharmacognosy and Natural Products: 7 https://
a lack of comprehensive and definitive research on efficacy,  

www.omicsonline.­org/pharmacognosy-natural-products.­php
some investigators are calling for the public to abstain from
use curcumin until both the benefits and potential side effects
are thoroughly documented [76]. In addition to turmeric,
one of the most commonly used and top selling herbs (from ners can check for regular FDA online alerts on fraudulent,
. Table  43.1) is Withania somnifera, or Ashwagandha, also
  adulterated, or contaminated supplements at 7 fda.­gov.  

known as Indian ginseng. The therapeutic use of Examples of products which have received warnings include:
Ashwagandha spans psychiatric disorders to fertility. Modern 1. Sexual enhancement: Tyrannosaurus (contained Viagra),
research is beginning to validate its plant extracts to support Rhino 69 (contained sildenafil), Triple Green Capsules
patients in obsessive-compulsive disorder [77], fertility [78], (contained Viagra), Big Penis Male Sexual Stimulant
sexual function [79], and anxiety [80]. (contained Viagra), Black Mamba (contained Viagra),
When reviewing the strength of the literature and drawing Kingdom Honey for Him (contained Cialis), African
clinical conclusions on individual supplements or categories, Viagra (contained Viagra), Duramaxxx (contained
consider the robustness of the research design. 7 Box 43.6
  Viagra), My Steel Woody (contained Viagra), and Own
lists some common peer-reviewed sources for information. Is the Knight 1750 (contained tadalafil and dapoxetine).
the research conducted in cell culture systems, in acceptable 2. Weight loss: Asia Slim (contained sibutramine, diaz-
preclinical or translational animal models, with human sub- epam, and bisacodyl), Queen Slimming Soft Gel
jects as uncontrolled observation study, or in an experimental (contained fluoxetine and sibutramine), Physic Candy
research design (the most rigorous) such as a prospective ran- (contained sibutramine), Skinny Bee Diet (contained
domized controlled trial [81]? Before making final judgments ­desmethylsibutramine), ABX Weight Loss (contained
on clinical application, also take into consideration if the sibutramine), Ultimate Lean (contained sibutramine),
dietary supplement product categories are generally consid- Dream Body Extreme Gold (contained sibutramine,
ered safe and supportive to the clinical area of concern. fluoxetine, and sildenafil), Ultimate Body Tox (contained
In addition to the numerous potentially beneficial dietary sibutramine), and Fruta Planta Life or Garcinia
supplements listed above, there remain several controversial Cambogia Premium (contained sibutramine).
categories that should be avoided. The majority of complaints 3. Sports/fitness: the 7 bodybuilding.­com company alone
 

to both FTC and FDA come from the dietary supplement conducted a nationwide recall of more than 50 supple-
specialty areas of sexual enhancement [82–88], weight loss ments because of possible adulteration by prescription
[89–93], and sports/fitness [94–98]. Complaints in these cat- and nonprescription steroids marketed as “Superdrol,”
egories range from false advertising, overaggressive sales tac- “Madol,” “Tren,” “Androstenedione,” and/or “Turinabol.”
tics, and unsubstantiated health claims to product Other individual products to avoid include Msten
adulteration, contamination with prescription medications, Extreme Mass Builder, Penta Built, Cannibal Pro Cutting
“filler” dietary supplements, unnecessary window dressing, Stack, Mass Destruction, Mayhem and Wolverine
or poor-quality and untested product. Healthcare practitio- Xtreme, or Beast Stack.
 764 E. R. Secor

If the pitches and marketing, such as a 110% money back from manufacturers within the nutraceutical marketplace.
guarantee, or the product itself seems too good to be true, Product safety depends on numerous factors which include
then it probably is [48, 59]. It is important to use common growing conditions, herbicides and pesticides used in cultiva-
sense by avoiding these categories of dietary supplements tion, formulation, additives, importation, the manufacturing
altogether and focusing on lifestyle modification such as processes and the use of multistage testing procedures, as well
healthy diet, exercise, stress reduction, and maintaining as industry manufacturing and government regulation. Those
proper sleep-work balance. manufacturers, who are reputable and of high quality, who
Clinically it is critical to address the patient’s interest in utilize good manufacturing practices, and who perform inde-
these products and bring questions back to the entire health- pendent quality control testing, should make testing results
care team. An appropriate care plan may include laboratory available (barring any intellectual property issues) for each lot
testing that could rule in or out the need for taking specific that they manufacture. Many will provide this information
nutrients, as well as aid in product dosage, duration of use, directly to the healthcare practitioner, which is critical to truly
and need for retesting. It is now common to test for many ensure product quality. In order to avoid unwanted exposure
vitamins and minerals, such as B6, B12, iron, zinc, magne- to adulterated and potentially contaminated dietary supple-
sium, calcium, and specialty supplements that may be related ments, avoid the “terrible three” categories which include
to biologically active biomarkers (homocysteine, folate, sexual enhancement, weight loss, and sports and fitness. Also
CoQ-10, essential fatty acids), as well as for steroid hormone avoid products that advertise by way of 2:30  a.m. infomer-
cascades (DHEA, pregnenolone, testosterone, and cortisol). cials. Acquiring a more comprehensive understanding of the
Also, with increasing age and prescription drug use, the dietary supplement landscape will help to ensure safer use,
potential for interactions increases. Evaluating the potential improve the clinical experience for those participating in
mechanisms of action of supplements and their pathways of healthcare, and maximize opportunities for health benefits.
detoxification, such as inhibition or induction of Cytochrome
P450 enzymes (CYP450), may be critical, especially for those
on life-sustaining medications which act through similar References
pathways. For supplements to be the most clinically relevant
and beneficial, they should be used with good clinical judg- 1. Cohen MH.  Complementary and integrative medical therapies,
ment in the context of the best available information. the FDA, and the NIH: definitions and regulation. Dermatol Ther.
2003;16:77–84.
2. IOM report. Complementary and alternative medicine in the United
States. National Academies Publication. Washington, D.C. 2005. http://
43.11  Summary www.­nationalacademies.­org/hmd/Reports/2005/Complementary-
and-Alternative-Medicine-in-the-United-States.­aspx.
For consumers and patients who commonly use integrative 3. Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the
medicine modalities, the overall goal of adding dietary sup- use of complementary health approaches among adults: United
States, 2002–2012. Natl Health Stat Report. 2015;79:1–16.
plements into a treatment plan is to maintain health, prevent
4. Radimer K, Bindewald B, Hughes J, Ervin B, Picciano MF. Dietary sup-
future health issues, lower the risk of requiring heroic inter- plement use by US adults: data from the National Health and nutrition
ventions, and reduce reliance on prescription medication. examination survey, 1999–2000. Am J Epidemiol. 2004;160(4):339–49.
The added goals of the treatment team are to help patients 5. Nahin RL.  Expenditures on complementary health approaches:
navigate the complex and fast-moving regulatory terrain of United States, 2012. Natl Health Stat Report. 2016;(95):1–11.
6. Egan B, Hodgkins C, S