F

MK
INTERNAL
MEDICINE
&
CLINICAL
SKILLS

MOSES KAZEVU
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MK INTERNAL MEDICINE &

CLINICAL SKILLS
By: Moses Kazevu

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FOREWORD
This review book is designed for use by medical students and the junior medical
doctor in the diagnosis, management and curative care of regional Adult internal
medicine conditions.
The book serves as a good guide and revision tool for board/shelf/licentiate
examinations.
Effort has been put in to simplify the literature and make it as practical as possible
while maintaining scientific accuracy.
Despite all efforts, it is possible that certain errors may have been overlooked in this
book. Please inform the authors of any errors detected.
NOTE: Information contained in this publication is copyrighted as such
photocopying of any part of this book without any written permission from the
author is prohibited by Law.
MOSES KAZEVU
(Tel: +260979161345)

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Contents
INTRODUCTION TO BEDSIDE MEDICINE ........................................................6
HISTORY TAKING ................................................................................................16
PHYSICAL EXAMINATION.................................................................................27
CARIDOVASCULAR CONDITIONS ...................................................................33
HEMATOLOGICAL CONDITIONS ...................................................................219
RESPIRATORY CONDITIONS ...........................................................................187
GASTROINTESTINAL CONDITIONS ...............................................................251
LIVER AND BILIARY TRACT DISEASE .........................................................298
RENAL CONDITIONS .........................................................................................308
ENDOCRINE CONDITIONS ...............................................................................345
NEUROLOGY .......................................................................................................391
INFECTIOUS DISEASES.....................................................................................486
MISCELLANEOUS ..............................................................................................575
RADIOLOGY ........................................................................................................614
COMMON PROCEDURES ..................................................................................619
COMMONLY USED DRUGS ..............................................................................627
TEST YOURSELF ................................................................................................630
ANSWERS TO TEST YOURSELF ......................................................................674

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INTRODUCTION TO INTERNAL MEDICINE

INTRODUCTION TO BEDSIDE MEDICINE

 The word “Patient” is derived from experience and there is always
the Latin “patiens”, meaning something new to learn.
sufferance or forbearance.  Initial aims of any first consultation
 In order to relief this suffering (the are to understand the patient’s own
purpose of medicine) it is perception of their problem and to
imperative that: start or complete the process of
 A diagnosis is made to know diagnosis.
how to approach treatment and  This requires sufficient
design an appropriate scheme knowledge of the disease and
of management for each its patterns of presentation,
patient. together with an ability to
 It is also important to understand interpret a patient’s signs and
each person fully (with every social symptoms.
class or ethnic and cultural  Difficulties posed by assessing the
background). patients themselves, or by the
 The role of the doctor is not only to variety of cultural and ethnic
elucidate the problems posed by backgrounds found in modern life
disease but also apply his or her must be accepted and factored into
skill to advise patients and families the interpretation of the data
how to manage these problems. acquired during the consultation.
 No patient should leave a medical  There are two main steps to making
consultation feeling that nothing a diagnosis:
can be done to help them, even a. To establish the clinical
when the disease is incurable. features by History taking and
 Clinical methods are the skills Examination-Clerking.
doctors use to achieve this aim of b. To interpret the clinical
excellence in clinical practice. database in terms of disordered
 Clinical methods are acquired by a function and potential
combination of study and causative pathologies.

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SETTING THE SCENE name that is very common in the

 Most medical consultations occur local community.
not only in the wards but in an  Carefully check the full name, date
outpatient or primary care setting. of birth and address. Make sure any
 A suitable environment, waiting previous records you have are those
area and all the associated staff of the correct patient, not of
makes the process of clinical someone else with a similar name.
diagnosis easier.  It is important that both patient and
 Meeting the patient in the waiting doctor feel at ease and neither feels
room allows the doctor to make an threatened by the encounter.
early assessment of their demeanor,  Avoid having patients full-face
their hearing, their walking and any across a desk.
accompanying persons.  Note-taking is important during
 Offer a greeting and make an consultations while being able to
introduction. see the patient and establish eye
 Patients are easily confused by contact and to show sympathy and
medical titles and hierarchies. awareness of their needs during the
Quickly assess the following discussion of symptoms, many of
questions: which may be distressing or even
 Does the patient smile or embarrassing.
appear furtive or anxious?  Arrange the seating so that it is
 Do they make good eye clear the patient is the center of
contact? attention rather than any others
 Are they frightened or present.
depressed?
 Are posture and stance
normal?
 Is the patient short of breath or
wheezing?
 In some conditions e.g. congestive
heart failure (CHF), uremia, severe
jaundice etc. the nature of the
problem is often immediately
obvious.
 It is important to identify the patient
correctly, especially if they have a

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COMMUNICATION
 Communication is of two types: Verbal communication and Non-verbal
communication.
NON-VERBAL COMMUNICATION
 Non-verbal communication is as important as what the patient says.
 There may be obvious contradiction e.g. a patient who does not admit to any
worries or anxieties but who clearly looks as if they have many.
 Particular gestures during the description of pain symptoms can give vital clinical
clues. (See box 1)
 While concentrating on the conversation with the patient, the doctor should
remain aware of other clues.

BOX 1
Particular gestures useful in analyzing specific pain
symptoms
 A squeezing gesture to describe cardiac pain
 Hand position to describe renal colic
 Rubbing the sternum to describe heartburn
 Rubbing the buttock and thigh to describe
sciatica
 Arms clenched around the abdomen to
describe midgut colic

VOCABULARY
 It is important to use vocabulary the patient will easily understand and use
appropriately.
 The patient must understand the basic words used and their interpretation of those
words must be understood and clarified by the doctor. (See Box 2)

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BOX 2
Words and phrases that need clarification:
 Ordinary English words: Diarrhea, Constipation,
Wind, Indigestion, Being sick, Dizziness,
blackouts, headache, double vision, pins and
needles, rash and blister

 Medical terms that may be used imprecisely by

patients: Arthritis, Sciatica, Migraine, Fits, Stroke,
Palpitation, Angina, Heart attack, Diarrhea,
Constipation, Nausea, Piles/hemorrhoids, Anemia,
Pleurisy, Eczema, Urticaria, Warts, Cystitis

 If the patient uses one of the ordinary English words listed in the box above their
meaning must be clarified.
 A patient who says they are dizzy could be describing actual vertigo, but
could just mean light-headedness or a feeling that they were going to faint.
 A patient saying that they have diarrhea could mean liquid stools passed
hourly throughout the day and night, or could mean a couple of urgent soft
stools passed first thing in the morning only.
 The doctor needs to use words that are almost certainly going to be clearly
understood by the patient and must clarify any word or phrase the patient uses to
avoid any possibility of ambiguity.

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INDIRECT AND DIRECT QUESTIONS
 Questions asked by the doctor can be divided into:
 Indirect or open-ended questions
o Serve as an invitation for the patient to talk about the general area that
the doctor indicates is of interest.
o These questions often start with phrases such as ‘Tell me more about’,
‘What do you think about”, ‘How does that make you feel’, ‘What
happened next’ or ‘Is there anything else you would like to tell me’.
o These questions inform the patient that the agenda is very much with
them, that they can talk about whatever is important, and that the doctor
has not prejudged any issues.
o If skillfully used, and if the doctor is sensitive to the clues presented in
the answers, a series of such questions should allow the doctor to
understand the issues that are most important to the patient.
o The patient will also be allowed to describe things in their own words.
Always listen carefully, and maintain eye contact. Do not take too many
notes!
 Direct or closed questions
 Many patients are in awe of doctors and have a conscious or subconscious need
to please and agree.
 If the doctor prejudges the patient’s problem and tends to direct the conversation
to fit the diagnosis that they have assumed too early, the patient can easily go
along with this and give simple answers that do not fully describe the situation.
The box below shows the extremely simple, common and important pitfall of
history taking. (See Box 3, Table 1.1 and Table 1.2)

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BOX 3
A general practitioner (GP) is seeing a 58-year-old man who
is known to be hypertensive and a smoker. The receptionist
has already documented that he is coming with a problem of
chest pain. The GP makes an automatic assumption that the
pain is most likely to be angina pectoris, because that is
probably the most serious possible cause and the one that
the patient is likely to be most worried about and starts
taking the history with the specific purpose of confirming or
refuting that diagnosis.

Table 1.1: Direct questioning

GP: I gather you’ve had some chest pain? The GP has only asked
Patient: Yes, it’s been quite bad. very direct and closed
GP: Is it in the middle of your chest? questions. Each answer
Patient: Yes. has begun with “Yes”.
GP: And does it travel to your left arm? The patient has already
Patient: Yes- and to my shoulder been quite firmly tagged
GP: Does it come on when you walk? with a ‘label’ of angina,
Patient: Yes. and anxiety has been
GP: And is it relieved by rest? raised by the specialist
Patient: Yes-usually. referral.
GP: I’m afraid I think this is angina and I will
need to refer you to a heart specialist.

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Table 1.2: Indirect questioning

GP: Tell me why you have come today. The GP has asked questions
Patient: Well, I have been having some which are completely open-
chest pain ended or leave the patient free
GP: Tell me more about what it’s like. to describe exactly what
Patient: It’s in the center of my chest and happens within a directed area
tends to go to my left arm. of interest. Clarifying questions
Sometimes it comes on when I’ve have been used. While being
been walking. reassuring, the GP expresses
GP: Tell me more about that. some concern about angina and
Patient: Sometimes it comes when I am is clear about the exact reason
walking and sometimes when I’m for the specialist referral (for
sitting down at home after a long clarification).
walk.
GP: If the pain comes on when you are
walking, what do you do?
Patient: I usually slow down, but if I’m in a
hurry I can walk on with the pain.
GP: I am a little worried that this might
be angina but some things suggest
it might not be, so I am going to
refer you to a heart specialist to
make sure it isn’t angina.

PATIENTS, ACCOMPANYING PERSONS AND

ADVOCATES
ANGRY PATIENTS
 Not all patients are overtly angry when they see a doctor, but anger expressed
during a consultation may be an important diagnostic clue while at the same time
getting in the way of a smooth diagnostic process.
 It is always important to acknowledge anger, try and discover what underlies it,
and apologize for simple things such as late running.
 In some patients, anger may be part of the symptomatology, or expressed as a
reaction to the diagnosis or treatment.

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THE WELL-INFORMED ACCOMPANYING PERSONS

PATIENT  Some people come to consultations
 20 or more years ago doctors often alone, others with one or more
looked after patients for a long time friends or family members.
without really explaining their  Always spend time during the
illness to them, and patients were initial exchange of greetings to
reasonably happy about this, taking identify who is present and to get
the attitude that ‘the doctor knows some idea of the group dynamics.
best’.  There is always a reason why
 This approach is now unacceptable people come accompanied but if
and the doctor must give the patient there appears to be too many people
as much information about their present or if the presence of others
illness as possible, particularly so might threaten the relationship with
that they can make informed the patient at any time in the
choices about treatments. consultation, it is appropriate to
 This change of approach has led to consider asking the others to leave,
many patients seeking information even if only briefly.
about their problems from other  Consider whether specific
sources, particularly the internet. questions about history should be
 The doctor should thus go through asked of those accompanying,
the information with the patient and either with the patient or separately
help them by showing what is with specific consent.
relevant and what is not.  Beware of a situation where the
 Generally, it is much easier and accompanying people answer all
more rewarding to look after well- the questions, even if there is no
informed patients, provided they do language difficulty.
not fall into the very small group  Reasons for this may include
who have such fixed and erroneous embarrassment in front of those
ideas about their problems that the accompanying, such as a teenager
diagnostic and treatment process is accompanied by parents. In such
impeded. circumstances it may be necessary
to leave parts of the history until
those accompanying can be
reasonably asked to leave.

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USING  This leaves the doctor bemused as
INTERPRETERS/ADVOCAT to what is really going on.
ES  History taking via an
 Consultation has to be undertaken advocate/interpreter usually takes
with the help of an interpreter. much longer than when the doctor
and the patient speak the same
 The most immediate solution may
language.
be to use a family member, but if
the issues are private or
embarrassing this often does not
work well and it is generally unwise
to use an underage family member
as an interpreter.
 The best solution is to have
available an independent
interpreter/advocate for the
consultation, although in areas
where many patients are not native
speakers, many such interpreters
may be needed for a range of
languages.
 The history taken via an interpreter
or advocate may be quite limited in
subtlety by the exigencies of the
double translation, and the doctor
therefore often utilizes a much
more direct style of questioning for
which the answers will be
unambiguous.
 Unfortunately, it is not unusual for
the interpreter/advocate and the
patient to have a few minutes of
conversation following an
apparently simple question from
the doctor but then a very short
answer is returned to the doctor.

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CLARIFYING DETAIL
 One of the basic principles of history taking is not to take what the patient says
at face value but to clarify it as much as possible.
 Almost all of the history will involve clarification, but there are specific areas
where this is particularly important.
PAIN
 Whenever a patient complains of pain you should follow a series of clarifying
question such as (‘SOCRATES’):
 S-site
 O- onset
 C-Character
 R-radiation
 A-alleviating factors
 T-time course
 E-Exacerbating factors
 S-severity and symptoms (Associated)
 Of all symptoms, pain is perhaps the most subjective and the hardest for the
doctor to truly comprehend.
 Some painful conditions have a classic site for the pain and the radiation
 Myocardial ischemia is classically felt in the center of the chest, radiating to
the left arm
 Pain from a hollow organ is classically colicky (such as biliary or renal colic)
 The pain of subarachnoid hemorrhage is classically very sudden, ‘like a
hammer blow on the head’
 Some pains have clear aggravating or relieving factors
 Duodenal ulcer pain is classically worse when hungry and better after food.
 Gastric ulcer pain is classically worse during feed and better during hunger.
 Pain for pericarditis is worsened by laying down and relieved by sitting and
leaning forward
 Colicky right upper quadrant abdominal pain accompanied by jaundice suggests
a gallstone obstructing the bile duct, headache accompanied by preceding
flashing lights suggests migraine.
 Some of these points will come out in the open-ended part of the history taking,
but others will need specific questions.

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HISTORY TAKING

HISTORY TAKING
 History taking is immensely skilled and fascinating.
 The medical history is the foundation of internal medicine. The answer to the
patient’s problems is in the history 90% of the time! The other 10% of the time,
you will need to use investigations to help you figure the answer out.
 The extent of which history taking skill increases with experience is much greater
than that for clinical examination.
 It is an art that has to be mastered to reach correct diagnosis.
 The sequence of history taking includes:
1. Collection of demographic data (i.e. name, age, sex/gender, residence,
religion, marital status)
2. Presenting complaints (Complaining of-C/O)
3. History of presenting complaints (Development of history) (HxPC)
4. Review of systems (ROS)
5. Past medical history (PMHx) and Past surgical history
6. Drug history and Allergies (specially to drugs and other allergies to other
material)
7. Family history
8. Social-economic history
9. Summary of history

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COLLECTION OF DEMOGRAPHIC DATA

 The process of history taking may begin by reading any referral documentation
and with the immediate introduction of doctor and patient.
 Collection of demographic data includes asking questions involving the patient’s
details i.e. name, age, sex/gender, residence, religion, tribe and marital status.
 Collection of this information is vital in leading to the correct diagnosis for
example, patients of a certain age, sex or even region of residence are prone to
certain diseases and conditions.
o Example 1: A Patients from the Eastern province presenting with signs
and symptoms of hepatocellular carcinoma is most likely to have this
malignancy. This is due to the storage of the groundnuts in the region
which happen to contain afla-toxins produced by Aspergillus that
participates in the development of this type of malignance.
o Example 2: Most patients with sickle cell are from Northern, and
Luapula province (i.e. the Bembas).
o Example 3: Most patients with benign prostatic hypertrophy are from
southern province (due to excessive use of herbal medicine to enhance
sexual activity in an attempt to satisfy their polygamous marriage
practices).
o It is also important to know that most malignancies are most likely to
occur at a certain age.
 With this demographic data, the physician is given a rough idea of how the
presenting complaints could most likely be linked with certain factors such as
age, sex, region of residence and tribe.
 The patient should be informed about the ongoing order of things in-order to
prevent them from feeling that their pressing problems are being ignored.
 A statement along the lines of ‘Before we discuss why you come today, I
want to ask you some background questions’ should inform the patient
satisfactorily.
 It is also important to indicate whether this is a hospital referral or a self-referral
along with the date and time of which the history was taken.

PRESENTING COMPLAINTS
 Once social introductions are established the doctor will usually begin with a
single open-ended question along the lines of ‘Tell me what has led to you
coming here today.’

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 This gives the patient a chance to begin with what they feel is most important to
them and avoids any pre-judgement of issues or exclusion of what at first may
seem less important.
 At this stage the patient may be very anxious and nervous and still making
their own assessment of how they will react to the doctor as a person.
 Therefore, a beginning that focuses on issues that may be more factual and
less emotive (emotional) can be more rewarding and lead to a more
satisfactory consultation.
 Try to understand the patient’s mood: sometimes the response to your initial
question will be vague or concrete or even hostile; the latter suggests emotional
conflict and needs to be talked through.
 It is very tempting to interrupt too early but once interrupted the patient rarely
completes what they were intending to say.
 Even when they seem to have finished giving their reasons for the
consultation always ask if there are any broader areas that still need
discussion before discussing each in detail.
 Complaints must be in chronological order and should be recorded in the patient’s
own words.
 Taking the history along a “time-line” will often build up a much better picture
of all the patient’s problems, how they have developed and how they now interact
with their life and work.
 It is also of importance to enquire about the duration of the complaint.
 These can be written in point form for example:
 Cough complaints 2/52
 Writing the duration of the complaint must be in a particular manner e.g. 1/7
representing 1 day, 2/52 representing 2 weeks, or 4/12 representing 4 months.

HISTORY OF PRESENTING COMPLAINTS

 This should be a story about how the symptoms developed. Use the patient’s own
words as much as possible.
 Avoid medical terminology (like the word ‘angina’) unless the patient actually
uses that word and when the patient uses medical terms it should be place in
inverted commas e.g. ‘orthopnea’.
 Usually a patient will say “chest pain” instead of “angina”.

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 Begin with the earliest symptoms related to the chief complain and proceed
chronologically.
 For example: “The patient described chest pain when walking up a hill four
weeks ago. This resolved with rest and recurred with activity. Eventually the
chest pain subsided and the patient began to experience shortness of breath
when walking short distances. One week ago, the patient began to notice that
they were short of breath when lying flat and began having swelling of his
legs.”
 Ask the patient to explain the illness in detail including:
 Mode of onset: acute, subacute or insidious
 Duration of illness
 Whether the disease has progressed or remains the same
 Associated symptoms
 Aggravating and relieving factors
 Positive history to rule out (r/o) involvement of other systems
 The history of presenting complaints must exhaust all possible symptoms of the
presenting symptoms for example if a patient presents with diarrhea for a duration
of 2 days, the history of presenting complaints must focus on the gastrointestinal
system.

REVIEW OF SYSTEMS
 This is done in order to find out any other possible symptoms that may have been
left out as well as to gather more details about the affected system of the
presenting problem.
 The system that is involved in the presenting complaint should be reviewed
within the history of presenting complaints.
 Usually the review of systems (ROS) is done from head to toe (Central nervous
system [CNS], Cardiovascular system [CVS], Respiratory system [RS],
Gastrointestinal tract [GIT], Genitourinary system [GUT], Musculoskeletal
system and skin [MSS]).
 Review every system every time you take a history, but when you present the
patient, only mention the ones that are important negatives and positives related
to the presenting complaint.
 If you don’t know which systems are relevant to the history of presenting
complaint, it is always better to include more information than less.

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DIRECT QUESTIONS ABOUT BODILY SYSTEMS
 Many diseases have features occurring in several bodily systems that at first may
not seem to be related to the patient’s main complaint.
 For example, a patient presenting with back pain may have had some hematuria
from the renal cell carcinoma that has spread and is causing pain.
 For this reason, any thorough assessment must include questions about all bodily
systems, and not just areas that the patient perceives as problematic.
 This area of questioning should be introduced with a statement such as ‘Now I
am going to ask you some extra questions.’
Table 2.1: Bodily systems and questions relevant to taking a full history from most patients. If the
specific questions have been covered by the history of the presenting problem, they do not need to
be included again. If the answers are positive then the characteristic of each must be clarified.
Cardiovascular system -Chest pain: location, character, radiation to neck, shoulder and arm,
alleviating and exacerbating factors?
-Shortness of breath: on exercise or at rest? Amount of exertion?
-Paroxysmal Nocturnal dyspnea: breathlessness at night that awakens
the patient from sleep?
- Orthopnea: difficulty in breathing especially when lying flat.
-Intermittent claudication: pain caused by too little blood flow usually
during exercise and especially in the legs
-Palpitations: patient can feel their own heartbeat/ pounding heart?
-Ankle swelling and swelling of legs
-Bluish discoloration: tongue, lips, hands and ear lobes?
Respiratory system -Cough- with or without sputum?
-Hemoptysis- blood in sputum?
-Pus in sputum
-Fever with chills and rigors?
-Night sweats?
-Wheezing?
Gastrointestinal system -Abdominal pain
-Nausea and/ or vomiting: color, smell, content, blood, frequency?
-Dysphagia: Difficulty in swallowing?
-Change in appetite: increase or decrease
- Weight loss or gain
-Dyspepsia: indigestion?
-Bowel pattern and any change: loose stools, constipation?
-Rectal bleeding: Black stools (melena), blood in stools
(hematochezia)?

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-Jaundice: Yellowish discoloration of skin and eyes?
Genitourinary system -Hematuria: Blood in urine?
-Nocturia: urination at night?
-Polyuria: increased frequency of urination?
-Dysuria: pain during urination?
-Menstrual irregularity- women
-Vaginal discharge in women
-Urethral discharge- men
-Suprapubic pain/ pain abdomen?
-Dribbling of urine?
-Delay in urination (urinary hesitancy)?
-Change in color of urine?
Musculoskeletal system -Joint pain
and Skin -Change in mobility: Stiffness in joints? Difficult in walking?
-Swelling of joints?
-Back or neck pain?
-Skin rash?
Central nervous system -Seizure/ tremors
-Collapse or blackouts or fainting
-Dizziness and loss of balance
-Transient loss of function (vision, speech, sight)
-Paresthesia: tingling, “pins and needles”
-Weakness or numbness in arms and legs
-Wasting
-Spasms and involuntary movements
-Pain in limbs and back
-Headache
-Change in sleep patterns
-Mood swings
-Memory loss
Endocrine -Swelling in the neck?
-Increased sweating?
-Intolerance to cold or hot weather?
-Generalized weakness/fatigability?
-Mood swings, irritability, restlessness?
-Protrusion of eyes?
-Skin changes?

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 If other systems do not show any positive signs towards the presenting complaint
it is vital to mention that the other systems were non-revealing.

PAST MEDICAL HISTORY

 There is a particular logic in taking the past medical history at this stage. For
many conditions that patients may bring to a new doctor, the distinction between
what is a current problem and what is past history is unclear and arbitrary.
 For example, a patient presenting with an acute exacerbation of chronic
obstructive pulmonary disease may have a history of respiratory problems
going back many years.
 It is important to ask if the patient was having a similar complaint in the past and
if they were treated for it.
 One way to figure out if they have any chronic medical problems is to ask if they
have ever gone to the clinic or if they are on any medication.
 The past medical history should include past admissions, history of similar
illness, chronic medical problems as well as history of blood transfusion.
 Area of interest may include History of Diabetes mellitus, Epilepsy, Asthma,
Tuberculosis, Hypertension, Human immunodeficiency virus (HIV), and sickle
cell disease (Remember D.E.A.T.H.S).
 At this point the patient will most likely continue to talk much more than the
doctor but it still remains vital for the doctor to steer and mould the process so
that the information gathered is complete, coherent and if possible logical.
 Some patients will present a clear, concise and chronologically perfect history
with little prompting, although these are in a minority.
 For most patients the doctor will need to do a substantial amount of clarifying
and summarizing, with statements such as:
 ‘You mean that’
 ‘Can I go back to when’
 ‘Can I check I have understood’
 ‘So up to that point you’
 ‘I am afraid I am not at all clear about’
 ‘I really do not understand; can we go over that again?”
 If the patient clearly indicates that they do not wish to discuss particular aspects
of the history, this wish must be respected and the diagnosis based on what
information is available.

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PAST SURGICAL HISTORY

 Previous surgical procedures-indications, procedure and any complications
involved.

DRUG, ALLERGIES AND TREATMENT HISTORY

 Past medication: What medication has the person taken for the condition or any
other underlying condition?
 Current medication:
 Is the patient on treatment now? What medication are they taking and what
are the dosages?
 Was the patient on alternative therapies like homeopathy and ayurvedic
medication.
 History of allergy to drugs such as sulfur containing drugs e.g. Fansidar, septrin
as well as penicillin associated allergies.
 It is also important to include history of previous immunization where applicable
(especially in children).

GYNAE HISTORY (IF APPLICABLE)

 Include:
 Last menstrual period
 Regularity of periods
 Amount and nature of flow
 Use of contraceptives (especially oral)

FAMILY HISTORY
 Number of siblings.
 History of similar complaints in family members.
 Any major illness in family members (D.E.A.T.H.S).
 Cause and age of death of family members.

SOCIAL-ECONOMIC HISTORY
 Education status.
 Occupation- to rule out occupational diseases.
 Lifestyle-sedentary or hard work.
 Social and financial status.
 Living conditions: number of room, ventilation, source of water and toilet use (in
door or outdoor).

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Internal medicine
 Diet- vegetarian or mixed diet.
 Smoking- duration, number of packs per day, type of cigarettes.
 Alcohol consumption- quantity, duration, type of alcohol
 Drug addictions.
 Tobacco and betel nut chewing.
 Sexual history including number of current partners (or number of partner in the
past month).
 History of recent travel.

SUMMARY OF HISTORY
 This is one sentence that summarizes the important parts of the history. Include
identifying information, presenting complaint, a very brief description of the
history of presenting complaints plus essential details from ROS, PMHx, Family
and social-economic Hx.
 For example: “This is D. J a young male newly diagnosed with Pulmonary
Tuberculosis, who presented with a 2-week history of difficult breathing
which was associated with chest pain, fever, weight loss, night sweats and a
TB contact.”
 In the summary do not use the name (use initials) and use an estimated age range
i.e.
 <45 years: young age
 45-65 years: middle age
 > 65 years: old age

IMMPRESSION AND DIFFERENTIALS

 These are based on the history given.
 The impression and differentials must be accurately related and correlated to the
information obtained in the history.

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Internal medicine

PHYSICAL EXAMINATION
 This is a brief overview of the physical exam. More detailed information on each
system is provided in the relevant subsequent chapter.
GENERAL EXAMINATION
 Always start with the general exam followed by Vitals.
 At the end of the general exam, report the vital signs. For example: “ill appearing
middle aged male, who was extremely wasted and lying in bed. The vital signs
are BP: 105/70mmHg, Pulse rate 105 beats/min (for pulse mention the rhythm
i.e. regular/irregular, character i.e. volume and rate as well as presence of radial-
radial synchronicity), Oxygen saturation of 92%, Temperature of 37.7 degrees
Celsius.”
SYSTEMIC EXAMINATION
 After reporting the general exam, report the systemic exam. Report the most
affected organ systems first. If the patient presents with diarrhea, present GI first,
then go on to other systems.
 Do a complete physical exam of each organs systems related to the presenting
complaint and for abnormal findings in other systems.
 Each organ system ought to be examined in the same order:
 Inspection
 Palpation
 Percussion
 Auscultation
 As a junior medical student/ doctor, it is best to report “On inspection… On
palpation…. On percussion… On auscultation…” this way you will not forget
any part of the examination and you will keep things in the correct order.
 The only exception to this rule would be for the CNS. Also for the CVS exam we
start out with the inverted J (check radial pulse, blood pressure and JVP, then
proceed to Inspection, palpation, percussion and auscultation with the
precordium and rest of the CVS exam).
 After all systemic examinations ALWAYS perform a bedside urinalysis.

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Internal medicine
SUMMARY
 This summary is two sentences. The first one is a repetition of the first summary,
the second sentence is a summary of the physical findings.
 For example, if the patient has a respiratory exam with decreased tactile
fremitus, stony dullness on percussion, and decreased breath sounds on
auscultation, you can say that they have exam findings consistent with a
pleural effusion.
 In the summary do not use the name (use initials) and use an estimated age range
i.e.
 <45 years: young age
 45-65 years: middle age
 > 65 years: old age

IMPRESSION/ DIFFERENTIALS/ PROBLEM LIST

 This includes the most likely causes of the presenting complaint.
 When listing differentials, it is important to list them in order of most likely cause
to least likely cause.
 It is also important to ensure that each of the differentials can be correctly
associated with the presenting complaints or any information elicited from the
history and physical exam.

PLAN
 Your plan should include both investigations and treatments (pharmacological
and non-pharmacological).
 It is best to organize your plan by starting with investigations and treatments you
want for each of your impressions.
 For example, for Retroviral disease I want to send a CD4 count, viral load and
get baseline labs (Full blood count, Urea & Electrolytes, Creatinine and Liver
enzymes-AST, ALT), for Tuberculosis I want to get sputum for Acid fast bacilli
(AFB), check Full blood count with differential count (FBC-DC), and get a chest
x-ray.
 This will help you in the future because your plan will be the same every time
you see that diagnosis.

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Internal medicine

PHYSICAL EXAMINATION

PHYSICAL GENERAL APPROACH

 The physical examination starts
EXAMINATION from the moment you meet the
 It is important to develop a routine patient- you will be able to notice
of physical examination that aspects of their general demeanor
combines speed with thoroughness, (general condition), nutrition and
sensitivity and alertness but which personality at first acquaintance
disturbs the patient no more than which will be important in your
necessary. approach to the history.
 The examination must be carried  Every moment of your contact with
out as gently as possible, without patient, every gesture and every
tiring the patient needlessly. communication is full of
 In severely ill patients it may be information.
necessary to postpone a routine  Ideally a chaperone should be
examination and to perform only present when a male doctor is
that required for provisional examining a female patient, both to
diagnosis and treatment. reassure the patient and to protect
 Different doctors use different the doctor from subsequent
routines in different circumstances. accusations of improper conduct.
Start the examination in a manner  A chaperone is essential when
that is relevant to the patient’s conducting an intimate
symptoms e.g. if the presenting examination such as vaginal or
symptom is sciatica, start with the rectal examination.
legs and the spine.
 A systematic approach to each
functional system is essential in
order to obtain information that is
both complete and relevant.
Always try to be thorough.

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Internal medicine
 In considering the patient’s general also reveal the degree of any pain or
appearance, it is important to make shortness of breath.
a rapid assessment of the degree of  The examination begins on meeting
illness. This is not making a the patient and continues until the
diagnosis. Simply consider the consultation ends.
question: ‘Does this patient look  An abnormal finding on
well, mildly ill or severely ill, thus examination may indicate the need
needing urgent attention?’ for further questions- do not
 Experienced nurses are often highly hesitate to revisit the history in the
skilled in this kind of assessment light of such findings at the end of
and their opinion should never be the examination.
ignored.  The general examination is usually
 Every moment of the consultation done in either sitting or lying
is important. position.
 Certain abnormalities may  A summary plan for the general
sometimes be recognized as soon as physical examination include
you meet the patient, and you may  General condition
well notice things about them  Mental state
during history taking e.g. shortness  Nutrition status
of breath, pallor, jaundice,  Hands
parkinsonism, stroke, skin rashes  Axillae
and other features may be  Neck
recognized immediately.  Face
 For a thorough examination the  Skin
patient should be asked to undress  Temperature
completely, or at least to their  Pulse
underclothes and to lie or sit on the  Respiration
couch or bed partially covered with  The object of a routine examination
a sheet or dressing gown. is to check the different bodily
 For restricted examinations such systems to exclude abnormality.
complete exposure is not necessary.  Always begin every examine by
 Watching the patient getting washing hands, requesting
undressed or dressed is often permission from the patient and
revealing of neurological and placing the patient in the right
rheumatological disorders and may position while having them
exposed appropriately.

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Internal medicine
 Always remember for every  Is he or she tall, short, fat, thin,
examination begins at the foot end muscular or asthenic?
of the bed then this is followed by  Is he or she wasted or obese?
proceeding to the right side of the  A history of weight gain or loss can
bed/patient. be checked by observation,
 Examine both sides of the body and remembering that fluid retention
not just focus on one side. (Edema) will increase weight.
 Obvious weight loss, even when
GENERAL APPEARANCE food intake has increased, is a
 Much can be learned from a general feature of thyrotoxicosis and
inspection of the patient’s diabetes mellitus.
physique. Ask yourself the  Psychogenic loss of appetite
following questions: usually affecting girls (anorexia
 Is the patient generally looking nervosa) causes extreme
well, stable, ill, or toxic? emaciation while physical activity
 Is the appearance consistent remains unimpaired.
with patient’s chronological
age? THE HANDS
 The patient’s hands should be
MENTAL STATE
carefully examined (from the right
 Make some initial assessment of side of the bed).
the patient’s intelligence and
 A range of abnormalities may be
mental and emotional state but
present in the structure and function
recognize that this initial
of the hands, including evidence of
impression may be inaccurate.
arthritis, neurological disease, liver
 Is the patient looking happy,
disease anemia and acromegaly.
sad/depressed or anxious?
 Classic appearances that should
 Is the patient cooperative and
always be sought include:
following orders?
 Finger clubbing,
 Is the person oriented in time,
 Koilonychias, which occurs in
place and person? (O.T.P.P)
long-standing iron deficiency
NUTRITIONAL STATUS anemia
 Comment on the nutritional status  Nailbed ‘splinter’
and general physique of the patient hemorrhages,
 Is the nutrition fair, good or  Dupuytren’s contracture
poor?

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Internal medicine
 Also check for capillary refill type, THE AXILLAE
peripheral cyanosis and palmar  Before proceeding to examine the
pallor. axilla, examine the epitrochlear
 Tremor should be assessed lymph node.
carefully, distinguishing between a  Examine the axillae.
fine tremor such as that due to  It is difficult to feel enlarged lymph
thyrotoxicosis and the coarse jerky glands unless the patient’s arm is
tremor of metabolic raised to allow the examining
encephalopathy. fingers to be pushed high into the
 In hypertrophic pulmonary axilla.
osteoarthropathy, bedside clubbing  The arm is then lowered in the
of the fingers there is tender flexed position to rest across the
thickening of the periosteum of the examiner’s arm and palpation is
radius, ulna, tibia and fibula. continued downwards along the
 At this moment you can also take chest wall.
vitals:
 Temperature: the person THE NECK
febrile or afebrile to touch.  The neck should be inspected and
Measure the axillary palpated.
temperature.  Swellings in the neck are usually
 Pulse: Count up to 30 seconds best felt from behind.
and multiple by 2. Comment  Careful note should be taken of
on the Rate, volume, regularity lymph glands and the thyroid.
of the pulse and presence  Carefully assess the major arteries
radio-radial as well as radio- and veins palpable in the neck.
femoral synchronicity.
 Respiratory rate: Count the
FACIAL APPEARANCE
patient’s respiration for a full  Observe the patient’s face.
minute starting when their  The expression and particularly the
attention is directed elsewhere. eyes, indicating real feelings better
This can be done the same than words. Some diseases e.g.
time the pulse is being done. Parkinson’s disease, depression,
 Blood pressure: measure using hypothyroidism, thyrotoxicosis,
appropriate cuff. acromegaly, CNIII and CNVII
palsies and paralysis of the cervical
sympathetic nerve (Horner’s

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Internal medicine
syndrome) produce characteristic may be seen on the face in
facial appearances. liver disease and rarely, as a
 Check the eyes for pallor, jaundice hereditary disorder.
 Parotid swellings are obvious on
THE FEET
inspection of the face.
 The feet must not remain obscured
 Check the mouth for cyanosis,
under bedclothes or socks during
dental caries, oral thrush, stigmata
the examination.
of anemia (angular stomatitis,
 Pitting edema may be recognized
atrophic glossitis) and any Kaposi’s
only in the ankles and dorsal
sarcoma lesions on the palate.
surfaces of the feet.
 The cheeks give information
 The condition of the skin of the feet
regarding the patient’s health:
is especially important in diabetics
 In anemia and
and the elderly.
hypopituitarism, they are pale
 In nephrotic syndrome they  Peripheral vascular disease will
are pale and puffy make the skin shiny and hair does
 In mitral stenosis there is not grow on ischemic legs or feet.
sometimes a bright  The dorsalis pedis and posterior
circumscribed flush over the tibial pulses may be reduced or
malar bone absent.
 In many persons who lead an  If the toes of an ischemic foot are
open-air life they are red and compressed their dull purple color
highly colored. will blanch and only slowly return.
 In congestive heart failure they  Passive elevation of an ischemic
may also be highly colored, leg will cause marked pallor of the
but the color is of a bluish tint foot as perfusion against gravity
which cannot be mistaken for falls.
the red cheeks of weather-  Painless trophic lesions often with
beaten people. deep ulceration on the soles are
 In some cases of systemic seen frequently in diabetic
lupus erythematosus there is a peripheral neuropathy (the diabetic
red raised eruption on the foot)
bridge of the nose that extends
on the cheeks in a ‘butterfly’
distribution.
 Telangiectasia, minute
capillary tortuosities or naevi,

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Internal medicine
ORDOURS
 The odor of alcohol is easily
recognizable on the breath although
patients may try and mask it by
sucking a mint but it does not
necessarily mean the patient’s
condition is due to alcohol
intoxication.
 The odor of diabetic ketosis has
been described as ‘sweet and
sickly’, that of uremia as
‘ammoniacal or fishy’ and that of
hepatic failure as ‘mousy’ but too
much reliance on such delicate
distinctions is unwise.
 Halitosis (bad breath) is common in
patients whose dental hygiene has
been poor and is associated
especially with chronic gingivitis
(periodontal or gum disease)

AFTER EVERY
EXAMINATION
 Always thank the patient and leave
them covered.
 Always wash hands.
 Summarize your findings and offer
a differential diagnosis based on
your findings.
 The general examination is always
followed by specific examination
of each individual system. This will
be discussed in each respective
chapter.

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Internal medicine

CARDIOLOGY

symptoms resembling those

CARIDOVASCULAR resulting from congestive heart
CONDITIONS failure.
APPROACH TO  Cardiac arrhythmias often develop
suddenly, and the resulting signs
CARDIOVASCULAR and symptoms- palpitations,
DISEASE dyspnea, hypotension, presyncope
CARDIAC SYMPTOMS and syncope- generally occur
 The symptoms caused by heart abruptly and may disappear as
disease result most commonly from rapidly as they develop.
myocardial ischemia from  Ischemic heart disease by far are
disturbance of contraction and/or the most common form of heart
relaxation of the myocardium, from disease in adults may present with
obstruction to blood flow, or from chest discomfort but also as heart
an abnormal cardiac rhythm or rate. failure, tachyarrhythmia and
 Ischemia is manifest most sudden cardiac death.
frequently as chest discomfort,  Myocardial or coronary function
while reduction of the pumping that may be adequate at rest may be
ability of the heart commonly leads inadequate during exertion. Thus
to fatigability and shortness of chest discomfort and/or dyspnea
breath or when severe produces that appear only during activity are
cyanosis, hypotension, syncope and characteristic of heart disease,
elevated intravascular pressure while the opposite pattern i.e.
behind a failing ventricle. appearance of these symptoms at
 Failing of a ventricle results in rest and their remission during
abnormal fluid accumulation, exertion, is rarely observed in
which in turn leads to dyspnea, patients with organic heart disease.
orthopnea and systemic or  Many patients with cardiovascular
pulmonary edema. disease may also be asymptomatic
 Obstruction to blood flow as in both at rest and during exertion, but
valvular stenosis, can cause may present an abnormal physical

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Internal medicine
finding such as a murmur, elevated DIAGNOSIS
arterial pressure or an abnormality  As outlined by the New York Heart
of the electrocardiogram (ECG) or Association, the elements of a
the cardiac silhouette on the chest complete cardiac diagnosis include
X-ray. consideration of the following:
 Patients may exhibit asymptomatic  The underlying etiology: is the
ischemia on an exercise stress test. disease congenital, infectious,
 In some asymptomatic patients the hypertensive or ischemic in
first clinical event may be origin?
catastrophic- sudden cardiac death,  The anatomic abnormalities:
acute myocardial infarction or which chamber are involved?
stroke. Are they hypertrophied,
 Dyspnea, one of the cardinal dilated, or both? Which valves
manifestations of heart failure, is are affected? Are they
not limited to patients with heart regurgitant and/or stenotic? Is
disease but is also observed in there pericardial involvement?
conditions as diverse as pulmonary Has there been a myocardial
disease, marked obesity and infarction?
anxiety. Similarly, chest discomfort  The physiologic disturbances:
may result from a variety of causes is an arrhythmia present? Is
other than myocardial ischemia. there evidence of congestive
 Whether heart disease is heart failure or of myocardial
responsible for these symptoms can ischemia?
frequently be determined by  Functional disability (status):
carrying out a careful clinical how strenuous is the physical
examination as well as performing activity required to elicit
certain noninvasive tests such as symptoms?
electrocardiography,
echocardiography, X-ray and
myocardial imaging.

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Table 4.1: New York Heart Association Functional classification

Class I (No limitation) No limitation of physical activity
No symptoms with ordinary exertion
Class II (Mild limitation) Slight limitation of physical activity
Ordinary activity causes symptoms
Class III (Moderate limitation) Marked limitation of physical activity
Less than ordinary activity causes
symptoms
Asymptomatic at rest
Class IV (Marked limitation) Inability to carry out any physical
activity without discomfort
Symptoms at rest

 The establishment of a correct and  Ask the patient to expose the

complete cardiac diagnosis often chest fully.
commences with the history and  Always remember to start your
physical examination. examination at the foot end of
the bed and then proceed to the
CARIDIOVASCULAR right side of the bed.
EXAMINATION
GENERAL INSPECTION
 Before starting the examination of
 From the foot-end of the bed:
the cardiovascular system
 Look around for any ECG
 Wash hands and introduce
equipment, heart monitoring
yourself to the patient.
equipment, oxygen masks and
 Confirm the patient’s details.
tanks, urinary bags and
 Explain the examination and
catheters, cannula in situ,
gain consent.
medicines, nutritional
 The entire cardiovascular
supplements and adjuncts that
examination is best performed
can be used for cardiovascular
with the patient sitting at 45
diseases.
degrees in cardiac position.
 Observe the patient’s general
(remember when presenting
appearance (age, state of
don’t forget to mention that
health, nutritional status and
you examined a patient
any obvious signs).
propped up in bed at 45
degrees).

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Internal medicine
o Is the patient  Presence of palmar pallor
comfortable? (Anemia)
o Is the patient in obvious  Presence of finger clubbing
discomfort or pain? (subacute infective [bacterial]
o Is the patient breathless or endocarditis, cyanotic
cyanosed? congenital heart disease-
o Are they in any obvious tetralogy of fallot, atrial
respiratory distress? myxoma [tumor])- there will
 Inspect the precordium for the be loss of Schamroth’s
presence of any abnormal window.
pulsation and the chest for any  Presence Tar staining-
scars, traditional markings, smoking associated with
median sternotomy (which atherosclerosis.
might have been performed for  Presence of splinter
coronary artery bypass hemorrhages (subacute
grafting, for valve surgery or infective endocarditis)
for the repair of a congenital  Presence of any nail signs-
defect). DO NOT MISS A Leukonychia
PACEMAKER IF IT IS (hypoalbuminemia) or
THERE! koilonychias (iron deficiency)
 Check for capillary refill time
INSPECTION (normal= <2s).
INSPECTION AND  On the palms check for
EXAMINATION OF THE Janeway’s lesion- non-tender
HANDS small erythematous or
 This would normally be done and hemorrhagic macular, papular,
reported as part of the general nodular lesions only a few mm
examination unless only a focused in diameter (infective
cardiovascular examination is endocarditis) and Osler’s
done. node- painful, red, raised
 From the right side of the bed, take lesions found on the hands and
both hands noting: feet caused by immune
 Temperature- febrile or complex deposition (infective
afebrile to touch? endocarditis, SLE,
 Color- presence of palmar disseminated gonococcal
erythema (chronic liver infection).
disease, polycythemia)

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Internal medicine
INSPECTION AND atherosclerosis of the aorta,
EXAMINATION OF THE thrombosis or embolism of
aorta
FOREARM AND ARM
 Radial, brachial, carotid, femoral,
 Determine the radial pulse and
popliteal and pedal pulses
assess: count for 30 seconds and
commonly assessed.
multiple by 2.
 Rate: palpate the right radial  Check for collapsing pulse (aortic
artery. Note tachycardia (>100 regurgitation)- feel the pulse on the
bpm) or bradycardia left hand side then while doing this
(<60bmp). lift the arm and note the pulse.
 Rhythm: note whether the Before doing so ask patient if it is
rhythm is regular (no missed ok to do this and if they do not have
or extra beats) or irregular. If any pain in the shoulder.
there is sinus arrhythmia, the  At this point do not forget to
heart rate will slow slightly palpate the epitrochlear lymph
whenever the patient breaths nodes.
out.  Measure blood pressure (state you
 Volume: Assess the volume would ideally do this in the exam of
(increased/decreased-full course if not done)
volume or thready?).  Blood pressure should be
 Synchronicity: is the radial pulse checked first in the sitting
synchronous with both the position in both arms. If you
contralateral radial pulse and the are concerned about
femoral pulsation? hypovolemia, check the blood
 Radial-radial delay indicates pressure and pulse in standing,
aortic coarctation, aneurysm sitting and lying positions.
of aorta, atherosclerosis of  Patients must be sitting with
aorta, pulseless disease feet flat on the floor with blood
(Takayasu’s disease), pressure cuff above the elbow,
peripheral embolism, pressure with the width of the cuff
of axillary artery by tumor, being at least 40% of the
lymph nodes circumference of the arm.
 Radial-femoral delay indicates  Place the diaphragm of the
aortic coarctation (it is an stethoscope over the brachial
important diagnostic clue in a artery on the ventral surface of
young hypertensive), the elbow.

37
Internal medicine
 Inflate the blood pressure cuff o Paradoxical pulse: more
until the pulse is totally than 10mmHg decline in
occlude, slowly deflate the systolic blood pressure
cuff and listen for the during inspiration
appearance of the korotkoff  Check jugular venous pressure
sounds:  Observe for a visible JVP along
o Phase 1: the first the border of
appearance of sound= the sternocleidomastoid
systolic blood pressure o Have the patient to turn
o Phase 2 and 3: his head slightly to the
increasingly loud sounds left side, look at the
o Phase 4: abrupt muffling internal jugular vein
of the sounds medial to the clavicular
o Phase 5: disappearance of head of
the sounds= diastolic sternocleidomastoid.
blood pressure Assuming that the patient
 At this point the axillary lymph is at 45 degrees, the
nodes can be palpated. vertical height of the
jugular distension from
INSPECTION AND the sternal angle should
EXAMINATION OF THE be no greater than 4 cm.
HEAD AND NECK o Kussmaul’s sign:
 Check carotid pulse- assess paradoxical rise in jugular
volume/character (assess each side venous pressure during
individually) NEVER PALPATE inspiration.
BOTH CAROTID PULSES  Check for hepato-jugular reflux:
SIMULTANEOUSLY. o Apply pressure to the
 Waveform of the carotid pulse liver (right upper
o Tardus et parvus: the quadrant)
carotid pulse is slow and o Observe for a rise in JVP
small o Positive result= Sustained
o Biphasic pulse: two rise greater or equal to
systolic peaks 4cm
o Alternating pulse:
alternating high and low
systolic peaks

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Internal medicine

Figure 1: Position of the patient during a cardiac examination. Measurement of JVP. Normally JVP
<4cm

 Waveform of JVP: venous filling of the

 “a” and “v” waves separated atrium)
by “x” and “y” descents. o y descent- opening of the
o a wave- right atrial tricuspid valve with rapid
contraction emptying of the right
o c wave- closure of the atrium
tricuspid valve  JVP during inspiration
o x descent- atrial declines.
relaxation  Giant “a” wave: forceful
o v wave- ventricular contraction against a stenosed
systole (with passive tricuspid valve or non-
compliant hypertrophied right

39
Internal medicine
ventricle, pulmonary INSPECTION AND
hypertension, and pulmonary EXAMINATION OF THE
stenosis.
FACE
 Cannon “a” wave: atrial
 Check cornea for corneal arcus
systole against a closed
(hyperlipidemia) / Xanthelasma
tricuspid valve caused by
(hypercholesterolemia)
atrial-ventricular dissociation
 Check for conjunctival pallor-
(complete heart block)
anemia and scleral jaundice
 Absent a waves: atrial
fibrillation.  Check Malar flush on cheeks-
 Large c-v waves: tricuspid Mitral stenosis
regurgitation.  Check for central cyanosis
 Giant “v” wave: sign of (hypoxia), Check for dentures and
tricuspid regurgitation oral hygiene (infective
 Prominent “x” and “y” endocarditis), high arched palate,
descents: constrictive glossitis
pericarditis.  Check for angular stomatitis (iron
 Absent y descent: cardiac deficiency anemia)
tamponade.  Check neck for tracheal centrality
INSPECTION OF THE
CHEST
 Inspect for scars: midline
sternotomy/ infraclavicular, lateral
thoracotomy.
Figure 2: JVP wave
 Inspect also for any tattoo marks.
 Kussmaul’s sign: an increase in  Chest deformities: pectus
JVP during inspiration. Seen in excavatum/ carinatum.
chronic constrictive pericarditis,  Check for activity in the
occasionally seen in tricuspid precordium
stenosis and CHF.  Normoactive precordium
 After measuring the JVP check the  Hyperactive precordium- left
ankles for edema. ventricular hypertrophy

40
Internal medicine
PALPATION OF CHEST  A heave has to do with the
 Place your right hand on the upward push on your hand
patient’s left chest with the butt of when you palpate the
the hand at the sternum and the precordium suggesting the
fingers into the axilla. presence of hypertrophy e.g.
 Apex beat: the lowest most parasternal heave in someone
lateral point at which the with severe pulmonary
cardiac impulse can be hypertension.
palpated. Normally located AUSCULATION OF CHEST
superior to the 5th intercostal
space and medial to the TECHNIQUE
midclavicular line.  Diaphragm of the stethoscope (the
o A “tapping” apex beat is flat big part containing the plastic)
likely to indicate mitral for high-pitched sounds.
stenosis, a “heaving”  Bell of the stethoscope (the smaller
apex beat is likely to part) to hear the low-pitched
indicate left ventricular sounds.
hypertrophy. SOUNDS
 Double thrust: a palpable 3rd
 S1- closing of the mitral and
and 4th heart sound.
tricuspid valves.
 Left parasternal thrust: thrust
 S2- closing of the aortic and
appreciated just to the left of
pulmonary valves. Split S2 occurs
the sternum.
during inspiration.
 Thrill: palpable vibrations on
 S3 and S4
the chest wall.
 Low frequency sounds. Occur
 Place your hand over the cardiac
during diastole after S2. Either
apex and on either side of the
one is called a ‘gallop’
sternum (parasternal heave) and
 Best heard with the bell of the
Feel for thrills (palpable murmurs)
stethoscope.
and heaves (ventricular
 Systolic clicks and opening snaps
hypertrophy)
are abnormal
 A Thrill is a vibratory sensation
 Early systolic click- can occur
on your hand frequently in the
with aortic stenosis right
auscultatory areas of the
before ejection murmur
valves. It is a murmur that you
 Late systolic click- mitral
can feel.
valve prolapsed

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 Early diastolic snap- mitral o Grade II: soft and
stenosis localized murmur
 For every murmur there should be: o Grade III: murmur of
 Location of maximal moderate intensity
impulse point that is immediately
 Time of the murmur: systolic audible
or diastolic o Grade IV: murmur of
o Systolic: midsystolic, loud intensity
pansystolic, late systolic o Grade V: murmur of
o Diastolic: early diastolic, loud intensity with a
mid-diastolic or pre- palpable precordial
systolic thrill
o Continuous: audible in o Grade VI: as above,
both phases of the cardiac except that the
cycle murmur is audible
 Pitch: This can be low- even as the
pitched, medium pitched or stethoscope is lifted
high pitched from the chest wall
 Quality: the frequency  Radiation of murmur: what
 Grade of the murmur direction does the sound travel
o Grade I: barely to? (neck, axilla, back?)
audible murmur

Figure 3: Common murmurs

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 Innocent murmurs: always mid-  Auscultate the carotids for murmur

systolic, rarely greater than grade 3. radiation/bruits using the bell
PROCEDURE
 Listen for heart sounds, additional
sounds, murmurs and pericardial
rub.
 Listen to heart sounds (with the
diaphragm first and then with the
bell)
 Aortic valve: 2nd intercostal
space (right sternal edge)
 Pulmonary valve: 2nd
intercostal space (left sternal
edge)
 Tricuspid valve: 5th intercostal
space (left sternal edge)
 Mitral valve: at region of apex
heart beat
 While listening to the heart sound at
the mitral area with the bell ask the
patient to turn to the left side
(accentuation maneuver), this helps
one to hear a mid-diastolic murmur
for mitral stenosis, ask them to take
a deep breath in and the out and
hold it.
 Auscultate the axilla to assess for
radiation of murmurs
 Ask patient to lean forward
(accentuation maneuver) and listen
to the aortic area with the
diaphragm. ask them to take a deep
breath in and the out and hold it.

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Figure 4: Auscultatory positions

 Positioning/maneuvers: some  High-pitched scratching noise

murmurs are louder when the audible during any part of the
patient is positioned differently cardiac cycle and over any part
 Lying on the left side: helps of the left precordium
with mitral regurgitation  Hyperkinetic venous hum can
 Inspiration: helps to hear be heard at the base of the
tricuspid regurgitation heart, and is particularly
 Leaning forward: helps to hear common in infants and usually
aortic regurgitation or disappears when lying flat.
pulmonic regurgitation
 Friction and venous harms
 Best heard in maintained
expiration with the patient
leaning forward.

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OTHER ORGANS TO EXAMINE DURING A FOCUSED

CARDIAC EXAM
 Percuss and auscultate the chest, especially at the lung bases (pulmonary edema
and pleural effusions)- use diaphragm.
 Palpate the abdomen to exclude ascites and/or an enlarged liver
 Check for the presence of an aortic aneurysm.
 Ballot the kidneys and listen for any renal artery bruits.
 Palpate for sacral edema (right heart failure)
 Feel the temperature of the feet and then palpate the:
 Femoral pulses
 Popliteal pulses
 Posterior tibial pulses
 Dorsalis pedis pulses
 To complete the examination, point out other investigations that should have been
done such as:
 Urinalysis
 Capillary blood glucose
 12 lead ECG
 CXR
 Echocardiogram
 Thank patient, cover them and ensure they are comfortable
 Summarize your findings and offer a differential diagnosis.

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CARDIAC PULSES
PULSE DESCRIPTION CLINICAL SIGNIFICANCE
ARTERIAL PULSATIONS
DMINISHED/EXAGGERATED/ASYMMETRIC PULSES
Diminished pulses Pulse is weak and thread  Atherosclerotic peripheral vascular
disease,
Small volume pulse  Low cardiac output conditions (e.g.
heart failure, cardiac tamponade,
critical aortic stenosis)
Exaggerated Pulse is strong  Aortic regurgitation
pulses  Coarctation (upper extremities only)
 Patent ductus arteriosus
 Hyperthyroidism
 Arteriovenous fistulas
Asymmetric pulses Radial-Radial/Femoral delay  Severe atherosclerotic vascular disease
 Takayasu’s arteritis
 Coarctation of the aorta
CAROTID PULSATONS
Delayed upstroke Delayed upstroke of carotid Aortic stenosis
pulse
Bisferiens pulse Two palpable peaks during  Mixed aortic stenosis, aortic
systole regurgitation and hypertrophic
cardiomyopathy
Dicrotic pulse Two palpable peaks- one in  Young patients with severe heart
systole and one in diastole failure
 Very low ejection fraction e.g. dilated
cardiomyopathy 2o to alcoholism
PERIPHERAL PULSES
Corrigan (water- Rapid rise and fall of the radial  Chronic, hemodynamically significant
hammer) pulse pulse accentuated by wrist aortic regurgitation
elevation  Persistent ductus arteriosus
 Aortic root aneurysm
Pulses paradoxus Drop in BP of >10mmHg during  Cardiac tamponade
normal inspiration  Severe asthma
 Constrictive pericarditis
 COPD
Pulsus alternans Alternation of amplitude with Severe systolic heart failure
every other heartbeat

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HEART SOUNDS AND MURMURS

HEART SOUNDS
 2 sounds are normally heard through a stethoscope during each cardiac cycle.
 Normally the valves on the left side of the heart close first. Valves on the right
side open first.
 The first is a low, slightly prolonged “lub” (first sound), caused by vibrations set
up by the sudden closure of the Atrioventricular valves at the start of ventricular
systole.
 The first sound has a duration of about 0.15s and frequency of 25 to 45Hz.
 Even though the valves close with only a separation of about 0.01s, the human
ear can appreciate only as a single sound.
 It is soft when the heart rate is low because the ventricles are well filled with
blood and the leaflets of the AV valves float together before systole.
 The second is a shorter, high-pitched “dup” (second sound) caused by vibrations
associated with closure of the aortic and pulmonary valves just after the end of
ventricular systole.
 The second sound last 0.12s with a frequency of 50Hz.
 It is loud and sharp when the diastolic pressure in the aorta or pulmonary
artery is elevated causing the respective valves to shut briskly at the end of
systole.
 The interval between aortic and pulmonary valve closure during inspiration is
frequently long enough for the second sound to be reduplicated (physiologic
splitting of the second sound).
 The two sounds created by physiologic splitting originate from the aortic (A2
component) and pulmonic valves (P2 component). They are heard as a single
sound during expiration but during inspiration the increased output of the right
heart causes the physiologic splitting.
 Splitting also occurs in various diseases e.g. pulmonary stenosis, atrial septal
defect (Left to right shunt), and advanced aortic stenosis.

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Figure 5: Splitting of the second heart sounds

 A soft, low-pitched third sound is heard about 1/3 of the way through diastole in
many normal young individuals. It coincides with the period of rapid ventricular
filling and is probably due to vibrations set up by the inrush of blood.
 The third sound when present has a duration of 0.1s
 In older adults it occurs with volume overload and often is a sign of cardiac
disease.
 A third heart sound is present in heart failure.
 A fourth sound can sometimes be heard immediately before the first sound when
atrial pressure is high or the ventricle is stiff in conditions such as ventricular
hypertrophy. It is due to ventricular filling and is rarely heard in normal adults.
 The third and fourth heart sound either singly or together will produce a gallop
rhythm.

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Heart sound Cause Duration and Frequency Comments
First Vibrations from closure of 0.15s and 25 to 45Hz Prolonged and
AV valves soft “Lub”
Second Vibrations from closure of 0.12s and 50Hz Short and high
semilunar valves pitched “Dub”.
Can undergo
physiological
splitting during
inspiration.
Third Rapid ventricular filling 0.1s Heard 1/3 way
phase through diastole,
Normal in young
individuals. In
adults it is
pathological and a
sign of heart
failure
Four Due to high atrial pressure Rarely heard in
or ventricular stiffening normal
such as in ventricular individuals
hypertrophy

CARDIAC MURMURS
 Murmurs or bruits are abnormal sounds heard in various parts of the vascular
system.
 Even though the two terms are used interchangeable, a murmur denotes a noise
heard over the heart whilst a bruits denotes a noise heard over blood vessels.
 Blood flow is laminar, non-turbulent and silent up to a critical velocity, above
this velocity and beyond an obstruction, blood flow is turbulent and creates
sounds. Blood flow speeds up when an artery or a heart valve is narrowed.
 A cardiac murmur or heart murmur is a sound produced when blood flows across
one of the heart valves that are loud enough to be heard with a stethoscope.
 There are 2 types of murmurs:
 Anatomical murmurs
o These are murmurs due to structural defects in the heart
o They can be due to narrowing or leaking of valves, or the presence of
abnormal passages through which blood flows in or near the heart.

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 Functional/ physiological murmurs
o These are murmurs primarily due to physiological conditions outside
the heart
o Functional murmurs are benign (“innocent murmurs”)
o These are usually soft systolic murmurs, especially children, who have
no cardiac disease. Systolic murmurs are also heard in anemic patients
as a result of low viscosity of the blood and associated rapid flow.
ANATOMICAL MURMURS
 The major but certainly not the only cause of cardiac murmurs is disease of the
heart valves.
 When the orifice of a valve is narrowed (stenosis), blood flow through it is
accelerated and turbulent.
 When a valve is incompetent, blood flow through it backward (regurgitation or
insufficiency) again through a narrow orifice that accelerated flow.
 The timing (systolic or diastolic) of a murmur due to any particular valve can be
predicted from knowledge of the mechanical events of the cardiac cycle.
 Murmurs due to disease of a particular valve can generally be heard best when
the stethoscope is directly over the valve.
 There are also other aspects of the duration, character, accentuation and
transmission of the sound that help to locate its origin in one valve or another.

Figure 6: Different murmurs

FUNCTIONAL MURMURS
 These are murmurs primarily due to physiological conditions outside the heart
 Functional murmurs are benign (“innocent murmurs”)
 These are usually soft systolic murmurs, especially children, who have no cardiac
disease. Systolic murmurs are also heard in anemic patients as a result of low
viscosity of the blood and associated rapid flow.
 These murmurs never exceed grade 3.

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GRADING OF MURMURS
 Grade I: barely audible murmur
 Grade II: soft and localized murmur
 Grade III: murmur of moderate intensity that is immediately audible
 Grade IV: murmur of loud intensity
 Grade V: murmur of loud intensity with a palpable precordial thrill
 Grade VI: as above, except that the murmur is audible even as the stethoscope is
lifted from the chest wall.
DESCRIBING MURMURS
 Location of maximal impulse point
 Time of the murmur: systolic or diastolic
 Systolic: midsystolic, pansystolic, late systolic
 Diastolic: early diastolic, mid-diastolic or pre-systolic
 Continuous: audible in both phases of the cardiac cycle
 Pitch: This can be low-pitched, medium pitched or high pitched
 Quality: the frequency
 Grade of the murmur
 Grade I: barely audible murmur
 Grade II: soft and localized murmur
 Grade III: murmur of moderate intensity that is immediately audible
 Grade IV: murmur of loud intensity
 Grade V: murmur of loud intensity with a palpable precordial thrill
 Grade VI: as above, except that the murmur is audible even as the stethoscope
is lifted from the chest wall
 Radiation of murmur: what direction does the sound travel to? (neck, axilla,
back?)

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RHEUMATIC FEVER
 This is a delayed non-Suppurative autoimmune complication of upper respiratory
infection with Lancefield group A beta-hemolytic streptococcus (Streptococcus
pyogenes) characterized by inflammation of connective tissue.
 Rheumatic fever causes chronic progressive damage to the heart and its valves.
 The dramatic decline in the incidence of rheumatic fever in the developed world
is thought to be largely due to antibiotic treatment of streptococcal infection,
though it started to decline before the era of antibiotics probably due to improved
socioeconomic status.
 Rheumatic fever predominantly affects the CNS, heart, blood vessels, joints, and
skin.
 Rheumatic fever is the commonest cause of heart disease in the developing
countries.
 The cause of rheumatic fever is unknown but this disease appears to be
autoimmune in nature.
PATHOPHYSIOLOGY
 Acute rheumatic fever is a sequel of a previous group A streptococcal infection
usually of the upper respiratory tract.
 One beta-streptococcal serotype (e.g. M types 3, 5, 18, 19 and 24) is linked
directly to acute rheumatic fever.
 Rheumatogenicity of GAS is important fact as not all GAS pharyngitis is
associated with development of rheumatic fever.
 Rheumatic fever follows Lancefield A Beta hemolytic streptococcus pharyngitis
within the interval of 2-3 weeks.
 The mechanism is elusive however the following are proposed:
 Dysfunction of the immune response
 Antigenic (molecular) mimicry
o Similarity between the carbohydrate moiety of GAS and glycoprotein
of the heart valve.
o Molecular similarity between some streptococcal antigens and
sarcolemma or other moiety of human myocardial cells.
o Antibodies produced in response to throat infection in a susceptible host
against M protein cross react with tissues of the body.
 Several host related factors have been identified to have operated in relation to
specific genetic function and difference in the immune response in individuals.

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 The disease involves the heart, joints, central nervous system, skin and
subcutaneous tissue. It is characterized by an exudative and proliferative
inflammatory lesion of the connective tissues especially that of the heart, joints,
blood vessels and subcutaneous tissue.
CLINICAL MANIFESTATIONS
 Acute rheumatic fever is associated with 2 distinct patterns of presentation:
 Sudden onset: typically begins as polyarthritis 2-6 weeks after streptococcal
pharyngitis and is usually characterized by fever and toxicity
 Insidious onset: subclinical and initial abnormality is mild carditis
 Age at onset influences the order of complications. Younger children tend to
develop carditis first, while older patients tend to develop arthritis first.
DIAGNOSIS: JONES CRITETERIA
 Major:
 Sydenham’s chorea
 Carditis
 Migratory polyarthritis
 Subcutaneous nodules
 Erythema marginatum
 Minor:
 Clinical
o Fever
o Arthralgia
 Laboratory
o Elevated acute phase reactants: ESR, CRP
o Prolonged PR interval
 For diagnosis: Supportive evidence of recent Group A streptococcal infection
(e.g. positive throat culture or rapid antigen detection test and/or elevated or
increasing Streptococcal antibody test-ASOT, AntiDNAse) plus
 2 Majors or
 1 Major + 2 minors
SYNDENHAM’S CHOREA
 Also known as St Vitus dance
 It is a characteristic movement disorder.
 It consists of rapid purposeless movements of the face and upper extremities.

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 Onset may be delayed for several months to years and may cases when the patient
is asleep.
 It is more common in females.
 Antibodies cross react with the basal ganglia
CARDITIS
 Occurs in 40-60% of patients and manifest as:
 New murmur
 Cardiomegaly
 Congestive heart failure
 Pericarditis with or without a pericardial rub and resolves with squeal of
constriction
 Valvular disease: mitral and aortic commonly affected. Heading of rheumatic
valvulitis will lead to fibrous thickening and adhesions resulting in
progressive valvular damage. In 80% mild valvulitis would resolve. There is
a risk of developing endocarditis on a damaged valve.
MIGRATTORY POLYARTHRITIS
 Occurs in 75% of cases and involves many joints at a time. The larger joints are
mainly affected.
SUBCUTANEOUS NODULES
 Occur in 10% of patients. They are firm painless nodules on the extensor surfaces
of wrists, elbows and knees.
ERYTHEMA MARGINATUM
 Occurs in about 5% of cases.
 This is a non-pruritic rash that starts as pink to red macules with a pale center
which may coalesce and spread centripetally with central clearing over the trunk
and proximal limbs.
LABORATORY INVESTIGATIONS
 Throat swab for microscopy, culture and sensitivity (20-40% culture yield)
 Streptococcal antibody tests:
 ASOT: positive in 80% of cases
 Anti-DNAse beta and Anti-hyaluronidase is positive in 95% of cases
 Full blood count
 Leukocytosis

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 Anemia due to suppression of erythropoiesis
 ECG: Prolonged PR interval
 Acute phase reactants (e.g. raised ESR and C-reactive protein)
TREATMENT
 Treatment of Group A streptococcal infection: regardless of organism detection
 Ampicillin 500mg PO QID or Amoxicillin 500mg PO TID for 10 days or
 Benzathine penicillin 1.2 million IU IM single dose
 Erythromycin 500mg PO QID for 10 days (for penicillin allergic patients)
 Teat manifestation of acute rheumatic fever:
 Arthritis: ASA 2g QID for 4-6 weeks, no indication for steroids
 Carditis: severe carditis with congestive heart failure should be treated with
o Prednisolone 60 to 80mg/day to be tapered as patient improves
o Start ASA during tapering phase to be given for 4-6 weeks
o CHF: treat with conventional therapy such as bed rest, dietary salt
restriction, digoxin and diuretics
 Sydenham’s chorea: in most cases it is self-limiting however in symptomatic
patients benzodiazepines (diazepam) or phenothiazine (haloperidol) may help
control symptoms.
 Prophylaxis: for all patients with rheumatic fever:
 First choice Benzathine penicillin 1.2 million IU IM every 4 weeks but if there
is high risk of recurrence it can be given every 3 weeks
 Oral penicillin V (250mg BID)
 Oral sulfadiazine (1g/day)
 Oral erythromycin for patients allergic to penicillin
 Most recommend treatment till the age of 18 or 21 years but more recently
lifelong prophylaxis has been advocated.
 Note: in a patient with an established RHD, it is advisable to get the
prophylaxis lifelong.

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VALVULAR DISEASES
 Valvular heart disease involve outflow obstruction (stenosis) or incompetence
(regurgitation) of one of the four valves of the heart.
 Valvular heart diseases of clinical significance thus include:
 Mitral stenosis
 Mitral regurgitation
 Aortic stenosis
 Aortic regurgitation
 The distribution of disease varies greatly based on population and risk factors.
 The most valvular disease are rheumatic, congenital or degenerative.
 The most common cause of valvular heart disease in Africa is Rheumatic heart
disease.
 Even though the definitive management for most valvular heart diseases is
surgical intervention to correct the underlying valvular abnormality, in the
current Zambian setup this is not affordable and not available in the country
hence the general management is treatment of congestive heart failure state.
MITRAL STENOSIS
 The mitral valve consists of the anterior and posterior leaflets, fibrous annulus,
chordae tendinae and the papillary muscles.
 The mitral valve has a normal surface area of about 4-6 cm2...
 Mitral stenosis is a valvulopathy that describes narrowing of the opening of the
mitral valve between the left ventricle and the left atrium.
 Note: Mitral stenosis can co-exist with mitral regurgitation (Mixed valve
disease).
ETIOLOGY
 The most common cause of mitral stenosis is rheumatic heart disease secondary
to previous rheumatic fever due to infection with group A -Hemolytic
streptococcus.
 The condition is more common in women than men.
 It is very common in developing countries manifesting below the age of 20
whereas there is generally a latent period of 20 to 40 years between the
occurrence of rheumatic fever and of mitral stenosis in developed countries.
 Inflammation leads to commissural fusion and a reduction in mitral valve
orifice area leading to the characteristic doming pattern (Fish mouth opening)
seen on echocardiography.

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 Over many years the condition progresses to valve thickening, cusp fusion,
calcium deposition, a severely narrowed (stenotic) valve orifice and
progressive immobility of the valve cusps.
 Other causes of mitral stenosis:
 Congenital mitral stenosis
 Senile calcification and fibrosis of the valve, valve ring and subvalvular
apparatus (chordae tendinae)
 Autoimmune disease: Rheumatoid arthritis, SLE
 Lutambacher’s syndrome, which is the combination of acquired mitral
stenosis and an atrial septal defect.
 Mucopolysaccharidoses
 Endocardial fibroelastosis
 Carcinoid tumors metastasizing to the lung, or primary bronchial carcinoid.
(note carcinoid tumors are more common in the GIT- Appendix thus they
most commonly cause tricuspid stenosis)
o Carcinoid tumors produce biologically active products that are growth
factors for fibroblast.
 Most patients remain asymptomatic until atrial fibrillation develops or until
pregnancy occurs when there is increased demand on the heart.
PATHOPHYSIOLOGY
 When the normal valve orifice area of 4-6 cm2 is reduced to <2 cm2, signs and
symptoms begin to show and when it is reduced to <1 cm2 severe mitral stenosis
is present.
 Stenosis of the mitral valve results in outflow obstruction from the left atrium to
left ventricle and therefore high atrial pressure. The elevated pressures lead to
atrial dilatation and often atrial fibrillation. Elevated atrial pressure causes
pulmonary pressures and pulmonary symptoms.
 In order that sufficient cardiac output will be maintained, the left atrial pressure
increases and left atrial hypertrophy and dilatation occur.
 Decreased filling of the left ventricle causes the left ventricle to generally
becomes smaller than normal.
 Stasis in the dilated atrium leads to the development of thrombi that can cause
systemic thrombo-embolism to cerebral system, kidney, spleen, bone, lung
and causing infarction in these areas.

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 Dilatation of the atria also predisposes the heart to atrial fibrillation (due to
re-entry of current in the hypertrophied atrium), atrial fibrillation also
increases stasis and this also contributes to formation of thrombi.
 Consequently, pulmonary venous, pulmonary arterial and right heart pressures
also increase.
 The increase in pulmonary capillary pressure is followed by the development of
pulmonary edema particularly when the rhythm deteriorates to atrial fibrillation
with tachycardia and loss of coordinated atrial contraction.
 This is partially prevented by alveolar and capillary thickening and pulmonary
arterial vasoconstriction (reactive pulmonary hypertension).
 Pulmonary hypertension leads to right ventricular hypertrophy, dilatation and
failure with subsequent tricuspid regurgitation.
CLINICAL PRESENTATION
SYMPTOMS
 Symptoms are generally those of left-sided heart failure.
 Patient may present with Pulmonary edema
 Exertional dyspnea: lungs are edematous and boggy making them difficult
for respiratory muscles to expand lungs in addition during exertion right heart
pumps more blood to the lungs and this further increases congestion and
pulmonary edema in lungs.
 Orthopnea: due to pulmonary edema
 Paroxysmal nocturnal dyspnea: due to pulmonary edema
 Cough with pink-frothy sputum
 Frank hemoptysis: due to rupture of pulmonary vasculature as a result of
pulmonary hypertension
 Recurrent bronchitis: infection is more likely in edematous lungs.
 After progression of disease there may be signs of right sided heart failure such
as ascites, tender hepatomegaly and pitting edema of the lower limbs.
 There may be hoarseness of the voice from recurrent laryngeal nerve
compression

SIGNS
FACE
 Severe mitral stenosis with pulmonary hypertension is associated with the so-
called mitral facies or malar flush.

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 This is a bilateral, cyanotic or dusky pink discoloration over the upper cheeks
that is due to arteriovenous anastomoses and vascular stasis.

PULSES
 Pulse may be associated with a small-volume which is usually regular early in
disease in patients with sinus rhythm
 Atrial fibrillation as disease progresses results in irregularly irregular pulse.
 The development of atrial fibrillation in these patients often causes a dramatic
clinical deterioration.
JUGULAR VEINS
 If right heart failure develops there is obvious distention of the jugular veins.
 If pulmonary hypertension or tricuspid stenosis is present, the ‘a’ wave will be
prominent provided that atrial fibrillation has not supervened.
PALPATION
 There is a tapping impulse felt parasternally of the left side. This is the result of
a palpable first heart sound combined with left ventricular backward
displacement produced by an enlarging right ventricle.
 A sustained parasternal impulse due to right ventricular hypertrophy may also be
felt.
AUSCULATATION
 If the mitral valve is still pliable there is a loud first heart sound.
 As the valve becomes calcific the sound is softer.
 When the valve suddenly opens with the force of the increased left atrial pressure,
an ‘opening snap’ will be heard.
 This is followed by a low-pitched ‘rumbling’ mid-diastolic murmur best heard
with the bell of the stethoscope held lightly at the apex with the patient lying on
the left side.
 The P2 component of the second heart sound may be loud if there is pulmonary
hypertension.
 If the patient is in sinus rhythm, the murmur becomes louder at the end of diastole
as a result of atrial contraction (pre-systolic accentuation).

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Figure 7: Mitral Regurgitation vs Mitral stenosis

INVESTIGATIONS
DIAGNOSTIC
BLOOD INVESTIGATIONS
 Antistreptolysin O titers (ASOT) to detect presence of rheumatic fever.

CHEST X-RAY
 Usually shows a generally small heart with an enlarged left atrium.
 Pulmonary venous hypertension is usually also present.
 Late in the course of the disease a calcified mitral valve may be seen on a
penetrated or lateral view.
 The signs of pulmonary edema or pulmonary hypertension may also be apparent
when the disease is severe.

ECHOCARDIOGRAM (IMAGING)
 It is the diagnostic tool of choice for diagnosing and assessing the severity of
mitral stenosis. It is used to estimate valve area and to measure the transmitral
pressure gradient. Mitral valve morphology on echocardiography determines a
patient’s suitability for percutaneous valvuloplasty.
 It also determines the left and right atrial and ventricular size and function.

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Figure 8: ECHO findings in Mitral stenosis

ELECTROCARDIOGRAM
 In sinus rhythm the ECG shows a bifid P wave (P- mitrale) owing to delayed left
atrial activation.
 However, atrial fibrillation is frequently present.
 As the disease progresses the ECG features of right ventricular hypertrophy (right
axis deviation and perhaps tall R waves in lead V1) may develop.

Figure 9: ECG findings in Mitral stenosis

CARDIAC CATHETERIZATION
 Rarely required and only used if co-existing cardiac problems (e.g. mitral
regurgitation or coronary artery disease) are suspected.
 Right heart catheterization may be required to determine pulmonary artery
pressure in patients referred for valve intervention
SUPPORTIVE
 Urinalysis
 FBC- to show infection
 U & Es

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MANAGEMENT
 Management is both:
 Medical and
 Surgical
MEDICAL MANAGEMENT
 Asymptomatic patients
 Annual checkups (history, physical examination, chest X-ray and ECG).
 Endocarditis prophylaxis
 Secondary prophylaxis for rheumatic fever
 Symptomatic patients:
 Diuretics may be helpful in reducing left atrial pressure and decreasing
symptoms. Long-acting nitrates can also be used for shortness of breath.
 Digoxin is indicated for patients with atrial fibrillation to control the heart
rate since tachycardia will further decrease left ventricular filling, reduce
cardiac output and increase left atrial pressure leading to more symptoms.
 Beta blockers or rate-limiting calcium channel blockers improve exercise
tolerance
 Anticoagulants e.g. Warfarin in patients with left atrium hypertrophy and
atrial fibrillation to prevent atrial thrombus and systemic embolization.
 Any addition lung infections especially pneumonia are treated with
antibiotics.
SURGICAL MANAGEMENT
 If pulmonary hypertension develops or the symptoms of pulmonary congestion
persist despite therapy, surgical relief of the mitral stenosis is advised.
 Indications:
 Severe symptoms
 Complications
 Surgical intervention includes:
 Percutaneous balloon mitral commissurotomy: first line choice
 Trans-septal balloon valvotomy.
 Closed valvotomy
 Open valvotomy (open commissurotomy-involves opening up the valve at
the junction of its leaflets)
o Contraindication of commissurotomy: left atrial thrombosis
 Mitral valve reconstruction

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 Mitral valve replacement
COMPLICATIONS
 Left atrial enlargement
 Esophageal compression
 Recurrent laryngeal nerve compression
 Atrial fibrillation
 Pulmonary hypertension
 Right ventricular failure
 Tricuspid or pulmonary regurgitation
 Infective endocarditis

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MITRAL REGURGITATION
 Mitral regurgitation can occur due to abnormalities of the valve leaflets, the
annulus, the chordae tendinae or papillary muscles or the left ventricle.
 A small amount is common in the population but clinically significant in 2%.
 The most common causes of mitral regurgitation are:
 Rheumatic heart disease
 Ischemic heart disease
 Infectious endocarditis
 Degenerative (myxomatous) disease
 Other causes include:
 Cardiomyopathies (dilated and hypertrophic)
 Rheumatic autoimmune disease e.g. SLE, collagen disease e.g. Marfan’s
syndrome and Ehlers-Danlos syndromes
 Drugs e.g. centrally acting appetite suppressants (fenfluramine) and
dopamine agonist (cabergoline).
ETIOLOGY
 Primary causes:
 Mitral valve prolapse (causes 50%)
 Rheumatic heart disease
 Calcification
 Infective endocarditis
 Congenital
 Papillary muscle rupture due to MI
 Appetite suppressants
 Trauma
 Secondary causes (functional):
 Left ventricular dilation due to Ischemic heart disease
 Dilated cardiomyopathy
 Hypertrophic cardiomyopathy
 Aortic regurgitation

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PATHOPHYSIOLOGY
 Regurgitation into the left atrium produces left atrial dilatation but little increase
in left atrial pressure if regurgitation is long standing as the regurgitant flow is
accommodated by the large left atrium.
 With acute mitral regurgitation the normal compliance of the left atrium does not
allow much dilation and the left atrial pressure rises. In acute mitral regurgitation
the left atrial v-wave is greatly increased and pulmonary venous pressure rises to
produce pulmonary edema.
 A proportion of stroke volume is regurgitated, the stroke volume increases to
maintain the forward cardiac output and left ventricle therefore enlarges.
 Chronic mitral regurgitation is a state of volume overload leading to the
development of left ventricular hypertrophy. The left atrium also enlarges to
accommodate the regurgitant volume. This compensated phase of mitral
regurgitation varies in duration but may last many years.
 The prolonged state of volume overload may eventually lead to decompensated
mitral regurgitation characterized by impaired left ventricular function, decreased
ejection fraction and pulmonary congestion.
CLINICAL FEATURES
 Mitral regurgitation may be asymptomatic and present for many years as the
cardiac dimensions greatly increase.
 Symptoms:
 Palpitation: due to increased stroke volume which is sensed as a palpitation
 Shortness of breath, Dyspnea and orthopnea: due to pulmonary venous
hypertension occurring as a direct consequence of mitral regurgitation and
secondarily to left ventricular failure.
 Fatigue and lethargy: due to reduced cardiac output
 Chest pain
 Symptoms of Right heart failure (in later stages of disease) it can also leads
to congestive cardiac failure.
o Painful hepatic congestion, peripheral edema may occur in patients with
MR who have associated pulmonary hypertension
 Cardiac cachexia
 Symptoms of atrial fibrillation (though this is commoner in mitral stenosis):
palpitations and an irregularly irregular pulse. Thromboembolism is less
common than in mitral stenosis but subacute infective endocarditis is much
more common.

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 Signs
 Hyperdynamic apex beat that is laterally displaced (forceful) and diffuse.
 If severe there may be a systolic thrill over the apex.
 Soft S1 and widely split S2 (due to incomplete apposition of the valve cusps
and their partial closure by the time ventricular systole begins)
 Pansystolic (holosystolic) murmur best heard at the apex and radiates to the
axilla (this is due to occurrence of regurgitation throughout the whole of
systole)
o It may also radiate to the upper sternal borders or the subscapular region.
 With a floppy mitral valve there may be a mid-systolic click which is
produced by the sudden prolapse of the valve and tensing of the chordae
tendinae that occurs during systole.
 LVF signs: S3 (Sudden rush of blood back into the dilated DDX of a Pansystolic
left ventricle-sometimes a short mid-diastolic flow murmur
murmur may follow S3), crackles
 The signs related to atrial fibrillation, pulmonary  Mitral regurgitation
hypertension and left and right heart failure develop later  Tricuspid
in the disease. regurgitation: Louder
 Acute mitral regurgitation e.g. due to infective on inspiration
endocarditis or papillary muscle rupture can present with  VSD: usually younger
pulmonary edema. patients and apex non-
displaced

Figure 10: Mitral Regurgitation vs Mitral stenosis

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INVESTIGATIONS
 Diagnostic: Echo
 Echo is used to determine the etiology and morphology of the mitral regurgitation
which are important in determining suitability for mitral valve repair.
 Chest X-ray:
 Enlarged left ventricle and atrium: double right heart border.
 Increased cardiothoracic ratio
 Valve calcification
 Pulmonary venous congestion
 Interstitial edema and Kerley B line
 ECG
 P-mitrale if sinus rhythm: bifid/broad P wave due to large left atrium and left
atrial delay.
 Tall R waves in the left lateral leads (leads I and V6) and Deep S waves in
the right sided precordial leads (e.g. leads V1 and V2) indicating left
ventricular hypertrophy.
o Note: SV1 plus RV5 or RV6 >35mm indicates left ventricular
hypertrophy
 Atrial fibrillation may occur
 Other tests:
 Cardiac MRI, angiography and Catheterisation if indicated
 BNP may provide prognostic information.

MANAGEMENT
 Can be
 Medical
 Surgical
MEDICAL MANAGEMENT
 Salt restriction
 Diuretics
 Digoxin: may be indicated in patients with severe regurgitation and dilated left
ventricle without frank LV failure

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 Vasodilators: Afterload reduction with vasodilators has shown to improve left
ventricular performance. ACE inhibitors are the preferred vasodilators. Sodium
nitroprusside can also be used.
 Manage atrial fibrillation and heart failure if present.
 Endocarditis prophylaxis is important essential.
 6 monthly follow up and annual echo if severe.
SURGICAL MANAGEMENT
 Mitral valve replacement is the definitive treatment.
 Anticoagulation: 3 months after valve repair or bioprosthetic replacement,
lifelong after metallic replacement.
 Indications:
 Symptomatic MR
 Acute severe MR (emergency)
 MR complications such as LVF, new-onset AF, pulmonary hypertension. In
MR secondary to ischemic HF, surgery should only be done alongside
planned coronary artery bypass graft.
COMPLICATIONS
 Structural changes:
 Left ventricular and atrial enlargement
 Congestive heart failure
 Pulmonary hypertension
 Atrial fibrillation
 Infective endocarditis

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AORTIC STENOSIS
 The aortic valve has an area of 3 to 4cm3.
 Aortic stenosis is the commonest valve disease, affecting 4% of elderly.
 It is a chronic progressive disease that produces obstruction to the left ventricular
stroke volume leading to symptoms of chest pain, breathlessness, syncope and
pre-syncope and fatigue.
ETIOLOGY
 Rheumatic carditis
 Congenital stenosis of the aortic valve
 Congenital bicuspid valve
 Senile/calcific aortic stenosis which is idiopathic results in calcification and
degeneration of the aortic leaflets.
PATHOPHYSIOLOGY
 Obstructed left ventricular emptying leads to increased ventricular pressure and
compensatory left ventricular hypertrophy.
 This results in relative ischemia of the left ventricular myocardium and
consequent angina, arrhythmias and left ventricular failure.
 The obstruction to left ventricular emptying is relatively more severe on exercise.
 Normally, exercise causes a many-fold increase in cardiac output but when there
is severe narrowing of the aortic valve orifice the cardiac output can hardly
increase.
 Thus, the blood pressure falls, coronary ischemia worsens, the myocardium fails
and cardiac arrhythmias develop.
 Left ventricular systolic function is typically preserved in patients with aortic
stenosis.
CLINICAL FEATURES
 No symptoms until stenosis is moderately severe (when the aortic orifice is
reduced to 1/3 of its normal size i.e. less than 1.5cm2)
 Symptoms: “SAD” triad
 Syncope (may occur on exertion)
 Angina
 Dyspnea on exertion
 Sign:

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 Pulse: carotid pulse is small volume and slow-rising or plateau in nature
(Parvus et Tardus)
 Precordial palpation:
o Apex beat is not usually displaced because hypertrophy (as opposed to
dilation) does not produce noticeable cardiomegaly.
o Sustained and obvious pulsations
o Double impulse is sometimes felt because of S4 or atrial contraction
(‘kick’)
o Systolic thrill in the aortic area.
 Auscultation
o Ejection systolic murmur that is usually ‘diamond-shaped’ (Crescendo-
decrescendo): the murmur is usually longer when DDX of systolic murmur
the disease is more severe as a longer ejection time
is needed.  Aortic stenosis: loud
o The murmur is usually rough in quality and best on expiration
heard in the aortic area. It radiates to the carotid  Pulmonary stenosis:
arteries and also the precordium. Pulmonary areaas, loud
o Intensity of murmur is not a good guide to severity on inspiration
of the condition because it is lessened by a reduced  Pan-systolic: mitral
cardiac output. In severe cases the murmur may be regurgitation, tricuspid
inaudible. regurgitation, VSD
o Other findings:  Late systolic: Mitral
 Systolic ejection click, unless the valve has valve prolapse
becomes immobile and calcified.  Hypertrophic
 Soft or inaudible aortic S2 when the aortic valve cardiomyopathy:
becomes immobile increases on standing.
 Reversed splitting of S2 (splitting on expiration)  Aortic sclerosis:
 Prominent S4 (due to atrial contraction, it is distinguished from
heard unless co-existing mitral stenosis aortic stenosis by lack
prevents this). of other signs

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Figure 11: Aortic stenosis vs Aortic regurgitation

INVESTIGATIONS
 Imaging:
 Chest X-ray:
o Usually normal, otherwise LVH, calcified valve, dilated ascending aorta.
o CXR may show a relatively small heart with a prominent dilated
ascending aorta. This occurs because of turbulent blood flow above the
stenosed aortic valve producing ‘post-stenotic dilation’
o The cardiothoracic ratio may be increased when there is heart failure
 ECG: LVH and left atrial delay
o P-mitrale (bifid P wave)
o Left bundle branch block
o AV block
o Poor R wave progression
 Echo with Doppler: confirms diagnosis and assesses degree of calcification,
LV function, aortic velocity, pressure gradient and valve area. These factors
help classify severity.
 Further investigations
 Cardiac MRI, stress testing, angiography or Catheterisation if indicated.
 Multi-slice CT can help evaluate severity and is useful when considering
TAVI
 BNP may provide prognostic information.

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Figure 12: ECHO severity of Aortic stenosis

MANAGEMENT
 It is
 Medical
 Surgical
MEDICAL MANAGEMENT
 Medical management is not effective and treatment with digitalis or cautiously
administered diuretics may only reduce symptoms.
 Patients with severe aortic stenosis should limit vigorous physical activity
 Endocarditis prophylaxis
 Treat any secondary heart failure
 6 monthly echo if severe
SURGICAL
 Aortic valve replacement is the only effective treatment that will relieve this
mechanical obstruction.
 Indications:
 Severe (<1cm2 opening) + symptoms of LVSD
 If severe but asymptomatic need to weight risks vs benefits. If undergoing
coronary artery graft bypass might as well be done.
COMPLICATIONS
 Left ventricular failure or congestive heart failure
 Aortic root dilation due to hemodynamic changes around valve
 Infective endocarditis
 Sudden cardiac death

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AORTIC REGURGITATION
 Aortic regurgitation may be acute or chronic.
ETIOLOGY
 Acute causes:
 Infective endocarditis
 Aortic dissection
 Chronic causes:
 Congenital: bicuspid valve
 Aortic root dilatation: Marfan’s, Ehlers-Danlos
 Inflammatory: SLE, RA or seronegative arthritis, rheumatic heart disease,
Takayasu’s, syphilis
 Appetite suppressants
 Hypertension
PATHOPHYSIOLOGY
 Aortic regurgitation is reflux of blood from the aorta through the aortic valve into
the left ventricle during diastole.
 If net cardiac output is to be maintained, the total volume of blood pumped into
the aorta must increase and consequently the left ventricular size must enlarge.
 Because of the aortic runoff during diastole, diastolic blood pressure falls and
coronary perfusion is decreased.
 In addition, the larger left ventricular size is mechanically less efficient so that
the demand for oxygen is greater and cardiac ischemia develops.
CLINICAL FEATURES
SYMPTOMS
 Symptoms occur late and do not develop until left ventricular failure occurs.
 Pounding of the heart because of increased left ventricular size and its vigorous
pulsation.
 Angina pectoris
 Varying grades of dyspnea
 Arrhythmias are relatively uncommon

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SIGNS
 Signs are due to Hyperdynamic circulation, reflux of blood into the left ventricle
and increased left ventricular size.
 Signs:
 De Musset’s sign- head nodding with each heartbeat.
 Becker’s sign- visible pulsation of retinal arteries (through an
ophthalmoscope)
 Muller sign- pulsation or bobbing of the uvula that occurs during systole.
 Dancing sign (Corrigan’s sign)- visible carotid pulsation
 Collapsing pulse (Waterhammer pulse/Corrigan’s pulse): Hyperdynamic
pulse with rapid increase then collapse. Reflects large volume pushing
against little resistance through floppy valve then
collapsing back down. DDX of diastolic murmur
 Quincke’s sign- capillary pulsation in nail bed  Aortic regurgitation
 Duroziez’s sign- a to and fro murmur heard when the
 Aortic dissection
femoral artery is auscultated with pressure applied
(causing aortic
distally (if found it is a sign of severe aortic
regurgitation)
regurgitation)
 Mitral stenosis
 Pistol shot femoral- sharp bang heard on auscultation
 Right sided valve
over the femoral arteries in time with each heart beat
disease: Pulmonary
 Hill sign: popliteal systolic blood pressure exceeds
regurgitation, tricuspid
brachial systolic blood pressure by 60mmHg or greater.
stenosis
(This is the most sensitive sign of severe aortic
regurgitation)
 There is a wide pulse pressure.
 The apex beat is displaced laterally and downwards and is forceful in quality.
 On auscultation:
 High-pitched early diastolic murmur best heard at the left sternal edge in the
fourth intercostal space with the patients leaning forward and the breath held
in expiration
 Because of the volume overload there is commonly an ejection systolic flow
murmur. The regurgitant jet can impinge on the anterior mitral valve cusp
causing a mid-diastolic murmur (Austin Flint rumble)

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Figure 13: Aortic stenosis vs Aortic regurgitation

INVESTIGATIONS
 ECHO with Doppler ultrasonography is diagnostic and provides information
about aortic valve morphology, aortic root size, and a semiquantitative estimate
of the severity of aortic regurgitation. It provides valuable information about left
ventricular size and function.
 ECG: LVH- tall R waves and deeply inverted T waves in left sided chest leads,
and deep S waves in right sided leads. Normal sinus rhythm.
 CXR: LVH, dilated ascending aorta
 Multi-slice CT may help visualize aortic root dilation in Marfan’s.
MANAGEMENT
 It is:
 Medical
 Surgical
 Medical:
 Salt restriction
 Diuretics
 Digoxin: may be indicated in patients with severe regurgitation and dilated
left ventricle without frank LV failure.

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 Vasodilators: reduce afterload to improve left ventricular performance and
reduce aortic regurgitation. ACEi are preferred. Therapy with long acting
Nifedipine in particular has been shown to delay the needed for surgery by 2
or 3 years.
 Manage LVF if present: ACEi (especially in HTN), beta blockers (especially
in Marfan’s)
 Monitor regular echo, 6 monthly if severe or every 2 years if mild-moderate.
 Surgical:
 Aortic valve replacement
o Recall: patients with chronic AR usually do not become symptomatic
until after the development of myocardial dysfunction
o When delayed too long, surgical treatment often does not restore normal
LV function therefore appropriate timing is necessary for surgical
intervention.

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OTHER VALVE PATHOLOGIES
MITRAL VALVE PROLAPSE
 This occurs when varying portions of one or both leaflets of the mitral valve
extend or protrude abnormally above the mitral annulus into the left atrium.
 It is seen in 5% of the population.
 It has different causes including:
 Clinical features:
 Common in females and more common in 14-30 age group
 Clinical course is often benign
 Most patients are asymptomatic and may remain so for their entire lives
 Some may manifest features of mitral regurgitation. They may have
palpitations and chest pain.
 Arrhythmias like premature ventricular contraction and ventricular
tachycardia may occur as complications.
 Mid-systolic click often accompanied by a late systolic murmur is the
auscultatory hallmark of mitral valve prolapse.
 Management:
 Asymptomatic patients need only reassurance
 Symptomatic with thickening of mitral valve:
o Endocarditis prophylaxis
o Beta blockers sometimes may relieve chest pain
 Severe symptoms from secondary MR: surgical treatment may be needed
(mitral valve repair and/or rarely replacement)

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Feature Pulmonary Pulmonary Tricuspid stenosis Tricuspid regurgitation

Stenosis Regurgitation
Etiology  Rheumatic  Pulmonary  Rheumatic  Functional: right
fever hypertension heart disease ventricle dilation (cor
 Congenital: (dilation of the (Mitral and pulmonale, myocardial
Tetralogy of pulmonary aortic valves infarction, pulmonary
Fallot, valve ring) are also hypertension)
Noonan,  Dilated affected)  Organic: rheumatic
rubella cardiomyopathy  Carcinoid heart disease, infective
 Carcinoid syndrome endocarditis, carcinoid
syndrome  Tricuspid syndrome, Ebstein’s
atresia anomaly (congenitally
 Atrial tumor malpositioned tricuspid
 Infective valve)
endocarditis  Congenital anomalies
(Tricuspid atresia)
Symptoms  Asymptomatic  Mild  Symptoms  Symptoms of right
(mild PS)  Asymptomatic associated with heart failure including
 Fatigue left-sided ascites and liver signs
 Syncope rheumatic (enlarged, pulsatile,
 Symptoms of valve lesion painful, jaundice)
right heart  Abdominal
failure pain (due to
hepatomegaly)
and swelling
(due to ascites)
 Peripheral
edema
 Dyspnea
Signs  Harsh mid-  Decrescendo  Prominent  Large venous ‘cv’
systolic diastolic jugular venous wave
ejection murmur a wave  Palpable liver that
murmur best beginning with  Pre-systolic pulsates in systole
heard on the pulmonary pulsation may  Left Parasternal heave
inspiration to component of be felt over the  Blowing pansystolic
the left of the S2 that is liver murmur best heard on
sternum in the difficult to  Mid-diastolic inspiration at the lower
second distinguish rumbling left parasternal edge.

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intercostal from the murmur after  Atrial fibrillation is
space. murmur of opening snap. common
 The murmur aortic Best heard in
may be regurgitation. left lower
associated parasternal
with a thrill area. It is
and radiates to louder on
the left expiration. It
shoulder may be missed
 Ejection click because of the
 Wide split S2: murmur of
P2 is delayed mitral stenosis
due to slow may co-exist.
emptying
through
narrow valve.
 Prominent a in
JVP
 S4
Investigations  CXR:  CXR:  Echo shows dilation of
prominent prominent the right ventricle with
pulmonary right atrial thickening of valve
artery. bulge
 ECG: right  ECG: enlarged
atrial and right atrium
ventricular (peaked tall P
hypertrophy waves >3mm
although it in lead II)
may  ECHO:
sometimes be thickened and
normal even immobile
in severe PS. tricuspid valve.
 Doppler Echo
is
investigation
of choice
Medical  Salt restriction Treatment rarely  Salt restriction  Treat functional cause
management  Diuretic necessary as it is  Diuretic
therapy asymptomatic therapy

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Surgical  Pulmonary  Tricuspid  Tricuspid valve
management valvotomy valvotomy replacement
(balloon  Tricuspid
valvotomy or valve
direct surgery) replacement

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SYSTEMIC HYPERTENSION
 This is persistent elevation in the arterial blood pressure that exceeds 140mmHg
systolic or 90mmHg diastolic on more than one occasion (at least 2-3 times).
 This is an arbitrary definition because a diastolic pressure of even 85mmHg
may be associated with increased cardiovascular morbidity and mortality.
 Unless acute end-organ damage e.g. hypertensive emergency is present or
Blood pressure is above 220/115 mmHg the diagnosis of hypertension
requires multiple blood pressure readings above 140/90mmHg on at least 2
different occasions.
 Hypertension is the most important modifiable risk factor for stroke, coronary
heart disease, myocardial infarction, congestive heart failure, end-stage renal
disease, retinopathy and peripheral vascular disease.
 Health care professionals must not only identify and treat patients with
hypertension but also promote a healthy lifestyle and preventive strategies to
decrease the prevalence of hypertension in the general population.
 The prevalence of hypertension increases in patients older than 60 years and it is
higher in blacks than whites.
 The age-adjusted prevalence of hypertension is slightly higher in men than in
women. The prevalence in women is closely related to age, with substantial
increase occurring after age 50. This may be related to hormonal changes
associated with menopause.
 The risk of hypertensive complications increases continuously throughout the BP
range.
 All adults should have blood pressure measured routinely at least every 5 years
until the age of 80 years. Seated blood pressure when measured after 5 minutes
resting with appropriate cuff size and arm supported is usually sufficient but
standing blood pressure should be measured in diabetic and elderly subjects to
exclude orthostatic hypotension.
 The cuff should be deflated at 2mm/s and the blood pressure measure to the
nearest 2mmHg.
 Two consistent blood pressure measurements are needed to estimate blood
pressure and more are recommended if there is variation in the pressure.
 A non-pathological rise in blood pressure is seen during pain and anxiety
(including white coat hypertension). However, this may suggest underlying
problem so consider follow up.

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CLASSIFICATION
 Hypertension is classified according to
 Etiology
 Degree of elevation of blood pressure
ETIOLOGY
 This is divided into
 Essential (primary) hypertension- most common (90-95%) and is due to a
combination of genetic, environmental factors and age. It usually develops
after the age of 30 but can develop earlier.
o A number of factors modulate the blood pressure including humeral
mediators, vascular reactivity, circulating blood volume, vascular
caliber, blood viscosity, cardiac output, blood vessel elasticity and
neural stimulation.
o Genetic factors- tends to run in families
o Fetal factors- low birth weight is associated with subsequent high
blood pressure. This relationship may be due to fetal adaptation to
intrauterine undernutrition with long-term changes in blood vessel
structure or in the function of crucial hormonal systems.
o Environmental factors- obesity, alcohol intake, salt intake, stress,
sedentary life style, smoking.
 There is evidence that a high potassium diet can protect
against the effects of a high sodium intake.
 Secondary hypertension- this is due to other causes (5-10%). All patients
below the age of 30 with hypertension and those with hypertension not
sufficiently controlled on 3 drugs should be assessed for these conditions.
o Renal:
 Chronic kidney disease (most common)
 Chronic pyelonephritis
 Diabetic nephropathy
 Acute and Chronic glomerulonephritis
 Chronic tubulointerstitial nephritis
 Polycystic kidney disease
 Urinary tract obstruction
 Renovascular disease- renal artery stenosis
 Renin-producing tumor

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o Endocrine:
 Cushing’s syndrome- hypercortisolemia
 Acromegaly
 Hyperthyroidism or hypothyroidism
 Hyperparathyroidism
o Adrenal:
 Conn’s syndrome- hyperaldosteronemia
 Pheochromocytoma- catecholamine producing tumor
 Adrenal hyperplasia
o Cardiovascular -coarctation of the aorta, vasculitis, and collagen
vascular disease
o Neurogenic: psychogenic, increased intracranial pressure, acute
spinal cord section
o Drugs: NSAIDs, oral contraceptives, cyclosporine, nasal
decongestants e.g. ephedrine, cocaine, amphetamines, steroids,
erythropoietin, carnenoxalone, liquorice, sympathomimetic,
vasopressin, monoamine oxidase inhibitors (with tyramine)
o Others: Obstructive Sleep apnea, Pregnancy or Pre-eclampsia
DEGREE OF EVELATION
CLASS BLOOD PRESSURE
SYSTOLIC DIASTOLIC
Blood pressure:
 Optimal <120 <80
 Normal 120-129 80-84
 Pre-hypertensive 130-139 85-89
Hypertension:
 Stage 1: mild 140-159 90-99
 Stage 2: moderate 160-179 100-109
 Stage 3 severe >180 >110
Isolated systolic hypertension:
 Stage 1 140-149 <90
 Stage 2 >160 <90

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 When systolic and diastolic blood pressure levels fall into different categories,
the higher category should be selected to classify the individual’s blood pressure
status.
 E.g. 160/92 mmHg should be classified as Stage 2 (moderate) hypertension
 174/120 mmHg should be classified as stage 3 (severe) hypertension
 Isolated systolic hypertension is defined as systolic blood pressure 140mmHg or
greater and diastolic blood pressure less than 90mmHg and staged approximately
(e.g. 170/82 mmHg is defined as stage 2 isolated systolic hypertension).
 The progression begins with prehypertension in persons aged 10-30 years (by
increased cardiac output) to early hypertension in persons aged 20-40 years (in
which increased peripheral resistance is prominent) to established hypertension
in person aged 30-50 years, and finally to complicated hypertension in persons
aged 40-60 years.
 Hypertensive urgency- severe hypertension (diastolic pressure greater than
130mmHg) but no end organ damage. The blood pressure should be lowered
over 24 hours.
 Hypertensive emergency- severe hypertension (diastolic pressure greater than
130mmHg) with end organ damage. The blood pressure should be lowered
aggressively over minutes to hours.
 Usually does not occur unless sudden increase in diastolic blood pressure to
<130mmHg. Was called malignant hypertension in the past.
 Signs of end organ damage include encephalopathy (headache, visual
impairment, seizures), blurry vision/retinal hemorrhage, angina, heart failure,
pulmonary edema, aortic dissection and acute kidney injury.
 Hypertensive crises: this is a diastolic pressure of 130mmHg with fundoscopic
findings of papilledema. Change in neurologic and mental status and abnormal
renal sediments are the hallmarks of hypertensive crisis.
 When associated with hemorrhages and exudates it is termed accelerated
hypertension however when associated with papilledema it is termed
malignant hypertension.
PATHOPHYSIOLOGY
 The pathogenesis of essential hypertension remains unclear.
 Hypertension is caused by a combination of cardiac output, peripheral vascular
resistance and sodium retention (regulated by the renin-angiotensin system).
 Peripheral vascular resistance and sodium retention are more important.
 All treatment of hypertension targets these factors.

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RISK FACTORS OF HYPERTENSION
 Modifiable:
 Age
 Gender: male sex
 Race: black race
 Non-modifiable:
 Arteriosclerosis
 Dyslipidemias/hypercholesterolemia
 Diabetes mellitus
 Smoking
 Obesity
 Sedentary lifestyle
 Excess alcohol intake
 Stress
CLINICAL FEATURES
 Most patients with hypertension are asymptomatic.
 The signs and symptoms may be attributed to end organ damage or associated
with the underlying secondary disease.
 The only reliable sign of hypertension is the blood pressure.
 Some symptoms:
 Headache: though popularly considered symptom of high BP, it is a
characteristic of only severe hypertension. Such headaches are localized to
the occipital region and present when the patient awakens in the morning but
subsides spontaneously after several hours.
 Blurred vision, Postural hypotension, Dizziness, palpitations, shortness of
breath sweating, easy fatigability and impotence
 Signs:
 Tachycardia
 Cerebral vascular insufficiency
 Lung crepitations
 Hypertensive retinopathy
 Symptoms related to vascular disease or evidence of target organ damage:
 Epistaxis, hematuria
 Retinal changes => blurring of vision
 Cerebrovascular disease:

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o TIAs: episodes of weakness or dizziness or stroke may occur
(hemorrhagic or ischemic)
 Cardiovascular damages: chest pain/angina pectoris or myocardial infarction
which may cause dyspnea due to heart failure
 Pain due to dissecting aorta
Underlying disease Comments
Chronic pyelonephritis  History of repeated UTIs
Pheochromocytoma  History of Sweating, labile hypertension, headache,
nervousness, postural dizziness, palpitations and
weight loss
Aldosteronism  History of polyuria, polydipsia and muscle weakness
secondary to hypokalemia
Cushing’s syndrome  History of weight gain, and emotional labiality
Hypo- or  History of cold or heat intolerance, sweating, lack of
hyperthyroidism energy, bradycardia or tachycardia
Drugs  Look for history of drug ingestion including oral
contraceptives, licorice and sympathomimetics
 There may be a history of known renal disease, abdominal masses, anemia and
urochrome pigmentation.
DIAGNOSIS
 Hypertension is diagnosed if the blood pressure is elevated on 3 separate
occasions. Once the diagnosis of hypertension has been made the following tests
should be ordered:
 Full blood count
 Urinalysis including microscopy, protein, blood and glucose
 Fasting blood glucose
 Urea and Creatinine: to check the function of kidneys
 Electrolytes
 Liver enzymes
 Lipid profile: Serum cholesterol, triglycerides, HDL and LDLs
 Chest X-ray
 ECG
 ECHO to detect left ventricular hypertrophy
 Fundoscopy

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 Special investigations to determine secondary cause:
o Thyroid function tests for hypo- and hyperthyroidism
o Renal ultrasound (with dopplers) for Renovascular disease,
o 24-hours urine assay of metanephrines and catecholamines for
pheochromocytoma.
o Overnight dexamethasone suppression test or 24-hour urine cortisol for
Cushing’s syndrome
o Serum renin/aldosterone for primary Aldosteronism,
 “Burn out” hypertension- occurs in patients who have had severe, long standing
hypertension but have now progressed to CCF (usually with dilated ventricles)
with decreased systolic function and a blood pressure that is now normal or low.
COMPLICATIONS OF HYPERTENSION
 End organ/target organ damage involves: the CNS, the eyes, the heart and the
kidneys.
 CNS complications:
 Hypertensive encephalopathy: this
consists of severe hypertension, altered
state of consciousness, increased
intracranial pressure with papilledema
and seizures. Focal neurologic deficits
are not common.
 Cerebrovascular accident:
o Transient ischemic attack:
episodic dizziness, unilateral
blindness, hemiparesis etc.
o Stroke: ischemic stroke (due to
atherosclerosis of cerebral
blood vessels) or hemorrhagic
stroke (as a result of elevated
arterial pressure and formation
of vascular micro-aneurysms).
 Cerebrovascular insufficiency
 Eye complications: Blurry vision, Retinal Figure 14: Target organ damage in hypertension
hemorrhage and Hypertensive retinopathy (Image adapted from Kumar and Clark)
(Grading below)

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 Grade 1: Silver wiring/increased reflectiveness (thickening of arterioles-
copper wiring=> silver wiring) and tortuosity
 Grade 2: grade 1 + Arteriovenous nipping produced when thickened retinal
arteries pass over the retinal veins
 Grade 3: grade 2 + cotton wool spots (flame-shaped hemorrhages and soft
exudates) due to small infarcts
 Grade 4: grade 3 + papilledema (blurring of the margins of the optic disc)

Figure 15: Fundus showing hypertensive changes: Grade 4 retinopathy with papilledema, hemorrhages
and exudates

Note: Grades 3 and 4 are diagnostic of malignant hypertension.

 Cardiovascular complications:
 Coronary artery disease/ischemic heart disease: angina pectoris and
myocardial infarction
 Aortic dissection
 Pulmonary edema
 Heart failure
 Peripheral vascular insufficiency
 Kidneys: hypertensive nephropathy and renal failure

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 Arteriosclerosis (hyperplastic arteriolosclerosis) of the afferent and efferent
arterioles and the glomerular capillary tuft impairs renal function.
 Patients may have proteinuria and microscopic hematuria and later on
develop chronic renal failure.
MANAGEMENT
 Evaluation involves:
 Diagnosis of hypertension
 Patient evaluation: Assessing lifestyle and other cardiovascular risk factors
or other diseases that will affect management (diabetes, hyperlipidemia,
smoking)
 Identify secondary cause of hypertension
 Assess for the presence of target-organ and cardiovascular disease (heart,
brain, kidney, peripheral vascular disease, retinopathy)
DIAGNOSIS OF HYPERTENSION
 Diagnosis is confirmed after an elevated blood pressure greater than
140/90mmHg, properly measured has been documented on at least 3 separate
occasions (based on the average of 2 or more readings at each of 2 or more visits
after initial screening).
 For accurate diagnosis ensure:
 Several determinations are made over a period of several weeks
 The patient should rest quietly for at least 5 minutes before the measurement.
 The proper cuff size is used (it must be large enough so that the bladder of
the cuff encircles more than 30% of the arm), as the improper cuff size may
influence blood pressure measurement, a wider cuff is preferable, particularly
if the patient’s arm circumference exceeds 30cm. If the cuff is too small the
blood pressure will be falsely elevated.
 Although somewhat controversial, the common practice is to document
phase V (a disappearance of all sounds) of Korotkoff sounds as the diastolic
pressure.
 At any given visit an average of 3 blood pressure readings taken 2 minutes
apart using a mercury manometer is preferable.
 Blood pressure should be measured in both the supine and sitting positions,
auscultating with the bell of the stethoscope.

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 On the first visit, blood pressure should be checked in both arms and in one
leg to avoid missing the diagnosis of coarctation of aorta or subclavian artery
stenosis.
PATIENT EVALUATION
 Predisposing factors for hypertension:
 Strong family history of hypertension
 Age: secondary hypertension often develops before the age of 35 or after 55
 Associated cardiovascular risk factors:
 Cigarette smoking
 Lipid abnormality or hypercholesterolemia
 Diabetes mellitus
 Family history of early deaths due to cardiovascular diseases
 Alcoholism
 Obtain a history of over the counter medication use, current and previous
unsuccessful antihypertensive medication trials.
 Physical examination
 General appearance:
 Round face and truncal obesity suggest Cushing syndrome
 Muscular development in the upper extremities out of the proportion of the
lower extremities suggestive coarctation of the aorta.
 Proper measurement of blood pressure:
 Compare the BP and pulses in the two upper extremities and in supine and
standing position.
 A rise in diastolic pressure when the patient goes from supine to standing
position is most compatible with essential hypertension while a fall in BP
in the absence of antihypertensive medication suggests secondary
hypertension
 Fundoscopic evaluation of the eyes:
 Grade 1: Silver wiring/increased reflectiveness (thickening of arterioles-
copper wiring=> silver wiring) and tortuosity
 Grade 2: grade 1 + Arteriovenous nipping produced when thickened retinal
arteries pass over the retinal veins
 Grade 3: grade 2 + cotton wool spots (flame-shaped hemorrhages and soft
exudates) due to small infarcts
 Grade 4: grade 3 + papilledema (blurring of the margins of the optic disc)

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 Palpation of all peripheral pulses should be performed: mainly palpation and
auscultation of carotid arteries. Femoral pulses should be felt and compared
with radial pulse. Radio femoral delay suggests coarctation of the aorta.
 Cardiac examination: this is performed to evaluate the signs of left
ventricular hypertrophy. These include displacement of apex, a sustained and
enlarged apical impulse and the presence of an S4. Occasionally a tambour
S2 is heard with aortic root dilatation.
 Abdominal examination:
 Look for renal artery bruit over the upper abdomen. The presence of a
unilateral bruit with both a systolic and diastolic component suggests
renal artery stenosis.
 Palpate for an abdominal aneurysm, enlarged kidneys of polycystic
kidney diseases.
LIFESTYLE MODIFICATION
 The goal of blood pressure management is to reduce blood pressure to
<140/90mmHg or <130/80mmHg in patients with diabetes, renal disease or
cardiovascular disease.
 All patients with prehypertension and stages 1 and 2 hypertension should be
counseled about lifestyle modification.
 Salt restriction (intake not more than 2.4g sodium or 6g sodium chloride): no
added salt or low-sodium diet
 Weight reduction: if over the ideal BMI (BMI 20-25)
 Exercise: aerobic physical activity (brisk walk for 30-45 minutes most days
of the week i.e. 3-4 times a week)
 Decrease of alcohol consumption (<3 units/day for men and <2 units/day for
women): alcohol potentiates the action of catecholamines and may
exacerbate hypertension
 Cessation smoking
 Stress relaxation techniques
 DASH diet (Dietary Approaches to Stop hypertension): a diet rich in fruits,
vegetables and low-fat dairy products with decreased saturated and
unsaturated fat.
 Patients with mild to moderate (grade 1-2) hypertension should be given 3
months to see if they respond to behavioral modification.
 If a brief trial of nonpharmacologic therapy fails, medications should be added
for those with stage 1 or stage 2 hypertension.

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 In general, any patient with severe (Grade 3) hypertension and/or signs of
complications (Stroke, Chronic kidney disease, Coronary artery disease,
Congestive cardiac failure, retinopathy etc.) should be started on antihypertensive
treatment immediately.
 Other modifiable cardiovascular risk factors (diabetes, hyperlipidemia,
smoking), should be screened and treated in hypertensive individuals.
 Patients should be counseled that, if they start antihypertensives, they will likely
need to take medication every day for life to prevent complications. They need
to take the medication even if they feel well. If they have side effects they should
come directly to see the doctor and not stop the medications until they are seen.
PHARMACOLOGICAL THERAPY
PRINCIPLES
 Classes of antihypertensives used include
 ACE inhibitors
 Angiotensin receptor antagonists
 Beta-blocker
 Calcium channel blocker
 Diuretics
 Step 1:
 Young Caucasians are more likely to
have high renin hypertension and
older patients and black patients
usually have low renin hypertension.
 If a drug with each pair is not tolerated,
the alternative drug type can be used
(e.g. If an ACE inhibitor is not
tolerated an angiotensin receptor
antagonist can be used)
 If a drug is not effective, a drug from
the other group should be selected.
Thus, if a calcium-channel blocker is
not helpful, an ACE
inhibitor/angiotensin receptor
antagonist should be tried. Almost all
patients will need more than one drug to effectively lower blood pressure.

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 Step 2: involves combining two drugs from different groups.
 Step 3: an ACE inhibitor (or angiotensin receptor antagonist) is combined with a
calcium channel blocker and diuretic. If triple therapy is not sufficient to achieve
target blood pressure readings, an alpha blocker, beta-blocker or spironolactone
or another agent may be used. It is not advised to combine a diuretic with a beta-
blocker since both aggravate diabetes.
 Step 4: add diuretic therapy, alpha blocker or beta blocker.
 Note: if the blood pressure remains elevated despite maximal dose of a first drug,
add another drug and then titrate to its maximal dose.
DRUG CLASS IMPORTANT CONSIDERATIONS
DIURETICS  Thiazide diuretics low dosage are well-established agents
and reduce risk of stroke in patients with hypertension.
 Side effects with higher doses: increased serum
cholesterol, impaired glucose tolerance, hyperuricemia
(which may precipitate gout) and hypokalemia
 Loop diuretics do have a hypotensive effect but are not
routinely used to manage Primary HTN
 Potassium sparing diuretics are not effective agents with
monotherapy treatment except spironolactone in the
treatment of hypertension and hypokalemia associated
with primary hyperaldosteronism
 Always monitor electrolytes with thiazide diuretics
BETA-ADRENOCEPTOR  No longer preferred as initial therapy for HTN but may
BLOCKERS be useful in younger people particularly those that cannot
tolerate ACE and ARBs as well as women of child
bearing potential.
 Should not be combined with thiazide type diuretics as
they increase the risk of developing diabetes (should be
combined with calcium channel blockers)
 Beta-blockers exert their effect by attenuating the effects
of the sympathetic nervous system and the RAAS
system.
 Major side effect: bradycardia, bronchospasm, cold
extremities, fatigue, bad dreams and hallucinations
 Always monitor heart rate
 These agents are especially useful in the treatment of
patients with both hypertension and angina.

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ANGIOTENSIN  Block the formation of angiotensin II a potent
CONVERTING ENZYME vasoconstrictor. They also block the degradation of
INHIBITORS bradykinin, a potent vasodilator.
 There is evidence that black African patients respond
less well to ACE inhibitors unless combined with
diuretics.
 Useful in diabetics with nephropathy where they slow
disease progression and in patients with symptomatic or
asymptomatic left ventricular dysfunction.
 Profound hypotension following first dose is
occasionally seen in sodium-depleted patients or in those
on treatment with large doses of diuretics.
 Renal function should be monitored during therapy as
deterioration may occur in patients with severe bilateral
renovascular disease (in whom the production of
angiotensin II is playing a major role in maintaining
renal perfusion by causing efferent arteriolar constriction
at the glomerulus)
 Most common side effect is a mild dry cough due to their
effect on bradykinin.
ANGIOTENSIN II  Share many actions of ACE inhibitors but since they do
RECEPTOR not have any effect on bradykinin they do not cause
ANTAGONISTS cough.
 They are used as an alternative in patients that cannot
tolerate ACE inhibitors
 Angioneurotic edema and renal dysfunction are
encountered less with this class as opposed to ACE
inhibitors
CALCIUM CHANNEL  Reduce blood pressure by causing arteriolar dilation as
BLOCKERS well as reduce cardiac contractility.
 They are useful in patients with concomitant ischemic
heart disease
 Major side effects (seen mostly with short acting):
headache, sweating, swelling of ankles, palpitations and
flushing
ALPHA BLOCKER  These agents cause postsynaptic alpha-1 receptor
blockade with resulting vasodilation and blood pressure
reduction.

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 Earlier short acting agents cause serious first dose
hypotension but the newer longer acting agents are far
better tolerated.
RENIN INHIBITORS  Aliskerin is the first orally active renin inhibitor which
directly inhibits plasma renin activity.
 It reduces the negative feedback by which angiotensin II
inhibits renin release. It has been used in combination
with ACE inhibitors and ARBs with a significant
reduction in blood pressure. However, a recent FDA
warning suggests avoiding these drugs with aliskerin
 Side effects are few but hypokalemia occurs.
OTHER VASODILATORS  Reserved for patients resistant to other forms of
treatment.
 Hydralazine can be associated with tachycardia, fluid
retention and a systemic lupus erythematosus-like
syndrome.
 Minoxidil can cause severe edema, excessive hair growth
and coarse facial features.
CENTRALLY ACTING  Methyldopa acts on central alpha-2 receptors usually
DRUGS without slowing the heard and is usually reserved for
patient with hypertension in pregnancy.

 Calcium channel blockers (like Nifedipine or Amlodipine) are all very effect in
Africans and good first antihypertensive drugs if you want to lower BP rapidly
(as in hypertensive urgency).
 For patients with DM or CCF and a normal or stable creatinine, ACE inhibitors
(like captopril or Lisinopril) are the best first antihypertensive.
 In patients with CAD, beta blockers are the first antihypertensive as they reduce
the risk of death from CAD
 Of note, most antihypertensives take 2-4 weeks to reach maximal effect so it is
good to wait 1 month before increasing the dose of a medicine or adding another
one.

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STEP ONE
 Option 1: Diuretics: start diuretics
 Amiloride and hydrochlorothiazide (5/50mg) PO OD
 Hydrochlorothiazde 25mg PO OD and Spironolactone 25-50mg PO BD to
QID
 Option 2: Calcium channel blocker
 Nifedipine retard 20mg PO BD or
 Amlodipine 2.5-10mg PO OD
 Option 3: Angiotensin converting enzyme inhibitors
 Captopril 25-50mg PO BD or TDS alternatively Enalapril 2.5-40mg PO OD.
 Those who cannot tolerate angiotensin converting enzyme inhibitors may be
given Angiotensin receptor antagonists [Losartan potassium 50-100mg PO
OD]
STEP TWO
 Use a combination of drugs from different groups:
 Diuretics + ACE inhibitors/ AR blocker
 Calcium channel blocker + ACE inhibitors/AR blocker
 Calcium channel blocker + Diuretic
STEP THREE
 Use a combination of diuretic + ACE inhibitor/ AR blocker + Calcium channel
blocker
STEP FOUR
 If not controlled as above, optimize the dose, add further diuretic therapy or
 Alpha blocker [Prazosin 0.5mg BD or TDS PO] initial should be at bed time to
avoid postural hypotension- then increase to 1-3mg BD or TDS after 3 to 7 days,
maximum daily dose 20mg or
 Add beta blocker- Atenolol 50-100mg PO OD, Propranolol 40-80mg PO BD or
TDS or
 Hydralazine 25-50mg PO BD or TDS
 Note: beta blockers are no longer preferred as a routine initial therapy for
hypertension, however can be used in younger people, patients with
cardiovascular risk or existing ischemic heart disease

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MANAGEMENT OF HYPERTENSIVE CRISES
 Hypertensive urgency- severe hypertension (diastolic pressure greater than
130mmHg) but no end organ damage. The blood pressure should be lowered
over 24 hours.
 Hypertensive emergency- severe hypertension (diastolic pressure greater than
130mmHg) with end organ damage. The blood pressure should be lowered
aggressively over minutes to hours.
 Usually does not occur unless sudden increase in diastolic blood pressure to
<130mmHg. Was called malignant hypertension in the past.
 Signs of end organ damage include encephalopathy (headache, visual
impairment, seizures), blurry vision/retinal hemorrhage, angina, heart failure,
pulmonary edema, aortic dissection and acute kidney injury.
 Hypertensive crises: this is a diastolic pressure of 130mmHg with fundoscopic
findings of papilledema. Change in neurologic and mental status and abnormal
renal sediments are the hallmarks of hypertensive crisis.
 When associated with hemorrhages and exudates it is termed accelerated
hypertension however when associated with papilledema it is termed
malignant hypertension.
 Note: in any patient with BP>222/120mmHg (very severe hypertension), assess
for signs of end organ damage and consider admission to the hospital.
Hypertensive emergency usually does not occur unless diastolic blood pressure
>130. Keep in mind that urgency is much more common than emergency.
 Signs of end organ damage:
 Hypertensive encephalopathy: visual impairment, confusion, headache and
seizures
 Acute retinal hemorrhage: sudden onset of blurry vision, massive
hemorrhage on ophthalmoscopy
 Myocardial ischemia or infarction: chest pain and ECG changes
 Pulmonary edema: shortness of breath, Chest X ray with pulmonary edema
 Acute kidney injury: recent onset of oliguria or anuria, elevated creatinine,
blood on urinalysis

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APPROACH TO THE PATIENT
 Rapid assess of the patient with brief history and targeted physical examination
(of the CNS, CVS, retina).
 Laboratory investigations:
 Full blood count
 Urinalysis
 Renal function test
 ECG
 General measures: look if the patient is in a stressful situation. Place the patient
in a quiet room and reevaluate after initial interview. Some patient’s BP lowers
below a critical level after relaxation.
 If the patient has hypertensive urgency (no signs of end organ damage) aim to
lower MAP by 25% over 2-3 days using oral medications. Start with Nifedipine
20mg PO BD and add other meds as necessary.
 If the patient has hypertensive emergency (signs of end organ damage), lower
the MAP by 25% over 1-2 hours using IV medication. Do not drop the diastolic
pressure to less than 95mmHg.
 Pharmacologic treatment:
 Start with Labetalol 50mg IV over at least a minute repeated after 5 minutes
if necessary, maximum dose is 200mg or
 Hydralazine 10mg IV stat followed by 5 mg
IV every 30 minutes until diastolic BP is
110mmHg or less or
 Sodium nitroprusside 0.5-8
micrograms/kg/min through continuous IV
infusion till BP is lowered to desired level.
 Furosemide 40-80mg IV may be used as
adjunctive therapy as a stat dose.
 As the patient’s BP stabilizes start long term oral
anti-hypertensive agents.
 Those patients with urgency could be discharged
with close follow- up and oral medication.

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HEART FAILURE
 This is a complex clinical syndrome caused by a structural or functional
abnormality in the cardiac muscle that impairs its ability to function as a pump
and meet the metabolic needs of the body.
 The body, sensing inadequate organ perfusion, activates multiple systemic neuro-
hormonal pathways which compensate initially by redistributing blood flow to
vital organs but later exacerbate the patient’s symptoms and lead to clinical
deterioration.
 Heart failure is a syndrome and not a complete diagnosis in itself: it’s important
to determine the underlying cardiac abnormalities.
 The incidence of CCF increases with age.
 The term ‘congestive heart failure’ is ill-defined but typically refers to heart
failure with fluid overload especially pulmonary edema.
CLASSIFICATION
 Heart failure can be classified:
 Anatomically
o Right sided heart failure
o Left sided heart failure
o Biventricular heart failure
 Functionally
o Heart failure with reduced ejection fraction (systolic heart failure)
o Heart failure with preserved ejection fraction (diastolic heart failure)
o High output heart failure
ETIOLOGY
UNDERLYING CAUSES
 The most common causes of heart failure include:
 Ischemic heart disease (35-40%)
 Cardiomyopathies (Dilated) (30-34%)
 Hypertensive heart disease (15-20%)
 Other causes include:
 Hypertrophic and restrictive cardiomyopathies
 Valvular heart lesions (mitral, aortic, tricuspid)
 Congenital heart disease (ASD, VSD)
 Alcohol and drugs (chemotherapy- doxorubicin)

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 Hyperdynamic state (anemia, thyrotoxicosis, hemochromatosis, Paget’s
disease)
 Right ventricular heart failure (RV infarct, pulmonary hypertension,
Pulmonary embolism, COPD)
 Tricuspid incompetence
 Pericardial disease (constrictive pericarditis, pericardial effusions)

LEFT VENTRICULAR FAILURE

 Manifestations are seen in the pulmonary circuit.
HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
 Left ventricular ejection fraction <40%. (normal ejection fraction ≥50%)
 Ejection fraction between 40-49% is a ‘mid-range’ grey area
 It is also known as systolic heart failure or left ventricular systolic dysfunction
(LVSD)
 Causes:
 Ischemic heart disease (IHD)/Myocardial infarction: commonest cause
 Hypertension
 Diabetes usually via IHD
 Valve disease
 Arrhythmias
 Drugs or alcohol
 Systolic heart failure: there is reduced cardiac contractility.
 The manifestations of systolic heart failure include: weakness, fatigue, reduced
exercise tolerance and other symptoms of hypoperfusion.
HEART FAILURE WITH PRESERVED EJECTION FRACTION
(HFpEF)
 Left ventricular relaxation failure leads to inadequate filling which decreases
stroke volume normal ejection fraction (≥50%).
 It is also known as diastolic heart failure.
 Causes:
 Hypertension: commonest cause
 Diabetes
 Constrictive pericarditis
 Cardiac tamponade

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 Restrictive cardiomyopathy
 Much more common in women than men, especially elderly women with
hypertension.
ETIOLOGY OF CHF CAUSES
Systolic dysfunction (inability to Hypertension (common)
expel blood) Ischemic heart disease
Idiopathic cardiomyopathy (like HIV)
Dilated cardiomyopathy
Valvular disease (common)
Alcoholic cardiomyopathy
Drug-associated cardiomyopathy
Myocarditis
Diastolic dysfunction (abnormal Hypertension
filling) Fibrosis
Ischemia
Aging process
Constrictive pericarditis (like in TB-
common)
Restrictive pericarditis (like in EMF-
common)
Hypertrophic cardiomyopathy

RIGHT VENTRICULAR FAILURE

 Manifestations are seen in the systemic circuit.
 Right ventricular systolic dysfunction due to:
 Cor pulmonale: primary lung disease (e.g. COPD) causing vasoconstriction
in poorly ventilated lung tissue to correct the decreased V/Q (ventilation
perfusion ratio) leading to pulmonary hypertension and right ventricular
failure
 Left ventricular failure due to pulmonary hypertension causing right
ventricular failure.
 Pulmonary valve stenosis (uncommon)
HIGH OUTPUT HEART FAILURE
 Normal heart but increased needs due to:
 Anemia
 Pregnancy

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 Hyperthyroidism
PRECIPITATING CAUSES
 The most common causes include
(1) H-Hypertension (systemic)
(2) E- Endocarditis (infection)
(3) A-Anemia
(4) R- Rheumatic fever and myocarditis
(5) T- thyrotoxicosis and pregnancy
(6) F-fever (infections)
(7) A-Arrhythmias (atrial fibrillation, complete heart block, sick sinus
syndrome)
(8) I-infarction (myocardial)
(9) L- Lung infection
(10) E- Embolism (pulmonary)
(11) S-Stress (emotional, physical, environment, dietary, fluid excess)
PATHOPHYSIOLOGY
 Heart failure may be classified as ‘acute’ or ‘chronic’, based on the time course
of the development of symptoms.
 Heart failure may be transient and reversible or permanent and thus chronic.
 When the heart fails, considerable changes occur to the heart and peripheral
vascular system in response to the hemodynamic changes associated with heart
failure.
 These physiological changes are compensatory and maintain cardiac output and
peripheral perfusion.
 The heart depends on a number of adaptive mechanism for maintenance of its
pumping function:
 Intrinsic mechanism
 The Frank-starling mechanism (cardiac dilation): increase in venous return
or end-diastolic volume results in increase in stroke volume and cardiac
output. It is the mechanism that matches cardiac output to venous return.
 Myocardial hypertrophy: increase in muscle mass helps maintain cardiac
performance. However, after initial beneficial effect, hypertrophy can lead
to ischemic changes, impairment of diastolic filling and alterations in
ventricular geometry.
 Extrinsic mechanism

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 Baroreceptor reflex: increases release of catecholamines, activation of
renin—angiotensin-aldosterone system and other neuro-humoral
adjustments.
 Renin-angiotensin aldosterone system.

 To compensate for the decreased cardiac output, the activity of the sympathetic
nervous system is elevated and the renin-angiotensin-aldosterone system is
activated.
 The change in activity of the sympathetic nervous system and the subsequent
stimulation of the adrenal medulla to release noradrenaline and adrenaline, results
in increased heart rate (tachycardia), increased contractility of the heart and
pronounced peripheral vasoconstriction in order to maintain blood pressure.
 The renin-angiotensin-aldosterone system is activated to correct the poor
perfusion to the kidneys due to the decrease in cardiac output.
 Vascular tone is further increased by angiotensin II and endothelin, a potent
vasoconstrictor released by vascular endothelial cells.
 Vasoconstriction increases afterload, which further reduces ejection fraction
and cardiac output.

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 The retention of salt and water are potentiated by the secretion of aldosterone
leading further congestion and edema.
 The stretch of the heart chamber walls leads to the release of atrial natriuretic
factor from the atrial wall and brain natriuretic factor from the ventricular wall.
 These peptides induce a decrease in blood volume and blood pressure
through sodium and water excretion as well as vasodilation of arterioles and
venules.
 Unfortunately, in the long term most of these compensatory mechanisms amplify
the problem rather than overcome it.
 The marked vasoconstriction increases the workload of the heart (afterload), it is
now harder to push blood out into the smaller-diameter vasculature than before
because of increased resistance.
 The heart also works harder when the heart rate increases.
 The increase in workload (afterload) means the myocardium requires more
oxygen but coronary blood flow is depressed due to the decrease in cardiac
output.
 There is also a progressive reduction in the sensitivity of the arterial baroreceptor
reflex to changes in blood pressure. This reflex is important in inhibiting
sympathetic activation when blood pressure rises. As a consequence, sympathetic
nervous system activity remains elevated in heart failure sufferers as do plasma
renin levels.

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 Coupled with the increased ventricular filling pressure caused by poor ventricular
emptying and the expansion of the intravascular volume, the ventricular chamber
wall is subjected to increased
stress.
 These stresses trigger myocardial
remodeling. As a consequence,
there is hypertrophy of the
ventricular myocardium, dilation
of the affected chamber (or
chambers) and further reductions
in contractility.
 An increased mass of cardiac
muscle also places increased
demands on oxygen consumption.
 Thus, the compensatory
mechanisms that (in a normal
heart) act to increase cardiac
output actually perpetuate and
worsen the heart failure.

Neuro-humoral changes Favorable effect Unfavorable effect

Increased sympathetic Increased heart rate, Arteriolar constriction
activity contractility, and increases afterload which
vasoconstriction leading to increases the oxygen demand
increased venous return and of the myocardium
filling
Increased Renin- Salt and water retention leading Vasoconstriction leading to
Angiotensin-Aldosterone to increase venous return increased afterload and cardiac
system remodeling
Increased Vasopressin Salt and water retention leading Vasoconstriction leading to
(ADH) to increase venous return increased afterload
Increased interleukins May have roles in myocytes Apoptosis
and TNFs hypertrophy
Increased Endothelin Vasoconstriction leading to Vasoconstriction leading to
increased venous return increased afterload

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 Chronic activation of the sympathetic nervous system and the renin-angiotensin-
aldosterone system is associated with remodeling of cardiac tissue, loss of
myocytes, hypertrophy and fibrosis.
 This prompts additional neurohormonal activation creating a vicious cycle that if
left untreated, leads to death.
 The severity of the clinical manifestations are commonly described according to
criteria developed by the New York Heart Association.
THE NEW YORK HEART ASSOCIATION FUNCTIONAL
CLASSIFICATION
 Class I- no limitation in physical activity. Normal physical exercise does not
cause fatigue, dyspnea or palpitations.
 Class II- mild limitation of physical activity. Comfortable at rest but normal
physical activity produces fatigue, shortness of breath or palpitations. (i.e. when
long distance walking, climbing 2 flights of stairs)
 Class III- marked limitation of activity. Comfortable at rest but gently exertion
causes marked symptoms of heart failure. (i.e. short distance walking, climbing
one flight of stairs
 Class IV- symptoms of heart failure occur at rest and are exacerbated by any
physical activity.
Grade Symptoms
I No symptoms
II Slight limitation, mild symptoms
III Marked limitation, symptoms with minor activity
IV Severe limitation, symptoms at rest

CLINICAL FEATURES
 CCF is characterized by shortness of breath, fatigue and signs of fluid retention.
 Most patients present with left heart failure which can progress to right heart
failure.
 Heart failure can be either compensated (when the patient is stable) or
decompensated (when the patient suddenly gets worse).
 Signs and symptoms of heart failure are:
 Symptoms: Exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea,
fatigue

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 Signs: cardiomegaly, S3 & S4 heart sounds, Elevated JVP, tachycardia,
hypotension, bi-basal crepitations, pleural effusion, peripheral ankle edema,
ascites, tender hepatomegaly
Left sided heart failure Right sided heart failure
Symptoms  Respiratory symptoms:  Liver congestion leads
 shortness of breath, to nausea, anorexia,
 Orthopnea (ask how many early satiety and right
pillow they sleep with) upper quadrant pain
 Paroxysmal nocturnal dyspnea  Epistaxis
(PND) and nocturnal cough  Nocturia: on lying flat,
 Pink frothy sputum fluid backs up from
 Wheeze legs to kidneys
 Other symptoms:
 Palpitations
 Poor exercise tolerance
 Fatigue
 Weight loss (cachexia) or
weight gain (fluid retention)
Signs  Cachexia  Increased JVP
 Cold peripheries  Peripheral edema
 Pulses Alternans: Arterial  Ascites
Amplitude Strong then Weak  Hepatomegaly
 Displaced apex beat (lateral  Right ventricular heave
displacement) due to pulmonary
 Crepitations (bi basal) hypertension
 S3 heart sound (‘gallop rhythm)
 S4 is commoner in diastolic heart
failure
 Crepitations

 Note: in biventricular failure there are features of both right sided and left sided
heart failure.

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DIAGNOSIS
 History and clinical examination
 Blood:
 FBC: anemia may mimic or exacerbate symptoms
 U+E and LFTs: liver and kidney function can be affected in heart failure and
are differential for fluid retention
 Thyroid function test: thyrotoxicosis can cause high output failure, while
hypothyroidism may cause symptoms of fatigue and edema
 Investigate cardiac risk factors: cholesterol, blood glucose
 Imaging
 Chest X ray
 Prominent pulmonary vessels (dilatation of pulmonary vessels) and
interstitial edema.
 Vascular redistribution (cephalization).
 Cardiomegaly (enlarged cardiac silhouette): increased cardiothoracic ratio
(normal ratio<50%)
 Pulmonary congestion: upper lobe diversions, fluid in fissures, Kerley B
lines, pleural effusions
 Echocardiography- wall thickness, cavity dimensions, ventricular function
(systolic <40% and diastolic dysfunction≥50%)
 ECG- abnormal in 80%
 Usually non-specific changes: Previous MI or AF (common) or axis
deviation (less common)
 Left ventricular failure
o Voltage criteria are met if the combined height of (S in V1) + (R in V5
or V6) is at least 7 large squares (35mm)
o LV strain pattern is ST depression and T inversion in V5-6
o Less commonly there is the mirror image ST elevation in V1-V3
 Right ventricular failure
o Tall R in V1 (>7 small squares or R>S in V1)
o Large S waves in V4-6.
o RV strain pattern is ST depression or T inversion in V1-3

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FRAMINGHAM CRITERIA FOR CHF
 Validate CHF with (2 major criteria) or (1 major and 2 minor)
 Major: paroxysmal nocturnal dyspnea or orthopnea, Elevated JVP,
pulmonary rales, S3, cardiomegaly on chest X-ray
 Minor: peripheral edema, night time cough, dyspnea on exertion (DOE),
pleural effusions, HR> 120, weight loss>4.5 kg in 5 days with diuresis.
MANAGEMENT
 Principles:
 Identify and treat the precipitating factors
 Control the congestive state
 Improve myocardial performance
 Prevention of deterioration of myocardial function (slowing progression of
heart failure)
 Treat underlying cause
GENERAL MEASURES
 Counseling
 Dietary salt restriction (<2g/day)
 Moderate fluid restriction. Get help if rapid gain e.g. 2kg in 3 days.
 Daily weighing
 Weight loss in obese patients (Avoid excess physical exertion, Note: exercise
may be advised within limit of the patient’s cardiac function)
 Stop smoking and alcohol
 Administration of oxygen if needed, exercise as tolerated for Class I and II.
 Treat co-morbidities such as IHD, AF and dyslipidemia.
PHARMACOLOGICAL THERAPY
HEART FAILURE WITH REDUCED EJECTION FRACTION
 Most patients are on four agents, all which except diuretics have a mortality
benefit.
CONTROL CONGESTIVE STATE
 Diuretics: are used in relieving congestion and reducing or preventing edema.
Most patients with heart failure have some degree of symptomatic congestion and
benefit from diuretic therapy.
 Usually a loop diuretic is required with the addition of a thiazide diuretic in
patients refractory to loop diuretics.

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 Furosemide
o Initial dose 20-40mg PO OD/BD or 20mg IV
o Maximum dose 400mg PO/day or 80mg IV/day
 Hydrochlorothiazide
o Initial dose 25mg PO/day
o Maximum dose 100mg PO/day
 Note: Loop and thiazide diuretics are useful for symptomatic relief; however,
they have not been shown to improve survival
 Side effects: azotemia, hypokalemia, metabolic alkalosis and elevation of
neurohormones
 Spironolactone: is an aldosterone inhibitor, reduces mortality in patients with
advanced heart failure. This drug should be reserved for patients with
moderately severe or severe heart failure (Class IV symptoms)
o Initial dose: 25mg PO/day or every other day
o Maximum dose: 50mg PO BD or higher
o Side effects: hyperkalemia (common so monitor potassium, the serum
potassium level is essential. As a result, this drug should be used in
patients with a creatinine above 2.5mg/dl), gynecomastia (in men)
ENCHACEMENT OF MYOCARDIAL CONTRACTILITY
 Digoxin:
 Inotropic effect and acts by inhibiting the Sodium-potassium ATPase and
increases intracellular calcium. This increases myocardial contractility.
 Neurohormonal modulation of centrally mediated parasympathomimetic and
sympathetic activity. By doing so it blocks the AV node and delays AV
conduction.
o Initial dose: 0.125mg PO/day
o Maximum dose: 0.25mg PO/day
 The use of digoxin can improve symptoms, reduce the duration and the need
for hospitalization in patients with heart failure but no effect on long term
survival.
 Digoxin is renally excreted and so dose adjustment is necessary in renal
failure.
 Digoxin use is recommended for patients with left ventricular systolic
dysfunction, particularly if they have atrial fibrillation.
 It is relatively contraindicated in some cardiac disease
o Cardiac outflow obstruction in MS (in the absence of atrial fibrillation)

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o Cor pulmonale
 Because of its narrow therapeutic index, it is associated with different side
effects
o GI: anorexia, vomiting, weight loss
o Neuralgia, delirium
o Yellow vision, Gynecomastia
o Arrhythmias of different types
 When electrolyte imbalance is suspected, digoxin should be withheld, and
patient observed for some days before reinitiating with a lower dose. One
should also give KCL as hypokalemia increases digoxin toxicity
 Vasodilator therapy: mainstay of chronic therapy, reduces mortality. May be used
in patients with severe heart failure. Through vasodilation there is a reduction in
the peripheral resistance and after load and improving cardiac performance.
 ACE inhibitors (1st line)- but must follow renal function. Enalapril has most
evidence and should be offered to all, and titrated to evidence-based dose.
ARBs can be substituted if intolerant.
 Isosorbide dinitrate
o Initial dose 10mg PO QID
o Maximum dose 80mg PO TDS
 Hydralazine (rarely used)
o Initial dose 10mg PO TDS
o Maximum dose 80mg PO TDS
 Hydralazine and nitrates in combination are effective afterload reducing
agents used in ACE intolerant patients
PREVENTION OF DETERIORATION OF MYOCARDIAL
FUNCTION
 The following drugs prevent deterioration in myocardial function by inhibiting
the neurohumeral mechanisms which causes cardiac remodeling and progression
of heart failure
 ACE inhibitors: improve mortality, symptoms and hospitalizations. They also
reduce afterload and cause neurohormonal modulation. The dose of ACE
inhibitors should be titrated to the maximum that can be tolerated
symptomatically or the target dose
 Captopril
o Initial dose: 6.25mg PO/day or every other day
o Maximum dose: 50-100mg PO QID

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 Enalapril:
o Initial dose: 2.5mg PO BD
o Maximum dose: 10-20mg PO BD
 Side effects: angioedema, acute renal failure in patients with bilateral renal
artery stenosis. It is contraindicated in patients with creatinine >3mg/dl,
cough
 Contraindications:
o Angioedema or anuric renal failure
o Pregnancy, Hypotension
o Creatinine >265mol/L (2mg/dl)
 Note the first 2 side effects are serious and necessitate immediate cessation
of the drug.
 Angiotensin II receptor blockers: these drugs are useful in patients who cannot
tolerate ACE inhibitors due to different side effects like cough, angioedema and
leukopenia.
 Losartan dose 25-50mg PO OD/BD
 Beta-blockers: for chronic therapy in patients with non-valvular CHF, not acute,
decompensated heart failure, reduces mortality. They are not indicated in
unstable heart failure, hypotensive states, severe fluid overload, sinus
bradycardia, AV block and asthma
 Carvedilol (best), metoprolol, atenolol
 Metoprolol dosage:
o Initial dose 6.25mg PO BD
o Maximum dose: 75mg PO BD
RIGHT VENTRICULAR FAILURE AND HEART FAILURE WITH
PRESERVED EJECTION FRACTION
 There is little evidence based treatment for RVF or heart failure with preserved
ejection fraction except for symptomatic relief with diuretics, management of co-
morbidities and lifestyle changes
 Long term oxygen therapy is beneficial in cor-pulmonale.
DRUGS CONTRAINDICATED IN HEART FAILURE
 NSAIDs especially diclofenac. Low dose aspirin is ok
 Steroids
 Most calcium channel blockers especially rate-limiting (verapamil, diltiazem)
 Pioglitazone, TCAs, Beta-agonists

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TREATMENT GUIDLINES
NYHC Comments Management
Class I Asymptomatic  Most patients do not require medicine but will require lifestyle
modifications
Class II Symptomatic  Captopril 12.5mg to 15mg PO BD or
on moderate  Lisinopril 5-10mg PO daily or
exertion  Enalapril 5-20mg PO daily (if patient develops a persistent dry
cough replace with Losartan 50mg PO daily)

 Hydrochlorothiazide 25mg PO daily or oral Furosemide 20-40mg

PO daily
 Beta blockers (Carvedilol 3.125mg PO BD, increase dose at least
every 2 weeks to 25mg BD, if patient is over 85kg then maximum
dose 50mg BD or use metoprolol 50-100mg PO daily)
Class III Symptomatic  Captopril 25mg PO BD/TDS or
on mild  Lisinopril 10-20mg PO daily or
exertion  Enalapril 5-20mg PO daily (if patient develops a persistent dry
cough replace with Losartan 50mg PO daily)

 Furosemide 40-80mg PO BD (monitor potassium levels)

 Digoxin 0.125mg-0.25mg PO daily
 Isosorbide nitrate 5mg to 10mg BD + hydralazine 5mg to 10mg BD
orally if patient cannot tolerate ACE inhibitors
 ASA 75mg PO OD
Class IV Symptomatic  Captopril 25mg PO BD/TDS or
at rest  Lisinopril 10-20mg PO daily or
 Enalapril 5-20mg PO daily (if patient develops a persistent dry
cough replace with Losartan 50mg PO daily)

 Furosemide 40-80mg IV BD (monitor potassium levels)

 Digoxin 0.125mg-0.25mg daily
 Isosorbide nitrate 5mg to 10mg BD + hydralazine 5mg to 10mg BD
orally if patient cannot tolerate ACE inhibitors
 Spironolactone 25-50mg PO OD/BD
 ASA 75mg PO OD
 Beta blockers should not be used in class IV CHF

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CARDIOMYOPATHIES
 Cardiomyopathies are a group of diseases affecting the myocardium that are not
a result of hypertension, valvular lesions, coronary heart disease, or pericardial
abnormalities.
 Cardiomyopathies are frequently associated with myocardial dysfunction and
subsequently heart failure.
 With few exceptions, histologic findings are non-specific, with myocyte
hypertrophy, cellular necrosis and fibrosis.
CLASSIFICATION
 Cardiomyopathies are classified into
 Primary myocardial involvement
o Idiopathic (causes Dilated (D), Restrictive (R) and hypertrophic (H)
cardiomyopathy)
o Familial (D, R, H)
o Eosinophilic endomyocardial disease (Loeffler syndrome) (R)
o Endomyocardial fibrosis (R)
 Secondary myocardial involvement
o Infective (D)
 Viral (HIV), bacterial, fungal, protozoal (Chagas), metazoan,
myocarditis
 Spirochetal disease
 Rickettsia disease
o Metabolic (D)
o Familial storage disease (D, R):
 Glycogen storage disease (D, R)
 Mucopolysaccharidoses
 Hemochromatosis
 Fabry’s disease
o Deficiency (D)
 Electrolytes
 Nutritional (vitamin B1 deficiency)
o Connective tissue disorders (D):
 SLA
 Polyarteritis nodosa

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 Rheumatoid arthritis
 Progressive systemic sclerosis
 Dermatomyositis
o Infiltrations and granulomas (R, D)
 Amyloidosis
 Sarcoidosis
 Malignancy
o Neuromuscular (D)
 Muscular dystrophy
 Myotonic dystrophy
 Friedreich’s ataxia (H, D)
o Sensitivity and toxic reactions (D):
 Alcohol
 Radiation
 Drugs
o Peripartum heart disease (D)
 Clinical classification of Cardiomyopathies also divides them into:
 Dilated/congestive cardiomyopathy (DCM):
o Pathological dilatation and impaired contraction of the left or both
ventricles.
o There is global hypokenisia of the myocardium (global impairment in the
contractility of the myocardium- “Large but hypokinetic heart”.)
 Remember segmental impairment in contraction is indicative of
ischemic heart disease.
o There is a systolic failure (as there is failure in pumping of the heart but
reserved diastolic filling action)- reduce ejection fraction.
o Caused by familial/genetic, viral and/or immune, alcoholic/toxic or
unknown factors or is associated with recognized cardiovascular disease.
 Hypertrophic obstructive cardiomyopathy (HCM)
o Left and/or right ventricular hypertrophy.
o It is often asymmetrical hypertrophy which usually involves the upper
part of the interventricular septum.
o Recall hypertrophy due to conditions like hypertension, valvular lesion
have symmetrical hypertrophy (normal shaped cavity).
o “hyperkinetic heart”
o Mutations in sarcoplasmic proteins cause disease in many patients.
o In all there is cases there is a mutation (autosomal dominant mutation)

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 50% of the cases are familial
 50% of the cases are sporadic
o As ventricle contracts strongly, septum becomes shorter and the
obstruction in 30-40% of patients bulges into the cavity producing a
dynamic obstruction to outflow of blood (hypertrophic obstructive
cardiomyopathy).
o This is the most common cause of sudden unexplained death especially
in young athletes during vigorous activity (exercise)
 During vigorous activities Heart becomes more dynamic and
obstruction becomes more pronounced and less blood is ejected from
the ventricle, pressure in aorta decreases and so very little heart
reaches myocardium this may precipitate severe myocardial
ischemia, arrhythmias and eventually death.
 Restrictive cardiomyopathy (RCM)
o This is due to pathologic infiltration (by amyloid, hemochromatosis,
sarcoid, granulomas) in the myocardium leading to myocardium
thickening with restricted filling and reduced diastolic size of either or
both ventricles with normal or near-normal systolic function. (diastolic
failure)
o It is idiopathic or associated with other diseases e.g. amyloidosis,
endomyocardial disease, sarcoidosis.
DILATED (CONGESTIVE) CARDIOMYOPATHY
 There is impaired left and/or right ventricular systolic dysfunction characterized
by an ejection fraction <40% with dilation of left ventricle.
 This is the most common type of cardiomyopathy.
PATHOPHYSIOLOGY
 Dilated cardiomyopathy (congestive) represents the final common morphologic
outcome of a variety of biological insults.
 It is a combination of myocyte apoptosis and necrosis with increased myocardial
fibrosis, produced mechanical function.
 Causes include (A, B, 3C, D, H, P):
 A-alcohol
 B- Beriberi (thiamine Deficiency-Vitamin B1)
 C- cocaine use
 C-coxsackie virus

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 C-Chagas disease
 D-drugs (anticancer drugs-doxorubicin/Adriamycin, amphetamines),
 H-HIV, HCV, hemochromatosis (bronze diabetes)
 P- Peripartum dilated cardiomyopathy (pregnancy)
 Genetic mutations- in dystrophin, and myocardium generally as well as
enzymes participating in oxidative phosphorylation, and beta-oxidation of
fatty acids.
CLINICAL MANIFESTATION
 A carful history is essential with particular emphasis on
 Family history of similar illness
 Exposure to cardiotoxins such alcohol
 Protracted “flu-like illness” or respiratory tract infection may suggest
previous myocarditis
 History of recent delivery or being in the last trimester of pregnancy
 Symptoms (similar to CHF/BVHF):
 Exertional dyspnea, fatigue, syncope, decreased exercise tolerance and
edema.
 Physical examination
 Hypotension, tachycardia
 Cardiomegaly (displaced apex beat)
 Findings of CHF: narrow pulse pressure, raised JVP, S3 and S4 gallops,
holosystolic murmur of mitral regurgitation.
 Functional mitral or tricuspid regurgitation.
 Evidence of fluid overload (e.g. crackles on lung exam, lower extremity
edema, ascites) and evidence of atrial fibrillation (irregularly irregular pulse)
or other arrhythmias.
COMPLICATIONS
 Syncope may result from arrhythmias (stretching the heart muscle).
 Systemic embolization often emanating from ventricular thrombus may occur.
 Mitral and tricuspid valve regurgitation (due to overstretching of the muscle from
the dilatation).
INVESTIGATIONS
 Chest radiography: enlargement of cardiac silhouette and evidence of pulmonary
congestion
 ECG:

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 Sinus tachycardia or atrial fibrillation,
 Ventricular arrhythmias,
 ST segment and T wave abnormalities
 Conduction disorders (Wide QRS, LBBB)
 Echocardiogram: left ventricular dilatation and dysfunction (ejection fraction
<40%)
 Other LAB investigations:
 Full blood count
 HIV test
 Renal function test- urea, electrolytes and creatinine
 Blood glucose (fasting or random)
 Lipid profile glucose
 Thyroid function tests
TREATMENT
 Medical therapy: standard therapy of systolic heart failure
 Salt restriction
 Diuretics
 Digitalis
 ACE inhibitors or Angiotensin II receptor antagonists
 Spironolactone
 Alcohol should be avoided
 Identify and treat underlying cause if it is treatable
 Surgical therapy: cardiac transplantation provides a median 10-year survival and
is effective palliation in appropriately selected individuals.
HYPERTROPHIC CARDIOMYOPATHY
 This is an autosomal-dominant disorder of myocardial structural proteins that
causes premature, severe left ventricular hypertrophy.
 A subset of hypertrophic cardiomyopathy cases may have asymmetric septal
hypertrophy and dynamic outflow tract obstruction.
 This is characterized by left ventricular hypertrophy (myocardial thickness
greater than 1.5 cm) typically of none dilated chamber without obvious causes.
 Other etiologies of left ventricular hypertrophy such as long-standing
hypertension and aortic stenosis need to be excluded before one can diagnose
hypertrophic cardiomyopathy.

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GENETIC PREDISPOSITION
 Hypertrophic cardiomyopathy is the most common genetic cardiovascular
disease.
 Half of patients with hypertrophic cardiomyopathy have a positive family history
with autosomal dominant transmission.
PATHOPHYSIOLOGY
 Generally ventricular hypertrophy involves the proximal portion of the
interventricular septum.
 As the septum thickens, it may narrow the outflow tract.
 In addition, systolic anterior motion of the mitral valve may occur and result in
left ventricular outflow tract obstruction and mitral regurgitation.
 When systolic anterior motion occurs, the mitral valve leaflets are pulled or
dragged anteriorly toward the ventricular septum, producing the obstruction.
 Consequently, the left ventricle has to generate much greater pressure to
overcome the outflow obstruction and to pump blood to the systemic circulation.
 Premature closure of the aortic valve may occur and is caused by the decline in
pressure distal to the left ventricular outflow obstruction.
CLINICAL FEATURES
 Clinical course is variable.
 Most patients are asymptomatic.
 Most common symptom is dyspnea on exertion.
 Patients may also complain of chest pain with exertion, syncope or near syncope
or palpitations.
 Congestive heart failure and atrial fibrillation along with their accompanying
symptoms may be part of the natural history of hypertrophic cardiomyopathy.
 Unfortunately, the first clinical manifestation of the disease may be sudden
cardiac death frequently occurring in young children and young adults often
during or after physical exertion. (this is usually common in athletes e.g.
wrestlers)
 Physical examination:
 Unless congestive heart failure has developed the lungs are usually clear and
the JVP is normal.
 Pulses Bisferiens: rapidly rising carotid pulse followed by a collapse in the
pulse and then a secondary rise.
 The point of maximal impulse may be double or triple, forceful and sustained

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 S4 gallop may be present
 Systolic murmur: the classic auscultatory findings for hypertrophic
cardiomyopathy is a crescendo-decrescendo systolic murmur along the left
sternal border that intensifies with a reduction in left ventricular volume e.g.
with the Valsalva maneuver or when standing and diminishes with increased
left ventricular volume e.g. hand grip or raising the legs when the patient is
in a supine position). In young adults, hypertrophic cardiomyopathy is the
most common etiology for sudden cardiac death
DIFFERANTIAL DIAGNOSIS
 Valvular aortic stenosis: the murmur of aortic stenosis radiates to the neck. Aortic
stenosis also has weak and delayed carotid upstrokes (parvus et Tardus).
 Hypertensive heart disease: not typically associated with asymmetric septal
hypertrophy or outflow tract obstruction.
DIAGNOSIS
 Chest X-ray
 May suggest left ventricular hypertrophy but will often be normal because
the hypertrophy in HCM involves the ventricular septum.
 ECG:
 Atrial fibrillation may be present as one of the complications of HCM.
 Echocardiography (gold standard at the diagnosis of HCM): on transthoracic
ECHO, the clinician should note:
 The thickness of the septum, location, and pattern of hypertrophy,
 Site and degree of left ventricular outflow tract obstruction,
 Presence of systolic anterior motion of the mitral valve,
 Presence of premature closure of the aortic valve and any change in severity
of obstruction with amyl nitrite.
 Pattern of hypertrophy varies, in classic obstructive phenotype the septum is
asymmetrically hypertrophied, the left ventricular cavity is small and
hypercontractile, often with diastolic dysfunction.
TREATMENT
MEDICAL
 Avoid competitive sport and strenuous exercise.
 Avoid dehydration, use diuretic with caution.

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 Beta-blockers are considered first-line therapy. By decreasing contractile force,
beta blockers decrease the outflow gradient and decrease oxygen demand. Beta
blockers also lengthen diastolic filling by slowing the heart rates. They help to
control chest pain.
 Calcium channel blocker: second-line therapy include verapamil and diltiazem.
Nifedipine, amlodipine and felodipine should be avoided because they cause
peripheral vasodilation which may result in decreased left ventricular filling and
worsening of symptoms of outflow tract obstruction.
 Atrial fibrillation is a common complication of HCM. Treatment of persistent
atrial fibrillation in HCM includes anticoagulation and rate control, preferably
with beta blockers.
 Digoxin should be avoided in HCM patients, particularly in those with resting or
latent obstruction because of its positive inotropic effect.
 Patients with HCM should receive prophylactic antibiotics for endocarditis
prevention before dental or invasive procedures. Turbulent flow through left
ventricular outflow tract striking the aortic valve as well as the mitral
regurgitation from systolic anterior motion of the mitral valve predispose to
endocarditis.
SURGICAL
 Septal myomectomy/myotomy may cause lasting symptomatic relief in ¾ of
severely symptomatic patients
 Alcohol ablation: ethanol injection in to the septal artery has also been reported
to reduce obstruction.
PREVENTION
 First degree relative of patients with HCM should be screened with ECHO.
RESTRICTIVE CARDIOMYOPATHY
 Restrictive cardiomyopathy is a disease of the myocardium that is characterized
by restrictive filling and reduce diastolic volume of either or both ventricles with
normal or near-normal systolic function.
CAUSES
 Infiltrative and granulomas:
 Amyloidosis
 Sarcoidosis: granulomas
 Hemochromatosis

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 Scleroderma
 Endocardial fibroelastosis (children): endocardium is massively fibrosed with
elastic tissue
 Radiation
 Fibrosis following cardiac surgery
 Eosinophilic endomyocardial disease (Loeffler syndrome)
 Familial
 Idiopathic
PATHOPHYSIOLOGY
 Infiltration or fibrosis of the myocardium causes impaired ventricular filling with
preserved systolic function.
 In end-stage disease, systolic dysfunction may develop.
 Restrictive cardiomyopathies present with a clinical heart failure syndrome that
is frequently indistinguishable from that caused by systolic dysfunction.
CLINICAL FEATURES
 History:
 Patients present with dyspnea, fatigue and peripheral edema (with
predominant ascites).
 Exercise intolerance and dyspnea are the prominent symptoms.
 Examination:
 Enlarged tender and pulsatile liver. (hepatosplenomegaly)
 JVP is elevated and it doesn’t fall normally during inspiration (Kussmaul’s
sign)
 Ascites
 The heart sounds may be distant but apical impulse is easily palpable unlike
in constrictive pericarditis.
DIFFERENTIAL DIAGNOSIS
 The clinical features are very similar to constrictive pericarditis.
 Clinical presentation and physical exam may yield findings identical to those
of restrictive cardiomyopathy.
 MRI shows pericardial thickening (>5mm) and right heart catheterization
demonstrates equalization of diastolic pressures in constrictive pericarditis.
 Hypertrophic cardiomyopathy
 Dilated cardiomyopathy

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DIAGNOSTIC WORK UP
 Chest X-ray: mild cardiac enlargement.
 ECG: low voltage (low QRS voltage), nonspecific ST-T wave changes and
conduction defects (AV conduction delay, bundle branch block).
 Echocardiography: increases left ventricular wall thickness, normal or mildly
reduced systolic function. Infiltrative causes can present with the characteristic
granular appearance of myocardium.
 Myocardial biopsy: detects infiltrative disease such as amyloidosis and
sarcoidosis.
TREATMENT
 Treat the underlying disease process (e.g. amyloidosis, sarcoidosis)
 Diuretics: reduce symptoms from venous congestion but overdiuresis leads to
decreased cardiac output due to preload dependence
 Beta blocker/calcium channel blockers: may improve diastolic function early in
disease process by slowing heart rate and increasing ventricular filling time.
Caution should be used in administration as this may result in a fall in cardiac
output. Avoid use of calcium channel blockers in amyloid heart disease because
they can cause significant negative chronotropy.
 Cardiac transplantation: remains an option for patients with intractable heart
failure without severe systemic disease.

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FEATURE DILATED HYPERTROPHIC RESTRICTIVE

Characteristics Left and/or right Disproportionate left Endomyocardial scarring or
ventricular ventricular myocardial infiltration in
enlargement, impaired hypertrophy, typically restriction to left and or right
systolic function, CHF, involving the septum ventricular filling with
arrhythmias, emboli more than the free wall, preserve systolic function
with or without an
intraventricular systolic
pressure gradient,
usually of a non-dilated
left ventricular cavity
Etiology A-alcohol Idiopathic Amyloidosis,
B- beriberi (thiamine Familial hemochromatosis
Deficiency-Vitamin Sarcoidosis
B1)
C- Coxsackie virus,
Chagas, cocaine
D-drugs (Doxorubicin-
Adriamycin)
H- HIV, HC,
hemochromatosis
P-Pregnancy
(postpartum)

History  Exertional Dyspnea  Dyspnea  Dyspnea

 Fatigue  Chest pain  Fatigue
 Syncope  Syncope  Peripheral edema
 Decreased exercise (usually ascites)
tolerance
 Edema
Physical  Elevated JVP  Crescendo-  Raised JVP that does not
examination  Displaced apex beat decrescendo murmur drop on Inspiration
 S3, S4 gallops that intensifies with (Kussmaul’s sign)
 Holosystolic a reduction in left  Hepatosplenomegaly
murmur of mitral ventricular volume  Peripheral edema
regurgitation e.g. standing,
 Pulmonary basal valvular maneuver
Crepitations and diminishes with

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 Irregularly irregular increased left
pulse (atrial fib) ventricular volume
e.g. hand grip or
raised legs in supine
position
 Pulsus Bisferiens
 S4 and sustained
apical impulse
CXR  Enlarged cardiac  Normal (ventricular  Mild cardiac Silhouette
silhouette hypertrophy cannot enlargement
 Evidence of be visualized
pulmonary because involves
congestion ventricular septum)
ECG  Evidence of left  Left ventricular  Low voltage QRS
ventricular hypertrophy and left complex
enlargement atrial enlargement  Conduction defects (AV
 Conduction along with a broad, conduction delay, bundle
disorders (wide deep Q wave in branch block)
QRS, LBBB) leads I and I and in
 Arrhythmias (atrial left precordial leads.
fib, non-sustained
VT)
ECHO  Dilated left ventricle  Left ventricular  Increased left ventricular
 Decreased ejection hypertrophy with wall thickness
fraction (<40%) systolic anterior  Normal or mildly
motion of mitral reduced systolic function
valve and left
ventricular outflow
tract obstruction.

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ARTERIOSCLEROSIS
 This literally means “hardening of the arteries”, it is a generic term reflecting
arterial wall thickening and loss of elasticity.
 3 distinct types are seen:
 Arteriolosclerosis: affects small arteries and arterioles and may cause
downstream ischemic injury.
o The two anatomic variants are hyaline and hyperplastic
arteriolosclerosis.
1. In Hyaline arteriolosclerosis there is deposition of
eosinophilic material which does not have any structural
detail, the underlying medial histology is obscure, arteries
become hard. This is seen in aging, essential hypertension and
diabetes mellitus
2. Hyperplastic arteriolosclerosis is an indication of malignant
hypertension.
 Monckeberg medial calcific sclerosis: Characterized by the presence of
calcific deposits in medium sized muscular arteries (e.g. radial artery or ulnar
artery), typically in persons older than 50.
o The lesions cause changes that are non-stenotic and so it is of little
clinical importance.
 Atherosclerosis: this is the most frequent and clinically important pattern. It
is a disease of intima in which there is formation of fibro-fatty plaque in
intima.
o It involves elastic arteries (aortic, carotid, and iliac arteries) and
medium sized muscular artery (coronary artery, popliteal artery,
Circle of Willes artery).
ARTERIOLOSCLEROSIS
 This characterized by hyaline thickening or proliferative changes of small arteries
and arterioles, especially in the kidneys and is usually associated with
hypertension or diabetes mellitus.
 Consist of two types:
 Hyaline arteriolosclerosis
 Hyperplastic arteriolosclerosis
 Hyaline arteriolosclerosis is characterized by:
 Hyaline thickening of arteriolar walls. In the kidneys it is referred to as
“Benign nephrosclerosis” and is associated with hypertension.

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 Hyperplastic arteriolosclerosis is marked by:
 Concentric, laminated, “onionskin” thickening of the arteriolar wall.
 Necrotizing arteriolitis, intramural deposition of fibrinoid material in
arterioles with vascular necrosis and inflammation.
 In the kidneys it is called “malignant nephrosclerosis” and is associated with
malignant hypertension
ATHEROSCLEROSIS
 It is characterized by the presence of intimal lesions called atheromas (or
atheromatous or atherosclerotic plaques).
 The atheromatous plaques are raised lesion composed of soft yellow,
grumous lipid cores (mainly cholesterol and cholesterol esters with necrotic
debris) covered by fibrosis.
 Atherosclerotic plaques can mechanically obstruct vascular lumina and are prone
to rupture, resulting in catastrophic vessel thrombosis.
 Plaques also weaken the underlying media, sometimes leading to aneurysm
formation.
 Atherosclerosis begins as an intimal process, the changes in the media occur
secondary to changes in the intima.
 Because coronary artery disease is an important manifestation of atherosclerosis,
epidemiologic data related to atherosclerosis mortality typically reflect deaths
caused by ischemic heart disease (IHD).
 Atherosclerosis causes more morbidity and mortality (roughly half of all
deaths) in the western world than any other disorder.
MAJOR CONSTITUTIONAL RISK FACTORS
NONMODIFIABLE FACTORS
 Age: between ages 40 and 60, the incidence of myocardial infarction in men
increases fivefold.
 Gender: premenopausal women are relatively protected against atherosclerosis
and its consequences compared with age-matched men. Thus, myocardial
infarction and other complications of atherosclerosis are uncommon in
premenopausal women in the absence of other predisposing factors such as
diabetes, hyperlipidemia or severe hypertension.
 Genetics: well-established familial predisposition to atherosclerosis and IHD is
multifactorial such as hypertension or diabetes, familial hypercholesterolemia,
that result in excessively high blood lipid levels.

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MAJOR MODIFIABLE FACTORS
 Hyperlipidemia: especially hypercholesterolemia; major risk factor for
development of atherosclerosis and is sufficient to induce lesion in the absence
of other risk factors.
 LDL cholesterol- “bad cholesterol”
 HDL cholesterol- “good cholesterol”
 Hypertension: can increase the risk of IHD by approximately 60%. Hypertension
also is the major cause of left ventricular hypertrophy (LVH) which also can
contribute to myocardial ischemia.
 Cigarette smoking: prolonged (years) smoking of one pack of cigarettes or more
daily increases the death rate from IHD by 200%.
 Diabetes mellitus: induces hypercholesterolemia, the incidence of myocardial
infarction is twice as high in diabetic as in non-diabetic individuals.
 Abdominal obesity.
ADDITIONAL FACTORS
 Inflammation as marked by C reactive protein.
 Hyperhomocystinemia
 Lipoprotein A
 Factors affecting hemostasis
Other factors: lack of exercise, living a competitive, stressful lifestyle (“Type A”
personality) and obesity
PATHOGENESIS
 There are 2 dominant theories regarding atherogenesis, one emphasizing intimal
cellular proliferation in response to endothelial injury and the other focusing on
repeated formation and organization of thrombi.
 The contemporary theory incorporates some aspects of both theories and also
includes risk factors. This theory is called the response to injury hypothesis.
 It views atherosclerosis as a chronic inflammatory response of the arterial wall to
endothelial injury.
 Lesion progression involves interaction of modified lipoproteins, monocyte-
derived macrophages, T lymphocytes and cellular constituents of the arterial
wall.

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RESPONSE TO INJURY HYPOTHESIS
 Atherosclerosis results from the following
pathological events:
 Chronic endothelial injury- and resultant
endothelial dysfunction, leading to
increased permeability, leukocyte
adhesion and thrombosis.
 Accumulation of lipoproteins (mainly
oxidized LDL and cholesterol crystals) in
the vessel wall
 Platelet adhesion
 Monocyte adhesion to the endothelium,
migration into the intima and
differentiation into macrophages and
foam cells.
 Lipid accumulation with macrophages,
which release inflammatory cytokines.
 Smooth muscle cell recruitment (from
media or circulating precursors) due to
factors released from activated platelets,
macrophages and vascular wall cells.
 Smooth muscle proliferation and ECM
production

MORPHOLOGY
GENERAL MORPOLOGY
 Grossly recognizable atherosclerosis begins
as a fatty streak and progress to a
fibroatheroma.
 Fatty streaks: begin as minute yellow, flat macules that coalesce into
elongated lesions, 1cm or more in length. They are composed of lipid filled
macrophages (foam cell) but are only minimally raised and do not cause any
significant flow disturbance.
 Atherosclerotic plaque (fibrous or fibro-fatty plaque): intimal thickening and
lipid accumulation. They are white to yellow raised lesions ranging from 0.3

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to 1.5 cm in diameter but can coalesce to form larger masses. Thrombus
superimposed over the surface of ulcerated plaques is red-brown in colour.
o Atherosclerotic plaques have 3 principal components:
a. Cells, including smooth muscle cells, macrophages and T
cells.
b. Extracellular matrix including collagen, elastic fibers and
proteoglycan
c. Intracellular and extracellular lipid
 Microscopic morphology
 Superficial fibrous cap: a thick fibrous cap is more stable and less likely to
develop complications (e.g. hemorrhage or rupture). The fibrous cap is
composed of smooth muscle cells and extracellular matrix (e.g. collagen).
 Atheromatous core: contains extracellular lipid, macrophages with
intracellular lipid and necrotic tissue (debris from dead cells, foam cells,
fibrin, variably organized thrombus, and other plasma proteins). The
cholesterol content is frequently present as crystalline aggregates that are
washed out during routine tissue processing and leave behind only empty
clefts.
 Shoulder of plaque: has macrophages, leukocytes (T-lymphocytes) and blood
vessels (due to neovascularization at the periphery of plaque).

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COMPLICATIONS OF ATHEROSCLEROSIS
 Complications include:
 Occlusion of vessel: symptoms, signs and results depend upon organ
supplied.
 Disruption of plaque: hemorrhage within plaque or rupture or ulceration of
plaque (with exposure of the thrombogenic components) can result in
thrombus formation.
o Myocardial infarction (coronary artery)
o Stroke (middle cerebral artery)
 Emboli: plaque can break free and carried in the blood stream farther down
the vessel.
 Aneurysm: Atherosclerosis begins as an intimal process but over time the
thickened intima puts pressure on and causes atrophy of the media, often
resulting in an aneurysm (i.e. dilation or saccular outpouching of vessel).
Aneurysm may rupture.
 Stenosis of medium sized vessels:
o Peripheral vascular disease e.g. popliteal
o Angina: coronary artery
o Ischemic bowel disease: mesenteric
 Peripheral vascular disease
o Clinical presentation: Claudication which is characterized by ache
or cramping in the extremities with exertion that is relieved by
standing still. Patients also have cool extremities, diminished distal
pulses, and shiny, hairless skin. Patients with severe peripheral
vascular disease have pain at rest. Ischemic ulcerations are a
common cause of morbidity.
o Cause: atherosclerosis of vessels of lower extremities.

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PREVENTION OF ATHEROSCLEROTIC VASCULAR DISEASE

 Primary prevention programs:
 Cessation of cigarette smoking
 Control of hypertension
 Weight loss
 Exercise
 Lowering total and LDL blood cholesterol levels while increasing HDL (e.g.
by diet or through statins)
 Secondary prevention programs: these can successfully reduce recurrent
myocardial or cerebral events
 Use of aspirin (Anti-platelet agent)
 Statins and beta-blockers (to limit cardiac demand)
 Surgical interventions (e.g. coronary artery bypass surgery, carotid
endarterectomy)

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ISCHEMIC HEART DISEASE/CORONARY HEART

DISEASE
 Ischemic heart disease (also known as coronary heart disease, coronary artery
disease) is the presence of symptoms or signs of cardiac ischemia.
 Ischemic heart diseases manifest due to an imbalance in myocardial oxygen
supply and demand that results in myocardial hypoxemia.
 Commonest cause of ischemia is atherosclerosis, the formation of lipid-laden
plaques in coronary artery walls.
 Other causes of mechanical obstruction include:
 Thrombosis
 Embolus
 Spasm
 Coronary arteritis (e.g. in SLE)
 Coronary ostial stenosis
 Other cause can be due to decrease in flow of oxygenated blood to the
myocardium due to:
 Anemia
 Carboxyhemoglobulinemia
 Hypotension causing decreased coronary perfusion pressure
 Symptoms occur when plaques:
 Grow and obstruct the vessel causing angina or
 Rupture and form a thrombus occluding the vessel and causing an acute
coronary syndrome
 IHD can present with
 Angina
 Stable angina (classical angina)
 Prinzmetal angina/Vasospastic angina
 Acute coronary syndrome (ACS)
 Unstable angina
 ST segment elevation myocardial infarction (STEMI)
 Non-ST segment elevation myocardial infarction (NSTEMI)

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PATHOPHYSIOLOGY
 Myocardial ischemia reflects an imbalance between myocardial oxygen supply
and demand. Myocardial oxygen demand is mainly determined by heart rate, the
force of ventricular contraction, and ventricular wall tension which is
proportional to the ventricular volume and pressure.
 Unless there is a proportionate rise in oxygen supply, conditions that increase
oxygen demand such as physical exertion result in ischemia.
 Atherosclerosis of coronary artery (CAD) is the most common cause of IHD.
 Atherosclerosis is focal narrowing of arteries which results from a plaque
formation. In CAD, atherosclerosis disrupts the normal functioning of the
vascular endothelium.
 Plaques are formed as a result of:
 Intimal smooth muscle proliferation probably as a result of endothelial
damage
 Lipid (cholesterol esters) are deposited at the center of plaques and also
within smooth muscle cells and macrophages (foam cells)
 A fibrous cap made of connective tissue covering the plaque
 As the stenotic lesion grows, perfusion pressure distal to the lesion decreases in
response, coronary arterioles dilate to maintain adequate blood flow preventing
ischemic symptoms at rest.
 During exertion the myocardial oxygen demand increases which cannot be
matched by the perfusion via the narrowed coronary artery.
 The resulting myocardial ischemia results in chest pain called angina pectoris
which is relieved by rest.
 Sometimes atherosclerotic plaques
may rupture and a fibrin thrombus is
formed over the plaque which
completely blocks the narrowed
coronary artery and results in
myocardial infarction.
 Note: for symptoms to occur
occlusion of coronary artery lumen
should exceed 70%.

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RISK FACTOR
 Modifiable risk factors:
 Hypertension: increases the risk of CAD both in men and women
 Dyslipidemia: increase in LDL, Increase in total cholesterol, increase in total
cholesterol: HDL ratio, and a reduction in HDLs.
 Diabetes mellitus: is associated with significant increase in risk of CAD
 Smoking: cigarette smokers are 60% more likely to develop CAD than non-
smokers.
 Excess alcohol
 Obesity
 Oral contraceptive pills: use of OCP is associated with increased risk of
CAD.
 Gout
 Non-modifiable risk factors:
 Age: the risk of CAD increases progressively with age. The risk of death
from CAD is 1.5 in 1000 individuals at age 50.
 Gender: IHD is more prevalent in men than in women. The difference is more
marked in premenopausal women compared to men of similar age.
 Ethnicity: especially South Asian ethnicity
 Medical history of atheroma: MI, stroke, or Pulmonary thromboembolism
 Family history: MI in 1st degree relative, male<55 years, female<65 years
ANGINA PECTORIS
 This is a chest pain or pressure produced by myocardial ischemia.
 It is usually caused by atherosclerosis i.e. ischemic heart disease (IHD). Less
commonly due to:
 Valve disease (especially aortic stenosis)
 Arrhythmias
 Hypertrophic cardiomyopathy
 Anemia
 Coronary vasospasm (e.g. cocaine-induced)
 It affects 1/10 over 65 years old and is commoner in males.
 Anginal pain is often precipitate by exertion. Other factors that increase
myocardial oxygen demand (e.g. emotional stress, eating meal, sexual
intercourse) may also precipitate angina.

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CLINICAL FEATURES
 The chest pain in angina is squeezing in type
or a feeling of pressure or tightness in the DIAGNOSTIC BOX:
chest. Sometimes it can be burning in nature  Angina pain is intermittent, stable with
or felt as epigastric discomfort. 3 classic features, remember ‘ECG’:
 Radiation: the pain radiates to the left  E- exertion as a precipitant
shoulder, left jaw, teeth or to the left arm.  C- constricting discomfort of
Sometimes it may radiate to the right arm. anterior chest, which may radiate to
 The pain in angina is often reproducible with neck, shoulders, jaw or arms
the same degree of physical exertion. The  G- Getting rest or Nitrates reliefs
symptom usually begins with low intensity, pain
increases over 2-3 minutes and often lasts  3/3= typical angina, 2/3= atypical
less than 15minutes. Episodes lasting more angina, 1/3= not angina
than 30 minutes suggest myocardial
infarction may have occurred.
TYPES OF ANGINA
 Chronic stable angina: angina which recurs under similar circumstances and with
similar frequency over time.
 Silent ischemia: for every episode of symptomatic ischemia that the patient
suffers, there are usually 4 to 5 episodes of silent (asymptomatic) ischemia. This
episode can be detected by ECG including stress ECG. Such episodes are less
severe in nature and shorter in duration.
 Unstable angina: this is when a change in status occurs. Unstable angina is
progressive and it may be ominous feature of imminent myocardial infarction:
 New onset angina: progresses in severity, duration or frequency over 1- or 2
months
 Resting angina: particularly worrisome because it implies decreased supply
rather than increased demand is causing angina. This suggests possible
occlusion is imminent.
 Prinzmetal angina (Vasospastic angina):
 This is a type of angina resulting from transient coronary spasm, which
usually but not always associated with fixed atherosclerotic lesion. The
spasm produces total but transient coronary occlusion.
 It usually occurs at rest (often at night) and episodes are frequently
complicated with ventricular arrhythmias.

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HISTORY
 A history of recurrent chest pain, obtain a detailed symptom history including:
onset, quality, location, duration, radiation and precipitating and relieving
factors.
 Determine the presence or absence of each of the 3 of the following symptoms
complex characteristics: remember ‘ECG’:
 E- exertion as a precipitant
 C- constricting discomfort of anterior chest, which may radiate to neck,
shoulders, jaw or arms
 G- Getting rest or Nitrates reliefs pain
 3/3= typical (definite) angina, 2/3= atypical (probable) angina, 1/3= not angina
 If patients’ symptoms are consistent with typical angina sub-classify the angina
as:
 Stable (unchanged for 2 or more months)
 Unstable:
 Rest
 New onset
 Increasing
 In patients with typical (Definite) or atypical (probable) angina, ask about
functional limitation.
 Ask about any episodes of dyspnea, palpitations or dizziness with or without
chest pain. If the patient has experienced any such episodes, ask about the same
symptom variables that are applicable to typical angina.
 Assess potential risk factors of CAD: lifestyle, habits, past medical history,
family history and hormone therapy.
 Ask about a history of symptoms such as exertional dyspnea, orthopnea and
bilateral leg swelling that suggest left ventricular (LV) dysfunction or heart
failure and nocturia.
 Ask about other potential causes of chest pain, especially if the symptoms have
changed, new symptoms have arisen or the patient is at low risk for CAD.
PHYSICAL EXAMINATION
 Complete physical examination
 Assess vital signs especially for hypertension, tachycardia, bradycardia,
arrhythmia and tachypnea.
 Examine the head and neck especially for:

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 Signs of anemia (mucous membrane pallor)
 Thyroid disease (exophthalmos, thyromegaly)
 Hypercholesterolemia (xanthelesma which is the deposit of lipids in the skin
of the eyelids)
 Atherosclerosis (Carotid bruit)
 Perform a general and peripheral vascular examination to identify signs of
generalized or peripheral atherosclerosis e.g. inequality of blood pressure in
arms, diminished pedal pulse and abdominal aneurysm.
 Examine the heart for evidence of hypertrophy, murmurs, S3 and S4 heart
sounds.
 Examine the lungs for crackles and other abnormal breath sounds.
 Examine the lower extremities for dependent (Ankle) edema, tendinous
xanthomas (lipid deposit), weak pulses or cutaneous signs of ischemia or
necrosis.
DIFFERENTIAL DIAGNOSIS
 Pleurisy
 Pneumonia
 Pericarditis
 Ischemia associated with aortic stenosis or hypertrophic cardiomyopathy
INVESTIGATIONS
 Blood investigations:
 Full blood count: to rule out anemia and infections
 Fasting blood glucose: for diabetes
 Serum lipid profile: for dyslipidemias
 Urea and electrolytes + creatinine: co-morbid CKD, ACEi baseline
 Imaging:
 Chest X ray: in patients with symptoms and signs of congestive heart failure
 Stress echocardiography (+ exercise or dobutamine stress)
 ECG: may be normal or may show Q waves or ST-T changes
 Resting ECG: This is an ECG taken when the patient is not in pain, it may
be normal. The presence of new horizontal or down sloping of ST segment
depression and new T-wave inversion are suggestive of myocardial
ischemia. ST segment elevation associated with pain which returns to
normal as the pain waves suggest variant angina.

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 Stress ECG: recording ECG during exercise increases the sensitivity and
specificity of ECG. This helps to quantify the patient’s exercise tolerance.
The presence of new horizontal or down slopping ST segment depression
has sensitivity of 70% and specificity of 90%.
 Stress radionuclide ventriculography
 Cardiac catheterization
MANAGEMENT
 This is aimed at either reducing myocardial oxygen demand or to compensate for
impaired flow through diseased coronary arteries or at increasing myocardial
oxygen supply (i.e. blood flow).
GENERAL MEASURES
 Lifestyle modification:
 Counsel patient about cessation of
smoking
 Diet (‘healthy’ diet like low fat and
low caloric diet with increased
habit of eating fruits and
vegetables)
 Regular exercise: about 30 minutes
a day but below angina threshold
 Weight reduction
 Treat comorbidities that can provoke
or exacerbate angina (e.g.
hypertension, diabetes mellitus,
hyperthyroidism, pulmonary
disorders, anemia)
 Short-acting nitrate:
 Glyceryl trinitate (GTN) Spray or
sublingual tablets
 Use before planned activity and
when symptomatic
 If pain continues for 5 minutes after
1st dose call ambulance and take 2nd
dose

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 Side effects: headache, flushing and lightheadedness
MEDICAL THERAPY
 Anti-anginals:
 First line: Beta blockers and/or calcium channel blockers. Use both if one is
insufficient
 Second line: Isosorbide mononitrate, nicorandil (potassium channel opener),
ivabradine (Funny channel blocker) or Ranolazine (‘late’ sodium channel
blocker). Can be used as monotherapy or in combination with 1st line drugs.
 Consider revascularization if not controlled by 2 drugs. Percutaneous
coronary intervention (PCI) for one or two vessels, coronary artery bypass
graft (CABG) for left main or triple vessel disease. Both relieve symptoms
but only CABG reduces mortality.
 CVD prevention:
 Aspirin for all (clopidogrel 2nd line) and consider statins and ACEi.
SURGICAL INTERVENTIONS
 Percutaneous transluminal coronary angioplasty
 Artherectomy
 Coronary artery bypass surgery
PROGNOSTIC INDICATORS
 The status of left ventricular (LV) function
 The location and severity of coronary artery narrowing
 The severity or activity of myocardial ischemia
 The presence of complex arrhythmias

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Mechanism of action Dose Indications and side effects

FIRST LINE
Beta blockers
Atenolol Inhibit beta- 25-100mg daily Indications: First line drug
Bisoprolol adrenoreceptors, reducing 2.5-10mg daily Caution: COPD, acute heart
Metoprolol heart rate, BP, and 25-100mg BD failure, AV conduction
myocardial oxygen or TDS Side effects: fatigue,
Propranolol consumption 20-80 mg PO peripheral vasoconstriction
BD to QID (cold peripheries), erectile
dysfunction, bronchospasm
Calcium channel blockers (Consider CCB when beta blockers are contraindicated or not tolerated)
Verapamil Inhibit calcium channels in 80-120mg TDS Diltiazem and verapamil-
(Phenylalkylamines) myocardium, cardiac (or 240-480mg contraindicated in severe
conductive tissue and daily slow bradycardia, left ventricular
vascular smooth muscle. release) failure with pulmonary
Diltiazem Diltiazem and verapamil 60-120mg TDS congestion, 2nd or 3rd degree
(benzothiapines) also slow down the heart AV block
Amlodipine rate 5-10 mg daily Side effects: constipation
(dihydropyridine) (verapamil), ankle edema
Note: drugs are effective (amlodipine, diltiazem),
especially in preventing reflex tachycardia
coronary spasms in variant (amlodipine)
angina
SECOND LINE
Nitrates/vasodilator
Glyceryl trinitrate Cause vasodilation through 0.3-1.0 mg Indications: Prophylaxis
nitric oxide and cGMP sublingual and treatment of angina-
cascade. They produce 2.0-3.0mg rapid onset. Repeat after 5
venodilation and to a lesser buccal min if symptomatic
extent arteriolar dilation. Side effects: headache and
These effects reduce BP flushing due to vasodilation
Isosorbide and reduce cardiac size. 10-60mg BD Indications: prophylaxis of
mononitrate angina
Side effects: headache and
flushing
Contraindicated with
phosphodiesterase type 5
inhibitors

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Other second line
Ivabradine Inhibits the pacemaker 2.5-7.5mg BD Indications: use in sinus
funny current (If) in the SA rhythm with or without a
node beta blocker
Side-effects: bradycardia
Contraindications: sick
sinus syndrome, AV block
Nicorandil Activates ATP sensitive 5-30mg BD It is used as adjunctive
potassium channels and has therapy
nitrate properties- Side-effects: headache,
peripheral and coronary flushing, oral ulceration.
vasodilation
Ranolazine May inhibit late sodium 375-750mg BD Used as an adjunct
channels in cardiac cells Metabolized by cytochrome
P450 3A4
Side-effects: constipation,
dizziness, lengthens QT
SECONDARY PREVENTION
Aspirin Antiplatelet 75mg daily Side-effects:
gastrointestinal bleeding
ACE inhibitor Block ACE enzyme Variable Used to treat other
conditions e.g.
hypertension, heart failure,
chronic kidney disease
Statins HMG CoA inhibitor Variable Used to reduce total
cholesterol to below
4mmol/L and LDL
cholesterol to below
2mmol/L

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ACUTE CORONARY SYNDROME
 This is usually due to rupture of atheromatous plaque in coronary artery leading
to thrombus formation and vessel occlusion locally or elsewhere in the heart.
 There are 3 acute coronary syndromes:
 ST segment elevation myocardial infarction (STEMI): increased troponin and
ST elevation on ECG. In practice ST elevation alone is sufficient to treat as
troponins take time to rise.
 Non-ST segment elevation myocardial infarction
Initial phase of infarction
(NSTEMI): increased troponin and ischemic symptoms
leads to subendocardial
or ECG changes
necrosis involving <50% of
 Unstable angina: prolonged, severe angina, usually at
the myocardial thickness
rest, possibly with ECG changes.
(subendocardial infarction).
 NSTEMI and unstable angina are often grouped together as
ECG shows ST-segment
non-ST elevation ACS (NSTEACS)
depression.
CLINICAL FEATURES Continued or severe
 Chest pain. It must be evaluated using SOCRATES ischemia leads to
 Site: central transmural necrosis
 Onset: usually sudden but can be more gradual. involving most of the
 Character: tight, crushing, but not sharp. myocardial wall (transmural
 Radiation: left arm, neck, jaw. Less commonly right arm, infarction). ECG shows ST
epigastrium, back segment elevation
 Associated symptoms: sweating, clamminess, SOB,
dizziness, faint, angor animi (an impending sense of doom)
 Timing: duration >15 minutes
 Exacerbating factor: Exertion, Emotion, Eating. Relieving factors: ACS less
likely if relieved by glyceryl trinitrate <5 mins.
 Severity: high but can atypically be low.
 Atypical presentations, more commonly seen in elderly or diabetic patients:
 Little or no chest pain
 SOB
 Sweating
 Nausea and vomiting
 Signs:
 Heart rate and blood pressure may be increased or decreased
 Pallor
 S3or S4 heart sounds (especially in STEMI)

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INVESTIGATIONS
 ECG: do immediately and if negative
repeat after 20 minutes if pain continues or
suspicion is high.
 ECG is diagnostic in 85% of cases.
 Transmural MI: ST segment elevation
in those leads reflecting the area of
myocardial infarction. As ST segments
fall, Q waves appear and T waves
become inverted
 Subendocardial infarction: ECG
findings are less certain and ST
segment depression may be the only
finding.
 Cardiac enzymes:
 Troponin T and I are cardiac specific.
Test on admission and at 3-6 hours.
Troponin peaks at 12-24 hours then
declines over 10 days. Troponin I is the
most sensitive and specific marker for
MI, levels rise 2-4 hours.
 Causes of raised troponin: “HEART
DIES”
o H-heart failure
o E-embolus (pulmonary)
o A-Atrial fibrillation
o R- Renal failure (due to
decreased clearance)
o T-Thrombus
o D- dissection of the aorta
o I- Inflammation (myo/pericarditis)
o E-Exercise (very strenuous)
o S-Sepsis
 Creatinine phosphokinase elevation appears 6 hours after infarction
 AST elevates 12 hours after infarction
 Lactate dehydrogenase starts elevation 24 hour after infarction

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 Cardiac imaging:
 Chest X-ray: rule out other causes and check for heart failure.
 Blood investigations:
 Full blood count: decrease hemoglobin may exacerbate heart strain and
baseline Hb and PLT needed before anticoagulation
 U and Es: baseline before anticoagulants and ACEi, and screens for co-morbid
renal disease from hypertension.
 Glucose: tight control improves outcomes.
 Lipids: check on admission, as cholesterol can dip 24 hours post-MI
 Exercise tolerance test: consider in decreased risk patients.
MANAGEMENT
Management of ACS
 General measures:
 Reassure and make the patient comfortable M-morphine
 Supply oxygen by mask
O- oxygen
 Secure IV line
 Give aspirin 160-325mg tablets- helps to prevent further N- Nitrates
platelet aggregation. Also give P2Y12 inhibitor A-Aspirin
(Clopidogrel, Ticagrlor or prasugrel) loading dose
 If patient is tachycardic/hypertensive beta-blockers IV
can be given (but not if unstable)
 Treatment of pain:
 Give morphine sulphate PRN: it is very effect analgesic for pain associated
with ACS. It is administered in small doses of 2-4mg IV every 5 minutes.
 Nitrates (Oral spray, sublingual tablets or IV infusion) can be added to
refractory cases. Nitroglycerin sublingual up to 3 times doses of 0.4mg should
be administered at about 5 minutes intervals for up to 3 doses.
 Anticoagulation:
 Unfractioned heparin or bivalirudin IV in those going for immediate or early
angiography. GP IIb/IIIa inhibitor IV (eptifibatide, tirofiban or abciximab) is
sometimes added as adjunctive antiplatelet but not routinely.
 Enoxaparin or fondaparinux SC for those without angiography planned
 Reperfusion with:
 Percutaneous coronary intervention (PCI) i.e. dilation of artery with balloon
catheter +/- stent placement for STEMI presenting within 12 hours of onset.
o If PCI not available within 120 minutes, consider thrombolysis
(alteplase, reteplase, or tenecteplase) and transfer to PCI center.

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 Thrombolytic agents: such as Streptokinase, t-plasminogen
activator, urokinase: these drugs are given to dissolve the
occlusive thrombus and promote reperfusion of the infarct
related artery reduces mortality from MI when administered
within 6 hours of the onset of chest pain
 Contraindication: history of cerebrovascular hemorrhage,
marked hypertension, bleeding disorder
o Patients persisting beyond 12 hours are essentially managed like
NSTEMI.
 Angiography +/- revascularization within 48 hours (‘early invasive strategy).
Revascularization is usually PCI but sometimes coronary artery bypass graft
(CABG) if left main or triple vessel disease can be done for NSTEACS.
o Immediate PCI if unstable, refractory chest pain, or acute severe heart
failure
o Conservative management otherwise.
 Secondary prevention
 ASA 75-150mg PO OD
 Beta blockers have short term and long term benefits for patients with AMI
o Short term benefit is they relieve pain and decrease the risk of
malignant arrhythmias
o Long term benefits: improved myocardial performance and facilitate
the healing process in post MI patients
o Metoprolol-25-200mg BD
o Atenolol 50-150mg PO OD
o Contraindications: Severe CHF, AV block
 ACE inhibitors: reduces mortality and improves long term survival post MI
by preventing cardiac remodeling which may have led to progressive heart
failure. They should be prescribed with 24 hours and maximum benefit is
achieved when they are given at higher doses than are recommended. In
patients with CHF ACE inhibitors are given indefinitely.
o Captopril: start with smaller dose 12.5mg PO day to gradually escalate
to 75mg PO BD
o Enalapril: start with 2.5mg PO daily and escalate gradually to 40mg PO
OD
 Statins. Evidence of short-term benefit is unclear, but it will be needed for
secondary prevention anyway.

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PROGNOSIS
 Depends on 2 factors:
 Extent of coronary artery disease in terms of the number of vessels affected.
 The extent of ventricular damage: left ventricular ejection faction (especially
<40% doubles yearly mortality)
COMPLICATIONS
SHORT TERM COMPLICATIONS
ELECTRICAL
 Heart block or sinus bradycardia following inferior MI (right coronary artery) as
supply to the AV and SA node is disrupted.
 Bundle branch block (Right or left bundle branch) following anterior MI (left
anterior descending artery)
 Ventricular fibrillation
STRUCTURAL
 Acute mitral regurgitation: may occur if the papillary muscles are affected by
infarction.
 Papillary muscle rupture
 Ventricular aneurysm: blood pools under dyskinetic, thin area of the left ventricle
walls. Causes persistent (>6 weeks) ST elevation. The infarcted myocardium may
evaginate and heal with fibrous connective tissue. It may be a source of cardiac
emboli
 Ventricular free wall rupture leading to hemopericardium
 Ventricular septal rupture. Causes pan-systolic murmur. May lead to cardiogenic
shock later
INFLAMMATORY
 Peri-infarction pericarditis
 Dressler’s syndrome: post AMI pericarditis which is believed to be autoimmune
in origin
LONG TERM COMPLICATIONS
 Myocyte death and decreased stroke volume leads to decreased heart rate and
blood pressure.
 The decreased in BP results in a sympathetic neurohumoral response and left
ventricular changes that result in heart failure.

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MANAGEMENT OF COMPLICATIONS
 Malignant arrhythmias:
 Cardiac defibrillation
 Prophylactic defibrillation
 Prophylactic lidocaine
 Other antiarrhythmic agent: bertyluim tosylate and procainamide
 Conduction disturbances:
 Sinus bradycardia: Atropine 2mg IV may restore conduction and restore heart
rate
 AV block: transcutaneous cardiac pacemakers
 Heart failure:
 Diuretics, salt restriction, ACE inhibitors, vasodilators. Use of digoxin is
controversial.
 Cardiogenic shock: do echocardiography to assess the ventricular function
 IV infusion of fluids to maximize left ventricular filling
 Use of vasopressors: Dobutamine, dopamine in IV infusion
 Intra-aortic balloon pumping
 Percutaneous transluminal angioplasty

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CARDIAC DYSRHYTHMIAS
 The heart beat is normally initiated by an electrical discharge from the sinoatrial
node (SA node). The atria and ventricle then depolarize sequentially as electrical
depolarization passes through specialized conducting tissue.
 The sinus node acts as a pacemaker and its intrinsic rate is regulated by the
autonomic nervous system, vagal activity decreases the heart rate and
sympathetic activity increases it via cardiac sympathetic nerves and circulating
catecholamines.
 Normally the parasympathetic system predominates, resulting in slowing of the
spontaneous discharge rate from approximately 100 to 70 b/m. A reduction of
parasympathetic tone or an increase in sympathetic stimulation leads to
tachycardia, conversely, an increased parasympathetic tone and decreased
sympathetic stimulation produces bradycardia.
 The sinus rate in women is slightly faster than in men.
 Normal sinus rhythm is characterized by P waves that are upright in leads I, and
II of the ECG but inverted in the cavity leads aVR and V1.
 If the sinus rate becomes unduly slow, another, more distal part of the conducting
system may assume the role of pacemaker. This is known as an escape rhythm
and may arise in the atrioventricular (AV) node or His bundle (junctional rhythm)
or the ventricles (idioventricular rhythm).
 A dysrhythmia is an abnormality of the cardiac rhythm.
 The heart may seem to skip a beat or beat irregularly or beat very fast or very
slow.
 Dysrhythmias may cause sudden death, dizziness, syncope, heart failure, chest
pain, palpitations or no symptoms at all.
 There are 2 main types of
 Tachyarrhythmias: the heart rate is fast (>100 b/m)
 Bradyarrhythmias: the heart rate is slow (<60 b/m during the day or <50 b/m
at night)
 Some dysrhythmias occur in patients with apparently normal hearts, and in others
arrhythmias originate from diseased tissue such as a scar, as a result of underlying
structural heart disease.
 When myocardial function is poor, arrhythmias are symptomatic and are
potentially life-threatening.

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Figure 16: An ECG showing normal sinus rhythm (PR interval <0.2s). P waves preceding each QRS
complex. The inversion of P waves is normal in leads aVR and V1 (Adapted from Kumar and Clark's
Clinical Medicine 8th edition)

CLASSIFICATION OF DYSRHYTHMIAS
 Arrhythmias can be classified by:
 Heart rate:
o Tachyarrhythmias (Heart rate >100bpm)
 Simple Tachyarrhythmias 100-150bpm
 Paroxysmal Tachyarrhythmias 250-350bpm
 Flutter (Atrial and ventricular) 250-350bpm
 Fibrillation (Atrial and ventricular) >350bpm

o Bradyarrhythmias (Heart rate <60bpm)

 Mild Bradyarrhythmias 40-60bpm
 Moderate Bradyarrhythmias- 20-40bpm
 Severe Bradyarrhythmias <20bpm
 Location:
o Supraventricular dysrhythmias
 SA node dysrhythmias: Sick sinus rhythm, Sinus tachycardia, Sinus
bradycardia
 Atrial dysrhythmias
- Paroxysmal atrial tachycardia
- Atrial flutter
- Atrial fibrillation
 Nodal/Junctional dysrhythmias:
- AV nodal re-entry tachycardia (paroxysmal supraventricular
tachycardia)
- Wolff-Parkinson-White syndrome
- Heart block

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o Ventricular dysrhythmias:
- Premature ventricular contraction
- Ventricular tachycardia
- Ventricular fibrillation
- Torsades de point
SICK SINUS SYNDROME (SINOATRIAL DISEASE)
 Sinoatrial disease can occur at any age but is common in older people. This is
due to fibrosis, degenerative changes or ischemia of the SA node.
 The condition is characterized by a variety of arrhythmias including:
 Paroxysmal atrial tachycardia
 Paroxysmal atrial fibrillation
 Sinus bradycardia
 Sinus arrest (sinoatrial block)
 Atrioventricular block
 It may present with palpitations, dizzy spells or syncope, due to intermittent
tachycardia, bradycardia, or pauses with no atrial or ventricular activity (SA
block or sinus arrest).
 A permanent pacemaker may benefit patients with troublesome symptoms due to
spontaneous bradycardias or those with symptomatic bradycardia induced by
drugs required to prevent Tachyarrhythmias.
 Atrial pacing may prevent episodes of atrial fibrillation. Pacing improves
symptoms but not improve prognosis and is not indicated in patients who are
asymptomatic.

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TACHYARRHYTHMIAS
 Tachyarrhythmias are more symptomatic when the arrhythmia is fast and
sustained.
 Tachyarrhythmias cause rapid palpitations, dizziness, chest discomfort or
breathlessness. Extreme tachycardias can cause syncope because the heart is
unable to contract or relax properly at extreme rates. Extreme tachycardias can
precipitate sudden death or cardiac arrest.
 Tachyarrhythmias are subdivided into:
 Supraventricular tachycardias: which arise from the atrium or the
atrioventricular junction. These usually produce narrow QRS complex
because the ventricles are depolarized in their normal sequence via the AV
node and bundle of His. Occasionally, however a supraventricular rhythm
can produce a broad or wide QRS complex due to coexisting bundle branch
block or the presence of an additional atrioventricular connection (accessory
pathway). Though this technically includes atrial fibrillation and flutter, SVT
usually refers to other causes especially atrial tachycardia, AV nodal reentry
tachycardia. Important SVTs include:
o Atrial tachycardia:
 Sinus tachycardia (regular rhythm)
 Paroxysmal atrial tachycardias
 Atrial flutter
 Atrial fibrillation
o Atrioventricular junction Tachyarrhythmias
 AV nodal re-entry tachycardia (paroxysmal supraventricular
tachycardia)

 Ventricular tachycardias: which arise from the ventricles. These usually

produced broad, bizarre QRS complexes because the ventricles are activated
in an abnormal sequence.
o Premature ventricular contraction
o Ventricular tachycardia
o Ventricular fibrillation
o Torsades de pointes

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PATHOPHYSIOLOGY OF TACHYARRHYTHMIAS
 There are 3 main mechanisms of tachycardia:
 Increased automaticity: the tachycardia is produced by repeated spontaneous
depolarization of an ectopic focus, often in response to catecholamines.
Increased automaticity is thought to produce sinus tachycardia, escape
rhythms and accelerated AV nodal (junctional) rhythms.
 Re-entry/circus movements: the tachycardia is initiated by an ectopic beat
and sustained by a re-entry circuit. Re-entry results in regular paroxysmal
tachycardias.
o Re-entry can occur when there are 2 alternative pathways with different
conducting properties (e.g. the AV node and an accessory pathway or an
area of normal and an area of ischemic tissue).
o Here, pathway A conducts slowly and recovers quickly, while pathway
B conducts rapidly and recovers slowly.
o In sinus rhythm, each impulse passes down both pathways before
entering a common distal pathway.
o As the pathways recover at different rates, a premature impulse may find
pathway A open and B closed.
o Pathway B may recover while the premature impulse is travelling
selectively down pathway A.
o The impulse can then travel retrogradely up pathway B, setting up a
closed loop or re-entry circuit.
o This may initiate a tachycardia that continues until the circuit is
interrupted by a change in conduction rates or electrical depolarization.

Figure 17: Mechanism of re-entry (Adapted from Davidson's Principles of Medicine 22nd Edition)

 Triggered activity: this can cause ventricular arrhythmias in patients with

coronary artery disease. It is a form of secondary depolarization arising from
an incompletely repolarized cell membrane.

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o Myocardial damage can result in oscillations of the transmembrane
potential at the end of the action potential. These oscillations which are
called ‘after depolarization’, may reach threshold potential and produce
an arrhythmia.
o If they occur before the transmembrane potential reaches its threshold (at
the end of phase 3 of the action potential), they are called ‘early after
depolarizations’.
o When they develop after the transmembrane potential is completed they
are called ‘delayed after depolarizations’.

Figure 18: Triggered activity due to early (E) or delayed (D) after depolarization reaching threshold
potential. (Adapted from Kumar and Clark's Clinical Medicine 8th edition)

SUPRAVENTRICULAR
TACHYCARDIA
 Supraventricular tachycardia (SVT)
arises from the atrium or the
atrioventricular junction.
 Conduction is via the HIS-Purkinje
system, therefore the QRS shape during
tachycardia is usually similar to that seen
in the same patient during baseline
rhythm.
 They are usually associated with a
narrow QRS complex and are
characterized by a re-entry circuit or
automatic focus involving the atria.

Figure 19: Causes of atrial tachyarrhythmias

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SINUS TACHYCARDIA
 Fluctuations of autonomic tone result in phasic changes of the sinus discharge
rate.
 During inspiration, parasympathetic tone falls and the heart rate quickens and on
expiration the heart rate falls.
 This variation is normal particularly in children and young adults. Typically,
sinus arrhythmia results in predictable irregularities of the pulse.
 In inappropriate sinus tachycardia there is a persistent increase in resting heart
rate unrelated to or out of proportion with the level of physical or emotional
stress.
 Sinus rate acceleration to more than 100b/min is known as sinus tachycardia.
 It is usually due to an increase in sympathetic activity associated with exercise,
emotion, pregnancy or pathology.
 Young adults can produce a rapid sinus rate, up to 200 b/min during intense
exercise.
 Etiology:
 Cardiac
o Acute heart failure
 Systemic
o Anxiety
o Exercise
o Emotion
o Pain
o Hypovolemia, hypoxia
o Fever
o Infections
o Pulmonary embolism
o Hyperthyroidism
o Anemia
o Thyrotoxicosis
o Pheochromocytoma
o Drugs e.g. Beta-agonist (bronchodilators)

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 ECG findings:
 Rate: >100b/min
 Rhythm: Regular
 P waves: normal (upright and uniform)
 PR intervals: normal (0.06-0.10 sec)
 QRS: normal (0.06-0.10 sec)
 Decreased RR interval

Figure 20: Sinus tachycardia

 Treatment should address underling cause.

 If necessary, beta-blockers may be used to slow the sinus rate e.g. in
hyperthyroidism, ivabradine an If (funny current/pacemaker current) blocker may
be useful when beta-blockade cannot be tolerated.

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PAROXYSMAL ATRIAL TACHYCARDIA
 A series of early beats in the atria speed up the heart rate.
 In paroxysmal tachycardia, repeated periods of very fast heartbeats begin and
end suddenly.
 These arrhythmias are sudden onset, often occurring in patients with otherwise
normal heart and characterized by a heart rate of 150-250b/min.
 Common causes:
 Exercise
 Fever
 Anxiety
 Thyrotoxicosis
 Hypoxemia
 Hypotension
 Heart failure
 Diagnosis: ECG faster rate with P waves followed by narrow QRS complexes
 Treatment
 If patient is stable- no need for treatment, identify and treat the underlying
cause.
 If the patient is hemodynamically unstable- there is need for treatment.
o The patient should be kept in a quiet room
o Mechanical treatment
 Carotid sinus massage
 Valsalva maneuver: abrupt voluntary increase in intrathoracic and
intra-abdominal pressure by straining.
 Head immersion in cold water
o Medical therapy
 Adenosine (drug of choice) 6mg IV push if no response give 12mg
IV push.
 Beta blockers-1-2mg IV bolus
 Calcium channel blockers (Verapamil 15-20mg IV over 2 minutes
and diltiazem)
 Digoxin can be helpful

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ATRIAL FLUTTER
 Rapidly fired signals cause the muscles in the atria to contract quickly, leading
to a very fast, steady heartbeat.
 It is characterized by an atrial rate of 250-350b/min and is usually conducted to
ventricles with block so that the ventricular rate is a fraction of the atrial rate.
 The block is usually regular so the ventricular rate is regular. Sometimes there
may be a varying block resulting irregular ventricular beat.
 Causes of atrial flutter:
 Coronary artery disease
 Pericarditis
 Valvular heart diseases
 Cardiomyopathy
 ECG: classic saw tooth pattern: 2 or 3 P waves (F waves) are followed by QRS
complex. The block is often in a ratio of 2:1 with an atrial rate of 240 b/min and
ventricular rate of 120b/min.

Figure 21: Atrial flutter. Some flutter waves are marked with an F. In this case the flutter frequency is
240/min. Every fourth flutter wave is transmitted to the ventricles and the ventricular rate is therefore
60bpm.

 Therapy:
 Drugs:
o Digoxin, esmolol, or verapamil to control ventricular rate
o Quinidine or other anti-arrhythmic agents (amiodarone) to restore sinus
rhythm
 Direct current cardioversion: if the patient is hemodynamically unstable

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ATRIAL FIBRILLATION
 Electrical signals in the atria are fired in a very fast and uncontrolled manner.
Electrical signals arrive in the ventricles in a completely irregular fashion, so the
heart beat is completely irregular.
 This is a supraventricular tachyarrhythmia with chaotic and irregular conduction
of depolarization through the atrium and the ventricles.
 It is the commonest arrhythmia affecting 10% over 80 years old and is commoner
in men.
ETIOLOGY
 Common causes ‘PIRATES’:
 P: Pulmonary (PE, Pleural effusion, COPD, lung cancer, pneumonia)
 I: ischemic heart disease (including acute MI/coronary artery disease) and
other cardiac diseases (HTN, HF, cardiomyopathy, pericardial disease,
myxoma, mitral stenosis/regurgitation/prolapse)
 R: rheumatic valve disease and mitral stenosis
 A: alcohol (“holiday heart”), smoking, caffeine
 T: thyrotoxicosis
 E: electrolyte imbalance (hypokalemia and hypomagnesemia)
 S: sugar (diabetes), Sepsis, Stress
 Idiopathic (lone) atrial fibrillation
CLASSIFICATION
 It is classified by time frame as:
 Acute Atrial fibrillation:
o Onset within previous 48 hours either ‘new-onset’ or ‘recurrent episodes’
 Chronic atrial fibrillation: sub-classified as
o Paroxysmal Atrial fibrillation: self-terminates <7 days, usually 48 hours.
o Persistent Atrial fibrillation: lasts >7 days or <7 days but requires
cardioversion, ‘Long standing’ if >1 year.
o Permanent Atrial fibrillation: refractory to cardioversion.
CLINICAL FEATURES
 Symptoms:
 Palpitations
 Syncope
 Shortness of breath
 Angina reflecting rate-related ischemia.

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 20% are asymptomatic
 Signs:
 Pulse: increased heart rate, irregularly irregular and apical pulse may be faster
than radial
 Decreased blood pressure
 Absent ‘a’ waves in JVP
 Symptoms of complications
 TIA/Stroke
 Pulmonary edema (acute heart failure)
INVESTIGATIONS
 ECG:
 Absent P waves, replaced with small irregular f waves reflecting
depolarization beginning randomly at various foci in the atrium.
 Irregularly irregular RR interval
 If HR>100, known as AF with rapid ventricular response or ‘fast AF’.
Prolonged episodes may lead to transient ischemic changes such as ST
depression, though persistent changes (and a compatible history) may
suggest MI as the underlying cause of the AF.
 If the ECG is normal but paroxysmal AF is suspected, use 24 ambulatory
ECG or consider an event recorder if episodes >24 hr apart.

Figure 22: Atrial fibrillation. Note absolute rhythm irregularity and bassline undulations (f waves)

 Blood:
 FBC: anemia may exacerbate heart failure
 U + E and TSH to look for cause
 Investigate other CVS factors: lipids, glucose
 LFTs and coagulation profile (pre warfarin)
 Imaging:
 Transthoracic echo: look for cardiac causes and complications. Especially
important if there is a suspicion of structural disease or pre-cardioversion.
Consider transesophageal echo if abnormality found.

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 Chest X-ray may show heart failure
MANAGEMENT
 Rate and rhythm control:
 Rate- slowing the heart is the first line for most patients.
o First line options: Beta blockers, Rate-limiting calcium channel blockers
(Verapamil and diltiazem), consider digoxin if they are sedentary. In
active patients it is ineffective at slowing sympathetic driven increased
heart rate.
 Digoxin 0.125-0.25mg PO OD / BD or
 Verapamil 40-80mg PO TDS or
 Diltiazem 60mg PO TDS
o Second line: combine any 2 of: beta blocker, diltiazem and/or digoxin
o As an alternate to continuous therapy in patients with paroxysmal AF,
offer PRNN sotalol or flecainide (“Pill in the pocket”) if they meet the
following criteria:
 Infrequent episodes
 Understand how and when to take it
 No structural (LVF, valvular) or ischemic heart disease
 SBP>100 and HR>70
o Consider no treatment at all if episodes are very infrequent.
 Rhythm control- regularizing the arrhythmia is an alternative in certain
patients.
o Offered if rate control has been unsuccessful or as an alternative 1 st line
treatment for:
 New-onset AF (<48 hours)
 AF with a reversible cause
 AF leading to HF or hemodynamic instability: reduced BP, chest
pain, loss of consciousness
 Patients in whom it is considered more suitable based on clinical
judgement e.g. younger patients especially if active and want to avoid
rate control.
o Electrical cardioversion:
 Preferred if patient hemodynamically unstable: SBP<90mmHg,
syncope, acute HF, MI.
 Shock carried out under short-acting general anesthetic followed by
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 If not anticoagulated give heparin or LMWH first but not if this
delays treatment in a life-threatening situation.
o Pharmacological cardioversion
 Indications: if symptoms are milder and situation is less urgent.
Bolus followed by infusion if AF continues. Again, anticoagulated
first.
 Drugs used: Flecainide or propafenone IV (Class Ic) if there is no
structural heart disease. Amiodarone (Class III) if there is no
structural or ischemic heart disease. It is given through central line
as it carries the risk of thrombophlebitis if given peripherally
 Amiodarone 200mg PO TDS 1st week then reduce to 200mg
PO BD (maintenance dose 200 to 400mg daily)
o Anticoagulants: if the atrial fibrillation has stayed for more than 1 week
to prevent thromboembolism.
 Warfarin 2.5mg-10mg PO OD (to maintain INR 2.5 to 3.5)
 ASA 75-150mg PO OD
 Use ASA if INR is not available
o Catheter ablation can be done for cases that do not respond to medical
therapy. As well as young individuals to avoid lifelong medication.
 Methods: radiofrequency, cryotherapy or microwave. Often targets
an area around the insertion of the pulmonary vein.
 ‘Ablate and pace’- ablation of the AV node followed by pacemaker
insertion can be considered in permanent AF with LV dysfunction
COMPLICATIONS
 Stroke (5 times risk)
 Acute heart failure
 Pulmonary edema
 Cardiomyopathy and heart failure

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VENTRICULAR TACHYARRHYTHMIAS
 Tachyarrhythmias originate from the ventricles.
 These include:
 Premature ventricular contraction
 Ventricular tachycardia
 Ventricular fibrillation
 Torsades de pointes
PREMATURE VENTRICULAR CONTRACTION
 Premature ventricular contractions (PVC) is a type of arrhythmia in which
occasional cardiac impulses are originating directly from the ventricles by
passing the normal conduction system.
 These are among the commonest arrhythmias.
 ECG: wide and bizarre QRS appearing in a relatively normal looking ECG.
 Therapy: most isolated PVCs are benign and need no treatment.
 If symptomatic or frequent:
 beta-blockers (propranolol 40-80mg PO TDS)
 Amiodarone 200mg PO TDS for 5-7 days then reduce to 200mg PO BD
(maintenance dose 100-200mg daily)
 Monitor for possible side effects: thyroid function test, LFTs, consult
ophthalmologist and CXR once a year.
VENTRICULAR TACHYCARDIA
 Ventricular tachycardia arises from the ventricles (ventricular ectopic focus), it
occurs paroxysmal and exceeds 120b/min (100-180bpm) with regular rhythm.
 It often occurs in a structurally abnormal heart. Injury to the ventricular
myocardium can leave strands of functioning tissue among damaged tissue,
creating the possibility of a re-entrant loop which is the commonest trigger for
VT.
 There is AV dissociation and the ventricular arrhythmia proceeds independently
of the normal atrial rhythm.
 During ventricular tachycardia, the ventricles do not have enough time to relax,
ventricular filling is impaired and the cardiac output significantly decreases.
When the ventricular tachycardia lasts for more than 30 seconds or requires
control because of hemodynamic collapse it is called sustained ventricular
tachycardia.

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 ECG: bizarre and wide QRS complexes coming in succession with no constant
relation to P waves.
 Therapy: since this is a life threating situation urgent intervention is needed.
 In cardiac arrest recall that ventricular fibrillation and pulseless VT are
shockable rhythm. Defibrillate at 50-100 + 200.
 If patient is stable, pharmacological treatment:
o Amiodarone 300mg IV over 10 min followed by infusion at 1mg/min for
6 hours
o Lignocaine 100mg IV bolus followed by infusion of 4mg/min for 30 min,
2mg/min for 2hours, then 1 mg/min
 In cases of multifocal ventricular tachycardia use magnesium sulfate 1-2 g
IV.
 Correct reversible causes hypokalemia, digoxin toxicity.
VENTRICULAR FIBRILLATION
 Electrical signals in the ventricles are fired in a very fast and uncontrolled
manner, causing the heart to quiver rather than beat and pump blood.
 It is characterized by lack of ordered contraction of the ventricles. Therefore,
there is no cardiac output.
 The patient is pulseless and becomes rapidly unconscious and respiration ceases
(cardiac arrest)
 Ventricular fibrillation is synonymous with death unless urgent conversion to
effective rhythm can be accomplished.
 There is irregular, chaotic ventricular activity without effective cardiac output
and without identifiable P waves, QRS or T waves on ECG. It is usually provoked
by a ventricular ectopic beat.

Figure 23: Ventricular fibrillation. Four beats of sinus rhythm followed by a ventricular ectopic beat that
initiates ventricular fibrillation. The ST segment during sinus rhythm is elevated owing to acute
myocardial infarction in this case.

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 Therapy: patients need cardiorespiratory resuscitation

 Cardiac resuscitation
 Mechanical ventilation
 Cardiac compression and intracardiac adrenaline
 DC cardioversion (Electrical defibrillation) using high voltage (recall
ventricular fibrillation is a shockable rhythm)
CARDIAC RESUSCITATION
 Check if patient is unresponsive by shaking him/her and shouting into one ear. If
no response perform ABCs.
 Call for help.
 A- airway and B-breathing
 Ensure airway is clear and patent
 Perform jaw thrust /chin lift to keep head in “sniffing air in the morning”
position.
 Endotracheal intubation or Supraglottic airway tube should be instituted.
 C-circulation
 If patient is unresponsive with absent or abnormal breathing, then external
chest compression should be started.
o The heel of one hand is placed over the center of the chest and the heel
of the second hand is placed over the first with the fingers interlocked.
o The arms are kept straight and the sternum is rhythmically depressed by
5-6 cm at a rate of approximately 100-120/min allowing for complete
recoil.
o Respiratory and circulatory support is continued by providing 2 effective
breaths for every 30 cardiac compressions (30:2 for one or two persons,
15:2 in pediatric patients). Compressions alone is good as compressions
with rescue breaths (American Heart Association updated guidelines)
 Gain venous access and start an intravenous infusion in a large peripheral or
central vein (an intraosseous needle may be used if IV access is not possible)
 Continuous ECG monitoring
 If the ECG shows a shockable rhythm- ventricular fibrillation or pulseless
ventricular tachycardia, then an unsynchronized shock of 150-200J biphasic (360
J monophasic) is delivered without delay via paddles or self-adhesive pads
followed immediately by 2 minutes of CPR.
 Intravenous amiodarone is the first-line drug in refractory VF/Pulseless VT.

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 When treating VF/VT cardiac arrest, adrenaline 1mg is given after the third
shock and then every 3-5 min.
 Amiodarone 300mg is also given after the third shock, particularly if VT/VF
have recurred after defibrillation.
 For non-shockable rhythm- asystole or pulseless electrical activity, 2 minutes of
CPR is delivered with 1mg of intravenous adrenaline (epinephrine)
 For both sides of algorithm, it is necessary to maintain:
 CPR,
 Ensure oxygenation and to
 Exclude/treat reversible causes (hypoxia, hypovolemia, hyper or
hypokalemia, hypothermia, Tension pneumothorax, tamponade, toxins,
thromboembolism)
POST RESUSCITATION
 Involves:
 Use of the ABCDE approach
 Controlled oxygenation and ventilation
 12 lead ECG
 Treat precipitating cause
 Temperature control/therapeutic hypothermia
 Studies have supported the use of therapeutic hypothermia in unconscious adult
patients with spontaneous circulation after an out-of-hospital cardiac arrest due
to ventricular fibrillation
 These patients should be cooled with careful temperature monitoring to 32-34oC
for 12-24 hours.
 External cooling methods including the use of cooling blankets, ice packs to the
groin, axillae and neck, wet towels and a cooling helmet.
 Invasive methods include intravenous infusions and peritoneal and pleural
lavage.
 Shivering should be prevented by the use of a neuromuscular blocker and
sedation to reduce oxygen consumption,

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 When an arrhythmia cannot be controlled by other treatments, there may be a

place for surgery. After locating the heart tissue that is causing the arrhythmia,
the tissue is altered or removed so that it will not produce the arrhythmia.

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TORSADES DE POINTES
 Polymorphic VT with a characteristic pattern of QRS complex of increasing and
decreasing magnitude.
 A complication of congenital or acquired long QT syndrome (LQTS)
 Clinical features:
 Sudden decrease in BP, dizziness and syncope
 Usually self-resolves but can progress to sustained VF or VF
 Management: IV magnesium sulphate
BRADYARRHYTHMIAS
 Bradyarrhythmias are a result of inadequate sinus impulse production or from
blocked impulse propagation.
 The heart beats slower than normal.
 They are not usually cause of concern unless the patient develops syncope or
presyncope.
 They include:
 Sinus bradycardia
 Sinus pause (arrest)
 AV block
 The incidence of bradycardia increases with age
 Etiologies include:
 Cardiac:
o Idiopathic senile degeneration,
o Ischemia (usually involving the inferior wall),
o Infectious processes (endocarditis, Chagas’ disease, Lyme disease),
o Infiltrative diseases (sarcoidosis, amyloidosis, hemochromatosis),
o Autoimmune disease (SLE, RA, scleroderma),
o Iatrogenic factors (heart transplant, surgery),
o Inherited/congenital disease (myotonic muscular dystrophy),
o Conditioned heart (trained athletes).
 Systemic:
o Autonomic (neurocardiac, carotid sinus hypersensitivity, situational),
o Medication (beta blockers, calcium channel blockers, clonidine, digoxin,
antiarrhythmics),
o Metabolic (electrolyte abnormalities),
o Metabolic (hypothyroidism, hypothermia),
o Neurologic (increased ICP, obstructive sleep apnea).

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 Symptoms of bradycardia may include dizziness, weakness, fatigue, heart failure,
syncope or presycope. Other symptoms are related to underlying cause of
bradycardia.
 When performing a physical examination look for evidence of decreased pulse
rate and evidence of the underlying cause of bradycardia.

PATHYPHYSIOLOGY OF BRADYARRHYTHMIAS
 Bradycardia may be due to:
 Reduced automaticity e.g. sinus bradycardia
 Blocked or abnormally slow conduction e.g. AV block
SINUS BRADYCARDIA
 A sinus rate of <60b/min during the day or <50 b/min at night is known as sinus
bradycardia.
 It is usually asymptomatic unless the rate is very slow.
 It is normal in athletes owing to increased vagal tone.
ETIOLOGY
 Causes are divided into:
 Cardiac
o Myocardial infarction: acute ischemia and infarction of the sinus node
o Sinus node disease (sick sinus syndrome): chronic degenerative changes
such as fibrosis of the atrium and SA node.
 Systemic
o Hypothermia
o Hypothyroidism
o Hyperkalemia
o Cholestatic jaundice
o Raised intracranial pressure (Cushing reflex)
o Drugs e.g. beta-blockers, alpha agonists (clonidine), digoxin, verapamil,
amiodarone, antiarrhythmic drugs, opioids and benzodiazepines.
o Neurally mediated syndromes e.g. carotid sinus syndrome, vasovagal
syndrome (syncope)
o Physiological states: high levels of fitness, pain
o Anorexia nervosa
 Sinus bradycardia can be acute and reversible or chronic and degenerative.

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 In sinus bradycardia the ECG shows normal P wave configuration consistent with
origin in sinus node area. The RR interval is increased.
MANAGEMENT
 Management of sinus bradycardia is first to identify and if possible remove any
extrinsic causes.
 Asymptomatic sinus bradycardia requires no treatment.
 Symptomatic acute sinus bradycardia (HR<35b/m) usually responds to
intravenous atropine 1mg IV may temporarily increase the sinus.
 Patients with recurrent or persistent symptomatic sinus bradycardia should be
considered for pacemaker implantation.
 Thromboembolism is common in tachy-brady syndrome and patients should be
anticoagulated unless there is a contraindication.
SINUS PAUSE (SINUS ARREST)
 This is failure of the impulse formation (Sinus arrest) or conduction from
(Sinoatrial exit block) the SA node.
 Its causes overlap with those of sinus bradycardia including:
 Sick sinus syndrome
 Hyperkalemia
 Inferior MI
 CVS drugs
 ECG findings:
 Rhythm: irregular whenever a pause (arrest) occurs
o Escape rhythm may take over,
 Junctional-narrow QRS 45-60bpm
 Ventricular- wide QRS 30-45bpm
 P waves: normal (upright and uniform) except in areas of pause (Arrest)
 PR intervals: normal (0.12-0.20 sec)
 QRS: normal (0.06-0.10 sec)

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Figure 24: Sinus pause (Arrest)

HEART BLOCK
 Heart block or conduction block may occur at any level in the conducting system.
 Block in either the AV node or the His bundle results in AV block, whereas block
lower in the conduction systems produces bundle branch block.
 Causes:
 RCA infarct (inferior MI) as this supplies the AV node
 Myocarditis
 Drugs: beta-blockers, calcium channel blockers, adenosine, digoxin,
cholinesterase inhibitors
 Idiopathic
ATRIOVENTRICULAR BLOCK
 There are 3 forms:
 First degree AV block: occurs between SA node and the AV node (i.e. within
the atrium)
 Second degree AV block
o Type I: occurs in the AV node. This is the only piece of conductive tissue
in the heart which exhibits the ability to conduct at different speeds.
o Type II: occurs after the AV node in the bundle of HIS or Purkinje fibers
 Third degree (complete) AV block: occurs anywhere from AV node down
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FIRST DEGREE AV BLOCK
 This is simple prolongation of the PR interval to >0.20s (200ms i.e. >5 small
squares).
 Recall the normal PR interval is 120-200ms (3-5 small squares)
 Every atrial depolarization is followed by conduction to the ventricles but with
delay.
 Etiology: medication, CHF, ischemia, electrolyte abnormalities.
 It rarely causes symptoms.
 ECG findings:
 Rate: depends on rate of underlying rhythm
 Rhythm: regular
 P waves: normal (upright and uniform)
 PR interval: Prolonged (>0.20 sec)
 QRS: normal (0.06-0.10s)

Figure 25: First degree AV block with a prolonged PR interval. Note ST depression is also present
(Adapted from Kumar and Clark's Clinical Medicine 8th edition)

 No therapy is needed.
SECOND-DEGREE AV BLOCK
 This occurs when some P waves conduct and others do not.
 There are several forms:
 Mobitz I block (Wenckebach block phenomenon)
 Mobitz II block
 Acute myocardial infarction may produce second-degree heart block.
 In inferior myocardial infarction, close monitoring and transcutaneous temporary
back up pacing are all that is required.

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 In anterior myocardial infarction, second-degree heart block is associated with a
high risk of progression to complete heart block and temporary pacing followed
by permanent pacemaker implantation is usually indicated.
 The conduction ratio is the number of P waves to QRS complexes e.g. 4:3
 A conduction ratio of 2:1 is untypable as it is hard to determine if there is
progressive PR prolongation.
 High grade second degree block is when 2 consecutive P waves fail to conduct
to the ventricles.
 The P waves are regular, distinguishing it from ectopic atrial contractions.
MOBITZ I BLOCK (WENCKEBACH BLOCK PHENOMENON)
 There is progressive PR interval prolongation until a P wave fails to conduct i.e.
the PR interval slowly increases then there is dropped QRS complex.
 The PR interval before the blocked P wave is much longer than the PR interval
after the blocked P wave.
 Etiology: medication, electrolyte abnormalities, ischemia.
 The phenomenon may be physiological and is sometimes observed at rest or
during sleep in athletic young adults with high vagal tone.
 ECG findings:
 Rate: depends on rate of underlying rhythm
 Rhythm: irregular
 P waves: normal (upright and uniform)
 PR interval: Progressively longer until one P-wave is blocked and a QRS is
dropped (blocked beat)
 QRS: normal (0.06-0.10sec)

Figure 26: Mobitz type I AV block. The PR interval gradually prolongs until the P wave does not conduct
to the ventricles (arrows) (Adapted from Kumar and Clark’s Clinical Medicine 8th edition)

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 It can be hard to distinguish from Mobitz 2 when increase in PR are small. Look
for the biggest increase, which is between the 1st and 2nd PR after the missed QRS.
 If symptomatic give atropine (0.5-2mg IV) or isoproterenol (1-4 microgram/min
IV).
 Persistent symptoms often require permanent pacemakers.
MOBITZ II BLOCK
 Occurs when a dropped QRS complex is not preceded by progressive PR interval
prolongation i.e. the PR interval is fixed but there are dropped beats.
 Always clarify the frequency of dropped beats e.g. 2:1, 3:1, 4:1.
 Etiology: ischemia, conduction system disease.
 ECG findings:
 Rate: atrial rate (usually 60-100b/min), faster than ventricular rate.
 Rhythm: atrial regular and ventricular irregular
 P wave: Normal (upright and uniform), more P waves than QRS complexes
 PR interval: normal or prolonged but constant
 QRS: usually wide (>0.10 sec)

Figure 27: Mobitz type II AV block. The P waves that do not conduct to the ventricles (arrows) are not
preceded by gradual PR interval prolongation. (Adapted from Kumar and Clark’s Clinical Medicine 8th
edition)

 High risk of progression to 3rd degree heart block so often requires pacemaker
treatment.
 Treatment: pacemaker

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THIRD DEGREE (COMPLETE) AV BLOCK
 Complete heart block occurs when all atrial activity fails to conduct to the
ventricles.
 There is dissociation of atrial beats and ventricular beats as the atrial impulses
fail to conduct to the ventricles and the ventricles beat on their own with a slower
rate.
 In patients with complete heart block the etiology needs to be established.
 In this situation life is maintained by a spontaneous escape rhythm.
 The heart rate drops significantly to a range of 20-40 b/min and patients become
symptomatic.
 ECG findings:
 Rate: Atrial (60-100 b/min), ventricular (40-60b/min) if escape focus is
junctional <40b/min. P wave rate>QRS rate.
 Rhythm: usually regular but atria and ventricles act independently.
 P waves: normal (upright and uniform) may be superimposed on QRS
complexes or T waves.
 PR interval: varies greatly
 QRS: can be narrow or wide
 Narrow complex escape rhythm (<0.12s QRS complex) implies that it originates
in the HIS bundle and therefore that the region of block lies more proximally in
the AV node.

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 The escape rhythm occurs with an
adequate rate (50-60 b/min) and is
relatively reliable.
 Broad complex escape rhythm
(>0.12s) implies that the escape
rhythm originates below the HIS
bundle and therefore that the region of
block lies more distally in the HIS-
purkinje system.
 The resulting rhythm is slow (15-
40b/min) and relatively unreliable.
Dizziness and blackouts (Stokes-
Adams attacks)
 Cannon A waves may be visible in the
neck and the intensity of the first heart
sound varies due to loss of AV
synchrony.
 Treatment: depends on etiology
 Recent- onset narrow complex
AV block due to transient causes
may respond to intravenous
atropine 0.5-2mg but temporary pacing facilities should be available for the
management of these patients.
 Chronic narrow complex AV block requires permanent pacing (dual
chamber) if it is symptomatic or associated with heart disease.
 Pacing is also advocated for isolated, congenital AV block even if
asymptomatic.
 Broad complex AV block requires permanent pacemaker implantation.

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Figure 28: Complete heart block. (a) congenital complete heart block. The QRS complex is narrow
(0.08s) and the QRS rate is relatively rapid (52b/min) (b) Acquired complete heart block. The QRS
complex is broad (0.13s) and the QRS rate is relatively slow (38b/min) (Adapted from Kumar and Clark’s
Clinical Medicine 8th Edition)

BUNDLE BRANCH BLOCK

 The HIS bundle gives rise to the right and left bundle branches.
 The left bundle subdivides into the anterior and posterior division of the left
bundles.
 Abnormalities seen in the bundle branch include:
 Bundle branch conduction delay (incomplete bundle branch block)
 Complete bundle branch block
 Hemiblock
 Bifascicular block
 Bundle branch blocks are usually asymptomatic.
 Right bundle branch block causes wide but physiological splitting of the second
heart sound.

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 Left bundle branch block may cause reverse splitting of the second sound.
 Patients with intraventricular conduction disturbances may complain of syncope.
This is due to intermittent complete heart block or to ventricular
tachyarrhythmias.
 Causes of bundle branch block are similar to those of complete heart block.

 In Bundle branch blocks there is blockage in the bundle branches which lie
between the Bundle of His and the Purkinje fibers.
 Depolarization instead spreads via the (slower) myocardium causing broad QRS
complexes
 The altered depolarization sequence also leads to altered repolarization and hence
ST-T changes.
BUNDLE BRANCH CONDUCTION DELAY (INCOMPLETE
BUNDLE BRANCH BLOCK)
 This produces slight widening of the QRS complex (up to 0.11s).
 It is known as incomplete bundle branch block.
COMPLETE BUNDLE BRANCH BLOCK
 This is associated with a wider QRS complex (>0.12s).
 The shape of the QRS depends on whether the right or the bundle is blocked.

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RIGHT BUNDLE BRANCH BLOCK (RBBB)
 Right bundle branch block occurs as an isolated congenital anomaly or is
associated with cardiac or pulmonary conditions.
 Causes:
 Increased RV pressure: Primary pulmonary hypertension, cor pulmonale,
pulmonary embolism.
 Acquired heart disease: anterior MI (Left anterior descending), myocarditis,
cardiomyopathy.
 Congenital
 Iatrogenic e.g. cardiac catheterization
 It can also be a normal ECG variant in healthy individuals
 Produces late activation of the right ventricle. This is seen as deep S waves in
leads I and V6 and as a tall late R wave in lead V1 (late activation moving towards
right and away from left sided leads).
 Right bundle branch block alone does not alter the electrical axis of the heart.
Axis deviations signify right ventricular hypertrophy (RV overload) or co-
existent fascicular block.
 The combination of right bundle branch block with left axis deviation is
associated with ostium primum atrial septal defects.

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Figure 29: Right bundle branch block: Note an rsR' pattern with the tall R' in lead V1-V2 and the broad S
waves in leads I and V5-V6 (Adapted from Kumar and Clark's Clinical Medicine)

LEFT BUNDLE BRANCH BLOCK

 Complete left bundle branch block is often associated with extensive left
ventricular disease.
 Causes:
 Anterior MI (LAD) may be the initial ECG sign
 Hypertension
 Myocarditis
 Cardiomyopathy
 Aortic valve disease
 Left bundle branch block produces the opposite- a deep S wave in V1 and a tall
late R wave in leads I and V6. Because left bundle branch conduction is normally
responsible for the initial ventricular activation, left bundle branch block also
produces abnormal Q waves.

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Figure 30: Left bundle branch block. The QRS duration is >0.12s. Note the broad notched R waves with
ST depression in leads I, AVL and V6 and the broad QS waves in V1-V3 (Adapted from Kumar and
Clark's Clinical Medicine 8th edition)

HEMIBLOCK
 Delay or block in the divisions of the left bundle branch produces a swing in the
direction of depolarization (cardiac axis) of the heart.
 When the anterior division is blocked (left anterior hemiblock), the left ventricle
is activated from inferior to superior. This produces a superior and leftwards
movement of the axis (left axis deviation).
 Delay or block in the postero-inferior division swings the QRS axis inferiorly to
the right (right axis deviation).
BIFASCICULAR BLOCK
 This is a combination of a block of any 2 of the following:
 Right bundle branch
 Left anterosuperior division
 Left postero-inferior division

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Figure 31: Bifascicular block. In addition to right bundle branch block, note left axis deviation and deep
S waves in leads III and AVF typical for left anterior hemiblock. (Adapted from Kumar and Clark’s
Clinical Medicine)

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INFECTIVE ENDOCARDITIS
 This is infection and inflammation of the endocardial surface of the heart usually
a valve, most commonly the mitral or aortic.
 Infective endocarditis usually follows transient bacteremia and turbulent flow
past valves leading to formation of vegetations on valves, containing bacteria,
fibrin and platelets.
 It can affect natural valves or prosthetic valves.
 Individuals with prosthetic or abnormal valves are at high risk, but half the cases
occur in those with normal valves.
 Disease is often systemic due to septicemia, and mutli-system due to septic or
sterile emboli and immune-complex deposition.
CLASSIFICATION
 The classic clinical presentation and clinical course of infective endocarditis is
divided into:
 Acute infective endocarditis (50% of cases): has a rapid onset and develops
over days-weeks. It is usually seen in normal heart valves and is due to
Staphylococcus aureus. It is a rapidly progressive illness with destruction of
valvular structures.
 Subacute infective endocarditis (Subacute bacterial infective endocarditis):
it has an insidious onset and develops over weeks to months. It usually seen
in abnormal valves and due to Streptococcus viridans.
ETIOLOGY
 Bacterial:
 Streptococcus viridans (this is the commonest cause in those with valve
disease, it is a bacterium which is a normal flora of the oral cavity. It accounts
for 50-60% of cases of subacute infective endocarditis)
 Staphylococcus aureus (this is commonest cause in IV drug users, acute
infective endocarditis and in individuals with prosthetic valve. 35-50% of
Staph bacteremia is complicated by infective endocarditis. In more than half
of cases endocarditis due to S. aureus occurs in the absence of underlying
valvular disease. Mortality range 40-50%)
 Enterococci are another common cause.
 Group D streptococci (the source for bacterium is the GIT or GUT. Causes
Subacute infective endocarditis)

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 Coagulase-negative S. aureus: causes approximately 30% of prosthetic valve
cases and 5% of natural valve cases. It causes subacute infective endocarditis.
 HACEK organisms (Haemophilus species, Actinobacillus,
actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens,
Kingella species). These group of organisms usually cause subacute disease
and account for 5% of infective endocarditis.
 Fungi:
 Candida
 Aspergillus
 Non-infective:
 SLE
 Cancer
PATHOPHYSIOLOGY
 All cases of infective endocarditis develop from a common shared process:
 Bacteremia (nosocomial or spontaneous) that delivers the organisms to the
valve’s surface
 Adherence of the organism to valvular structures
 Eventual invasion of the valve leaflets and formation of vegetations.
 Infective endocarditis develops most commonly on the mitral valve, closely
followed in descending order of frequency by the aortic valve, the combined
mitral and aortic valve, the tricuspid valve and rarely the pulmonic valve.
Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.
 Turbulence in blood flow damages valvular surface and endocardium which
creates a favorable situation for formation of sterile thrombus (vegetation) made
of platelets and fibrin.
 The micro-organisms that most commonly produce endocarditis resist the
bactericidal action of complement and possess fibronectin receptor for the surface
of fibrin and platelet thrombus.
 Either a spontaneous bacteremia or one that is the result of an invasive procedure
gives access to the bacteria to adhere to the sterile platelet/fibrin vegetation. Most
cases of subacute disease are secondary to the bacteremia that develop from the
activities of daily living (e.g. brushing teeth, bowel movements)
 The complications of acute bacterial endocarditis result from intracardiac disease
and metastatic infection produced by suppurative emboli. Because of their
shortened course, immunological phenomena are not a part of acute infective
endocarditis.

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RISK FACTORS
 Increased turbulent flow:
 Valve disease
 Prosthetic valves
 Structural disease: unrepaired PDA, VSD, HCM
 Rheumatic heart disease
 Increased pathogen entry and bacteremia:
 IV drug use
 Hemodialysis
 Dermatitis
 Chronic disease:
 Diabetes
 Kidney disease
CLINICAL FEATURES
SUBACUTE INFECTIVE ENDOCARDITIS
 The patient suspected of subacute bacterial infective endocarditis (SBE) should
be asked about invasive procedures that may be causing bacteremia. Most causes
are due to S. viridans related to dental procedures.
 Symptoms of are subtle and non-specific.
 SBE is suggestive by a history of a slowly progressive
Key diagnostic features of
process characterized by:
infective endocarditis:
 Fever (low grade), rigors and night sweats
Murmur + fever
 Fatigue/malaise
 Anorexia
 Back pain
 Weight loss
 Less common developments are a cerebrovascular accident or congestive heart
failure.
 When appropriate therapy is delayed for weeks or months, additional clinical
features, embolic or immunological in origin develop
 Common physical findings:
 Fever: low grade. 3-15% of patients may have normal or subnormal
temperature.
 Murmurs: seen in 99% of cases. The absence of a murmur should cause
clinicians to reconsider the diagnosis of IE. The major exception is right-

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sided infective endocarditis in which only 1/3 of cases have detectable
murmur.
 Peripheral stigmata suggestive of SBE (rare now because of introduction of
antibiotics)
o Petechiae: most common peripheral lesion. Seen in palpebral
conjunctivae, the dorsa of the hands and feet, the anterior chest,
abdominal walls, oral mucosa and soft palate.
o Splinter hemorrhages (Subungual hemorrhages): these are linear and red
lesions that do not extend for the entire length of the nail
o Finger and toe clubbing: especially in patients with extended course of
untreated infective endocarditis.
o Janeway lesions: painless (‘Gentle’) plantar/palmer lesions
o Osler’s nodes: painful (‘Ouch’) infarcts in distal phalanges of
fingers/toes
o Arthritis: asymmetrical and limited to 1-3 joints
o Splenomegaly
 Embolic manifestations: causes infarcts and abscesses most commonly affecting
brain (stoke), lung and spleen.
 Acute meningitis with sterile spinal fluid
 Hemiplegia due to embolization in distribution of the middle cerebral artery
 Unilateral blindness caused by occlusion of a retinal artery
 Myocardial infarction resulting from embolization to a coronary artery
 Splenic infarction
 Renal regional infarcts producing pain
 Immunological manifestations: this is due to immune complex disposition and
vasculitis. It is suggestive of SBE:
 Petechiae and splinter hemorrhages: commonest signs
 Janeway lesions
 Osler’s nodes
 Roth spots: retinal hemorrhages with pale centers
 Glomerulonephritis
 Presence of rheumatoid factor

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ACUTE INFECTIVE ENDOCARDITIS
 History of antecedent procedures or illicit drug use must be investigated
 Aggressive disease.
 Onset of illness is abrupt with rapidly progressive destruction of the infected
valve.
 The valve leaflets are destroyed rapidly by bacteria that multiply very fast within
the ever-growing friable vegetations.
 Clinical symptoms of acute IE result from either embolic or intracardiac
suppurative complications.
 There is an acute onset of high grade fever and chills and rapid onset of
congestive heart failure.
 Complications develop within a week and they include
 Dyspnea and fatigue of severe congestive heart failure
 Neuropsychiatric complications from CNS involvement
 Roth spots
 Murmurs: most commonly murmur of aortic regurgitation. Because of rapid
onset, the left ventricle does not have a chance to dilate. In this situation the
classic findings of increased pulse pressure that are seen in chronic AR are
absent.
 Janeway lesions
 Acute septic monoarticular arthritis
 Purulent meningitis
RIGHT-SIDED INFECTIVE ENDOCARDITIS
 Is associated with a very low rate of congestive heart failure and valvular
perforation.
 Pulmonary infarcts may result from emboli of right-sided infective endocarditis.
INVESTIGATIONS
 Blood cultures: gold standard for diagnosis for documentation of a continuous
bacteremia (>30 min in duration)
 Draw 3-5 different sets from at least 3 different sites before starting
antibiotics over 6 hours if subacute
 Draw 3 sets from different sites before stating antibiotics over 1 hour 30
minutes if acute.
 There is a 90% sensitivity

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 Echocardiography: Transthoracic echo then transesophageal echo if negative
(Transesopheal echo mores sensitive at detecting IE)
 Electrocardiography: increased PR interval. Monitor this to decide whether
surgery is required.
 CXR: cardiomegaly
 Bloods:
 FBC: normocytic anemia, increased neutrophils
 Increased ESR/CRP
 Rheumatoid factor may be positive (due to IE itself or RA)
DIAGNOSIS: DUKE CRITERIA
 Diagnosis requires any 2 of:
 2 major
 1 major plus 3 minor
 5 major
 Major:
 Positive blood culture for typical microorganisms that cause IF from 2
separate blood cultures or persistent.
 Positive Echocardiogram:
o Definitive vegetation (oscillating intracardiac mass on valve or
supporting structure)
o Abscess
o New partial dehiscence of prosthetic valve
o New valvular regurgitation (increase or change in pre-existing murmur
not sufficient)
 Minor:
 Predisposition: predisposing heart condition or IV drug abuse
 Fever greater than 38.0oC
 Embolic phenomena: Major arterial emboli, septic pulmonary infarcts,
mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages,
Janeway lesions
 Immunologic phenomena: Glomerulonephritis, Osler’s nodes, Roth’s spots,
rheumatoid factor
 Microbiologic evidence: positive blood culture not meeting major criterion
(e.g. 1 positive culture)
 Echocardiogram: consistent with IF but not meeting major criterion (i.e.
positive echo for other abnormality)

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MANAGEMENT
 Admit and treat as inpatient to allow monitoring of the development of
complications and the response to the antibiotic therapy.
 General measures:
 No special diet however if CCF develops then sodium restriction may be
necessary.
 Limitation of activity is determined by the severity of illness, complications
(e.g. stroke) and the presence of significant CCF.
 Medical therapy:
 Aimed at:
o Eradicating the infectious agent from the thrombus
o Treating the complications of valvular infection
 Intravenous antibiotics
o Treat for 4-6 weeks including at least 2 weeks IV initially.
o SBE:
 Crystalline penicillin 3-4 million IU IV every 4 hours for 4-6 weeks’
plus
 Gentamicin 1mg/kg (80mg) IV TDS for 2 weeks’ plus
o Prosthetic valve endocarditis:
 Vancomycin 1g IV BD for 6 weeks’ plus
 Gentamicin 1mg/kg (80mg) IV TDS for 2 weeks’ plus
 Rifampicin 300mg PO/TDS for 6 weeks
o Acute IF where S. aureus is suspected e.g. hospital acquire infection
 Flucloxacillin if native valve add rifampicin 300mg PO TDS 2 weeks
and gentamicin 1mg/kg (80mg) IV TD for 2 weeks if prosthetic
valve.
 Treating complications
o Mild CHF resulting from valvular insufficiency or myocarditis may be
managed with standard medical therapy for CHF.
o Although thrombosis is a key element of infective endocarditis,
anticoagulation with heparin or Warfarin is controversial and it should
be avoided
 Surgery (needed in 15-25% of patients with IE)
 Debridement, repair or replacement may be required.
 Indications
o Acute AR with sever heart failure

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o Fungal endocarditis
o Refractory Heart failure
o Persistent sepsis or emboli despite adequate antibiotic therapy
o Poor response to antibiotics
o Mobile vegetation >10mm in size
o Prosthetic valve dysfunction associated with CHF
o Valve ring abscess near a prosthetic valve
PREVENTION
 Prophylactic antibiotics for high-risk dental procedure in patients at risk of IE
e.g. prosthetic valve is controversial some recommend for it while others don’t.

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MYOCARDITIS
 Myocarditis is inflammation of the myocardium often resulting from infectious
process, which subsequently leads to myocardial destruction and a dilated
cardiomyopathy.
 The acute picture is nonspecific unless overt congestive heart failure develops.
ETIOLOGY
 Infectious:
 Viral infections: Coxsackievirus B, HIV myocarditis (overt involvement is
seen in 10 % of HIV patients)
 Bacterial myocarditis: Not common usually occurs as a complication of
infective endocarditis. Diphtheric myocarditis may develop in ¼ of patients
with diphtheria
 Fungal myocarditis
 Protozoal myocarditis: Chagas disease caused by a protozoon Trypanosoma
cruzi and transmitted by an insect vector. It is one of the most common causes
of heart disease in Central and South America.
 Rickettsial myocarditis: associated with Typhus, Lyme disease
 Spirocheatal myocarditis: associated with Relapsing fever.
 Non-infectious:
 Hypersensitivity and toxic reactions to:
 Drugs: Doxorubicin (anti- neoplastic agent)
 Radiation
 Giant cell myocarditis: is a rare form of myocarditis of unknown etiology
PATHOPHYSIOLOGY
 Myocarditis is defined as inflammatory changes in the heart muscle.
 It characterized by an interstitial mononuclear cell infiltrate with an attendant
myocyte necrosis.
 It is not known whether the infiltrate is caused by a direct invasion of the infective
agents or by a systemic immune response.
 In the chronic stage, cytotoxic T lymphocytes infiltrate the myocardium and
mediate an autoimmune response with myocardial autoantibody activity directed
against cardiac myosin. This autoimmune process persists after the viral particles
are no longer detected.
 Coronary artery thrombus formation, luminal obstruction, ischemia, and

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dysrhythmias compound the deleterious effects of the inflammatory response.
CLINICAL FEATURES
 Variable presentation.
 Patients may present with a nonspecific illness characterized by fatigue, mild
dyspnea, or fulminant congestive heart failure (CHF).
 Myocarditis may even cause sudden death in some patients.
 Majority of cases of myocarditis are subclinical.
 An antecedent viral syndrome has been documented in 60% of patients with
myocarditis.
 The typical time interval between the onset of the viral illness and cardiac
involvement is 2 weeks.
 Fever is present in 20% of cases. Fatigue, myalgia and, malaise are common
symptoms
 Chest pain or chest discomfort is reported in 35% of cases.
 The chest pain is often pleuritic quality with precordial pain of a sharp
stabbing nature. Sometimes it may be substernal and squeezing, more typical
of ischemic pain.
 Dyspnea on exertion is common and orthopnea and shortness of breath at rest
may be noted if CHF is present.
 Palpitations are common.
 Syncope signals development of AV block or malignant dysrhythmias and may
lead to sudden death in patients with myocarditis.
 Physical examination:
 Patients with mild cases of myocarditis have a nontoxic appearance and
simply may appear to have a viral syndrome.
 Tachypnea and tachycardia are common. Tachycardia is often out of
proportion to fever.
 More acutely ill patients have signs of left ventricular failure including:
o Raised JVP, bilateral basal crepitations on the chest, ascites and
peripheral edema.
o S3 gallop may be noted with significant cardiac enlargement (displaced
apical impulse).
o S1 is soft or muffled.
o Cyanosis may be noticed.

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o Hypotension caused by left ventricular dysfunction is uncommon in the
acute setting. A poor prognosis is indicated when hypotension is
present.
o Cardiogenic shock is observed in fulminant cases and has a high
mortality.
o Murmurs of mitral or tricuspid regurgitation may be present due to
ventricular dilation.
 In cases where a dilated cardiomyopathy has developed, signs of peripheral
or pulmonary thromboembolism may be found.
 Associated pericarditis may manifest with a pericardial friction rub.
Pericardial effusion is common, but signs of tamponade (e.g., hypotension,
jugular venous distention, muffled heart sounds) are rare. Pleural friction rub
might be heard because Pleuritis can occur with cases of acute myocarditis.
DIAGNOSIS AND INVESTIGATIONS
 Since many cases of myocarditis are not clinically obvious, a high degree of
suspicion is required for the making a diagnosis of acute myocarditis.
 Erythrocyte sedimentation rate (ESR) is elevated in 60% of patients with acute
myocarditis.
 Leukocytosis is present in 25% of cases.
 Chest x-ray: often reveals a normal cardiac silhouette, but pericarditis or overt
clinical CHF may be associated with cardiomegaly. Vascular redistribution,
interstitial and alveolar edema and pleural effusion may also be noticed.
 Echocardiography: Dilated chambers and reduced ejection fraction indicating left
ventricular systolic dysfunction.
 ECG: Sinus tachycardia is the most frequent finding. ST-segment elevation
without reciprocal depression, particularly when diffuse, is helpful in
differentiating myocarditis from acute myocardial infarction
MANAGEMENT
 Patients with mild symptoms and no signs of cardiac failure or dysrhythmia may
be treated on an outpatient basis.
 The medical treatment of myocarditis is directed towards amelioration of
associated complications including CHF and cardiogenic shock, arrhythmias, and
thromboembolism.
 Left ventricular dysfunction with signs of CHF should be treated with;
 Low sodium diet

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 Limitation or avoidance of exercise as exercise may have deleterious effect.
 Diuretics
 Digoxin: should be given with caution as patients with myocarditis are
sensitive for digitalis toxicities.
 ACE inhibitors and vasodilators
 In general, sympathomimetic and beta-blocker drugs should be avoided
because they increase the extent of myocardial necrosis and mortality.
 Arrhythmias:
 Detection of dysrhythmia with inpatient cardiac monitoring.
 Medical therapy for arrhythmias
 Implantation of cardiac pacemakers.
 Avoiding risk of thromboembolism:
 Anticoagulants such as Warfarin or Heparin may be given.
 Nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in the
early course of disease because of inhibition of prostaglandin production,
worsened myocyte function, and increased myocardial necrosis.

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PERICARDITIS AND PERICARDIAL EFFUSION

 Pericarditis is an inflammation of the pericardium surrounding the heart.
 Pericarditis is most commonly due to secondary causes. Primary pericarditis is
almost invariably due to viral infection.
 Pericarditis is one cause of fluid accumulation in the potential space and cardiac
tamponade is the hemodynamic result of fluid accumulation
PATHOPHYSIOLOGY
 The pericardium consists of an outer fibrous layer (parietal pericardium) and an
inner serious layer (visceral pericardium). Normally the 2 layers are separated by
a small quantity of fluid (15-50ml).
 The pericardium serves as a protective barrier from the spread of infection or
inflammation from adjacent structures. It also prevents sudden dilation of the
cardiac chambers during exercise and hypervolemia. It restricts the anatomic
position of the heart and minimizes friction with the surrounding structures.
 Approximately 120ml of additional fluid can accumulate in the pericardium
without an increase in pressure.
 Further fluid accumulation can result in marked increases in pericardial pressure,
eliciting decreased cardiac output and hypotension (Cardiac tamponade). The
rapidity of fluid accumulation influences the hemodynamic effect.
CLASSIFICATION
 Pericarditis can be classified according to:
 Etiological classification
 Clinical classification
ETIOLOGICAL CLASSIFICATION
 Infectious pericarditis
 Viral: Coxsackie, Herpesviridae (CMV, EBV, HSV), Flu, mumps, HIV
 Pyogenic: Staphylococcus aureus, Streptococcus, Haemophilus
 Tuberculous (this is common in HIV positive patients)
 Fungal
 Non-infectious pericarditis
 Uremia
 Acute myocardial infarction and post MI (Dressler’s syndrome)
 Neoplasm
 Drugs: procainamide, hydralazine

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 Hypothyroidism
 Idiopathic
 Hypersensitivity/autoimmune
 Rheumatic fever
 Rheumatoid arthritis
 SLE
 Sarcoidosis
 Posttraumatic
CLINICAL CLASSIFICATION
 Acute pericarditis (<6 weeks)
 Effusive (serous or sanguineous)
o Serous pericarditis is associated with SLE, rheumatic fever, Scleroderma,
uremia, tumors and a variety of viral infections. It is characterized by
production of clear, straw-colored, protein-rich exudate containing small
numbers of inflammatory cells.
 Fibrinous or serofibrinous pericarditis: is characterized by a fibrin-rich
exudate. It may be caused by uremia, myocardial infarction, radiation to chest
(e.g. in the treatment of breast cancer and mediastinal tumor) or acute
rheumatic fever.
 Purulent or suppurative pericarditis is characterized by grossly cloudy or
frankly purulent inflammatory exudate. It is almost always caused by
bacterial infection
 Hemorrhagic pericarditis is characterized by a bloody inflammatory exudate.
It usually results from tumor invasion of the pericardium, but can also result
from TB or other bacterial infection.
 Subacute pericarditis (6 weeks to 6 months)
 Effusive-constrictive
 Constrictive
 Chronic pericarditis (over 6 months)
 Constrictive
 Effusive
 Adhesive (non-constrictive)
CLINICAL FEATURES
 Retrosternal or precordial chest pain which is described as sharp or stabbing.

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 Pain may be sudden or gradual onset and may radiate to the back (left
trapezial ridge), neck, left shoulder or arm
 Movement or inspiration may aggravate the pain
 Pain may be most severe when the patient is supine and can be relieved when
the patient leans forward while sitting.
 Associated symptoms:
 Low grade intermittent fever
 Dyspnea
 Cough
 Dysphagia
 In TB pericarditis: fever, night sweats and weight loss are commonly seen (80%)
 Some patients may present with acute abdominal pain.
 Cardiac tamponade:
 May present with anxiety, dyspnea, orthopnea, fatigue or altered mental
status.
 History of medical illness associated with pericardial disease e.g. end stage
renal disease.
 Traumatic tamponade may present with acute dyspnea or altered mental
status.
 A waxing and waning clinical picture may be present in intermittently
decompressing tamponade
 Physical findings
 Pericarditis:
o Pericardial friction rub (classic sign of acute pericarditis): this is scratchy,
leathery sound heard during both systole and diastole. It is best heard at
the lower sternal border or apex when the patient is positioned sitting
forward. Friction rub may be distinguished from a cardiac murmur by its
changing character from heartbeat to heartbeat and patient position
changes. A friction rub is closer to the ear on auscultation than a murmur.
o Fever: usually low grade but it can reach 39oC
o Tachypnea and dyspnea. Dyspnea may be severe with myocarditis,
pericarditis and tamponade.
o Ewart signs: Dullness and bronchial breathing between the tip of the left
scapula and the vertebral column.
o Hepatomegaly and ascites may be found
o Cardiac arrhythmias: premature atrial and ventricular contractions
occasionally are present

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 Cardiac tamponade:
o As volume of pericardial fluid increases the capacity of the atria and
ventricles to fil is mechanically compromised, leading to reduce stroke
volume and tamponade. It is influenced by volume and rate of
accumulation.
o Beck triad:
 Jugular venous distention: increased JVP
 Hypotension
 Muffled heart sounds
o Neck vein distension is a common finding but Kussmaul’s sign is absent.
o Hypotension to the extent of shock: may occur when the cardiac stroke
volume is significantly reduced and tissue perfusion is compromised.
o Pulses paradoxus: abnormal fall in blood pressure by more than 10mmHg
during inspiration
o Narrow pulse pressure: indicates reduced left ventricular stroke volume
o Cyanosis
o Varying degrees of altered consciousness
INVESTIGATIONS
 Blood investigations:
 Full blood count with differential
 ESR: elevated
 HIV testing
 Antinuclear antibody (ANA)
 Rheumatoid factor
 Imaging:
 Chest X-ray
o Bottle-shaped heart can be seen with excessive pericardial fluid
accumulation.
o In cardiac tamponade (or large effusions), the chest X-ray may
demonstrate an enlarged cardiac silhouette after 200-250ml of fluid
accumulation. This occurs in patients with slow fluid accumulation
compared to a normal cardiac silhouette seen in patients with rapid
accumulation and tamponade. Thus the chronicity of the effusion may be
suggested by the presence of a huge cardiac silhouette.
 ECHO: minimal pericardial effusion in pericarditis and significant
pericardial effusion in chronic pericarditis or cardiac tamponade.

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 ECG
o Acute pericarditis: diffuse ST segment elevation with reciprocal
depression and depression of PR segment is unique to acute pericarditis
in 80% of viral pericarditis.
o Cardiac tamponade or massive effusion: electrical alternans is
pathognomic of cardiac tamponade and is characterized by alternating
levels of ECG voltage of the P wave, QRS complex and T wave. This is
a result of the heart swinging in a large effusion. Low voltage of ECG.
TREATMENT
 Acute pericarditis:
 Treatment of pain and inflammation
o NSAIDs: ASA, indomethacin and ibuprofen are effective in reducing the
inflammation and reliving the chest pain
o Steroid therapy: intractable cases of pericarditis that fail to respond to
NSAID.
 Specific therapy should be directed towards the cause of pericarditis. E.g.
patients with TB pericarditis should be treated with anti TB along with
steroids.
 Cardiac tamponade: Patients with evidence of cardiac tamponade need
emergency Pericardiocentesis i.e. removal of fluid from pericardial sac.
 Prognosis largely depends upon the etiology of the pericardial infection or
inflammation as well as the presence of a pericardial effusion and/or tamponade.
COMPLICATIONS
 Recurrence (15-32%)
 Cardiac tamponade
 Chronic constrictive pericarditis
 Cardiac perforation at time of Pericardiocentesis
 Bronchopericardial fistula: this was noted as complication of MDR TB in a
patient with HIV

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SHOCK AND HYPOTENSION

 Hypotension is a state of low blood pressure with systolic blood pressure (SBP)
<90mmHg or mean arterial pressure <65.
 In relative hypotension the SBP is >30mmHg below baseline
 Shock is a state of cardiovascular failure resulting in impaired tissue perfusion
and disturbed cellular metabolism and function as a result of decreased oxygen
supply.
 Clinically shock can be defined as a 20% sudden blood loss or shift from
peripheral circulation.
 Adequate blood flow to tissues depends on:
 Blood volume
 Myocardial contractility
 Peripheral resistance
 Any disturbance in the above 3 can lead to shock.
 Pump failure leads to cardiogenic or obstructive failure
 Peripheral circulatory failure leads to hypovolemic (decreased blood volume)
or distributive shock (decreased peripheral resistance).
CLASSIFICATION OF SHOCK
 Shock can be classified into:
 Hypovolemic (Oligemic) shock: due to diminished blood volume (loss of
fluid/blood- hemorrhagic shock)
 Cardiogenic shock: due to inefficient myocardial function (decreased cardiac
contractility)
 Distributive shock: due to peripheral blood pooling. Can either be
o Septic shock: due to systemic infection
o Neurogenic shock: due to peripheral vasodilation, reduced peripheral
resistance and peripheral pooling of blood.
o Anaphylactic shock: due to antigen-antibody reaction that also leads to
peripheral pooling of blood e.g. injection of anti-tetanic serum
o Endocrinal shock: due to acute severe hormonal imbalance e.g. in adrenal
insufficiency or pituitary failure. It may present with a combination of
any of the above types.
 Obstructive shock: due to decreased blood flow to the left ventricle as in
cardiac tamponade, pulmonary embolism, and tension pneumothorax.
 Patients may have more than 1 type of shock e.g. hypovolemic and septic.

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PATHOPHYSOLOGY
 This includes cellular changes, microcirculatory changes, acid-base imbalances
and systemic changes.
 Cellular changes:
 Tissue hypo-perfusion resulting in a decrease in oxygen delivery to the tissue
and cells undergo anaerobic metabolism producing lactic acid (causing
metabolic acidosis).
 This continues until cellular glucose is depleted resulting in stoppage of cell
metabolism release of auto-digestive enzymes and rupture of plasma and
lysosomal membranes.
 Microcirculatory changes:
 Under the effect of catecholamines the precapillary sphincters constrict, less
blood enters the capillaries and the capillary circulation becomes sluggish.
 Untreated hypovolemia thus leads to hypoxia.
 Under normal conditions only one third of the capillary bed is open at a time.
 Under ischemic conditions however the body reacts by opening more
capillaries this results in:
o Further slowing of the capillary circulation, the so called slugging of
blood.
o Slugging encourages spontaneous coagulation of blood in these
capillaries.
o If extensive, it is called disseminated intravascular coagulation (DIC).
o This depletes coagulation factors and induces bleeding in the rest of the
body (consumption coagulopathy)
 A sluggish circulation and DIC compound tissue hypoxia and affect the
function of capillary endothelium. The result of the latter is leakage of large
protein molecules from the vessels into interstitial space dragging with them
huge amounts of fluid. This third space loss of fluid reduces blood volume.
 Acid-base imbalance: Shock is accompanied by metabolic acidosis which is
caused by accumulation of lactic acid as a result of anaerobic metabolism and
renal failure as a result of prolonged ischemia, aggravates acidosis.
 Systemic changes:
 Sympathetic response: release of catecholamines & stress hormones
(Cortisol, glucagon), release of ADH and activation of renin-angiotensin-
aldosterone system.

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 Cardiovascular: reduced coronary artery perfusion and direct depression of
myocardium by tumor necrosis factor
 Respiratory: metabolic acidosis results in tachypnea which causes carbon
dioxide washout and compensatory respiratory alkalosis. Leakage and
swelling can develop in the lungs, causing difficulty in breathing (respiratory
distress- ARDS)
 GIT: mucosal hypoperfusion causes mucosa death and stress ulcers. Mucosal
death may also result in bacterial translocation, septicemia and multi-organ
failure.
 Liver: ischemic hepatic dysfunction
 Renal: renal hypoperfusion decreases GFR, urine output and may lead to pre-
renal failure and acute tubular necrosis.
 Ischemic perfusion syndrome:
o It is due to systemic hypoperfusion, tissue hypoxia and local activation
of inflammatory mediators.
o Further injury occurs once normal circulation is restored to tissues:
 Myocardial depression
 Cellular and humoral elements activated by hypoxia are flushed back
into circulation causing more endothelial injury e.g. acute lung
injury, acute renal injury
o It only can be minimized by decreasing the period of hypoperfusion.
STAGES OF SHOCK
 Initial: decreased oxygen and increased lactate.
 Compensatory stage:
 Increased respiratory rate
 Sympathetic response: increased heart rate, fluid retention
 Increased renin and ADH secretion
 Progressive/decompensated stage: If compensatory mechanisms and treatment
are unsuccessful.
 Worsening hypotension due to vasodilation, blood pooling in capillaries,
and fluid leak from vessels.
 Altered mental status
 Electrolyte imbalances
 Refractory: irreversible

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GENERAL CLINICAL FEATURES OF SHOCK
 Change in mental status: a continuum from agitation, confusion/delirium,
obtundation/coma.
 Hypotension: absolute (systolic blood pressure <90mmHg) or relative (a drop in
systolic blood pressure >40mmHg), which is why a patient may be in shock with
a high or normal blood pressure.
 Increased heart rate, pulse may be thread (barely perceptible). Capillary refill >2s
 Oliguria (<30ml/hr)- from shunting of renal flow to other vital organs,
intravascular volume depletion or both.
 Cool, clammy skin- compensatory peripheral vasoconstriction redirects blood
from the peripheral to the vital organs (heart, brain, splanchnic). However, in
early distributive shock or terminal shock the skin may be flushed or hyperemic
due to failure of compensatory vasoconstriction.
 Metabolic acidosis- increased lactate production from anaerobic respiration when
shock progresses to circulatory failure and tissue hypoxia along with decreased
clearance of lactate by the liver, kidneys and skeletal muscle.
APPROACH TO THE PATIENT WITH SHOCK
HISTORY
 Look for underlying causes, try to classify the type of shock. Often limited due
to confusion or obtundation.
 Ask for any history of:
 Bleeding? Trauma? Hematemesis? Hematochezia? Melena? (if so suspect
hypovolemic shock)
 Coronary artery disease? Valvular heart disease? CCF? (if so suspect
cardiogenic shock)
 History of fever? Pneumonia? Meningitis? (if so suspect septic shock)
EXAMINATION
 General examination: ill appearing, confused, lethargic, unresponsive and
temperature >38oC or <36oC.
 Neurologic: meningism and focal neurologic deficits
 Cardiac: Tachycardic (HR> 100), hypotensive (SBP <100), Dizziness,
Orthostatic hypotension, S3 heart sound, murmur, Extremities may be warm/well
perfused or cold/blue, Capillary refill brisk or slow, Chest pain
 Pulmonary: Evidence of pneumonia, use of accessory muscles of respirations,
Respiratory rate >30, Oxygen saturation <95%.

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 Gastrointestinal: Abdominal pain, Tense/Rigid abdomen (may indicate
perforated viscus, hemorrhage, peritonitis), rebound tenderness, guarding,
melena or blood on rectal exam.
 Renal: Flank tenderness (pyelonephritis), Urine output <0.5ml/kg/hr or <30ml/h
INVESTIGATIONS
 Blood investigations:
 Urea and electrolytes (Sodium, potassium, chloride and bicarbonate) +
Creatinine
 Liver enzymes
 Serum glucose
 Full blood count (leukocytes and bandemia in sepsis)
 Clotting profile: Bleeding time, Prothrombin time and activated partial
thromboplastin time to rule out bleeding tendencies
 Blood culture
 Cardiac enzymes
 Arterial blood gas/lactate (if available)
 Imaging:
 Chest and abdominal X-ray
 ECG
 Echocardiogram
 Ultrasound- Focused assessment with sonography for trauma (FAST)
 Septic work up: CXR, blood culture, sputum microscopy culture and sensitivity,
urine dipstick, microscopy, culture and sensitivity, lumbar puncture.
MANAGEMENT
 Management depends entirely on the type of shock.
 Shock is always an emergency and must be treated rapidly as it is life threatening.
 Treat the underlying cause
 Management includes:
 Frequent monitoring of vital signs
 2 large bore IV cannulas- 18 gauge (green) or greater.
 Foley catheter and monitoring of urine output.
 Aggressive colloid (normal saline or ringers lactate) fluid resuscitation for
hypotension- especially in hypovolemic + septic shock (may require >10 L)
 Intubation if in respiratory distress
 Packed red cells if bleeding/hypovolemic

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 Stop any antihypertensive or diuretics. Give pressors (dopamine,
dobutamine, epinephrine, neosynephrine etc.) if shock is present despite
aggressive fluid resuscitation.
 Hypovolemic shock:
o IV fluids
o Check electrolytes
o Fix underlying condition e.g. diabetic ketoacidosis
o Send for X-match for urgent transfusion if hemorrhage (most common
cause of hypovolemic shock)
 Cardiogenic shock:
o IV fluids may be harmful
o IV Lasix and or dopamine may help
o Fix underlying cause e.g. valve replacement
 Septic shock:
o Search for source and start empiric antibiotics based on likely type of
infection.
o Give IV fluids
 Anaphylactic shock:
o IV fluids
o Subcutaneous epinephrine 0.3ml 1: 1000 solution if severe
o Antihistamines and corticosteroids may help
 Adrenal insufficiency: give hydrocortisone 100mg TDS x 5/7
 Obstructive shock
o IV fluids
o Urgent ECG
o CXR to confirm
o Thrombolysis for Pulmonary embolism
o Chest tube for tension pneumothorax
o Pericardiocentesis for tamponade.

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HYPOVOLEMIC SHOCK
ETIOLOGY
 This is due to diminished blood volume as a result of:
 Whole blood loss i.e. hemorrhage which can be traumatic or pathological
o Trauma
o Ruptured abdominal aortic aneurysm
o Aortic dissection
o Upper GI bleeding
o Ruptured ectopic pregnancy
 Plasma loss as in burns, heat exhaustion or peritonitis
 Water and electrolyte loss (especially Sodium) as in: severe vomiting,
diarrhea, intestinal obstruction and fluid sequestration (as in acute
pancreatitis).
STAGES
 Compensated stage: in this stage the body employs the physiological
mechanisms, in a trial to restore blood volume or at least, preserve the normal
function of the vital organs (brain, kidneys, heart and lung). With loss of >15%
of blood volume, the compensatory mechanisms usually fail.
 Decompensated stage (40% blood loss): if the cause of shock is not treated
successfully and after failure of compensatory mechanisms there will be
progressive poor perfusion and micro-circulatory changes with deterioration of
functions of the brain, kidney, heart and lung.
 Refractory stage: The shock can no longer be reversed. Failure of vital organs
and death occurs imminently.
CLINICAL FEATURES
 Of shock
 Symptoms:
o Weakness and fainting
o The patient feels cold and thirsty
 Signs:
o Patient is cold and clammy with a narrow pulse pressure
o Decrease in blood pressure: SBP<90 or 60 below normal
o Orthostatic hypotension can be an early sign of hypovolemia.
o Capillary refill>2s
o Oliguria: <30ml/hr

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o Altered mental status (may vary from anxious to drowsy but the patient
usually remains alert).
o Hypotension, tachycardia (increased heart rate, pulse may be thread-
barely perceptible) and decreased pulse pressure (thready pulse)
 Of the cause
 Sites of bleeding
 Signs of internal hemorrhage
 Burns
 Intestinal obstruction
 In hemorrhagic shock, trauma or signs of GI bleeding (melena, abdominal
pain)
 Of complications:
 Anuria
 Acute respiratory depress syndrome
INVESTIGATIONS
 Blood investigations:
 Full blood count (check Hemoglobin, hematocrit)
 Cross match (for blood transfusion) as well as group and save
 Urea and electrolytes (Sodium, potassium, chloride and bicarbonate) +
creatinine
 Clotting profile: Bleeding time, Prothrombin time and activated partial
thromboplastin time to rule out bleeding tendencies
 Liver function tests
 Serum glucose
 Arterial blood gasses: lactate >2 suggests hypoperfusion
 Imaging:
 Chest X-ray and ECG: to exclude cardiogenic causes
 Abdominal ultrasound: to rule out internal hemorrhage
 Head CT scan: if the patient with head injury or unconscious
MANAGEMENT
RESUSCITATION
 ABCs
 Airway should be patent by: Pulling the tongue forward, aspiration of
secretions, and tracheostomy if needed

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 Breathing should be maintained by: oxygen mask and ambu bag. Administer
oxygen.
 Circulation:
o 2 large bore IV cannula 18G (green) or bigger: one for IV fluids and the
other for sampling (if no veins available/all collapsed)
o Stop any external bleeding by compression.
 Drugs: analgesics for any pain
 Insert an NGT to evacuate the stomach (if surgery may be needed)
 Insert a urinary catheter to monitor urine output Recall:
 Elevate legs and head down to restore cerebral blood
60% of the body is fluid. It is
flow (Trendelenburg’s position)
distributed in 3 compartments:
 Give sufficient warmth (but avoid over warmth)
 2/3 is intracellular fluid
FLUID ADMINISTRATION  1/3 is extracellular fluid
 Crystalloids: may be the only fluid given to patients o ¾ (75%) of ECF is in
with hypovolemia caused by loss of water and the interstitium
electrolytes. o ¼ (25%) of ECF is in
 Normal saline: to replenish equivalent loss of both the intravascular
water and electrolytes. compartment
 Ringer: gives potassium supply (after ensuring good
urine output) in prolonged shock
 Lactated Ringer’s solution: also a buffer, in prolonged shock and acidosis
 Note: Glucose 5% is not used in shock because glucose is rapidly
redistributed this leads to an increase in the amount of ECF (without
electrolytes) causing dilutional hyponatremia and increased ICF with brain
edema and increased intracranial pressure.
 Fluid therapy:
 Resuscitation:
o 500ml crystalloid bolus over <15minutes. 250ml if old or heart failure.
o Reassess and re-give up to 2L
o Don’t wait until SBP is under 90. A SBP of 110 in the presence of
increased heart rate suggests impaired output.
 Replacement:
o Estimate fluid losses, and replace gradually over 2-3 days i.e. in addition
to maintenance fluids.
 Maintenance:
o Basic needs:

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 25-30ml/kg/day water. 20-25ml/kg/day if old, kidney or heart failure
or malnourished. So just over 1ml/kg/hr
 1mmol/kg/day of sodium, potassium and chloride. In general, don’t
give >10mmol/hr
 50-100g/day of glucose.
o Management:
 Usually need around 2-3 liters per day so around 100ml/hr is typical
e.g. 1L over 8-10 hours. 500ml over 8 hours if old or heart failure.
 1L of normal saline contains 154mmol of both sodium and chloride
and 1 L of Hartmann’s solution contains 131 mmol of sodium and
111mmol of chloride (plus 5 mmol of potassium). So 500ml of each
roughly covers daily needs.
 Typical daily regimen may be 1L 5% dextrose with 20mmol
potassium, then 500ml normal saline with 20mmol potassium, then
1L 5% dextrose with 20 mmol potassium.
 Monitor potassium to determine needs
 Monitor increase in chloride daily if on normal saline due to risk of
increased chloride ions.
 Colloids: contain large insoluble molecules increasing oncotic pressure and in
theory keeping the fluid in the intravascular compartment longer. In clinical
trials, however, colloids have shown no benefit (and sometimes harm) relative to
crystalloids.
 Plasma substitutes: needs matching and adequate storage
 Dextran (polysaccharide polymers): high molecular and low molecular
weight
 Blood and blood products:
 Red blood cells
o Indications:
 Decreased Hb (Hb<7g/dl)
 Hb <8g/dl in patients with ACS
 Major hemorrhage (given in combination with FFP and platelets)
o 1 unit of blood increases Hb by 1g/dl
o 1 unit of whole blood is around 450ml while 1 unit of packed cells is 250-
300ml.
o Prescribe 1 unit at a time, checking response (symptoms and/or Hb) after
each.
o If unused must return to fridge within 30 minutes for reuse.

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o RBCs typically given over 2-3 hours but can be up to 4 hours most other
products are given over 30 minutes.
o Assess patient at baseline, 15 minutes and at the end of transfusion.
 Fresh frozen plasma (FFP)
o Human plasma which contains clotting factors (II, V, VIII, IX, X, XI and
antithrombin III)
o Indications
 Major hemorrhage
 Warfarin reversal (INR>1.5)
o Cryoprecipitate is another alternative to FFP, though less used now. It is
the precipitate from human plasma, and contains fibrinogen, factor VIII
(8), vWF and factor XIII (13)
 Platelets
o Indications:
 Platelet <50K/L and bleeding
 Platelet <20 K/L and septic
 Platelet <10 K/L
 Stop any anti-platelets if giving
Transfusion reaction Signs Management
Mild  <2oC rise in  Pause transfusion and assess
temperature patient
 Rash/Urticaria  Consider paracetamol or
chlorphenamine
 Re-start transfusion with close
observation
Severe  o
>2 C rise in  Stop transfusion and replace
temperature any fluid needs with saline
 Rigors  Call hematology, contact lab to
 Loin or back pain return product, and complete
 Anxiety or angor incident report
animi
 Unexpected
increased heart rate
 Infusion site pain

 Transfusion associated circulatory overload (TACO):

 Commonest cause of transfusion-associated death

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 Presents with 6 hours of transfusion with acute respiratory distress,
pulmonary edema, increased heart rate and increased BP.
 Risk factors: age <3 or >60, low birth weight, heart failure, kidney failure
 Blood products are prescribed in mls in neonates to reduce TACO
 Transfusion-related acute lung injury (TRALI)
 Very uncommon
 Respiratory distress, decreased BP
 Usually due to FFP or platelets
 Other complications:
 Anaphylaxis
 Hemolytic anemia
 Increased potassium
 Infection
MONITORING
 Monitor:
 Pulse and ECG
 Blood pressure
 Temperature
 Urine output (optimum urinary output= 0.5-1ml/kg/hr)
 Arterial blood gasses (normal PO2=80-100mmHg, normal PCO2= 35-
45mmHg)
DRUGS
 Drugs that increase BP by increasing cardiac contractility (inotropes) and/or
vasoconstriction (vasopressors). Many also increase heart rate (positive
chronotropy).
 Indicated in shock for which IV fluids are insufficient or inappropriate.
 Delivery is typically as an infusion through a central line.
 Many commonly used agents are synthetic versions of endogenous
catecholamines

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Drug Mechanism of action Dosage Side-effect
Noradrenaline Vasopressor via alpha 1 0.05-1.0mcg/kg/min Peripheral
(norepinephrine) agonism but also administration carries
inotropy via Beta 1 a risk of extravasation
First line agent agonism at higher doses. and hence tissue
for shock in Reflex bradycardia from necrosis via
many ICUs increased BP typically vasoconstriction.
cancels out chronotropic However short term
effect. delivery via a large,
Adrenaline Acts on all adrenergic 0.05-1.0mcg/kg/min proximal peripheral
(epinephrine) receptors. At lower line is sometimes
doses works primarily acceptable.
Most commonly on beta 1 (inotropy and
used for chronotropy) and beta 2 Ischemia especially
anaphylaxis and (airway and vessel to the GIT, kidney
cardiac arrest dilation) and alpha 1 and extremities
(vasoconstriction) at
higher doses (including Atrial and ventricular
cardiac arrest dose) arrhythmias
Dobutamine Inodilator with inotropy Dobutamine 5-10
via beta 1 agonism and microgram/kg/min IV
Used in acute vasodilation via beta 2. infusion
heart failure
Dopamine DA agonist at lower Give dopamine 5-10 Risk of
doses, alpha and beta micrograms/kg/min IV Tachyarrhythmias
effects at higher doses infusion (dilute 400mg Evidence suggests
in 500ml of 5% dextrose that dopamine
infusion rate to be inhibits secretion of
calculated according to prolactin and could
body weight) increase lymphocytes
 Start 5mcg/kg/min, apoptosis
titrate to effects. (impairment of
immune response to
sepsis)

TREAMENT OF CAUSE AND COMPLICATIONS

 Treat the underlying cause.

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CARDIOGENIC SHOCK
 This is due to inadequate blood flow to vital organs due to inadequate cardiac
output despite of normal blood volume.
 It is characterized by
 SBP <90mmHg
 Mean arterial pressure drop >30mmHg
 Urine output <0.5ml/kg/hr
 Heart rate >60bpm
ETIOLOGY
 Primary pump failure due to:
 MI (commonest cause) or its complications e.g. ventricular septal rupture
 Severe arrhythmias
 Massive pulmonary embolism
 Cardiac tamponade
 Myocarditis
 Severe valve disease
 Trauma
 High spinal anesthesia
CLINICAL FEATURES
 Of shock:
 Clinical picture similar to hypovolemic shock.
 Comatose
 Patient is cold and clammy and pulse pressure may be narrow
 Peripheral cyanosis
 Poor urine output
 Increased JVP and decreased heart rate
 Of the cause: enlarged liver, chest pain, pulsus alternans, ‘gallop’ rhythm,
murmur, basal crackle, pulmonary edema.
INVESTIGATIONS
 Blood investigations:
 Full blood count (check Hemoglobin, hematocrit)
 Cross match (for blood transfusion) as well as group and save
 Urea and electrolytes (Sodium, potassium, chloride and bicarbonate) +
creatinine

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 Clotting profile: Bleeding time, Prothrombin time and activated partial
thromboplastin time to rule out bleeding tendencies
 Liver function tests
 Serum glucose
 Arterial blood gasses: lactate >2 suggests hypoperfusion
 Imaging:
 Cardiorespiratory: ECG, CXR (enlarged heart, pulmonary venous
congestion) and echo
 Abdominal ultrasound: to rule out internal hemorrhage
 Head CT scan: if the patient with head injury or unconscious
MANAGEMENT
 Management aims at:
 Improving cardiac output:
o Correct dysrhythmias
o Optimize preload
o Improve contractility
o Reduce afterload
 Minimizing cardiac work:
o Maintain normal temperature
o Sedation
o Intubation and mechanical ventilation
o Correct anemia
 ICU care
 Give oxygen
 Regular monitoring of temperature, heart rate, blood pressure and cardiac
monitoring.
 Give dopamine 5-10 micrograms/kg/min IV infusion (dilute 400mg in 500ml of
5% dextrose infusion rate to be calculated according to body weight)
 Start 5mcg/kg/min, titrate to effects.
 Evidence suggests that dopamine inhibits secretion of prolactin and could
increase lymphocytes apoptosis (impairment of immune response to sepsis).
 Dobutamine 5-10 microgram/kg/min IV infusion
 Prophylactic anticoagulation with ASA 75mg PO OD.
 Treat underlying cause
 If in heart failure and BP goes above 90mmHg treat as class IV.

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 Captopril 25mg BD/TDS or Lisinopril 10-20mg OD or Enalapril 5-20mg
OD (if patient develops dry cough Losartan 50mg OD)
 Furosemide IV 40-80mg OD or BD (monitor potassium levels)
 Digoxin 0.125mg-0.25mg daily
 Isosorbide dinitrate 5-10mg BD + hydralazine 25-50mg BD orally if patient
cannot tolerate ACEi.
 Spironolactone 25-50mg OD or BD
 ASA 75mg OD

DISTRIBUTIVE SHOCK
 Vasodilation leads to a relative (though not absolute) deficiency in volume.
SEPTIC SHOCK (ENDOTOXIC SHOCK)
 Septic shock is a type of distributive shock though it may also include an element
of hypovolemic shock as altered capillary permeability leads to volume loss from
the vasculature.
 It is the most serious type of shock and the most difficult to treat.
ETIOLOGY
 Gram negative bacilli (commonest cause)
 Staphylococci
 Candida
PREDISPOSING FACTORS (IMMUNOSUPPRESION)
 Extremes of age
 Malignancy
 Malnutrition
 Diabetes mellitus
 Chemotherapy, corticosteroids or immunosuppressants
 HIV infection
PATHOPHYSIOLOGY
 Bacterial endotoxins are released when immune cells (i.e. macrophages) kill
gram negative bacteria.
 Immune cells release cytokine, TNF and IL-2 which damage capillary
endothelium leading to edema and vasodilation (rapid shifting of blood bypassing
capillary) and tissue ischemia.

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 Septic shock starts as maldistribution of blood followed by myocardial
depression and hypovolemia.
CLINICAL FEATURES
 Hyper-dynamic (warm) septic shock (early phase): diagnosis is difficult and high
index of suspicion is required to detect it at early stage.
 Restless and confusion
 Skin: flushed, warm and dry
 Vitals:
o Fever >38oC + Chills
o Mild decreased in arterial blood pressure, pulse pressure may be wide
with a low DBP.
o Tachycardia
o Tachypnea
 High cardiac output
 Hypo-dynamic “cold” septic shock (Late phase): picture similar to hypovolemic
shock with reduced cardiac output
 Skin: cold and clammy
 Vitals:
o SBP<90mmHg
o Tachycardia
o Tachypnea
 Oliguria
 Multi-organ failure starts at this stage.
DIAGNOSIS
 To diagnose septic shock, the following 2 criteria must be met
 Evidence of infection, through a positive blood culture
 Refractory hypotension (Despite adequate fluid resuscitation and cardiac
output)
 In addition to the 2 criteria above 2 or more of the following must be met (SIRS)
 RR >20bpm (high respiratory rate)
 WBC <4000 cells/mm3 or > 12 000 cells/mm3
 Temperature >38oC or <36oC
 HR>90b/min
 Arterial blood gasses PaCO2 <32mmHg

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MANAGEMENT
 Give oxygen
 Give fluids:
 Ringer’s lactate + Plasma
 If low hematocrit packed RBCs or whole blood transfusion
 Drugs
 Inotropes and vasopressors: dopamine and dobutamine
 Give if patient remains hypotensive despite adequate fluid replacement.
 Give dopamine 5-10 micrograms/kg/min IV infusion (dilute 400mg in 500ml
of 5% dextrose infusion rate to be calculated according to body weight)
o Start 5mcg/kg/min, titrate to effects.
o Evidence suggests that dopamine inhibits secretion of prolactin and could
increase lymphocytes apoptosis (impairment of immune response to
sepsis).
 Dobutamine 5-10 microgram/kg/min IV infusion
 Antibiotics: parenteral combined broad-spectrum started early without waiting
for culture and sensitivity results (3rd generation cephalosporin e.g. ceftriaxone +
Aminoglycoside e.g. gentamicin + Metronidazole) then changed to culture and
sensitivity.
 Monitor vitals and urine output regularly.
 ASA 75mg OD for DVT prophylaxis
 Proton pump inhibitors to prevent stress ulcers.
 Use of corticosteroids in septic shock remains controversial.

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HEMATOLOGICAL CONDITIONS
 Blood is a connective tissue in fluid form.
 It consists of:
 Plasma: plasma proteins, water, electrolytes, complement system and
coagulation factors.
 Formed elements: red blood cells (erythrocytes), white blood cells
(leukocytes), and platelets (thrombocytes/megakaryocytes).
 Plasma is the liquid component of blood which contains soluble fibrinogen.
Serum is what remains after the formation of the fibrin clot.
 In adults red blood cells, many white blood cells and platelets are formed in the
red marrow of the bone marrow.
 In the fetus, blood cells are formed in the mesoderm cells of the yolk sac (in the
first trimester), the liver and spleen (in the second trimester) and the bone marrow
(in the third trimester).
 Synthesis of blood cells outside the bone marrow is termed extra-medullary
hematopoiesis.
 The bone marrow of essentially all the bones produces blood cells until the age
of 5 and then afterwards only the axial skeleton (vertebrae, sternum, pelvis, ribs,
cranial bones) and the proximal ends of the limb retain hemopoeitic function.

INTEPRETATION OF A HEMOGRAM
 The 8 parameter cell counter will give the following:

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 WBC count: white blood cell count
 RBC count: red blood cell count
 Hb: Hemoglobin
 Hct: Hematocrit / Packed cell volume (PCV)
 MCV: Mean cell volume
 MCH: Mean cell hemoglobin
 MCHC: Mean cell hemoglobin concentration
 RDWt: red blood cell distribution width

 In addition to these above parameters the 18 parameter cell counter also has
 White blood cell Differentials:
o Neutrophils count and percentage
o Lymphocyte count and percentage
o Monocytes count and percentage
o Eosinophil count and percentage
o Basophils count and percentage
 Pct: Plateletcrit
WHITE BLOOD CELL COUNT
 This is the number of white blood cells in 1 cubic mm of whole blood.
 The normal value is 4.0-11.0 million cells per microliter (106/L).
 A rise in this number (lymphocytosis) may indicate an infection
 A decrease in this number (leukopenia) may indicate bone marrow failure.
 On its own is not a useful parameter.
 The differential count is more specific:
 Neutrophils= 3-6 (109/L)
 Lymphocytes= 1.5- 4 (109/L)
 Monocytes= 0.3-0.6 (109/L)
 Eosinophils= 0.15-0.30 (109/L)
 Basophils= 0-0.1 (109/L)

RED BLOOD CELL COUNT

 This is the number of erythrocytes in 1 cubic mm of whole blood.
 The normal values include:

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 Men= 4.5-6.0 million cells per microliter (106/L)
 Women= 3.9-5.0 million cells per microliter (106/L)
 RBC count will be low with iron deficiency, blood loss, hemolysis and bone
marrow suppression
 RBC count increases when one moves to a higher altitude or after prolonged
physical exercise and can also reflect the body’s attempt to compensate hypoxia
(such as is seen in the obese and smokers)
 It increases with erythrocytotic states such as polycythemia vera,
eyrthrocytosis of chronic hypoxia, dehydration, stress polycythemia and
thalassemia minor.
HEMOGLOBIN
 Normal hemoglobin values:
 Men= 13.5-17.5 g/dl
 Women= 11.5- 16.0 g/dl
 In anemia there is a decrease of hemoglobin.
 In polycythemia there is an increase of hemoglobin.

HEMATOCRIT/ PACKED CELL VOLUME (PCV)

 Normal PCV
 Men= 0.4-0.54 L/L (45-54%)
 Women= 0.37-0.47 L/L (37-47%)
 Normal value of PCV is 45% but in females it is slightly lower due to their
reduced RBC count.
 PCV is increased in polycythemia and severe dehydration.
 It is reduced in anemia.
BLOOD INDICES
MEAN CELL VOLUME (MCV)
 Indicates the average volume of a single RBC.
 It is expressed in cubic microns.
 The normal value is 80-96 fL
 An alteration of MCV helps in identification of microcytic, normocytic and
macrocytic anemia.

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MEAN CELL HEMOGLOBIN (MCH)
 This gives an idea about the average hemoglobin content in a single red cell.
 Normal range varies between 27 and 32 pico grams.
MEAN CELL HEMOGLOBIN CONCENTRATION
 It indicates the relative percentage of hemoglobin in the red cell.
 This is the most important absolute value in the diagnosis of anemia.
 Its normal value is 32.0-36.0 mg/L.
 When MCHC is normal the RBC is normochromic.
 When MCHC decreases the RBC is known as hypochromic.
 A single RBC cannot be hyperchromic because the amount of hemoglobin cannot
increase beyond normal.
RED BLOOD CELL DISTRIBUTION WIDTH (RDW)
 This shows the variation in red cell size. This is calculated by dividing the
standard deviation of the red cell width by the mean cell width x 100. An elevated
RDW suggests variation in red cell size (anisocytosis)
 The normal value is 11-15%.
 In sickle cell anemia, and iron deficiency there is increased RDW.
 In beta-thalassemia trait, the RDW is usually normal.

PLATELETS
 The normal platelet count is 150-400 (109/L).
 Platelet increase (thrombocytosis) and decrease (thrombocytopenia) is seen in
different pathological states.

THROMBOCYTOPENIA THROMBOCYTOSIS

 Decrease in platelet count below  Increase in platelet count over 450

150 000/cu mm of blood 000/cu mm of blood
 Occurs in:  Occurs in
 Acute infections  Allergic conditions
 Acute leukemia  Asphyxia
 Aplastic and pernicious anemia  Hemorrhage
 Chicken pox and smallpox  Bone fractures
 Splenomegaly  Surgical operations

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 Scarlet fever  Splenectomy
 Typhoid fever  Rheumatic fever
 Tuberculosis  Trauma (wound or injury or
 Purpura damage caused by external
 Gaucher’s disease damage)
 Parturition

RED BLOOD CELL DISORDERS: ANEMIA

 Erythropoiesis is the process which produces red blood cells (erythrocytes).
 We make approximately 1012 new red cells each day.
 The process of erythropoiesis is stimulated by hypoxia (a decrease in oxygen
partial pressure) which is detected by the kidneys, which then secretes the
hormone erythropoietin (EPO). EPO stimulates the proliferation, differentiation
and release of red cell precursors into erythrocytes. 90% of EPO is produced in
the peritubular interstitial cells of the kidney and 10% in the liver and elsewhere.
 All blood cells are derived from pluripotent stem cells. These stems cells have 2
properties- the first is self-renewal, i.e. the production of more stem cells and the
second is its proliferation and differentiation into progenitor cells, committed to
one specific cell line.
 In the process of red blood cell maturation, a cell undergoes a series of
differentiations:
 A pluripotent hematopoietic stem cell (hematocytoblast) becomes
 A common myeloid progenitor cell and then
 A unipotent stem cell, then
 A pronormoblast also commonly called a proerythroblast or a rubriblast.
 This becomes an early normoblast (basophilic normoblast) and then
 An intermediate normoblast (polychromatophilic normoblast), then
 A late normoblast (orthochromatic normoblast). At this stage the nucleus is
expelled before the cell becomes

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 A reticulocyte.

Figure 32: Hematopoiesis

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Figure 33: Genesis of normal RBCs and characteristics of RBCs in different types of anemia. Image
adapted from Guyton and Hall Textbook of Medical Physiology

 Normoblasts progressively contain more hemoglobin (which stains pink) in the

cytoplasm, the cytoplasm stains paler blue as it loses its RNA and protein
synthetic apparatus while nuclear chromatin becomes more condensed.
 The nucleus is fully extruded from the late normoblast within the marrow and a
reticulocyte stage results which still contains some ribosomal RNA and is still
able to synthesize hemoglobin.
 A single pronormoblast usually gives rise to 16 mature red blood cells.
 The whole process of erythropoiesis takes 7 days.
 The stage from the pluripotent hematopoietic stem cell to reticulocyte takes
roughly about 5 days. Reticulocytes are released into the circulation and they
mature into erythrocytes in 1-2 days.
 Reticulocytes account for 1% of the red blood cells in the circulation.
 As erythrocytes are differentiating and maturing their size reduces and their color
changes from basophilic to polychromatic to eosinophilic (orthochromatic)
because of the appearance of hemoglobin and the loss of protein synthetic
apparatuses.
 The process of erythropoiesis requires vitamin B12 (cobalamin), Vitamin B8
(folic acid) and iron.

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 A feedback loop involving erythropoietin helps regulate the process of
erythropoiesis so that in non-disease states, the production of red blood cells is
equal to the destruction of red cells and the red cell number is sufficient to sustain
adequate tissue oxygen levels but not so high as to cause sludging, thrombosis or
stroke.
 Erythropoietin is bound by circulating red blood cells therefore low circulating
numbers leads to a relatively high level of unbound EPO, which stimulates the
production of RBCs in the bone marrow.
 Recent studies show that a peptide hormone called hepcidin may play a role in
the regulation of hemoglobin production and thus erythropoiesis.
 The liver produces hepcidin.
 Hepcidin controls iron absorption in the GUT and iron release from the
reticuloendothelial tissue.
 Hepcidin is implicated in the pathophysiology of anemia of chronic disease.
 Anemia is a disorder of the red blood cell. It is a significant reduction in red cell
mass and a corresponding decrease in the oxygen carrying capacity of the
blood.
 Anemia is present when there is a decreased level of hemoglobin in the blood
below the reference level for the age, sex and pregnancy state of the individual.
 In women of child bearing age, their blood values are 10% lower than men.
Therefore, anemia may be defined as HCT of less than 10% below the
mean values for age, sex and altitude.
TABLE: CRITERIA OF ANEMIA IN ADULTS AT SEA LEVEL
Factor Women Men
RBC x 1012/L < 4.0 <4.5
Hgb (g/dl) <12 <14
Hct (%) <37 <40

 Note:
 From the age 2 years to puberty, Hb less than 11g/dl indicates anemia
 As newborn infants have a high hemoglobin (Hb), 14g/dl is taken as the lower
limit at birth.
 Alterations in total circulating plasma volume as well as of total circulating
hemoglobin mass determine the hemoglobin concentration.
 Reduction in plasma volume (as in dehydration) may mask anemia or even
cause (apparent, pseudo) polycythemia conversely an increase in plasma

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volume (as with splenomegaly or pregnancy) may cause anemia even with a
normal total circulating red cell and hemoglobin mass.
 After acute major blood loss, anemia is not immediately apparent because the
total blood volume is reduced. It takes up to a day for the plasma volume to
be replaced and so for the degree of anemia to become apparent.
Regeneration of hemoglobin takes substantially longer.
 The initial clinical features of major blood loss are therefore a result of
reduction in blood volume rather than anemia.
 Anemia is a manifestation of an underlying pathological condition; it results
from:
 Under production
 Increased destruction/ hemolysis
 Blood loss/bleeding
 Multifactorial: a combination of these
APPROACH TO ANEMIA
HISTORY swelling and visual disturbances
 Obtain a thorough history to help (due to retinal hemorrhages).
determine underlying cause.  Other symptoms include anorexia,
 Geographic location: parasites indigestion, nausea, bowel
e.g. schistosomiasis irregularity (Due to shunting of
blood from the splanchnic bed),
PRESENTING SYMPTOMS irritability, difficult in
 Depend on acuteness and severity concentration, worsened dementia,
of anemia. Also depend on the age menstrual irregularities and
of patient, presence of underlying impotence or decreased libido.
disease. PAST MEDICAL, SURGICAL
 Symptoms can occur when anemia AND DRUG HISTORY
is chronic, most patients are
asymptomatic.  History of similar illness
 Non-specific symptoms include  Underlying disease
lightheadedness, dizziness,  Exposure to drugs/toxins e.g.
throbbing headache, syncope, methyldopa
tinnitus, fatigue, palpitations, chest FAMILY HISTORY
pain (angina), exercise and cold
intolerance, dyspnea, intermittent  Family history of anemia
claudication (limping), ankle

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OBSTETRIC AND GYNAE  Bleeding disorder:
HISTORY splenomegaly,
petechiae/purpura
 Pregnancies (multiple pregnancies,
grand Multiparity) INVESTIGATIONS
 Menstrual history: excessive  Full blood count
menstrual bleeding, prolonged  Hb
menses  RBC indices: MCV (normal
NUTRITION HISTORY 80-96 fL), MCH (27-32pg),
MCHC (31-35), Hct- 32-36%
 Diet: amount, quality and  Platelet count
frequency  WBC differential
 Peripheral blood smear: RBC
PHYSICAL EXAMINATION
morphology
 A comprehensive examination with
 Normochromic normocytic:
emphasis to the following should
normal individual and in
be made.
anemia of chronic disease
 General: pallor of mucus
 Anisopoikilocytes: variation in
membranes, bleeding sites, signs of
size and shape may be seen in
Hyperdynamic circulation
iron deficiency anemia
(tachycardia, bounding pulse,
 Hypochromic microcytic
cardiomegaly and systolic flow
anemia: iron deficiency,
murmur), heart failure (S3 gallops),
anemia of chronic disease,
orthostatic hypotension.
thalassemia and sideroblastic
 Specific: anemia (SBA)
 Iron deficiency: koilonychias  Macrocytic RBC- Macro-
(spoon shaped nails), angular ovalocytes with
stomatitis hypersegmented neutrophils
 Folate: glossitis indicate megaloblastic anemia
 Vitamin B12: glossitis, and myelodysplasia
neurologic abnormalities  Schistocytes (fragmented
(peripheral neuropathy- pins RBC/ Helmenth cells)-
and needles) microangiopathies, DIC,
 Hemolytic anemia: Jaundice vasculitis, prosthetic heart
 Thalassemia: bone deformities valve
 Sickle cell disease: leg ulcers

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 Consider colonoscopy/endoscopy,
urinalysis/urine cytology for
hematuria, pelvic ultrasound for
fibroids.

 NOTE: Anemia is not a diagnosis

and a cause must be found.

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Figure 34: Some Red Cell Anomalies

 Anemia can be classified according to:

 Etiology
 Severity
 Red cell size
CLASSIFICATION OF ETIOLOGIES
 Anemia can arise due to either:
 Decreased production/ impaired RBC production
 Increased destruction or blood loss

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Decreased production Increased destruction of loss
Nutritional deficiencies Blood loss
 Iron deficiency*  Acute or chronic GI bleeding*
 Vitamin B12 deficiency  Menstrual bleeding*
 Folate deficiency*  Trauma
Bone marrow suppression Hemolysis
 Infections*: HIV, tuberculosis,  Hereditary hemolytic anemia
malaria, schistosomiasis,  Hemoglobinopathies:
hookworm, hepatitis sickle cell disease*,
 Drugs: isoniazid, chloramphenicol, thalassemia
alcohol, zidovudine, 5-Flucytosine,  Enzymopathies: G6PD
hydroxyurea deficiency*, Pyruvate
 Chronic disease*: renal and liver kinase deficiency
disease, rheumatologic diseases,  Membranopathies:
hypothyroidism hereditary spherocytosis,
eliptocytosis
 Acquired
 Microangiopathic
hemolytic anemia: TTP,
HUS, DIC, eclampsia,
HELLP syndrome
 Autoimmune hemolytic
anemia
 Paroxysmal nocturnal
hemoglobinuria
 Hypersplenism
 Infections: Malaria*
Hemoglobinopathies: Thalassemias
Myelodysplastic syndromes
* These are common causes of anemia in adults in Africa.

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CLASSIFICATION OF ANEMIA ACCORDING TO SEVERITY
 Anemia is classified as follows:
 Mild: 8-12g/dl hemoglobin
 Moderate: 7-8g/dl hemoglobin
 Severe: <6g/dl hemoglobin
2. Anemia of chronic disease
3. Sideroblastic anemia
CLASSIFICATION OF 4. Thalassemia
ANEMIA BY SIZE
 This classification gives a good
indicator of the underlying
etiology.
 Anemia can be divided into
 Microcytic anemia: MCV< 80-
96 fL
 Normocytic anemia: MCV=
80-96 fL Figure 35: Causes of microcytic anemia
 Macrocytic anemia: MCV> 80- IRON DEFICIENCY ANEMIA
96 fL  This is the most common type of
MICROCYTIC ANEMIA anemia worldwide.
 Microcytic anemias are due to  Iron deficiency anemia occurs
decreased production of when the body iron stores become
hemoglobin (either due to iron, inadequate for the need of normal
protoporphyrin, or the globin part) RBC production.
 RBC progenitor cells in the  It is due to decreased levels of iron.
bone marrow are large and Decreased iron leads to decreased
normally divide multiple times heme and hemoglobin thus
to produce smaller mature cells resulting in a microcytic anemia.
(MCV= 80 to 100 fL)  Iron deficiency anemia is a
 Microcytosis is due to an manifestation of disease, not by
“extra” division which occurs itself a complete diagnosis (i.e. it is
to maintain hemoglobin always secondary to something).
concentration. (to keep the IRON METABOLISM
RBC “nice and pink”).
 Daily 10-30mg iron ingested, 5-
 Microcytic anemia includes: 10% absorbed to balance precisely
1. Iron deficiency

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the amount lost (1 mg) under  Stored intracellular iron is bound to
physiologic condition. Absorption ferritin, which prevents iron from
may be increased to20-30% in iron forming free radicals via the
deficiency and pregnancy. phenton reaction.
 Amount absorbed can increase up  2/3 is stored as ferritin and 1/3
to 5-fold if the body iron stores are as hemosiderin.
depleted or erythropoiesis is  Ferritin is a water soluble
accelerated. complex of iron and protein. It
 Iron is consumed in heme (meat- is more easily mobilized than
derived) and non-heme (vegetable- hemosiderin for Hb formation.
derived and cereals fortified with It is present in small amounts in
iron) forms. plasma.
 Absorption of heme occurs in  Hemosiderin is an insoluble
the duodenum while that of iron protein complex found in
non-heme occurs in the macrophages in the bone
proximal jejunum marrow, liver and spleen.
 Enterocytes have heme (Haem Unlike ferritin it is visible by
carrier protein 1-HCP1) and light microscopy in tissue
non-heme (divalent metal sections and bone marrow films
transporter 1- DMT1) after staining by Perls’ reaction
transports. The heme form is
STAGES OF IRON
more readily absorbed.
DEFICIENCY ANEMIA
 Absorption is facilitated by:
 Storage iron is depleted- decreased
stomach acidity (keeps iron in
ferritin and increased total iron
reduced ferrous state Fe2+ and
binding capacity.
not ferric state Fe3+), Vitamin C
 Serum iron is depleted- decreased
(Ascorbic acid), Citrates.
serum iron and decreased iron
 Absorption is limited by:
saturation.
phosphates, oxalates, tannates
(tea) and pyrates (plant food)  Normocytic anemia- bone marrow
 Enterocytes transport iron makes fewer, but normal-sized
across the cell membrane into RBCs (Iron deficient
blood via ferroportin. erythropoiesis).
 Transferrin transports iron in  Microcytic, hypochromic- bone
the blood and delivers it to liver marrow makes smaller and fewer
and bone marrow macrophages RBCs.
for storage.

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ETIOLOGY  Decreased absorption e.g. post-
 Poor diet: gastrectomy
 Infants- breastfeeding (human
CLINICAL FEATURES
milk is low in iron as such it is
 Insidious onset and progressive in
seen in infants where
course.
introduction of mixed feeding
 Patients often present with
is delayed).
nonspecific symptoms (mentioned
 Children- poor diet.
earlier on) along with/without some
 Other causes: malnutrition,
specific symptoms:
malabsorption (celiac disease)
 Pica: craving for unusual food
and gastrectomy (Acid aids
substance (amylophagia,
iron absorption by maintaining
geophagia, pagophagia)
the Fe2+ state which is more
 Brittle nails, Koilonychia,
readily absorbed than Fe3+).
atrophy of papillae of tongue
 Chronic bleeding:
(atrophic glossitis), brittle hair.
 Adults (20-50 years)- peptic
 Angular stomatitis
ulcer disease in males and
 Plummer-Vinson syndrome-
menorrhagia or pregnancy in
iron deficiency anemia with
females.
esophageal web (dysphagia)
 GIT e.g. esophageal varices,
and atrophic glossitis, presents
hiatal hernia, peptic ulcer
with anemia, dysphagia and a
disease, aspirin ingestion,
beefy red-tongue. It is also
carcinoma of stomach, caecum,
known as Paterson-Kelly
colon or rectum, Hook worm
syndrome.
(Ancyclostoma duodenale and
 The diagnosis of iron deficiency
Nector americanus) and
anemia relies on a clinical history
schistosomiasis infestation,
which should include questions
colitis, piles, diverticulosis.
about:
 Rarely hematuria,
 Dietary intake,
hemoglobinuria, pulmonary
 Self-medication with NSAIDs
hemosiderosis, self-inflicted
(GIT bleeding),
blood loss.
 Presence of blood in feces (may
 Increased demands:
be a sign of hemorrhoids or
 Prematurity in newborns
carcinoma of bowel)
 Rapid growth (as in adolescent)
 In women a careful enquiry
growth spurt
about the duration of periods,
 Pregnancy

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the occurrence of clots and the  Decreased MCV, MCH,
number of sanitary towels or MCHC, reticulocyte count
tampons (normal 3-5/day) used  Diagnosis: MCV< 80fL, blood
should be made. smear shows hypochromic red
cells, pencil shaped
INVESTIGATIONS
(Poikilocytosis), anisocytosis,
 Full blood count:
target cells.

 Laboratory measurements of iron  Microcytic hypochromic RBCs

status: with target cells and increased
 Serum iron- measure of iron in red cell distribution width (as
the blood. (normal- 13-32 above)
mol/L)  Decreased serum iron
 Total iron binding capacity  Decreased ferritin
(TIBC)- measure of transferrin  Increased total iron binding
molecules in the blood. Each capacity
transferrin molecule binds 2  Decreased % saturation
atoms of ferric iron. (<19%)
 % saturation- percentage of  Increased free erythrocyte
transferrin molecules that are protoporphyrin (FEP): it is
bound by iron (normal is 33%) increased during early phase of
 Serum ferritin- reflects iron iron deficiency, lead poisoning,
stores in macrophages and the sideroblastic anemia and in
liver. erythropoeitic porphyria.
 Laboratory findings:

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 Investigations to establish the  Inadequate response may
underlying cause: imply:
 Stool for occult blood o Continuing hemorrhage
 Stool for ova and parasites o Non-compliance
 CXR to exclude pulmonary o Wrong diagnosis
hemosiderosis o Mixed deficiency-
 U/A for hematuria or associated folate or Vit B12
hemosiderinuria deficiency
 Pelvic- gynecologic studies o Another cause for anemia
 Upper and lower GI radiologic e.g. malignancy,
and endoscopic studies inflammation
 Bronchoscopy o Malabsorption-rare cause
o Use of slow release
MANAGEMENT
preparations
 Identify and treat underlying cause.
 Parenteral iron:
 Iron replacement: ferrous sulfate  Indications: oral iron
200mg TDS (This gives 180mg intolerance despite
ferrous iron). modification in dosage
 Side effect: GI upset, nausea, regimen, malabsorption,
dyspepsia, inability or unwillingness to
constipation/diarrhea. If these take orally.
side effects are not tolerable,  Iron-dextran complex or iron
reduce dose or change brand sorbitol citrate can be used IM
e.g. to ferrous gluconate or IV
(300mg BD giving 70mg iron)
 Dose (ml)= 0.0442
or ferrous lactate syrup
(desired Hb- Observed
 Response to treatment: an expected Hb) x weight (kg) +
daily rise of hemoglobin by 0.1- (0.26 x weight Kg)
0.2g/dl.
 An increase in Hb ANEMIA OF CHRONIC
concentration of at least 2gm/dl DISEASE
after 3 weeks of therapy is  This is associated with chronic
considered as a good response inflammation (e.g. endocarditis or
 Treatment should be continued autoimmune conditions) or
for 3 months after resolution of malignant disease.
anemia to replenish the iron  It is the most common type of
stores. anemia in hospitalized patients.

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 Etiologies:  Normal or raised ferritin
 Infectious: TB, lung abscess, because of the inflammatory
osteomyelitis, pneumonia, process,
bacterial endocarditis.  Decreased % saturation and
 Non-infectious: rheumatoid  Increased free erythrocyte
arthritis, lupus, connective protoporphyrin.
tissue disease, sarcoidosis,
MANAGEMENT
Crohn’s disease, malignancy
 Treatment is treat underlying cause,
(carcinoma, lymphoma,
 Exogenous recombinant EPO
sarcoma).
therapy is useful in a subset of
PATHOGENESIS patients especially those with
 Chronic disease results in cancer and anemia of renal disease
production of acute phase reactants as well as inflammatory disease
from the liver, including hepcidin. (rheumatoid arthritis, inflammatory
 Hepcidin sequesters iron in bowel disease).
storage sites by (1) limiting  Correct reversible contributors
iron transfer from macrophages (iron, folate, cobalamin
to erythroid precursors and (2) supplements if necessary)
suppressing erythropoietin
(EPO) production.
 The aim is to prevent bacteria
from accessing iron, which is
necessary for their survival.
 Decreased availability of iron
results in microcytic anemia.
 Other cytokines produced during
inflammation reduce life span of
RBC (80 days) rendering
erythropoietin inadequate.
CLINICAL FEATURES
 Clinical features: normocytic
anemia (Early stages) and
microcytic anemia (Late stages)
 Laboratory findings:
 Reduced serum iron and TIBC,

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SIDEROBLASTIC ANEMIA
 Anemia due to defective protoporphyrin synthesis (heme synthesis).
 Decreased protoporphyrin leads to microcytic anemia.
 They can be inherited or acquired disorders.
SYNTHESIS OF PROPTOPORPHYRIN
 Protoporphyrin is synthesized via a series of reactions:
 Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to
aminolevulinic acid. This is the rate limiting step and requires vitamin B6 as
a co-factor.
 Aminolevulinic acid dehydrogenase (ALAD) converts Aminolevulinic acid
to porphobilinogen.
 Additional reactions convert porphobilinogen to protoporphyrin.
 Ferrochelatase attaches protoporphyrin to iron to make heme (final reaction
occurs in the mitochondria).
 Iron is transferred to erythroid precursors and enters mitochondria to form heme.
If protoporphyrin is deficient, iron remains trapped in mitochondria.
 Iron-laden mitochondria form a ring around the nucleus of erythroid
precursors, these cells are called ringed sideroblasts (hence the term
sideroblastic anemia)- Stain used is Prussian blue (Pearls’ reaction).

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CLASSIFICATION
 Sideroblastic anemia can be classified as congenital or acquired
 Congenital defect most commonly involves ALAS (rate-limiting enzyme)-
sex linked recessive trait
 Acquired causes include:
o Primary: myelodysplasia (myelodysplastic syndromes),
o Secondary
 Malignant diseases of the marrow (myeloproliferative disorders,
myeloid leukemia)
 Drugs e.g. cycloserin, lead (inhibits ALAD and Ferrochelatase),
alcohol (mitochondrial poison)
 Vitamin B6 deficiency- required cofactor for ALAS, most commonly
seen as a side effect of isoniazid treatment for tuberculosis.
LABORATORY FINDINGS
 Laboratory findings:
 Increased ferritin
 Decreased TIBC
 Increased serum iron
 Increased % saturation
 A similar picture is seen in hemochromatosis (iron overload state)
MANAGEMENT
 Treat the underlying cause.
 Pyridoxine (100-400mg PO daily in divided doses), folic acid therapy (5mg PO
daily): may bring some response
 Repeated transfusion is ultimate choice.

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STATE FERRITIN TIBC SERUM %

IRON SATURATION
Normal 30-300 g/L (11.6- 300 pg/dl 13- 33
114nmol/L) in males, 31mol/L
15-200 g/L (5.8-96
nmol/L)
Iron Low High Low Low
deficiency
anemia
Anemia of Normal or High Low Low Low
chronic
disease
Sideroblastic High Normal High High
anemia

THALASSEMIA
 Heterogeneous group of genetic disorders (autosomal recessive) which results
from a reduced rate of synthesis/dysfunction of alpha (coded for by 4 alleles on
chromosome 16) or beta chains (coded for by 2 alleles on chromosome 11) of
adult hemoglobin (HBA).
 Alpha thalassemia: leads to impaired oxygen transport and extravascular
hemolysis (splenic clearance).
 Beta thalassemia: leads to failed erythropoiesis with the buildup of alpha
chains causing cell destruction. Compensatory erythroid hyperplasia
(increased immature RBCs) cases bone growth.
 Changes in normal ratio results in each of the disorders. Normally, there is
balanced (1:1) production of alpha and beta chains. The defective synthesis of
globin chains in thalassemia leads to ‘imbalanced’ globin chain production,
leading to precipitation of globin chains with red cell precursors and resulting in
ineffective erythropoiesis.
 Precipitation of globin chains in mature red cells leads to hemolysis.
 Due to inherited mutations carriers are protected against Plasmodium falciparum
malaria.
 Thalassemias are divided into alpha and beta Thalassemias.
 Alpha Thalassemias are common in South-east Asia, Africa and India.

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 Beta Thalassemias are common in Mediterranean, Middle east, Central and South
Asia, China.
 Normally there are 3 types of hemoglobin:
 HbF (2alpha, 2 gamma)-1%,
 HbA (2 alpha, 2 beta)-97-99% and
 HbA2 (2 alpha and 2 delta)-2.5%.
 In thalassemia there is a decrease in the amount of either alpha or beta chain. As
a result, HbA is reduced, while there is an increase in variant forms of
hemoglobin such as HbA2 and HbF.
 Severity of the disease reflects how many alleles are affected: out of 4 for alpha
(which has 2 genes) and out of 2 for beta (just 1 gene).
 In general symptoms are worse in beta-thalassemia patients, as the most severe
alpha-thalassemia doesn’t survive pregnancy or early life.
ALPHA THALASSEMIA
 Alpha Thalassemia leads to impaired oxygen transport and extravascular
hemolysis (via splenic clearance).
 Alpha thalassemia is usually due to gene deletion, normally 4 alpha genes are
present on chromosome 16.
 One gene deleted (Alpha thalassemia silent carriers/ alpha thalassemia Minima)-
asymptomatic
 Clinical course: Normal life span
 Hematocrit- 28-40%
 Hemoglobin electrophoresis: normal
 Blood picture is usually normal
 Two genes deleted (alpha thalassemia trait/ alpha thalassemia minor)- mild
anemia (Microcytic anemia may be the only sign) with slightly increased RBC
count.
 Cis deletion is when both deletions occur on the same chromosome, seen in
Asians.
 Trans deletion is when one deletion occurs on each chromosome, seen in
Africans including African Americans.
 HbH bodies may be seen on staining a blood film with brilliant cresyl blue.
 Three genes deleted (Hemoglobin H disease)- moderate to severe anemia, beta
chains form tetramers (HbH) that damage RBCs. HbH is seen on electrophoresis.
 Clinical course: chronic hemolytic anemia (Hb 7-11mg/dl), exacerbated by
stress, and splenomegaly

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 Hematocrit- 22-32%
 Hemoglobin electrophoresis- 10-40% HbH
 HbH does not transport oxygen and precipitates in erythroblasts and
erythrocytes.
 Four genes deleted- lethal in utero (hydrops fetalis), gamma chains form
tetramers (Hb Barts) that damage RBCs. Hb Barts is seen on electrophoresis.
 Clinical course: universally lethal as neonate due to intrauterine hemolytic
anemia
 Hb Barts cannot carry oxygen and is incompatible with life. Infants are either
stillborn at 28-40 weeks or die very shortly after birth. They are pale,
edematous and have enormous livers and spleens- a condition called hydrops
fetalis.
BETA THALASEMMIA
 Usually due to gene mutations (point mutations in promoter or splicing sites) seen
in individuals of African and Mediterranean descent.
 The mutations result in defects in transcription, RNA splicing and
modification, translation via frame shift and nonsense codons producing
highly unstable beta-globin which cannot be utilized.
 Two beta genes are present on chromosome 11, mutations result in absent (0) or
diminished (+) production of the beta-globin chain.
 There is an excess of alpha chains which precipitate in erythroblasts and red cells
causing ineffective erythropoiesis and hemolysis. The excess alpha chains may
combine with whatever beta, delta and gamma chains produced resulting in
increased quantities of HbA2, and HBF at best small amounts of HbA.
 Beta thalassemia minor (trait) (/+) is the mildest form of the disease and is
usually asymptomatic with an increased RBC count.
 Here one allele is normal and one allele is reduced in function.
 Microcytic hypochromic RBCs (low MCV and MCH) and target cells are
seen on blood smear.
 Clinical notes: asymptomatic, mild microcytic anemia. They are not
transfusion dependent and live a normal lifespan.
 Hemoglobin electrophoresis shows:
o Slightly decreased HbA (28-80%, normal 97-99%)
o Increased HbA2 (4-8%, normal 2.5%) and
o HbF (1-5%, normal 1%).
 Beta thalassemia intermedia (+/+):

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 Here both alleles are reduced in function.
 Thalassemia intermedia may be due to a combination of homozygous mild
+ and -thalassemia, where there is reduce -chain precipitation and less
ineffective erythropoiesis and hemolysis.
 Hematocrit is variably low
 Clinical notes: they present earlier with Mild bony anomalies and mild
hepatosplenomegaly and moderate anemia (Hb 7-10mg/dl).
 Recurrent leg ulcers, gallstones and infections are also seen. It should be
noted that these patients may be iron overloaded despite a lack of regular
blood transfusions. This is caused by excessive iron absorption which results
from the underlying dyserythropoiesis.
 Lifespan: adult
 Hemoglobin electrophoresis shows:
o HbA 0-20%
o HbA2 0-10%
o HbF 90-100%
 These patients may variably be dependent on transfusions.
 Beta thalassemia major (Cooley’s anemia) (0/0) is the most severe form of
disease and presents with severe anemia a few months after birth (3-6 months),
high HbF at birth is temporarily protective.
 Here both alleles are absent.
 Hematocrit is <10% without transfusions.
 Clinical notes: These present very early, bony anomalies,
hepatosplenomegaly, jaundice and transfusional iron overload.
 Hemoglobin electrophoresis shows:
o HbA 0%
o HbA2 4-10%
o HbF 90-96%
 Life span: 20-30 years
 This condition is transfusion dependent
 Alpha tetramers aggregate and damage RBCs resulting in ineffective
erythropoiesis and extravascular hemolysis (removal of circulating RBCs by
the spleen)
 Massive erythroid hyperplasia ensues resulting in (1) expansion of
hematopoiesis into the skull (reactive bone formation leads to hair-on end
appearance on X-ray) and facial bones (‘chipmunk face’) and (3) risk of
aplastic crisis with parvovirus B19 infection of erythroid precursors.

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 Chronic transfusions are often necessary leading to risk for secondary
hemochromatosis.
 Smear shows microcytic, hypochromic RBCs with target cells and nucleated
RBCs.
 Hb electrophoresis shows little or no HbA with increased HbA2 and HbF.
 Presents with hepatosplenomegaly, bone expansion, infections

CLINICAL PRESENTATION
 Presents anytime from neonate to adult, but later onset tends to be milder.
 In general symptoms are worse in beta-thalassemia patients, as the most severe
alpha-thalassemia doesn’t survive pregnancy or early life.
 Signs and symptoms:
 Hemolytic anemia: fatigue, shortness of breath, pallor, jaundice (commoner
in beta thalassemia)
 Splenomegaly (alpha thalassemia) or hepatosplenomegaly with abdominal
distension (beta thalassemia)
 Failure to thrive, growth restriction
 Facial dysmorphia: frontal bossing, maxillary hypertrophy, large head.
(Commoner and more prominent in beta thalassemia)
 Osteopenia (beta thalassemia)

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INVESTIGATIONS
 Diagnosis:
 Hb electrophoresis
 Gap-PCR detects common deletion to confirm diagnosis. Other mutations
may require DNA sequencing.
 Bloods:
 FBC: decreased Hb, Decreased MCV, decreased MCH. Unlike iron
deficiency, RBC count may be normal or high
 Increased Reticulocytes
 Peripheral smear: Microcytosis, hypochromia and basophilic stippling (Beta
thalassemia only). With increasing severity increased nucleated RBCs, tear

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drop (dacrocytes-this is a type of poikilocyte shaped like a teardrop) and
target cells are seen.
 LFT: increased unconjugated bilirubin (beta thalassemia). Increased liver
enzymes if there is iron overload.
 Iron studies: increased iron and increased ferritin in severe disease. Due to
disease itself or frequent transfusions
 Imaging:
 Skull x ray: bone abnormalities
 Chest x ray: rib deformities, cardiomegaly
 Abdominal Ultrasound: for organomegaly
 ECG and ECHO for cardiac function
 Note: Liver biopsy and/or MRI can be done if there is iron overload.
MANAGEMENT
 Asymptomatic carriers require no specific treatment. Just avoid iron
supplements.
 Long term folic acid supplements are required.
 Regular transfusions should be given to keep the Hb above 10mg/dl. Blood
transfusions may be required every 4-6 weeks.
 Transfusion indications:
 Symptomatic anemia, or aplastic or hyperhemolytic crisis.
 Regular transfusion for thalassemia major or if there is growth impairment.
 Iron chelation if there is overload:
 Parenteral desferrioxamine is given as an overnight subcutaneous infusion on
5-7 nights each week. Ascorbic acid 200mg daily given as it increases the
urinary excretion of iron in response to desferrioxamine.
 Deferiprone an oral iron chelator can be taken once a day and is similar in
effectiveness to desferrioxamine.
 May cause hearing loss and visual impairment so check both regularly.
 Splenectomy:
 Indication: Hypersplenism with increasing transfusion requirements,
 Splenectomy is usually delayed until after the age of 6 years because of the
risk of infection. Prophylaxis against infection is required for patients
undergoing splenectomy.
 Avoid if possible.
 Patients with thalassemia major are at an increased risk for development of
post-splenectomy syndrome. This syndrome is characterized by severe

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infections with encapsulated organisms (Streptococcus pneumoniae,
Haemophilus influenzae, Neisseria meningitidis)
 Bone marrow transplantation:
 Used in sever, transfusion-dependent disease
 Curative
 Parental diagnosis and gene therapy should also be done.
 Patients’ partner should be tested: if both partners have beta-thalassemia trait,
there is one in four chance of such pregnancy resulting in a child having beta-
thalassemia major. Therefore, couples in this situation must be offered prenatal
diagnosis.
COMPLLICATIONS AND PROGNOSIS
 Complications:
 Iron overload affecting liver, heart, pancreas, and pituitary gland
 High-output heart failure
 Gallstones
 Hypersplenism
 Aplastic crisis due to parvovirus B19 infection
 Prognosis:
 HbH: generally, good
 Beta thalassemia major: without treatment, death occurs in less than 5 years
from heart failure or anemia. Regular transfusions and iron chelation allow
near-normal life expectancy.

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MACROCYTIC ANEMIA
 This is anemia with MCV>100.
 It can be divided into megaloblastic and non-megaloblastic types depending on
bone marrow findings.
MEGALOBLASTIC ANEMIA
 Characterized by presence of erythroblasts with delayed nuclear maturation
because of defective DNA synthesis (megaloblasts) in the bone marrow.
 Megaloblasts are large and have large immature nuclei. The nuclear chromatin is
more finely dispersed than normal and has open stippled appearance. In addition,
giant metamyelocytes are frequently seen in megaloblastic anemia. These cells
are about twice the size of normal cells and often have twisted nuclei.
 Causes include:
 Vitamin B 12 deficiency or abnormal vitamin B12 metabolism,
 Folate deficiency or abnormal folate metabolism.
 Other defects of DNA synthesis such as congenital enzyme deficiencies such
as congenital enzyme deficiencies in DNA synthesis (e.g. orotic aciduria) or
resulting from therapy with drugs interfering with DNA synthesis (e.g.
hydroxycarbamide (hydroxyurea), azathioprine, Zidovudine-AZT)

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 Myelodysplasia due to
dyserythropoeisis
 Folate and vitamin B12 are necessary
for synthesis of DNA precursors.
 Folate circulates in the serum as
methyltetrahydrofolate (methy
THF), removal of the methyl group
allows for participation in the
synthesis of DNA precursors.
 Methyl group is transferred to
Vitamin B12 (Cyanocobalamin).
 Vitamin B12 then transfers it to
homocysteine producing
methionine.
 Lack of folate or vitamin B12 impairs
synthesis of DNA precursors
 Impaired division and enlargement
of RBC precursors leads to
megaloblastic anemia.
 Impaired division of granulocytic
precursors leads to hypersegmented
neutrophils.
 Megaloblastic change is also seen
in rapidly-dividing (e.g. intestinal) Figure 36: DNA precursor synthesis
epithelial cells.
 Pathogenesis:
 It’s a descriptive morphologic term in which maturation of the nucleus is
delayed relative to that of the cytoplasm. The delay in maturation of the
nucleus is attributed to defective DNA synthesis. This condition leads to
megaloblastic marrow and ineffective erythropoiesis.
 The immature erythroblasts are destroyed within the bone marrow
(intramedullary hemolysis) which results in megaloblastic anemia.
 Laboratory findings:
 Anemia (MCV >96fL unless there is co-existing cause of microcytosis when
there may be a dimorphic picture with a normal/low average MCV)
 Leucopenia and thrombocytopenia if severe.

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 The peripheral blood film shows oval macrocytes with hypersegmented
polymorphs with 6 or more lobes in the nucleus.

Figure 37: Macrocytes and a hypersegmented neutrophil (Arrowed) on a peripheral blood film

VITAMIN B12 DEFICIENCY

 Vitamin B12 is synthesized by certain microorganisms, and humans are
ultimately dependent on animal sources.
 It is found in meat, fish, eggs and milk but not in plants. It is not usually destroyed
by cooking.
 Daily diet contains 5-30 micrograms of Vitamin B12 of which 2-3 micrograms
is absorbed.
 The average adult stores some 2-3mg mainly in the liver and it may take 2 years
or more after absorptive failure before B12 deficiency develops, as the daily
losses are small (1-2 micrograms).
 Dietary vitamin B12 is complexed to animal-derived proteins.
 Salivary gland enzyme (e.g. amylase) liberate vitamin B12, which is then
bound to R-binder (also from the salivary gland) and carried through the
stomach.
 Pancreatic proteases in the duodenum detaches vitamin B12 from R-binder.
 Vitamin B12 binds intrinsic factor (made by gastric parietal cells) in the small
bowel, the intrinsic Factor-Vitamin B12 complex is absorbed in the ileum.
 Vitamin B12 deficiency is less common than folate deficiency and takes years to
develop due to large hepatic stores of vitamin B12.
 For Vitamin B12

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 Source: animal products (meat, dairy products)
 Daily requirements= 2-5 micrograms
 Body storage= 3-5 (4) mg
 Time to develop anemia= 3-4 years
 Cooking: little effect
 For folate
 Source: vegetables, fruits and animal products
 Daily requirements= 100mg (50-200mg)
 Body storage= 5-20mg
 Time to develop anemia= 4-6 months
 Cooking: easily destroyed
CAUSES OF VITAMIN B12 DEFICIENCY
 Nutritional: especially in vegans, alcoholics
 Malabsorption
 Gastric causes
o Adult (addisonian) pernicious anemia: this is the most common cause
o Congenital lack or abnormality of intrinsic factor
o Total or partial gastrectomy
 Intestinal causes
o Chronic tropical sprue
o Ileal resection and Crohn’s disease
o Increased competition (fish tapeworm, intestinal bacterial overgrowth)
o Pancreatic insufficiency and damage to the terminal ileum (e.g. Crohn
disease or Diphyllobothrium latum-fish tapeworm)
 Pernicious anemia is the most common causes of vitamin B12 deficiency.
Malabsorption of vitamin B12 because of pancreatitis, coeliac disease or
treatment with metformin is mild and does not usually result in significant
vitamin B12 deficiency.
 Pernicious anemia is an autoimmune destruction of parietal cells (body of
stomach) leads to intrinsic factor deficiency.
 It is seen in all races but frequently in fair-haired and blue-eyed individuals
and those who have blood group A. It is more common in females than males.
 There is an association with other autoimmune disease, particularly thyroid
disease, Addison’s disease and vitiligo.

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 Parietal cell antibodies are present in the serum in 90% of patients.
Conversely, intrinsic factor antibodies although found in only 50% of
patients are specific for this diagnosis.
 2 types of intrinsic factor antibodies are found:
o A blocking antibody which inhibits binding of intrinsic factor to B12
o Precipitating antibody which inhibits the binding of B12-intrinsic factor
complex to its receptor site in the ileum
 Clinical features: neurologic changes (numbness, paresthesia, decreased
vibratory and positional sense, ataxia)- subacute combined degeneration of the
spinal cord, glossitis
 Smear shows hypersegmented neutrophils.
 Treatment: replacement of B12.
 Dose: initial dose: 6 x 1000micrograms over 2-3 weeks and maintenance:
1000microgram every 3 months for the rest of their life.
 Alternatively, oral B12 2mg/day is used as 1-2% of an oral dose is absorbed
by diffusion and therefore does not require intrinsic factor. (compliance in
elderly patients is a problem)
 Clinical improvement may occur within 48 hours and a reticulocytosis can
be seen some 2-3 after starting therapy peaking at 5-7 days. Improvement of
the polyneuropathy may occur over 6-12 months but longstanding spinal cord
damage is irreversible. Hypokalemia can occur and if severe supplements
should be given. Hyperuricemia also occurs but clinical gout is uncommon.
 Prophylactic therapy is indicated with total gastrectomy and Ileal resection.
 Additional measures:
 Correct underlying cause
 Antibiotics for bacterial overgrowth and treatment of fish tapeworm.
FOLATE DEFICIENCY
 Dietary folate is obtained from green vegetables and some fruits.
 Absorbed in the jejunum.

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 Folate deficiency develops within months (4-
6 months) as body stores are minimal.
 Etiology: malnutrition (alcoholic, elderly),
decreased absorption (sprue), impaired
metabolism (methotrexate- folate antagonist
that inhibits dihydrofolate reductase,
trimethoprim, antimalarials), increased
demand (pregnancy, cancer and hemolytic
anemia)
 Clinical and laboratory findings include:
 Macrocytic RBCs and hypersegmented
neutrophils (>5 lobes)
 Glossitis
 Decreased serum folate
 Increased homocysteine
 Normal methylmalonic acid
 Unlike B12 deficiency, neuropathy does
not occur.
 Treatment: folate repletion.
 5mg PO daily
 Treatment should be given for about 4 months to replace body stores. Treat
any underlying cause.
 Prophylactic therapy is indicated in pregnancy, severe hemolytic anemia in
patients with dialysis and premature newborns.
 Response to therapy:
 Feeling of general well-being is restored in 48 hours.
 Reticulocytosis begins in 3-4 days and peaks in 7-10 days.
 If both folate and vitamin B12 deficiency present give Vitamin B12 first.
MACROCYTOSIS WITHOUT MEGALOBLASTIC CHANGES
 A raised MCV with macrocytosis on the peripheral blood film can occur with a
normoblastic rather than a megaloblastic bone marrow.
 A common physiological cause of macrocytosis is pregnancy. Macrocytosis may
also occur in newborn
 Common pathological causes:
 Alcohol excess
 Liver disease

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 Reticulocytosis
 Hypothyroidism
 Some hematological disorders (e.g. aplastic anemia, sideroblastic anemia,
pure red cell aplasia)
 Drugs (e.g. hydroxyurea, azathioprine)
 Cold agglutinins due to autoagglutination of red cells (the MCV decreases to
normal with warming of the sample to 37 oC)
 In all these conditions, normal levels of Vitamin B12 and folate will be found.
The exact mechanisms in each case are uncertain but in some there is increased
lipid deposition in the red cell membrane.
 An increased number of reticulocytes also leads to a raised MCV because they
are large cells.
 A high alcohol consumption is a frequent cause of a raised MCV and in such
patients the MCV can be used as a surrogate marker for monitoring excessive
alcohol consumption. A full blown megaloblastic anemia can also occur in people
who use alcohol to excess, this is due to a toxic effect of alcohol on erythropoiesis
and/or to dietary folate deficiency.
NORMOCYTIC ANEMIA
 This is anemia with normal-sized RBCs (MCV= 80-100fL)
 It is due to increased peripheral destruction or underproduction
 Reticulocyte count helps to distinguish between these 2 etiologies.
 Includes anemia of chronic disease, endocrine disorders (hypothyroidism,
hypopituitarism and hypoadrenalism), acute blood loss and Hematological
disorder (pure cell anaplasia and some hemolytic anemias).
 Anemia of chronic disease as above.
 Hypothyroidism: treatment is thyroid replacement.
 Acute blood loss: can be normocytic before iron stores are reduced.
 Pure red cell aplasia: destructive antibodies or lymphocytes leading to ineffective
erythropoiesis, associated with thymoma and parvovirus.
 Diagnosis: lack of erythroid precursors on bone marrow biopsy
 Treatment: supportive care

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ANEMIA DUE TO MARROW FAILURE (APLASTIC ANEMIA)
 Aplastic anemia is defined as pancytopenia with hypocellularity (aplasia) of the
bone marrow.
 There are no leukemic, cancerous or other abnormal cells in the peripheral blood
or bone marrow. It is usually an acquired condition but may rarely be inherited.
 It is due to a reduction in the number of pluripotential stem cell together with a
fault in those remaining or an immune reaction against them so that they are
unable to repopulate the bone marrow.
 Failure of one cell lineage can also happen, when it affects the red cell precursors
it is called pure red cell aplasia.
CAUSES
 Primary:
 Inherited e.g. Fanconi’s anemia
 Idiopathic acquired (67% of cases)
 Secondary:
 Chemicals e.g. benzene, toluene, glue sniffing
 Drugs
o Chemotherapeutic antibiotics e.g. chloramphenicol, gold, penicillamine,
phenytoin, carbamazepine, carbimazole, azathioprine
 Insecticides
 Ionizing radiation
 Infections:
o Viral e.g. hepatitis, EBV, HIV, erythrovirus
 Paroxysmal nocturnal hemoglobinuria
 Miscellaneous e.g. pregnancy
CLINICAL FEATURES
 Features of marrow failure:
 Anemia
 Bleeding
 Infection
 Bleeding is often the predominant initial presentation of aplastic anemia with
bruising with minimal trauma or blood blisters in the mouth.
 Physical findings:
 Ecchymoses
 Bleeding gums

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 Epistaxis
 Mouth infections are common. Lymphadenopathy and hepatosplenomegaly are
rare in aplastic anemia.
INVESTIGATIONS
 FBC: Pancytopenia
 The virtual absence of reticulocytes
 Bone marrow aspirate: a hypocellular or aplastic bone marrow with increased fat
spaces.
TREATMENT
 Treat underlying cause if possible
 Supportive care while awaiting bone marrow recovery and specific treatment to
accelerative recovery.
 Transfusions of red cells and platelets as necessary.
 Prevent and Treat infections promptly with broad-spectrum parenteral
antibiotics.
 Definitive treatment is bone marrow transplantation for patients under the age of
40 with an HLA identical sibling donor where it gives a 75-90% chance of long-
term survival. Immunosuppressive therapy used is antithymocyte globulin (ATG)
and cyclosporine. It is recommended for:
 Patients with severe disease over the age of 40
 Younger patients with severe disease without an HLA-identical sibling donor
 Patients who do not have severe disease but who are transfusion dependent.
 Steroids should not be used to treat severe aplastic anemia except for serum
sickness due to ATG.
 The most reliable determinants for the prognosis are the number of neutrophils,
reticulocytes, platelets and the cellularity of the bone marrow.
 Bad prognosis (severe aplastic anemia) is associated with presence of 2 of the
following:
 Neutrophil count <0.5 x 109/L
 Platelet count of <20 x 109/L
 Reticulocyte count of < 40 x 109/L

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HEMOLYTIC ANEMIA
 Due to red cell destruction and increased red cell turnover. Bone marrow is able
to compensate 5 times the normal rate.
 The red cell normally survives about 120 days but in hemolytic anemias the red
cell survival times are considerably shortened.
 Breakdown of normal red cells occurs in the macrophages of the bone marrow,
liver and spleen.
 Shortening of the red cell survival does not always cause anemia as there is a
compensatory increase in red cell production by the bone marrow. If the red cell
loss can be contained within the marrow’s capacity for increased output, then a
hemolytic state can exist without anemia (compensated hemolytic disease).
 The bone marrow can increase its output 6 to 8 times by increasing the proportion
of cells committed to erythropoiesis (erythroid hyperplasia) and by expanding the
volume of active marrow.
 Immature red cells (Reticulocytes) are released prematurely. These cells are
larger than mature cells and stain with a light blue tinge on a peripheral blood
film (the description of this appearance on a blood film is polychromasia) due to
the presence of residual ribosomal RNA.
 Reticulocytes may be counted accurately as a percentage of all RBCs on blood
film using a supravital stain for residual RNA (e.g. new methylene blue).
 Hemolysis can occur due to:
 Extravascular hemolysis: red cells are hemolyzed by macrophages in the
reticuloendothelial system particularly in the spleen.
 Intravascular hemolysis: res cells are hemolyzed in circulation. The liberated
hemoglobin is liberated. It initially binds to plasma haptoglobins but these
soon become saturated. Excess free plasma hemoglobin is filtered by the
renal glomerulus and enters urine, although small amounts are reabsorbed by
the renal tubules. In the renal tubular cells, hemoglobin is broken down and
becomes deposited in cells as hemosiderin. Some of the free plasma
hemoglobin is oxidized to methaemoglobin.
 Clinical features: jaundice, hepatosplenomegaly, dark urine.
 Etiology can be classified as:
 Congenital
 Hemoglobinopathies: sickle cell disease*, thalassemia
 Enzymopathies: G6PD deficiency*, Pyruvate kinase deficiency
 Membranopathies: hereditary spherocytosis, elliptocytosis

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 In born errors of metabolism
 Acquired
 Microangiopathic hemolytic anemia: TTP, HUS, DIC, eclampsia,
HELLP syndrome
 Autoimmune hemolytic anemia
 Warm type
 Cold type
 Alloimmune
 Hemolytic transfusion reactions
 Hemolytic disease of the newborn
 After allogenic bone marrow or organ transplantation
 Paroxysmal nocturnal hemoglobinuria
 Hypersplenism
 Infections: Malaria*
 Labs: increased reticulocyte count, indirect hyperbilirubinemia, Schistocytes on
blood smear.
 Treatment: treatment of underlying cause of hemolysis.
Type of anemia Treatment
Hereditary  Splenectomy
spherocytosis  Vaccines for encapsulated organisms e.g. pneumococci and lifelong
and penicillin prophylaxis.
Elliptocytosis
G6PD  Any offending drug should be stopped
 Underlying infection should be treated
 Blood transfusion may be life-saving
 Splenectomy is not usually helpful
Pyruvate kinase  Blood transfusions may be necessary during infections and
deficiency pregnancy. Splenectomy may improve the clinical condition and is
usually advised for patients requiring frequent transfusions.
Autoimmune  Corticosteroids (Prednisolone in doses of 1mg/kg daily)
 Splenectomy is the most effect second-line therapy
 Immunosuppressive drugs e.g. azathioprine and rituximab may be
effective when patients fail to respond to steroids and splenectomy
 Blood transfusion
Paroxysmal  Blood transfusion
nocturnal
hemoglobinuria

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SICKLE SYNDROMES

SICKLE SYNDROMES
 Sickle cell disease is a hereditary  Depending on the type of
form of chronic hemolysis ranging hemoglobin chain combinations, 3
from asymptomatic to severe, clinical syndromes occur:
overwhelming crisis. It is  Homozygous HbSS have the
characterized by irreversibly most severe disease.
sickled cells and recurrent painful  Combined heterozygosity
crises. (HbSC) for HbS and C who
 Sickle cell disease is an autosomal suffer intermediate symptoms.
recessive hereditary disease.  Heterozygous HbAS (sickle
 Sickle cell hemoglobin (HbS) cell trait) have no symptoms.
results from a single-base mutation
PATHOGENESIS
of adenine to thymine on
 Deoxygenated HbS molecules are
chromosome 11, which produces a
insoluble and polymerize. This
substitution of valine to glutamic
increases viscosity.
acid at the sixth codon of the beta
 Polymer formation at
chain.
concentrations exceeding
 In the homozygous state (sickle cell
30g/dl.
anemia) both genes are abnormal
 Polymers form a gel-like
(HbSS), whereas in the
substance containing Hb
heterozygous state (sickle cell trait
crystals called tachoids.
HbAS) only one chromosome
 Flexibility of the cells is decreased
carries the gene.
and they become rigid and take up
 Carriers are protected against
their characteristic sickle
Plasmodium falciparum.
appearance.
 As the synthesis of HbF is normal,
 This process is initially reversible
the disease usually does not
but with repeated sickling the cells
manifest itself until the HbF
eventually lose their membrane
decreases to adult levels at about 6
flexibility and become irreversibly
months of age.
sickled.
 The sickle cell gene is commonest
 This is due to dehydration,
in Africans (up to 25% frequency in
partly caused by potassium
some populations).
leaving the red cells via

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calcium activated potassium CLINICAL FEATURES OF
channels called the Gados SICKLE CELL ANEMIA
channel.  The physiological changes in RBCs
 These irreversibly sickled cells are result in a disease with the
dehydrated and dense and will not following cardinal signs
return to normal when oxygenated.  Hemolytic anemia
 Sickling produces:  Painful vaso-occlusive crisis
 Shortened red cell survival (most common clinical
 Impaired passage of cells manifestation)
through the microcirculation,  Multiple organ damage from
leading to obstruction of small microinfarcts, including heart,
vessels and tissue infarction skeleton, spleen and central
 Precipitating factors for sickling: nervous system.
 Hypoxia
 Dehydration VASO-OCCLUSIVE CRISES
 Cold  An early presentation may be acute
 Acidosis pain in the hands and feet: dactylitis
 Infection and fever due to vaso-occlusion of the small
 Living at high altitude vessels. (hand-foot syndrome)
 A crisis may occur without the  Severe pain in other bones e.g.
presence of these factors. femur, humerus, vertebrae, ribs,
 Adhesion proteins on activated pelvis occurs in older
endothelial cells (VCAM-1) may children/adults.
play a role particularly in vaso-  Attacks vary from person to person.
occlusion when rigid cells are  Fever often accompanies the pain.
trapped, facilitating  Triggers of vaso-occlusive crisis
polymerization. include:
 HbS releases its oxygen to the  Hypoxemia: may be due to
tissues more easily than does acute chest syndrome or
normal Hb and patients therefore respiratory complications
feel well despite being anemic  Dehydration: acidosis results in
(except of course during crises or a shift of the oxygen
complications). dissociation curve
 Changes in body temperature

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PULMONARY <20% if there is no
HYPERTENSION improvement
 This occurs in about 30-40% of  Ventilation (CPAP) may be
patients and is associated with an necessary
increased mortality.  Infections can be due to Chlamydia
 The hyperhemolytic paradigm and mycoplasma, as well as
(HHP) proposes that hemolysis in Streptococcus pneumoniae.
sickle cell disease leads to ANEMIA
increased cell-free plasma Hb  Chronic hemolysis produces a
which consumes NO, leading to a stable hemoglobin level usually 6-
state of NO deficiency, endothelial 8mg/dl but an acute fall in Hb level
dysfunction and a high prevalence can occur due to:
of pulmonary hypertension.  Splenic sequestration
ACUTE CHEST SYNDROME  Bone marrow aplasia
 This is caused by infection, fat  Further hemolysis due to drugs,
embolism from necrotic bone acute infection or associated
marrow or pulmonary infarction G6PD deficiency.
due to sequestration of sickle cells. SPLENIC SEQUESTRATION
 It comprises shortness of breath,  Vaso-occlusion produces an acute
fever, cough, chest pain, tachypnea, painful enlargement of the spleen.
leukocytosis, hypoxia, pulmonary  There is a splenic pooling of red
infiltrates in the upper lobes and cells and hypovolemia, leading in
new chest X-ray changes due to some to circulatory collapse and
consolidation. death.
 The presentation may be gradual or  There will be severe hemolysis,
very rapid, leading to death in a few rapid splenomegaly and a high
hours reticulocyte count.
 Management is with  The condition occurs in childhood
 Pain relief before multiple infarctions have
 High flow supplemental occurred.
oxygen and antibiotics  Multiple infarctions lead to a
(ANcefotaxime and fibrotic non-functioning spleen.
clarithromycin) which should
 Treatment is by splenectomy but
be started immediately.
this predisposes the patient to
 Exchange transfusion will
infection especially by
reduce the amount of HbS to

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encapsulated organisms e.g.  Hypoxia causes bone marrow
Haemophilus influenza, changes exacerbated by
Streptococcus pneumoniae and episodic occlusion of the
Salmonella micro-circulation by the
 Liver sequestration can also occur. abnormal sickle cells leading to
infarction of bone and marrow.
BONE MARROW APLASA  There is compensatory bone
(APLASTIC CRISIS) marrow hyperplasia, secondary
 This most commonly occurs osteomyelitis and secondary
following infection with growth defects.
erythrovirus B19 (previously called  Infections are common in tissues
Parvovirus B19) which invades susceptible to vasooclusion e.g.
proliferating erythroid progenitors. bones, lungs, kidneys.
 There is a rapid fall in hemoglobin  Eye: background retinopathy,
with no reticulocytes in the proliferative retinopathy, vitreous
peripheral blood, because of the hemorrhages and retinal
failure of erythropoiesis in the detachments all occur. Regular
marrow yearly eye checks are required.
LONG TERM PROBLEMS  Cardiac problems: cardiomegaly,
arrhythmias, dilation of both
 Growth and development: young
ventricles & left atrium and iron
children are short but regain their
overload cardiomyopathy.
height by adulthood. They however
Myocardial infarctions occur due to
remain normal weight. There is
thrombotic episodes which are not
often delayed sexual maturation
secondary to atheroma.
which may require hormone
therapy.  Neurological complications: in
25% there are transient ischemic
 Bones: vaso-occlusive episodes
attacks, fits, cerebral infarction,
lead to chronic infarcts causing
cerebral hemorrhage and coma.
avascular necrosis of hips,
Strokes occur in about 11% of
shoulders, compression of
patients under 20 years of age.
vertebrae and shortening of bones
Most common finding is
in the hands and feet. Osteomyelitis
obstruction of a distal intracranial
is common in SCD and is caused by
internal carotid artery or a proximal
Staphylococcus aureus and
middle cerebral artery. Other
salmonella.
complications include ptosis

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 GIT: Cholelithiasis-pigment stones  FBC: low Hb levels (6-8mg/L) and
occur as a result of chronic a high reticulocyte count (10-20%)
hemolysis, Chronic hepatomegaly  Urea and electrolytes
and liver dysfunction are caused by  Liver function tests (ALT & AST)
trapping of sickle cells  Pulmonary function tests
 Genitourinary: Chronic  CT before lumbar puncture
tubulointerstitial nephritis occurs,  Blood cultures
kidneys lose concentrating capacity  Chest XR
(isosthenurea).  MRI: for early bone marrow
 Priapism: an unwanted painful changes
erection occurs from vasooclusion  CT for subtle regions of
and can be recurrent. This may osteonecrosis and to exclude renal
result in impotence. Treatment is medullary carcinoma in patients
with an alpha-adrenergic blocking presenting with hematuria.
drug, analgesia and hydration.
 Tc bone scan to detect early
 Dermatological: Leg ulcers occur osteonecrosis.
spontaneously or following trauma
 Transcranial Doppler U/S: to detect
and are usually over the medial or risk of stroke in children
lateral malleoli. They often become
 Abdominal U/S: for cholecystitis,
infected and are quite resistant to
cholelithiasis, or an ectopic
treatment, sometimes blood
pregnancy and to measure
transfusion may facilitate ulcer
splenomegaly and hepatomegaly.
healing
 Echocardiography for pulmonary
 Pregnancy: impaired placental
hypertension
blood flow causes spontaneous
abortion, intrauterine growth MANAGEMENT
retardation, pre-eclampsia and fetal PRINCIPLES
death. Painful episodes, infections 1. Avoid and treat precipitating
and severe anemia occur in the factors quickly.
mother. 2. Rehydration
INVESTIGATIONS 3. Pain control: opioids (morphine),
NSAIDs
 Hb electrophoresis (diagnostic)
4. Oxygen and antibiotics are only
 Hemoglobin solubility
given if specifically, indicated
testing/sickling test
 Antibiotics: cefuroxime,
 Peripheral smear
amoxicillin/clavulanate,

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penicillin VK, ceftriaxone, sequestration, aplastic crisis or
azithromycin, cefaclor hyperhemolytic crisis.
5. Prophylaxis is with penicillin 8. Bone marrow transplantation is the
500mg daily and vaccination with only cure
polyvalent pneumococcal and  Hydroxyurea has been given to
Haemophilus influenzae type b patients with SCD, it increases HbF
vaccine but has carcinogenic effect
6. Folic acid is given to all patients (leukemia)
with hemolysis  15mg/kg/day increased by
7. Transfusion: for sudden, severe 2.5mg over 12 weeks
anemia due to acute splenic depending on response

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LEUKEMIAS
 There are 4 main subtypes:
 Acute myeloid leukemia (AML)
 Acute lymphoblastic leukemia (ALL)
 Chronic myeloid leukemia (CML)
 Chronic lymphocytic leukemia (CLL)

LYMPHOMA

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HEMOSTATIC DISORDERS
 Platelets (small plates) or thrombocytes are formed elements of blood.
 1/3 of platelets are sequestered in the spleen and 2/3 circulates for about 7 to 10
days.
 They are the smallest blood cells (2-5 microns) and are colorless.
 They have several shapes (spherical, rod shaped, oval, disk-shaped when
inactivated, dumbbell shaped, comma shaped, cigar shape of any other unusual
shape).
 They have no nucleus.
 Inactivated platelets are without processes/filopodia and activated platelets
develop filopodia/Processes.
 Normal platelet count: 150 000 to 400 000/mm3 of blood.
 Platelets life span varies from 8 to 12 days with an average of 10 days.
 Platelets are destroyed by tissue macrophage system in the spleen.
 Splenomegaly causes reduction in the platelet count.
 Splenectomy is followed by an increase in the platelet count.
 Platelets have the following properties:
 Adhesiveness: when platelets come in
contact with any wet surface or rough
surface, these are activated and stick to
the surface. Factors responsible for
adhesiveness are collagen, thrombin,
ADP, thromboxane A2, calcium ions
and vonWillebrand factor.
 Aggregation: platelets stick to each
other. This occurs due to ADP and
thromboxane A2
 Agglutination: clumping together of
platelets. This occurs due to the actions
of some platelet-activating factors.
 Physiological variations:
 Age: platelets are less in infants and
each normal level at the 3rd month after
birth.
 Sex: no difference in count between males and females however it rises
during ovulation and is reduced during menstruation in females

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 High altitude: increases platelets
 After meal: platelet count increases

 Pathologically platelets are also influenced by nutritional

state: Decreased in severe iron, folic acid or vitamin B12
deficiency.
 Platelets are acute phase reactants hence may be increased
in patients with systemic inflammation, tumors, bleeding
and mild iron deficiency hence the term secondary or
reactive thrombocytosis is used. It is mediated by cytokines
IL-3, 6 and 11.

HEMOSTASIS
 Integrity of the blood vessel is necessary to carry blood to
tissues.
 Damage to the wall of blood vessels is repaired by
hemostasis which involves formation of a thrombus (clot)
at the site of vessel injury.

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 Hemostasis is the spontaneous arrest or prevention of bleeding from the
injured/damaged vessels by the physiological process.
 Hemostasis occurs in 3 steps:
 Vasoconstriction
 Platelet plug formation (Primary hemostasis)
 Coagulation of blood (Secondary hemostasis)
VASOCONSTRICTION
 Immediately after injury the blood vessel constricts (initial constriction) and
decreases the loss of blood from the damaged portion.
 Usually arterioles and small arteries constrict.
 Vasoconstriction is purely a local phenomenon. It is brought about by:
 Neural reflex resulting in release of vasoconstrictors.
 Local smooth muscle spasm due to injury
 Release of endothelin from injured endothelium
 When blood vessels are cut, the endothelium is damaged and collagen is exposed.
 Platelets adhere to the exposed collagen and become activated.
 Activated platelets secrete serotonin and other vasoconstrictor substances to
cause vasoconstriction
 Adherence of platelets to collagen is accelerated by VonWille brand factor (this
factor acts as a bridge between a specific glycoprotein present on the surface of
platelets and collagen fibrils).
 During adhesion, Platelets use GPIb receptor to bind to VonWille brand
factor
 Note: VonWille brand factor is derived from alpha granules of platelets and
endothelial cell (Weibel-Palade bodies)
PLATELET PLUG FORMATION
 Following injury platelets come in contact with damaged collagen fibers and
endothelial cells of the vessel wall and change their characteristics (they begin to
swell and assume irregular forms with large number of pseudopodia protruding
to the surface)
 Contractile proteins of platelets contract and cause dense granules inside the
platelet containing multiple factors including ADP and thromboxane A2.
 Note: Phospholipase A2 converts phospholipids to arachidonic acid and
eventually forms thromboxane A2 in the cyclooxygenase pathway.
 ADP and thromboxane A2 attract more and more platelets and activate them.

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 ADP also induces the platelets to produce GPIIb/IIIa receptor which is essential
for platelet aggregation. The linker molecules between these platelets is
fibrinogen.
 All the platelets aggregate to form a loose temporary platelet plug or a temporary
hemostatic plug which closes the ruptured vessels and prevents further blood loss.
 Platelet activating factor (PAF) a cytokine released by neutrophils, monocytes
and platelet cell membrane lipids accelerates platelet aggregation.
BLOOD COAGULATION
 Coagulation is a process by which soluble fibrinogen is converted to fibrin.
 Note: blood coagulation does not necessarily need platelets, red blood cells and
white blood cells.
 In coagulation the temporary platelet plug is converted into a definitive
hemostatic plug by the process of clot formation (blood coagulation) which
involves a complex series of events.
 Fibrinogen is converted to fibrin. Fibrin threads get attached to the loose platelet
plug, which blocks the ruptured part of the blood vessel and prevents further
blood loss.

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CLOTTING FACTORS
 There are 13 clotting factors involved in the coagulation of blood, they are given
roman numeral.
 To indicate the activated form of the factor, a small letter “a” is added after the
roman numeral such as factors VIIa to indicate activated factor VII.
 Clotting factors were named after the scientist who discovered them or as per the
activity except for factor IX (Christmas Factor) which was named after the patient
in whom it was discovered.
 They include:
 Factor I- fibrinogen
 Factor II- prothrombin
 Factor III- Tissue factor/Thromboplastin
 Factor IV- Calcium
 Factor V- labile factor
 Factor VI- presence has not been proven
 Factor VII- stable factor
 Factor VIII- antihemophilic factor
 Factor IX- Christmas factor
 Factor X- Stuart Prower factor
 Factor XI- plasma thromboplastin antecedent
 Factor XII- Hageman factor
 Factor XIII-fibrin stabilizing factor
 To remember these factors, use the mnemonic: “Foolish People Try Climbing
Long Slopes After Christmas Some People Have Fallen”
 Note: This mnemonic does not include factor VI because its presence has not
been proven
 Note: Factor II, VII, IX and X are vitamin K dependent factors.
MECHANISM OF ACTION
 Clot formation is initiated under the following conditions:
 Trauma to the vascular wall and adjacent tissue
 Trauma to blood
 Contact of blood with damaged endothelial cells or collagen or other tissue
elements outside the vessels.
 Blood clotting involves a cascade of reactions in which activation of one factor
leads to activation of subsequent factor

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 Most of the clotting factors are proteins in form of enzymes that exist in an
inactive proenzyme form.
 The conversion of an inactive enzyme to an active enzyme leads to activation of
subsequent enzymes in a “water-fall sequence” until the final active enzyme
thrombin is formed from prothrombin.
 Stages of clotting:
 Formation of prothrombin activators
 Conversion of prothrombin to thrombin
 Conversion of fibrinogen into fibrin
 Prothrombin activators convert prothrombin to thrombin.
 Formation of prothrombin activators occurs through 2 pathways:
 Extrinsic
 Intrinsic
 These 2 pathways converge into a common pathway.

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FIBRINOLYSIS
 Fibrinolytic mechanisms are also put into place to remove the blood clot.

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LABORATORY TESTS
 Bleeding time: this is the time between a skin prick and the arrest of bleeding.
Normal bleeding time is 1 to 6 minutes. It indicates the platelet count and their
function as well as health of capillaries.
 Prothrombin time: this is the time taken by blood to clot after adding tissue
thromboplastin to it. Normal prothrombin time is 11-16s. It is a marker of the
extrinsic pathway.
 Partial thromboplastin time/ activated partial thromboplastin time: this is the time
taken for blood to clot after adding an activator such as phospholipid, along with
calcium to it. Normal PTT is about 40s. PTT is used to monitor heparin therapy.
It is a marker of the intrinsic pathway.
 International normalization ratio (INR): this is the ratio of a patient’s PT to mean
PT for the lab raised to the power of the international sensitivity index.
 Normal population: 0.8-1.2
 Standard therapy: 2.0-3.0
 High dose therapy: 3.0- 4.5
PRIMARY HEMOSTATIC DISORDERS
 Disorders of primary hemostasis are defects of initial platelet plug formation i.e.
the platelet or vessel endothelium.
 It is characterized by bleeding from small vessels and capillaries resulting in
mucocutaneous bleeding.
 Petechial (pinpoint or punctate) hemorrhages occur in the  Petechiae: pinpoint
skin and mucus membranes with bleeding and oozing from hemorrhages which do
the nose (epistaxis), gums, genitourinary (hematuria and not go white when
menorrhagia) and gastrointestinal tract (hemoptysis, GI pressed.
bleeding).  Purpura: purple
 Multiple petechial subcutaneous hemorrhages may coloring of the skin
sometimes be described as a “rash”. similar to a bruise
 Bleeding begins immediately after trauma and either measuring 3mm or
responds to simple measures such as pressure and packing or more and can be cause
requires systemic therapy with glucocorticoids, by blood disease and
desmopressin, plasma fraction and platelet concentrate. not by trauma.
 Ecchymoses: bleeding
under skin greater than
1cm.

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 Primary hemostasis disorders are characterized by:
 Prolonged bleeding time (test has suboptimal accuracy and is rarely
performed clinically)
 Normal prothrombin time (PT)
 Normal activated partial thromboplastin time (APTT or PTT)
 Causes of primary disorders of hemostasis include:
 Lesions of vasculature
 Platelet disorders:
o Quantitative disorder (thrombocytopenia)
o Qualitative disorder (platelet dysfunction)
LESIONS OF VASCULATURE
 Usually no laboratory abnormalities are associated with bleeding due to small
blood vessel dysfunction but a prolonged bleeding time is sometimes noted.
 Examples include:
 Simple purpura: easy bruising, especially of the upper thighs in otherwise
health persons
 Senile purpura: Hemorrhagic areas on the back of the hands and forearms of
older persons. This condition is presumed to arise from age-dependent
atrophy of vascular supportive tissues.
 Scurvy:
o Due to Vitamin C deficiency.
o Clinical characteristics:
 Extensive primary hemostatic bleeding with gingival hemorrhages
 Bleeding into muscles and subcutaneous tissue
 Hemorrhagic perifollicular hyperkeratotic papules, each papule
surrounding a twisted, corkscrew-like hair.
 Henoch-Schonlein purpura (allergic purpura)
o This condition is a form of hypersensitivity (type III-immune complex)
vasculitis resulting from an immune reaction that damages the vascular
endothelium.
o Characteristic features include hemorrhagic urticarial (palpable purpura),
the purpuric rash is on the buttock and extensor surfaces accompanied by
fever, arthralgia (painful joint swelling) and gastrointestinal (abdominal
pain) and renal involvement (joint pain).
o It is usually self-limiting however sometimes may cause renal failure.

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 Hereditary hemorrhagic telangiectasia: This is an autosomal dominant
disorder marked by localized malformation of venules and capillaries of the
skin and mucous membranes, often complicated by hemorrhage.
 Connective tissue disorders: Includes Ehlers-Danlos syndrome, an inherited
disorder caused by abnormalities of collagen or elastin and manifested by
vascular bleeding, articular hypermobility, dermal hyper-elasticity and tissue
fragility.
 Amyloidosis: Can cause vessel damage
 Rickettsial and meningococcal disease:
o Include Rocky mountain spotted fever and meningococcemia.
o These disorders involve vascular endothelium and immune complex
deposition, leading to necrosis and rupture of small blood vessels.
PLATELET DISORDERS
QUANTITATIVE DISORDER
 Thrombocytopenia may follow 1 of 3 mechanisms:
 Decreased bone marrow production
o This is commonly associated with stem cell injury.
o It affects multiple hematopoietic cell lines, hence varying degrees of
accompanying anemia and leucopenia.
o Bone marrow aspirate or biopsy shows a reduce number of
megakaryocytes.
o Common causes:
 Marrow aplasia
 Fibrosis
 Infiltration of the marrow with malignant cells
o Less common:
 Cytotoxic drug use
 Rarely congenital megakaryocytic hypoplasia and thrombocytopenia
 Increased splenic sequestration
o Usually follows condition causing splenomegaly e.g. portal hypertension
and splenic infiltration with tumor cells as in myeloproliferative
disorders or lymphoproliferative ones.
 Accelerated destruction of platelets
o Non-immunologic: associated with abnormal vessels, fibrin thrombi and
valve prosthesis. Examples include vasculitis, hemolytic uremic
syndrome, TTP and DIC

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o Immunologic: platelets coated with antibody, immune complexes or
compliments are rapidly cleared by mononuclear phagocytes in the
spleen or other tissues, may follow viral or bacterial infections, drugs etc.
o Drug induced thrombocytopenia: these include chemotherapeutic agents
(especially carboplatin, alkylating agents, anthracycline and
antimetabolites), antibiotics (sulfonamides, penicillines and
cephalosporines), Heparins (highest incidence is with unfractionated
products) and cardiovascular agents (thiazide diuretics rarely angiotensin
converting enzyme inhibitors). Most drugs induce thrombocytopenia by
eliciting an immune response in which platelets are innocent bystanders.
The best proof of drug induced thrombocytopenia is prompt rise in the
platelet count when the suspected drug is discontinued.
 To determine the etiology one should do
 An estimate of splenic size by bed side palpation supplemented by
ultrasound.
 Platelet count
 Bleeding time
 Blood smear
 Assessment of marrow morphology by examination of an aspirate or biopsy
 Dominant features include petechial cutaneous bleeding, intracranial bleeding
(with severe thrombocytopenia) and oozing from mucosal surfaces.
 Petechiae are a sing of thrombocytopenia and are not usually seen with
qualitative disorders.
 Quantitative platelet disorders are characterized by:
 Decreased platelet count. When platelet count is reduced there will be
reactive marrow megakaryocytosis.
o Bone marrow aspiration reveals decreased megakaryocytes when caused
by decreased platelet production and increased megakaryocytes when
caused by increased platelet destruction.
 Prolonged bleeding time.
 Implicated conditions: acute leukemia, myelopthisis, aplastic anemia, splenic
sequestration, Multiple transfusion, Disseminated intravascular coagulation
(DIC), idiopathic thrombocytopenic purpura (ITP), thrombotic
thrombocytopenic purpura (TTP)

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 Acute leukemia: causes decreased production because of replacement of bone
marrow by blast cells.
 Myelopthisis: causes decreased production because of bone marrow replacement
usually by tumor cells.
 Aplastic anemia: often caused by exposure to toxic agents such as benzene. It can
also be due to autoimmune destruction by cytotoxic T-cells.
 Splenic sequestration: results in loss of circulating platelets.
 Multiple transfusions result in dilution
 Disseminated intravascular coagulation (DIC): Results in depletion of platelets
through consumption
 Thrombocytopenia can be secondary to other disease e.g. AIDS and systemic
lupus erythematosus.
IDIOPATHIC/IMMUNOLOGIC THROMBOCYTOPENIC PURPURA
(ITP)
 This is also known as immune (or autoimmune) thrombocytopenic purpura. It is
an autoimmune production of IgG against platelet antigens e.g. GPIIb/IIIa.
 The IgG antibodies are produced by the plasma cells in the spleen. The antibody
platelets are consumed by splenic macrophages resulting in thrombocytopenia.
 It is the most common cause of thrombocytopenia in children and adults.
 In children (2-6 years), it is usually acute, self-limiting reaction to viral infection
or immunization.
 It accounts for 90% of pediatric cases
 60% recover in 4 to 6 weeks and over 90% recover within 3 to 6 months.
 In adults it is a chronic disorder.
 It runs an indolent course.
 Women aged 20-40 are afflicted most commonly and outnumber men by a
ratio of 3:1.
 It presents acutely or more often with prior history of easy bruising and
menometrorrhagia.
 There is immune mediated platelet destruction as well as platelet dysfunction.
 Characteristics:
 Antiplatelet antibodies that coat and damage platelets, which are then
selectively removed by splenic macrophages
 Maternal IgG antibodies in affected mother can cause fetal thrombocytopenia
 ITP shows thrombocytopenia with normal or increased megakaryocytes.

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 For a diagnosis of ITP there shouldn’t be an exposure to thrombocytopenic
agents, or splenomegaly.
 Investigations:
 Platelet count: decreased, often <50 000/microliter
 Full blood count
 Normal PT and PTT
 Serology for HIV and screening for SLE
o HIV infection is a common cause of immunologic thrombocytopenias in
young adults.
 Ultrasound of the abdomen to look for splenomegaly
 Bone marrow aspirate to look for reactive thrombocytosis (increased
megakaryocytes)
 Treatment:
 Depends on age, severity and anticipated natural history.
 Specific treatment may not be necessary unless platelet count is <20 000/ml
 Steroids:
o Symptomatic patients with ITP are placed on prednisolone 60mg/day for
4 to 6 weeks then tapered slowly over another few weeks.
o Children respond well but adults may show early response, but often
relapse.
o Those patients who fail to maintain a normal platelet count after a course
of steroids are eligible to splenectomy (steroids responsive but dependent
patients are most likely to respond to splenectomy)
 Intravenous immunoglobulins (IVIG) or anti-Rho (win Rho) (reserved for
those with severe thrombocytopenia and clinical bleeding who are refractory
to other measures) it is used to raise the platelet count in symptomatic
bleeding but its effect is short lived. The spleen destroys the infused
immunoglobulins and not the platelets.
 Platelet transfusion is considered only in those with eminent CNS bleeding
as a temporary measure.
 Emergency splenectomy: for those who are desperately ill and refractory to
medical measures.
o Splenectomy eliminates primary source of antibody and site of
destruction.

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o Note: failure to respond to splenectomy
may signify presence of accessory spleen
which may be evidenced by peripheral
blood smear examination for Howell Jolly
body (fragments of nuclear material in
RBCs) which appears in the circulation of
asplenic patients. Such patients may need
immunosuppressive therapy or
plasmapheresis.

 Antiretroviral treatment for those dually

infected with HIV increases platelet count.
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
 Characteristics:
 Platelet derived hyaline microaggregates in
small vessels (microvascular platelet thrombi)
 Thrombocytopenia: platelets are consumed as
microthrombi are formed.
 Microangiopathic hemolytic anemia: the
microcirculatory lesions produce mechanical
damage to red blood cells as they squeeze
through narrowed vessels, resulting in helmit
cells and Schistocytes.
 Causes include deficiency of von Willebrand
factor metalloprotease. Enzyme deficiency results in accumulation of very high
molecular weight multimer of vWF, promoting platelet microaggregate
formation.
 Note: microangiopathic hemolytic anemia is seen also in hemolytic uremic
syndrome (HUS)
 HUS is due to endothelial damage by drugs or infection.
 Classically seen in children with E. coli O157:H7 dysentery, which results
from exposure to undercooked beef.
 E. coli verotoxin damages endothelial cells resulting in platelet
microthrombi.
 Clinical findings (HUS and TTP):
 Skin and mucosal bleeding

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 Microangiopathic hemolytic anemia
 Fever
 Renal insufficiency (more common in HUS)- thrombi involve vessels of the
kidney
 CNS abnormalities (more common in TTP)- thrombi involve vessels of the
CNS
 Laboratory findings:
 Thrombocytopenia with increased bleeding time
 Normal PT/PTT (coagulation cascade is not activated)
 Anemia with Schistocytes
 Increased megakaryocytes on bone marrow biopsy
 Treatment involves plasmapheresis and corticosteroids, particularly in TTP.
QUALITATIVE DISORDER
 These platelet-mediated bleeding disorders occur in spite of a normal platelet
count.
 They result in mucocutaneous bleeding and are often associated with a prolonged
bleeding time.
 Causes:
 Defects of platelet adhesion:
o Von Willebrand disease (discuss under combined hemostasis disorders),
an autosomal recessive disorder characterized by unusually large
platelets lacking platelet-surface glycoprotein needed for platelet
adhesion.
o Bernard-Soulier syndrome is due to a genetic GPIb deficiency required
for platelet adhesion. Blood smear shows thrombocytopenia with
enlarged platelets.
 Defects of platelet aggregation: can either be
o Acquired (aspirin induced- inhibition of COX-1 and COX-2 leading to
failure of synthesis of thromboxane A2)
o Inherited (Glanzmann thrombasthenia, inaggregability of platelets due to
hereditary deficiency of platelet surface GPIIb-IIIa required for
formation of fibrinogen bridges between adjacent platelets)
 Uremia disrupts platelet function and causes both adhesion and aggregation
impairment.

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SECONDARY HEMOSTATIC DISORDERS
 Secondary hemostasis stabilizes the weak platelet plug. It occurs via the
coagulation cascade.
 Coagulation cascade generates thrombin which converts fibrinogen in the
platelet plug to fibrin.
 Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus
 Factors of the coagulation cascade are produced by the liver in an inactive state.
Activation requires:
 Exposure to an activating substance
o Tissue thromboplastin activates factor VII (extrinsic pathway)
o Subendothelial collagen activates factor XII (intrinsic pathway)
 Phospholipid surface of platelets
 Calcium (derived from platelet dense granules)
 Disorders of secondary hemostasis are caused by deficiencies of plasma clotting
factors.
 Manifestations include:
 Bleeding from larger vessels resulting in hemarthroses (blood in joints)
 Large hematomas
 Large ecchymoses
 Extensive bleeding with trauma (rebleeding after surgical procedures)
 Bleeding time or platelet count is not affect (thus distinguishing secondary
hemostatic disorders from primary hemostatic disorders).
 Laboratory results:
 Abnormalities in PT: It measures the extrinsic (factor VII) and the common
pathway (Factors II, V, X and fibrinogen). It reflects deficiency of fibrinogen
or factors, II, V, VII and X
o PT is a better measure of Warfarin therapy
 Abnormalities in APTT (or PTT): It measures the intrinsic (Factors XII, XI,
IX, VIII) and common pathway (Factors II, V, X and fibrinogen). It reflects
deficiency of all the coagulation factors except factors VII and XIII
o PTT is a better measure of Heparin therapy
 Thrombin time: reflects deficiency of fibrinogen
 They include:
 Classic hemophilia (Hemophilia A, Factor VIII deficiency)
 Christmas disease (Hemophilia B, Factor IX deficiency)
 Vitamin K deficiency

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CLASSIC HEMOPHILIA
 This is an X-linked recessive disorder with worldwide distribution and varies in
severity depending on the factor VIII activity (absence or low level of plasma
factor VII).
 Characteristics include: bleeding into muscles, subcutaneous tissue and joints. As
well as postsurgical bleeding.
 Clinical features:
 Profuse post circumcision hemorrhage in infants
 Recurrent painful hemarthroses and muscle hematomas
 Spontaneous intracerebral hemorrhage is an important cause of death
 Transfusion related disorders: hepatitis (HBV, HCV) and HIV infection are
frequent complications of repeated coagulation factors transfusions.
 The disorder is associated with a prolongation of APTT (PTT) and normal
bleeding time, platelet count, PT and thrombin time. There is a decrease in factor
VIII amounts.
 Because 30% of cases are attributable to new mutations, a positive family history
may not always be present. If family history is present inheritance is X-linked
recessive.
 Female carrier usually have >50% factor VII activity and usually fall within
normal range. Females may rarely be symptomatic due to homozygosity,
hemizygosity (Turner syndrome) and asymmetric lionization.
Coagulation factor activity (% of normal) Clinical manifestations
<1  Severe disease
 Frequent spontaneous bleeding
 Episode from early life
 Joint deformity and crippling
1-5  Moderate disease
 Post-Traumatic bleeding
 Occasional spontaneous episodes
of bleeding
5-20  Mild disease
 Post-Traumatic bleeding

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 Treatment:
 Factor VII replacement
o Spontaneous bleeding is usually controlled if patient’s factor VIII
activity is >20%
o For major surgery or serious post-traumatic bleeding or hemorrhage
occurring in dangerous sites.
o Factor VIII level should be raised to 100% and maintained above 60%
until healing occurs.
 Desmopressin

CHRISTMAS DISEASE
 This is a deficiency of clotting factor IX (Christmas factor).
 Incidence is approximately one fifth that of classic hemophilia.
 Hemophilia B is indistinguishable from classic hemophilia in mode of
inheritance and clinical features.

VITAMIN K DEFICIENCY
 Vitamin K is activated by epoxide reductase in the liver.
 Activated Vitamin K gamma carboxylates factors II, VII, IX, X and proteins C
and S. Gamma carboxylation is necessary for factor function.
 In adults, Vitamin K deficiency is most often caused by fat malabsorption from
pancreatic or small-bowel disease (recall fat soluble vitamins are A, D, E, K).
Long-term antibiotic therapy-disrupts vitamin K producing bacteria in the GI
tract.
 In neonates, vitamin K deficiency cause hemorrhagic disease of the new born,
which is due to deficient exogenous vitamin K in breast milk in association with
incomplete intestinal colonization by vitamin K synthesizing bacteria.
 Vitamin K injection is given prophylactically to all newborns at birth to
prevent hemorrhagic disease of the new born.
 Results in decreased activity of factors II, VII, IX and X and are reflected by
prolongation of the PT and APTT.

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Features Hemophiliac Factor IX Von Willebrand’s
deficiency disease
Inheritance Sex linked Sex linked Autosomal
recessive recessive dominant
Site of bleeding Body cavities, Body cavities, Both
joint & joint & mucocutaneous
intramuscular intramuscular and other
spaces spaces mentioned sites
Platelet count Normal Normal Normal
Bleeding time Normal Normal Prolonged
Prothrombin Time Normal Normal Normal
Partial Prolonged Prolonged Prolonged or
thromboplastin normal
time
VIII Low Normal Low
VWF Normal Normal Low
Factor IX Normal Low Normal

COMBINED HEMOSTATIC DISORDER

 Include:
 Von Willebrand disease
 Coagulopathy of liver disease
 Disseminated intravascular coagulation
 Dilutional coagulopathy
VON WILLEBRAND DISEASE
 This is the most common hereditary bleeding disorder.
 It is an autosomal disorder marked by deficiency of vWF, a large multimeric
protein synthesized by endothelial cells and megakaryocytes.
 vWF is a carrier protein for factor VIII (antihemophilic factor) and the two
proteins circulate together as a complex. It also mediates adhesions of platelets
of subendothelium at sites of vascular injury.
 Characteristics:
 Impaired platelet adhesion
 Prolonged bleeding time
 Functional deficiency of factor VIII

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THROMBOTIC DISORDERS
THROMBOSIS
 Thrombi can occur in an artery or vein.
 Thrombosis occurring in the veins is commonly seen in the veins of the leg and
the pelvis.
 Thrombosis is a pathologic formation of an
intravascular blood clot.
 Most common locations are in the deep veins
(DVT) of the leg below the knee.
 The thrombus is characterized by:
 Lines of Zahn: characterized by alternating
layers of platelets/fibrin and RBCs
 Attachment to vessel wall
 Both features distinguish thrombus from
postmortem clot.
Figure 38: Lines of Zahn (alternating layers of
 There are 3 major risk factors for thrombosis platelets/fibrin and RBCs)
(Virchow’s triad):
 Disruption in blood flow (stasis)
 Endothelial cell damage
 Hypercoagulable state
DISRUPTION IN BLOOD FLOW
 Stasis or turbulence of blood flow increases risk for thrombosis.
 Examples:
 Immobilization- increased risk for DVT
 Cardiac wall dysfunction e.g. arrhythmia i.e. atrial fibrillation or myocardial
infarcation
 Aneurysm
ENDOTHELIAL CELL DAMAGE
 Endothelial damage disrupts the protective function of endothelial cells,
increasing the risk for thrombosis.
 Endothelial cells prevent thrombosis by several mechanisms:
 Block exposure to subendothelial collagen and underlying tissue factor
 Production of prostacyclin (PGI2)- blocks platelet aggregation and NO- causes
vasodilation

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 Secretion of heparin-like molecules- augment antithrombin III (ATIII) which
inactivates thrombin and coagulation factors
 Secretion of Tissue plasminogen activator (tPA)- converts plasminogen to
plasmin which
o Cleaves fibrin and serum fibrinogen
o Destroys coagulation factors
o Blocks platelet aggregation
 Secretion thrombomodulin- redirects thrombin to activate protein C, which
inactivates factors V and VIII
 Causes of endothelial damage include atherosclerosis, vasculitis and high levels
of homocysteine
 Vitamin B12 and folate deficiency result in mildly elevated homocysteine
levels, increasing the risk for thrombosis.
o Recall: folic acid (tetrahydrofolate, THF) circulates as methyl-THF in
the serum
o Methyl is transferred to cobalamin (vitamin B12) allowing THF to
participate in the synthesis of DNA precursors
o Cobalamin transfers methyl to homocysteine resulting in methionine
o Lack of vitamin B12 or folate leads to decreased conversion of
homocysteine to methionine resulting in buildup of homocysteine
 Cystathionine beta synthase (CBS) deficiency results in high homocysteine
levels with homocystinuria
o CBS converts homocysteine to cystathionine, enzyme deficiency leads
to homocysteine buildup
o It is characterized by vessel thrombosis, mental retardation, lens
dislocation and long slender fingers
HYPERCOAGULABLE STATE
 Due to excessive pro-coagulant proteins or defective anticoagulant proteins.
 It may be inherited or acquired.
 Classica presentation is recurrent DVTs or DVT at a young age. Usually occurs
in the deep veins of the legs. Other sites include the hepatic and cerebral vein
 Examples:
 Protein C and S deficiency (autosomal dominant) decreases negative feedback
on the coagulation cascade
o Protein C and S normally inactivate factors V and VIII
o Increased risk for warfarin skin necrosis

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 Warfarin blocks epoxide reductase in the liver that blocks the
ability to activate vitamin K (factors II, VII, IX and X, protein C
and S cannot be synthesized effectively)
 Initial stage of warfarin therapy results in a temporary deficiency
of proteins C and S (due to shorter half-life as protein C and S
degrade faster in comparison to the factors) relative to factors II,
VII, IX and X
 In pre-existing C or S deficiency, a severe deficiency is seen at
the onset of warfarin therapy increasing risk for thrombosis,
especially in the skin.
 Factor V leiden is a mutated form of factor V that lacks the cleavage site for
deactivation by protein C and S. This is a common inherited cause of
hypercoagulable state.
 Prothrombin 20210A is an inherited point mutation in prothrombin that results
in increased gene expression. Increased prothrombin results in increased
thrombin, promoting thrombus formation
 Antithrombin III deficiency:
o Decreases the protective effect of heparin-like molecules by the
endothelium, increasing the risk for thrombus.
o Heparin-like molecules normally activate ATIII which inactivates
thrombin and coagulation factors.
o In ATIII deficiency, PTT does not with standard heparin dosing.
o Pharmacologic heparin works by binding and activating ATIII
o High doses of heparin activate limited ATIII, Coumadin is then given
to maintain an anticoagulated state.
 Oral contraceptives are associated with a hypercoagulable state: Estrogen
induces increased production of coagulation factors, thereby increasing the
risk for thrombus
 Note: heparin therapy is monitored using the PTT and you would expect it to rise.

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SUPERFICIAL THROMBOPLEBITIS
 This commonly involves the saphenous veins and is often associated with
varicosities.
 Occasionally the axillary vein is involved usually as a result of trauma. There is
local superficial inflammation of the vein wall, with secondary thrombosis.
 The clinical picture is of a painful, tender, cord-like structure with associated
redness and swelling.
 The condition usually responds to symptomatic treatment with rest, elevation of
the limb and analgesics (e.g. NSAIDs)
 Fodaparinux 2.5mg OD SC has been seen to significantly reduce the rate of
thromboembolic events (pulmonary embolism and deep vein thrombosis)
DEEP VEIN THROMBOSIS
 This is formation of an intravascular thrombus (blood clot) in the deep veins.
 A thrombus forms in the vein and any inflammation of the vein wall is secondary
to this.
 Thrombosis commonly occurs after periods of immobilization but it can occur in
normal individuals for no obvious reasons.
 A deep vein thrombosis in the legs occurs in 50% of patients after prostatectomy
(without prophylactic heparin) or following a cerebral vascular event or an
obstetric operation.
 Thrombosis can occur in any vein of the leg or pelvis, but is particularly found in
veins of calf. Around 10% progress to the proximal leg and become (more)
symptomatic.
 Axillary vein thrombosis occasionally occurs, sometimes related to trauma but
usually for no obvious reason.
 50% of untreated proximal thrombi progress to pulmonary embolism (PE), the
commonest type of venous thromboembolism.
 Less commonly, PEs are caused by fat, fluid, or infective emboli.

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RISK FACTORS FOR VENOUS THROMBOEMBOLISM
 Non-modifiable
 Age >60years
 Personal history or first degree relative with a history of venous
thromboembolism
 Modifiable Virchow’s triad for thrombi
 Active cancer or cancer treatment: there is activation of formation
thrombin. Prostate and ovarian are particularly  Endothelial dysfunction
associated. (damage)
 Critical care admission (immobility), immobility leads  Stasis
to venous status  Hypercoagulabile state
 Dehydration
 Known thrombophilia
 Obesity (BMI >30)
 Significant medical comorbidities e.g. heart disease, metabolic, endocrine or
respiratory pathologies, acute infectious diseases, inflammatory conditions,
IBD, Nephrotic syndrome, Polycythemia rubra vera.
 Use of hormone replacement therapy or estrogen containing contraceptive
therapy: estrogen increases fibrinogen, prothrombin and clotting factor
levels.
 Varicose veins with phlebitis
 Pregnancy/childbirth
CLINICAL FEATURES
 The individual may be asymptomatic, presenting with clinical features of
pulmonary embolism.
 Sudden onset of unexplained dyspnea (this may be the only sign)
 Pleuritic chest pain and Hemoptysis are present only when infarction has
occurred.
 Tachypnea, pleural rub, coarse crepitation, pericardial effusion, tachycardia,
atrial fibrillation, pulsus paradoxus, raised JVP, right ventricular heave,
gallop rhythm, widely split second heart sound or signs of right ventricular
overload with a right ventricular heave and loud pulmonary second sound
may be seen on examination
 A major presenting feature is pain in the calf, often with swelling, redness and
engorged superficial veins.
 The affected calf is often warmer and there may be ankle edema.

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 Homan’s sign (pain in the calf on dorsiflexion of the foot) is often present but is
not diagnostic and occurs with all lesions of the calf.
 The Moses’ sign (Bancroft’s sign) is also found in patients with DVT of the
lower leg involving the posterior tibial veins. The sign is positive if pain is
elicited when the calf muscle is compressed forwards against the tibia but not
when the calf muscle is compressed from side to side. This sign is neither
sensitive or specific for DVT.
 The Lowenberg’s sign is also a clinical sign found in patients with DVT of
the lower leg. The sign is positive when pain is elicited rapidly when a blood
pressure cuff is placed around the calf and inflated to 80mmHg. This sign is
neither sensitive or specific for DVT.
 These signs should be carried out with caution as they run the risk of
dislodging the thrombus complicating into pulmonary embolism.
 Thrombosis in the illiofemoral region can present with severe pain but there are
often few physical signs apart from occasional swelling of the thigh and/or ankle
edema.
 Complete occlusion particularly of a large vein can lead to a cyanotic
discoloration of the limb and severe edema, which can very rarely lead to venous
gangrene.
INVESTIGATIONS
 Clinical diagnosis is unreliable but combined with D-dimer level it has a
sensitivity of 80%.
 D-dimer are products of thrombolysis and once seen are indicative of a lysis
of a thrombi
 Confirmation of an illofemoral thrombosis can usually be made with B mode
venous compression ultrasonography or Doppler ultrasound with a sensitivity
and specificity over 90%.
 Below-knee thromboses can be detected reliably only by venography with non-
invasive techniques, ultrasound, fibrinogen scanning and impedance
plethysmography have a sensitivity of only 70%.
 A venogram is performed by injecting a vein in the foot with contrast which will
detect virtually all thrombi that are present.
 Chest X-ray in suspected PE: may show wedge-shaped infarct (rare) but more for
ruling out other conditions.
 Other investigations:
 Baseline aPTT before heparin and baseline INR before warfarin.

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 ECG in PE: most commonly sinus tachycardia (50%). Less commonly (20-
30% each), RV strain (T wave inversion in V1-V3), S1Q3T3 (Prominent S
in lead I, and Q wave and inverted T in lead III), right bundle branch block
and right axis deviation.
 Unprovoked venous thromboembolism: consider thrombophilia screen.
Look for underlying cancer only if suggested by history, exam and basic
bloods.
 Arterial blood gasses in PE: decreased oxygen and carbon dioxide partial
pressure, increased pH.
TREATMENT
 The main aim of therapy is to prevent pulmonary embolism and all patients with
thrombi above knee must be anticoagulated.
 Anticoagulation of below-knee thrombi is now recommended for 6 weeks as 30%
of patients will have an extension of the clot proximally.
 Bed rest is advised until the patient is fully anticoagulated.
 The patient should then be mobilized with an elastic stocking giving graduated
pressure over the leg.
 Low molecular weight heparin e.g. Enoxaparin have replaced unfractionated
heparin as they are more effective, they do not require monitoring and there is
less risk of bleeding.
 Enoxaparin 1.5mg/kg SC every 24 hours until INR> 2 for >24 hours.
 Alternatively, 1mg/kg SC every 12 hours
 It should be administered the same time each day.
 DVTs are being treated at home with LMW heparin.
 Warfarin is started after 1 or 2 days of heparin therapy and the heparin stopped
when the INR is in the target range.
 Warfarin should not be started alone because it is pro-coagulant in the first
days, it inhibits the synthesis of factors II, VII, IX and X as well as Protein C
and protein S. The half-lives of already synthesized Protein C are shorter than
the clotting factors so there is increased risk for coagulation.
 Warfarin should be started within 72 hours of starting Enoxaparin.
 Continue enoxaparin and warfarin for a minimum of 5 days and until
therapeutic oral anticoagulation effect has been achieved (INR 2.0-3.0,
Target INR should be 2.5)
 Average administration is up to 7 days. Stop heparin after and continue with
Warfarin.

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 Anticoagulants do not lyse the thrombus that is already present
 Unfractionated heparin should only be used if LMWH is unavailable
o Loading dose 5000 units SC followed by 15 000 units every 12 hours
with Lab monitoring preferably on a daily basis and dose adjusted
accordingly.
o Alternatively loading dose 75units/kg IV injection, followed by
continuous intravenous infusion 18 units/kg/hour, with Lab monitoring
preferably on a daily basis and dose adjusted accordingly
 Warfarin dosage:
 Initial dose (induction dose): 2-5mg PO every day for 2 days or 10mg PO for
2 days in healthy individuals
 Maintenance dose 2-10 mg PO per day
 The duration of warfarin treatment is debatable-3 months is the period usually
recommended but 4 weeks is long enough if a definite risk factor (e.g. bed rest)
has been present.
 Recurrent DVTs need permanent anticoagulants.
 Thrombolytic therapy is occasionally used for patients with a large illiofemoral
thrombosis.
Medications Pros Cons Test used to monitor
Unfractionated Short half-life, can turn off Requires Need to monitor PTT and
heparin quickly if the patient bleeds. continuous IV platelet count at least daily
Although falling out of favor, infusion (for heparin induced
still appropriate for acute thrombocytopenia)
coronary syndromes, Long-term use is
cardiopulmonary bypass, acute associated with Reversible with protamine
thrombotic events, mechanical osteoporosis sulfate.
heart valves and anticoagulation
in renal failure Carries a risk of
heparin induced
thrombocytopenia
LMWH No need to monitor PTT as Excretion is Will not prolong PTT, if
dosing is weight based. impaired in renal monitoring is required,
failure (Creatinine measure- Factor Xa activity
clearance should
be greater than
30ml/min)

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Not reversible
with protamine.
Requires injection.
Warfarin Oral Slow to reach Monitor with INR,
therapeutic effect, appropriate INR and duration
requires the vary by clinical situation
addition of heparin
with starting for an Reversible with FFP or
acute clot. vitamin K
Teratogenic, many
drug interactions.
Warfarin skin
necrosis (Rare)
Direct Used for anticoagulation in Irreversible Monitor with PTT
thrombin patients with heparin induced thrombin
inhibitors thrombocytopenia inhibitors, require
(Leepirudin or continuous IV
argatroban) infusion

COMPLICATIONS
 Cellulitis/ thrombophlebitis: can resemble, cause or follow DVT.
 Post-thrombotic syndrome: varicose vein-like symptoms (itch, swelling, dull
pain), venous ulcers. It can occur up to 12 months post DVT. Prevention:
compression stockings on the affected leg for 2 years after DVT, though the
evidence is weak.

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PROPHYLAXIS
 Patients at risk for venous thromboembolism
 Medical patients with reduced mobility for more than 3 days or if their
mobility is reduced and they have more than 1 risk factor for venous
thromboembolism
 Surgical and trauma patients are at risk:
o If they undergo surgical procedure with a combined anesthetic and
surgery of >90min (60 min if surgery on pelvis or lower limb)
o If they are admitted with an acute inflammatory or intra-abdominal
condition
o If they have significantly reduced mobility
o If they have more than 1 risk factor for venous thromboembolism.
 Patients at risk should be considered for pharmacological prophylaxis
(fondaparinux or LMW heparin or unfractionated heparin if renal impairment)
unless they have a risk factor for bleeding that outweighs the benefits of venous
thromboembolism prophylaxis.
 Risk factors for bleeding:
 Active bleeding
 Acquired bleeding disorders (e.g. acute liver failure)
 Concurrent use of anticoagulants (such as warfarin with INR >2)
 Lumbar puncture/epidural/spinal anesthesia within the previous 4 hours or
expected within 12 hours
 Acute stroke
 Thrombocytopenia (Platelets <75 x 109/L)
 Uncontrolled systolic hypertension (>230/120 mmHg)
 Untreated inherited bleeding disorders (hemophilia and von Willebrand’s
disease)
 Patients should also be encouraged to mobilize where possible and mechanical
venous thromboembolism (anti-embolism stockings (thigh or knee length), foot
impulse devices, intermittent pneumatic compression devices (thigh or knee
length) may be appropriate in certain patients.
 On discharge patients should be provided with advice on the signs and symptoms
of venous thromboembolism and if prescribed pharmacological or mechanical
prophylaxis advice on their usage.

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PULMONOLOGY

RESPIRATORY CONDITIONS
APPROACH TO RESPIRATORY CONDITIONS
 Patients with disease of the respiratory system generally present because of
symptoms, an abnormality on a chest radiography or both.
 Most patients with respiratory disease will present with one or more of the
following symptoms:
 Breathlessness
 Cough
 Sputum
 Hemoptysis
 Wheezing
 Pain in chest
 Dyspnea (shortness of breath) and cough are common presenting symptoms for
patients with respiratory system disease.
 Less common symptoms include hemoptysis (coughing up blood), and chest
pain, often with a pleuritic quality.
ASSESSING RESPIRATORY SYMPTOMS
DYSPNEA
 Breathlessness inappropriate to the level of physical exertion or even occurring
at rest is called dyspnea.
 Its mechanisms are complex and not just dependent on lowered blood oxygen
tension (hypoxia) or raised blood carbon dioxide tension (hypercapnia).
 People with cardiac disease may become dyspneic as well as those with primary
respiratory problems.
 To assess dyspnea a few questions, need to be asked:
 Is the dyspnea related only to exertion?
 How far can the patient walk at a normal pace on the level?

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 Is there variability in the symptom? Are there good days and bad days and
very importantly, are there any times of day or night that are usually worse
than others?
o Variable airways obstruction due to asthma is very often worse at night
and in the early morning.
o People with pre-dominantly irreversible airways obstruction due to
chronic obstructive pulmonary disease (COPD) will often say that as
long as they are sitting in bed they feel quite normal; it is exercise that
troubles them.
 When evaluating a patient with shortness of breath, one should determine:
 Time course over which the symptom has become manifest:
o Patients who were well previously and developed acute shortness of
breath (over a period of hours to days) can have acute disease affecting
the airways (an acute attack of asthma), the pulmonary parenchyma
(acute pulmonary edema or an acute infectious process such as bacterial
pneumonia), the pleural space (a pneumothorax), or the pulmonary
vasculature (a pulmonary embolus)
o A subacute presentation (over days to weeks) can suggest an
exacerbation of preexisting airways disease (asthma or chronic
bronchitis), an indolent parenchymal infection (PCP in AIDS,
mycobacterial or fungal pneumonia), a noninfectious inflammatory
process that proceeds at a relatively slow pace (Wegener’s
granulomatosis, Eosinophilic pneumonia, bronchiolitis obliterans with
organizing pneumonia and many others), neuromuscular diseases
(Guillain-Barre syndrome, myasthenia gravis), pleural disease (pleural
effusion from a variety of possible causes) or chronic cardiac disease
(CHF).
o Chronic presentation (over months to years) often indicates COPD,
chronic interstitial lung disease or chronic cardiac disease. Chronic
disease of airways (not only COPDs but also asthma) are characterized
by exacerbations and remissions. Patients often have periods when they
are severely limited by shortness of breath, but these may be interspersed
with periods in which symptoms are minimal or absent.
o Many diseases of the pulmonary parenchyma are characterized by a
slow but unavoidable progression.

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COUGH
 Cough may indicate the presence of lung disease, but cough per se is not useful
for the differential diagnosis.
 A cough may be dry or it may be productive.
 The presence of sputum accompanying the cough often suggests airway disease
and may be seen in asthma, chronic bronchitis, or bronchiectasis.
 Other further questions can be asked to assess cough, such as:
 How long has the cough been present? A cough lasting a few days following
a cold has less significance than one lasting several weeks in a middle-aged
smoker, which may be the first sign of malignancy.
 Is the cough worse at any time of day or night? A dry cough at night may be
an early symptom of asthma, as may cough that comes in spasms lasting
several minutes.
 Is the cough aggravated by anything, for example dust, pollen or cold air?
The increased reactivity of the airways seen in asthma, and in some normal
people for several weeks after viral infections may present in this way.
 Is the cough productive or not? If productive what is the nature of the
sputum? Blood or mucopurulent?
 Severe coughing, whatever its cause, may be followed by vomiting.
HEMOPTYSIS
 Hemoptysis (coughing of blood in sputum) should never be dismissed without
very careful evaluation of the patient.
 The potentially serious significance of blood in the sputum is well known and
fear often leads patients not to mention it: a specific question is always necessary:
 Is there any blood in the sputum?
 Is it fresh or altered?
 How often has it been seen?
 For how long?
 Blood may be coughed up alone, or sputum may be bloodstained.
 Sometimes patients may find it difficult to describe whether it comes from gums,
nose or even from the stomach.
 They should always be asked about associated conditions such as epistaxis
(nosebleeds), subsequent development of melena (altered blood in the stool)
which occurs in the case of upper GI (gastrointestinal) bleeding.
 Hemoptysis can originate from disease of the airways, the pulmonary
parenchyma or the vasculature.

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 Diseases of the airways can be inflammatory (acute or chronic bronchitis,
bronchiectasis, or cystic fibrosis) or neoplastic (bronchogenic carcinoma or
bronchial carcinoid tumors).
 Parenchymal disease causing hemoptysis may be either localized (pneumonia,
lung abscess, tuberculosis or infection with Aspergillus) or diffuse (Good
pasture’s syndrome, idiopathic pulmonary hemosiderosis)
 Vascular diseases potentially associated with hemoptysis include pulmonary
thromboembolic disease and pulmonary arteriovenous malformations.
SPUTUM
 Is sputum produced?
 What does it look like?
 Children and some adults swallow sputum, but it is always worth asking for
a description of its color and consistency.
 Yellow or green sputum is usually purulent.
 People with asthma may produce small amounts of very thick or jelly-like
sputum, sometimes in the shape of a cast of the airways. Eosinophils may
accumulate in the sputum in asthma, causing a purulent appearance even
when no infection is present.
 How much is produced?
 When severe lung damage in infancy and childhood was common,
bronchiectasis was often found in adults. The amount of sputum produced
daily often exceeded a cupful. Bronchiectasis is now rare and chronic
bronchitis causes the production of smaller amounts of sputum.
WHEEZING
 Always ask whether the patient hears any noises coming from the chest.
 Even if a wheeze is not present when you examine the patient, it is useful to know
that they have noticed it on occasions.
 Sometimes wheezing will have noticed by others (especially by a partner at night,
when asthma is worse) but not by the patient.
 Sometimes stridor may be mistaken for wheezing by both the patient and doctor.
This serious finding usually indicates narrowing of the larynx, trachea or main
bronchi.
 Stridor is an abnormal, high pitched musical breathing sound caused by upper
airway narrowing or obstruction. It is often heard during inspiration
frequently without the aid of a stethoscope.

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 Wheezing refers the high-pitched sound which is most prominent during
expiration. It is usually heard clearly upon auscultation (with a stethoscope)
although at times it may be audible, especially to the patient without any need
for a stethoscope.
CHEST PAIN
 Chest pain is caused by disease of the respiratory system usually originating from
involvement of the parietal pleura. As a result, the pain is accentuated by
respiratory motion and is often referred to as pleuritic.
 Pleuritic pain is sharp and stabbing.
 Common examples include primary pleural disorders such as neoplasms or
inflammatory disorders involving the pleura or pulmonary parenchymal
disorders that extend to the pleural surface such as pneumonia or pulmonary
infarction.
 A spontaneous pneumothorax causes pain which is worse on breathing but which
may have more of an aching character than the stabbing pain of pleurisy.
 If a pulmonary embolus causes infarction of the lung, pleurisy- and hence
pleuritic pain-may occur but an acute pulmonary embolus can also cause pain
which is not stabbing in nature.

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PHYSICAL EXAMINATION OF THE RESISPIRATORY
SYSTEM
 Before the examination ensure that you wash your hands.
 Always greet the patient, and introduce yourself.
 Confirm patient details
 Explain the procedure and gain consent.
 When examining a female patient presence of chaperone is a must to avoid any
misunderstandings.
 Always perform examination standing on the right side of the patient.
 Adequate exposure (expose the chest area) is a necessity but try to avoid
unnecessary exposure. Cover the patient after finishing the examination.
 A bare below the elbows dress code should be adopted.
GENERAL EXAMINATION
GENERAL INSPECTION
 Ideally the patient is examined in sitting position.
 Position the patient at 45 degrees and ask him/her to remove his/her top(s).
 From the foot-end of the bed comment on the presence of any respiratory adjuncts
(oxygen tank), sputum containers, inhalers or other medicines.
 Ask if any items identified belong to the patient or they have just been placed
there.
 Inspect sputum containers for mucus if present.
o Mucoid sputum is characteristic in patients with chronic bronchitis when
there is no active infection. It is clear and sticky and not necessarily
produced in a large volume.
o Sputum may become mucopurulent or purulent when bacterial infection
is present in patients with bronchitis, pneumonia, bronchiectasis or a
lung abscess.
o In bronchiectasis and lung abscess the quantities may be large and the
sputum is often foul-smelling.
o Occasionally asthmatics have a yellow tinge to the sputum, owing to the
presence of many eosinophils. A particularly tenacious form of mucoid
sputum may also be produced by people with asthma and sometimes
they cough up casts of the bronchial tree particularly after an attack.

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o Patients with bronchopulmonary aspergillosis may bring up black
sputum or sputum with black parts in it: this is the fungal element of the
Aspergillus.
o When sputum is particularly foul-smelling the presence of anaerobic
organisms should be suspected.
o Pink or white frothy sputum may be brought up by very ill patients with
pulmonary edema, for example in acute left ventricular failure.
o Rusty-colored sputum is characteristic of pneumococcal lobar
pneumonia.
o Blood may be coughed up alone, or bloodstained sputum produced, with
bronchogenic carcinoma, pulmonary tuberculosis, pulmonary
embolism, bronchiectasis or pulmonary hypertension (e.g. with mitral
stenosis).
 Observe the position the patient assumes during respiration.
 Patients with severe asthma or COPD exacerbation may sit and lean forward
with shoulders arched forward to assist accessory muscles of respiration.
 Examine the following:
 Look for any obvious discomfort or pain
 Use of accessory muscles of respiration (pectoralis, sternocleidomastoid,
scalene and trapezius)
 Is the patient breathless (Shortness of breath) or cyanosed (hypoxia)?
 Is the patient coughing?
 Inspect the sputum for color, volume, blood and type (mucoid, purulent or
mucopurulent)
 Listen to the patient’s voice for presence of hoarseness
o Hoarseness is commonly seen in recurrent laryngeal nerve palsy in cases
of carcinoma lung.
 Stridor
o Ask the patient to cough and then breathe deeply with mouth wide open.
Listen for any stridor.
o Stridors are high pitches, creaking sounds, predominantly of inspiratory
origin.
 Note:
o The rate, depth and regularity of the patient’s breathing.
o The normal rate of respiration in a relaxed adult is about 14-16 breaths
per minute.

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 Tachypnea is increased rate of respiration observed by the
doctor.
 Dyspnea is the symptom of breathlessness experienced by
patient.
 Apnea is a cessation of respiration.
o Any deformities, thoracotomy scars and markings of the chest and spine
 Barrel chest
 Pectus excavatum
 Pectus carinatum
 Kyphosis
o Any asymmetry of chest expansion
INSPETION AND EXAMINATION OF THE HANDS
 From the right side of the bed, take both hands and assess them for color and
temperature.
 Examine both hands for:
 Clubbing
o Clubbing is seen in respiratory conditions such as bronchial carcinoma
(squamous cell type), fibrosing alveolitis, chronic Suppurative lung
disease (bronchiectasis, lung abscess, empyema), pulmonary fibrosis
(e.g. idiopathic lung fibrosis), pleural and mediastinal tumors (e.g.
mesothelioma) and cryptogenic organizing pneumonia.
 Pallor
 Peripheral cyanosis: which is caused by poor peripheral perfusion.
 Tar staining on the fingers and nails seen in chronic smokers.
 Radial pulse (rate, rhythm and character of the radial pulse) and respiration
rate
o A bounding pulse is due to carbon dioxide retention.
o In a significant asthma attack the pulse rate is usually raised. The systolic
blood pressure also falls during the severe inspiratory effort of acute
asthma, and the degree of this fall (the degree of pulsus paradoxus) can
be used as a measure of asthma severity.
 Check the Blood pressure
 Examine for tremors in arms
 Ask patient to hold their arms stretched out with hands at the same level and
their fingers splayed out.
 You can even place a paper on top to check for tremors.

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 Tremors indicate use of beta-agonists.
 Examine for flapping tremors (Asterixis)
 Ask the patient to stretch the arms in front of them with the wrist dorsiflexed
and fingers extended.
 Presence of irregular jerky flexion-extension movements at wrist and
metacarpophalangeal joints is a positive sign.
 It is seen in patients with hypercapnic respiratory failure (carbon dioxide
retention)/ severe COPD, severe cirrhosis of liver and hepatic
encephalopathy.
 At this point one can even palpate the epitrochlear lymph nodes.
 Palpate axillary lymph nodes and lymph nodes in the neck. Note for the size,
consistency and whether they are fixed to the surrounding structure.
 Palpate for the scalene lymph nodes, its enlargement may be the first sign of
metastatic lung cancer.
INSPECTION OF THE HEAD AND NECK
 Look for signs of secondary polycythemia as well as central cyanosis
 Examine the eyes for pallor (Anemia) and jaundice
 Examine the eyes also for an injected conjunctiva (a sign of polycythemia
seen in chronic smokers especially)
 Examine the nose for:
 Deviated nasal septum
 Nasal polyp
 Post nasal drip
 Examine the oral cavity for:
 Hygiene
 Dental caries
 Tonsils
 Purple lesions on the palate (Kaposi’s sarcoma)
INSPECTION OF THE CHEST
 Inspect the position of the trachea:
 Trail’s sign: it is the prominence of clavicular head of sternocleidomastoid
muscle to the side to which the trachea is deviated.
 Inspect the chest movements and note any scars (e.g. lobectomy), markings and
chest deformities
 Ask patient to place hands on the hips and bring the elbows forward.

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 Inspect for symmetrical chest expansion.
PALPATION OF THE CHEST
 Feel the position of the trachea. This is done by placing the index and ring finger
on the medial ends of the clavicle and feeling for the tracheal rings with the
middle finger. Crico-sternal distance (3/4 fingers=normal).
 Palpate for the apex beat which is normally in the 5 th intercostal space
midclavicular line as it may be displaced due to pneumothorax, or a massive
pleural effusion.
 Check the symmetry of the chest movements by palpation.
 Start by placing hands on lower chest with the thumbs touching each other in
the midline and ask the patient to take deep breaths.
 Observe symmetry of thumb movement.
 Move your arms upwards and repeat the process.
 A unilateral decrease in expansion may signify a consolidation or collapse.
 Bilateral decrease in expansion may signify COPD/Pulmonary fibrosis.
 Check for tactile fremitus
 It is the palpation of chest wall for vibrations transmitted from larynx through
the lungs on the chest wall.
 To check for vocal fremitus, use the ulnar border of the hand (or the flat of the
hand) to palpate over the chest wall.
 Keep your ulnar boarder of the hand on the chest and ask the patient to repeat
words like ‘One one one’.
 Feel the vibrations on the chest wall.
 Increased tactile fremitus is seen in consolidation (pneumonia) and decreased
tactile fremitus is seen in pleural effusion, COPD or severe asthma.
PERCUSSION OF THE CHEST
 Percuss the anterior chest and axillae.
 Press the middle finger of your left hand firmly over the intercostal spaces
parallel to the ribs, with other fingers not touching the chest. This finger is
called the pleximeter.
 Strike the center of the middle phalanx of the left finger with your right middle
finger at 90 degrees.
 The striking movement must be loose swinging movement at the wrist joint
and not the elbow joint.

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 The striking finger must be moved immediately to prevent dampening of the
produced sounds. The striking finger is called the plexor.
 Always percuss from resonant to dull areas for better appreciating the change
in note of percussion.
 Always compare by percussion on the opposite side.
 With the patient sited with arms on the side percuss the medial third of the
clavicle, infra-clavicular noting:
o Resonant sound (normal)
o Hyperresonant (pneumothorax)
o Dull (consolidation/ collapse)
o Stony dull (pleural effusion)
 Tenderness during percussion is a sign of emphysema or parietal pleural effusion.
AUSCULTATION
 Listen to the breath sounds. Assess breath sound quality (vesicular/bronchial)
 Use the diaphragm of the stethoscope (even though the bell is preferred for
auscultation of breath sounds).
 While auscultating, make sure that the patient is relaxed and is breathing
through the mouth
 Avoid auscultating within 3cm of midline anteriorly and posteriorly as breath
sounds are directly transmitted from the trachea or bronchi in this region.
 Auscultate each side alternately and compare the findings.
 Auscultation after asking the patient to cough helps differentiate coarse
crepitation and rhonchi from pleural rub.
 Crepitation and rhonchi disappear after coughing whereas pleural rub persists.
 When auscultating note the following:
o Intensity/loudness
o Character
o Comparison of inspiration and expiration element in terms of intensity,
duration and pitch
o Presence of intermediatory pause between inspiration and expiration
o Presence of added sounds.
 Auscultation areas-
o Anterior: from above clavicle down to 6th rib
o Lateral- up to 8th rib
o Posterior- from above the scapula to the level of 11th rib
 Abnormal sounds:

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o Crepitations/Crackles, Rales- Can be coarse or fine
o Rhonchi
o Pleural rub: gratting sound of pleural membranes rubbing against each
other.
 Check for vocal resonance:
 Every time the stethoscope is placed on the patients’ chest the patient says
‘one one one’.
 Increased vocal resonance is indicative of consolidation
 Decreased vocal resonance is indicative of pleural effusion

 Note: after examination of the front chest, ask the patient to lean forward and
place their hands crossed on their shoulder
 Inspect the posterior chest wall for deformities, scars and chest markings
 Check for tactile fremitus
 Percuss the back of the chest
o This is done by making the patient sit with his hands over his shoulder
and head bent forwards. This position helps increasing the surface area
between the scapulae for percussion.
o Percuss in-between the spine and the scapular.
o Avoid percussing in the midline as the spine and musculature produces
dull note.
 Listen to the breath sounds
 Check for vocal resonance
 Thank the patient and ensure they are dressed or appropriately covered.
 To complete examination perform:
 Oxygen saturation
 Sputum analysis
 Chest X-ray
 Summarize findings and offer differential diagnosis.

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INTERPRETING THE SIGNS
 Developing an appropriate differential diagnosis on the basis of the signs you
have elicited requires practice.
 Keep the following in mind
 If movements are diminished on one side, there is likely to be an abnormality
on that side.
 The percussion note is dull over a pleural effusion and over an area of
consolidation- the duller the note, the more likely it is to be a pleural effusion.
 Over a pneumothorax, the percussion note is more resonant than normal but
the breath sounds, vocal resonance and tactile vocal fremitus are quite or
reduced. Pneumothorax is easily missed.
 The breath sounds, the vocal resonance and the tactile vocal fremitus are
quitter or less obvious over a pleural effusion and louder or more obvious
over an area of consolidation.
INVESTIGATIONS
 Any patient with the following should have chest x-ray:
 Severe or persistent shortness of breath
 Cough
 Hemoptysis
 Chest pain
 Chest trauma
 Evidence of tuberculosis or malignancy by history or pulmonary findings on
physical examination
 See radiology chapter 14 for interpretation of chest X-rays.
 Other pulmonary investigations include:
 Sputum analysis: Microscopy, culture and sensitivity
 Spirometry
 Bronchoscopy
 CT/MRI of the thorax

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PULMONARY INFECTIONS
PNEUMONIA
 This is an acute inflammation of the lung parenchyma distal to the terminal
bronchioles including respiratory bronchioles, alveolar ducts, alveolar spaces and
interstitial tissue.
 It can affect:
 The entire lobe: lobar pneumonia
 A segment of a lobe: Segmental/lobular pneumonia
 Alveoli contiguous (adjacent) to Bronchi-Bronchopneumonia
 Interstitial tissue- Interstitial pneumonia/atypical
 The differences between the above are made on X-ray.
 Pneumonia is usually caused by bacteria but can also be caused by viruses and
fungi.
 Clinically, it usually presents as an acute illness with cough, purulent sputum
(rusty color), breathlessness and fever together with physical signs or radiological
changes compatible with consolidation of the lung.
 A pulmonary consolidation is a region of lung
tissue (normally compressible) that has been
filled with fluid instead of air. It occurs through
accumulation of inflammatory cellular exudate
in the alveoli and adjoining ducts.
 The liquid can be pulmonary edema,
inflammatory exudate, pus, inhaled water or
blood (from bronchial tree or hemorrhage from
a pulmonary artery)
 Consolidation must be present to diagnose
pneumonia.
 In the elderly there is a subtler presentation of
symptoms.
 About 50% of pneumonia is pneumococcal. Figure 39: Chest X-ray showing lobar
pneumonia (left lower lung zone)

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PREDISPOSING FACTORS FOR PNEUMONIA
 Preceding respiratory viral infections
 Alcoholism
 Cigarette smoking
 Underlying diseases such as heart failure, COPD
 Age extremes
 Immunosuppressive therapy and disorders
 Decreased consciousness, coma, seizure etc.
 Surgery and aspiration of secretions
CLASSIFICATION OF PNEUMONIA
 Pneumonia can be classified:
 Morphologically/anatomical
 Etiologically
 Setting in which it is contracted
MORPHOLOGICAL/ ANATOMICAL CLASSIFICATION
 Pneumonia can be classified as:
 Lobar pneumonia: involving the entire lobe
 Segmental/lobular pneumonia: involving part of the lobe
 Bronchopneumonia: involving the alveoli contiguous (adjacent) to Bronchi
 Interstitial pneumonia: involving the interstitial tissue.
ETIOLOGICAL CLASSIFICATION
 Cause of pneumonia can be
 Infectious
 Non-infectious
INFECTIOUS
 Bacterial:
 Streptococcus pneumoniae (50%)
 Haemophilus influenzae (7%)
 Klebsiella pneumoniae
 Pseudomonas aeruginosa
 Legionella pneumophilia (3%)
 Staphylococcus aureus (2%)
 Moraxella catarrhalis (2%)

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 Mycoplasma pneumoniae
 Chlamydophila pneumoniae
 Chlamydophila psittaci
 Coxiella burnetti (Q fever)

 Viral:
 Influenza viruses (A and B)
 Parainfluenza virus
 Cold viruses: adenovirus, corona virus, Astrovirus

 Fungal/Parasitic
 Pneumocystis Jirovercii pneumonia
 Aspergillosis
NON-INFECTIOUS
 This includes aspiration pneumonia
 Chemical insult such as in the aspiration of vomit
o Aspiration pneumonia is seen in patients at risk for aspiration (e.g.
alcoholics and comatose patients)
o Most often due to anaerobic bacteria in the oropharynx (e.g.
Bacteroides, Fusobacterium and Peptococcus) and other microbes such
as Enterobacteriacae, S. pneumoniae, S. aureus
o Classically results in a right lower lobe abscess: anatomically the right
main stem bronchus branches at a less acute angle than the left.
 Radiotherapy
 Allergic mechanisms
SETTING ACQUIRED
 Pneumonia is usually classified by the setting in which the person has contracted
their infection:
 Community acquired pneumonia: with no underlying immunosuppression or
malignancy.
 Hospital acquired pneumonia
 Pneumonia in the immunocompromised (through genetic defect,
immunosuppressive medication or acquired immunodeficiency such as HIV)

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COMMUNITY ACQUIRED PNEUMONIA
 Occurs across all ages however is commoner at the extremes of age.
 Pneumonia can be classified either according to the organisms responsible for the
infection or by the site of disease.
 Classification according to etiology includes:
 Bacterial pneumonia: pneumococcus is the commonest cause overall.
Usually produce lobar or bronchopneumonia.
o Streptococcus pneumoniae (pneumococcal pneumonia)-50% of cases
o Haemophilus influenza-7% of cases
o Staphylococcus aureus-2% of cases
o Mycoplasma pneumoniae- 5-15% of cases
o Chlamydia pneumoniae-10% of cases
o Legionella pneumophila-3% of cases
o Oral anaerobic bacteria
o Mycobacterium tuberculosis
 Viral pneumonia: usually produce atypical pneumonia.
o Influenza A + B
o Respiratory syncytial virus
 Fungal pneumonia: Pneumocystis Jirovercii (causing pneumocystis
pneumonia-PCP) which is common in the immunosuppressed.
 Classification according to site of disease includes:
 Lobar pneumonia: consolidation affects one whole lobe
 Segmental/lobular: lobules of the lung are affected, and the infection is
centered on the bronchi and bronchioles.
 Bronchopneumonia: the alveoli adjacent to the bronchi are affected.
 Interstitial pneumonia (atypical pneumonia): inflammation within the
interstitium- there is an increase in lung markings on CXR.
LOBAR PNEUMONIA
 This is characterized by consolidation of an entire lobe of the lung.
 Usually bacterial, most common causes are Streptococcus pneumoniae (95%)
and Klebsiella pneumoniae.
 Classic gross phases of lobar pneumonia:
 Congestion- due to congested vessels and edema. This lasts less than 24
hours.
 Red hepatization- due to exudate, neutrophils, and hemorrhage filling the
alveolar air spaces, giving the normally spongy lung a solid consistency.

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There is a firm, ‘meaty’ and airless appearance of the lung (it looks like a
liver).
 Gray hepatization- due to macrophage mediated degradation of red cells and
fibrin within the exudate. There is less hyperemia.
 Resolution- lysis and removal of the fibrin via sputum and lymphatics. It
begins after 8-9 days (without antibiotics) and there is sudden improvement
of the patient’s condition.
 This type of pneumonia usually develops in the distal airspaces adjacent to the
visceral pleura and then spreads to produce consolidation of all or part of the lobe.
 On X-ray this appears as:
 Unifocal (but may be multifocal)
 Homogenous lung opacity limited by fissures with air bronchograms (which
become less obvious as the disease progresses).
 Round shaped pneumonia that may simulate a lung mass. (cavitations are
unlikely)
 A Parapneumonic effusion
 Note: lobar volume usually remains unchanged (but rarely it increases)

Figure 40: Lobar pneumonia: note the consolidation of the right lung.

 Radiographic resolution is fairly rapid- 1 week; total resolution happens within

2-6 weeks.
 Chest X-ray must be repeated 6 weeks after discharge unless complications
occur to rule out an underlying bronchial malignancy predisposing to
pneumonia by causing obstruction.

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BRONCHOPNEUMONIA/LOBULAR
 Characterized by scattered patchy consolidation centered around bronchioles,
often multifocal and bilateral. With worsening disease, the opacities may become
more homogenous.
 Pleural effusion or empyema, cavitation, pneumothorax and atelectasis are
common.
 Caused by a variety of bacterial organisms.

Figure 41: Bronchopneumonia

INTERSTITIAL PNEUMONIA (ATYPICAL PNEUMONIA)

 Characterized by diffuse interstitial infiltrates.
 Presents with relatively mild upper respiratory symptoms (minimal sputum and
low fever), ‘atypical presentation’.
 Most often caused by bacteria or viruses.

Figure 42: Atypical pneumonia

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TYPES OF PNEUMONIA
CAUSES OF LOBAR PNEUMONIA
ORGANISM COMMENTS
Streptococcus  Most common cause of community acquired pneumonia.
pneumoniae  Seen in middle-adults and elderly.
Klebsiella  Affects malnourished and debilitated individuals, especially elderly in
pneumoniae nursing homes, alcoholics and diabetics (enteric flora that is aspirated)
 Thick mucoid capsule results in gelatinous sputum (current jelly)
 Often complicated by abscess.
CAUSES OF BRONCHOPNEUMONIA
ORGANISM COMMENTS
Staphylococcus  Most common cause of secondary pneumonia (bacterial pneumonia
aureus superimposed on a viral upper respiratory tract infection)
 Often complicated by abscess or empyema
Haemophilus  Common cause of secondary pneumonia and pneumonia superimposed on
influenza COPD (leads to exacerbation of COPD)
Pseudomonas  Pneumonia in cystic fibrosis patients
aeruginosa
Moraxella  Community-acquired and pneumonia superimposed on COPD (leads to
catarrhalis exacerbation of COPD)
Legionella  Community-acquired pneumonia
pneumophila  Pneumonia superimposed on COPD or pneumonia in
immunocompromised states.
 Transmitted from water source.
 Intracellular organism that is best visualized by silver stain.
CAUSES OF INTERSTITIAL (ATYPICAL) PNEUMONIA
ORGANISM COMMENTS
Mycoplasma  Most common cause of atypical pneumonia, usually affects young adults.
pneumoniae  Complicates include autoimmune hemolytic anemia (IgM against antigen
on RBCs causes cold hemolytic anemia) and erythema multiforme.
 Not visible on gram stain due to lack of cell wall
Chlamydia  Second most common cause of atypical pneumonia in young adults
pneumoniae
Respiratory  Most common cause of atypical pneumonia in infants.
syncytial virus
Cytomegalovirus  Atypical pneumonia with post-transplant immunosuppressive therapy

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Influenza virus  Atypical pneumonia in elderly, immunocompromised and those with
preexisting lung disease.
 Also increases risk for superimposed S aureus or H influenza bacterial
pneumonia
Coxiella burnetti  Atypical pneumonia with high fever (Q fever).
 Coxiella is a Rickettsial organism that causes pneumonia and does not
require arthropod vector for transmission and does not produce a skin
rash.

RISK FACTORS FOR COMMUNITY ACQUIRED PNEUMONIA

AGE <16 or >65 years
CO-MORBIDITIES HIV infection, diabetes mellitus,
chronic kidney disease, malnutrition,
recent viral respiratory infection
OTHER RESPIRATORY Cystic fibrosis, bronchiectasis, COPD,
CONDITIONS obstructing lesion (endoluminal cancer,
inhaled foreign body)
LIFESTYLE Cigarette smoking, excess alcohol,
intravenous drug use
IATROGENIC Immunosuppressant therapy (including
prolonged corticosteroids)

CLINICAL FEATURES
 Clinical features vary according to the immune state of the patient and the
infecting agent.
 Symptoms:
 Fever and chills: this can be as high as 39.5- 40.5oC. If swinging fevers are
present, this often indicates empyema.
 Cough: may be dry or productive and hemoptysis can occur.
o In pneumococcal pneumonia, sputum is characteristically rust-colored
or yellow-green (indicating pus).
 Chest pain: pleuritic in nature due to inflammation of pleura (mediated by
bradykinin and prostaglandin E2).
o The pleuritic chest pain is worsened during inspiration and coughing
 Breathlessness: alveoli become filled with pus and debris, impairing gas
exchange.

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 In the elderly community acquire pneumonia (CAP) can present with
confusion or nonspecific symptoms such as recurrent falls. CAP should
always be considered in the differential diagnosis of sick elderly patients
given their frequently atypical presentation.
 Where symptoms have been present for several weeks or have failed to
respond to standard antibiotics, the possibility of Tuberculosis should always
be remembered.
 Signs:
 Tachypnea and increased pulse rate
 Cyanosis may be present
 There will be dullness to percussion
 Bronchial breathing (Increased breath sounds): may be heard over areas of
consolidated lung.
 Coarse crepitations are often heard on auscultation, due to consolidation of
the lung parenchyma.
 A pleural rub may be heard early on in the illness
 Elevated WBC count.
 Extrapulmonary manifestation: may be indicative of causative agent.
Pneumonia Manifestations
Legionella  Myalgia, arthralgia and malaise
pneumonia  Headache
 Meningoencephalitis and other neurological abnormalities (less
common)
 Abdominal pain, diarrhea and vomiting (common)
 Hepatitis
Mycoplasma  Myalgia, arthralgia and malaise
pneumonia  Myocarditis and pericarditis
 Erythema multiforme and erythema nodosum
 Stevens-Johnson syndrome (Rare complication of pneumonia)
Pneumococcal  Labial herpes simplex reactivation
pneumonia

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 The type and extent of depends on the severity of the illness, which also guides
where the patient should be managed and predicts their outcome.
 Severity is commonly assessed by CURB-65 or CRB=65 score. The CRB=65
score is used in the community where the serum urea level is not usually
available. 1 point for each
 C- confusion present (abbreviated mental test score <8/10)
 U- urea levels >7 mmol/L
 R- respiratory rate >30/min
 B- systolic BP <90 or diastolic BP <60
 65- age>65
 Score 0-1: treat as outpatient
 Score 2: Admit to hospital
 Score 3+: Often require ICU care. Mortality rates increase with increasing
score.
 Other severity scores are also used e.g. Pneumonia Severity index (PSI)
INVESTIGATIONS
 The clinical presentation varies between different causative organisms but there
is considerable overlap.
 Streptococcus pneumoniae is the commonest single cause and all treatment and
investigation strategies need to cover this. The most likely causative pathogens
must be treated while considering alternative less common infectious causes
(such as tuberculosis) or an alternative pathology (e.g. lung cancer).
 All patients admitted to hospital should have a chest X-ray, blood tests and
microbiological tests.
 Chest X-ray: must be repeated 6 weeks after discharge unless complications
occur to rule out an underlying bronchial malignancy predisposing to
pneumonia by causing obstruction
o Strep. Pneumoniae: consolidation with air bronchograms, effusions and
collapse due to retention of secretions can all be seen. Radiological
abnormalities can lag behind clinical signs. A normal CXR on
presentation should be repeated after 2-3 days where community
acquired pneumonia is suspected.
o Mycoplasma: Usually one lobe is involved but infection can be bilateral
and extensive

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o Legionella: There is lobar and then multi-lobar shadowing with the
occasional small pleural effusion. Cavitation is rare.
 Sputum gram stain and culture: required for all patients
o S. pneumoniae: gram positive diplococci
o S. aureus: gram positive organisms commonly in clusters like a bunch
of grapes or in rods.
o Blood culture should be done for all patients who have moderate to
severe community acquired pneumonia, ideally before antibiotics are
administered. In S. pneumoniae infection, positive blood culture
indicates more severe disease with greater mortality.
 Blood tests: Full blood count, urea & electrolytes, biochemistry, C-reactive
protein, HIV testing
o Strep pneumoniae: WBC> 15 x109/L (90% polymorphonuclear
leukocytosis), ESR> 100mm/hour, CRP> 100mg/L.
o Mycoplasma: WBC is usually normal. In the presence of anemia,
hemolysis should be ruled out (direct Coomb’s test and measurement of
cold agglutinins).
o Legionella: there is Lymphopenia without marked leukocytosis,
hyponatremia, hypoalbuminemia and high serum levels of liver
aminotransferases.
 Pulse oximetry and arterial blood gas analysis is necessary if oxygen
saturation is below 94%.
MANAGEMENT OF PNEUMONIA
 Antibiotics
 Administer first dose within 4 hours of presentation in hospital and treatment
should not be delayed while investigations are awaited.
 The antibiotic regimen should be adjusted specifically once culture and
sensitivity results are available.

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TYPE OF PNEUMONIA MANAGEMENT
EMPERICAL TREATMENT
 Benzyl penicillin 1-2 MU IV QID for 5 days (as soon as the symptoms and respiratory
rates are controlled change to oral medication i.e. Amoxicillin 500mg for remaining
days) or
 Ceftriaxone 1-2g daily for 7 days. If allergic to penicillin use
 Erythromycin 500mg PO QID for 7 days
MILD FORM OF COMMUNITY ACQUIRED PNEUMONIA
Uncomplicated “Typical”  Can be treated as outpatient
pneumonia  Amoxicillin 500mg PO TDS for 7-10 days or
 Ampicillin 500mg PO QID for 7-10 days or
 Procaine penicillin 600, 000 IU IM every 12 hours
 Supportive therapy
“Atypical Pneumonia”  Erythromycin 500mg PO QID for 7-10 days or
 Doxycycline 100mg PO BD for 7-10 days
 Supportive therapy
SEVERE FORMS OF COMMUNITY ACQUIRED PNEUMONIA
Community acquired  High dose of crystalline penicillin 3-4 million IU IV
every 4-6 hours or
 Ceftriaxone 1g IV daily or BD or
 Ampicillin 500mg IV QID or Cefotaxime
 In severely ill patients erythromycin or a
fluoroquinolone can be added.
 Choice of antibiotics may be modified based on culture
and sensitivity results if available
 If the patient improves IV treatment can be changed to
oral after 3-4 daus to complete a 7-10 days course
Aspiration pneumonia  Gentamycin 5mg/kg BD or 10mg IM OD
 Ciprofloxacin 10mg/kg TDS

SUPPORTIVE THERAPY
 Oxygen: supplemental oxygen should be administered to maintain saturations
between 94% and 98% provided the patient is not at risk of carbon dioxide
retention due to loss of hypoxic drive in COPD. In patients with known COPD,
oxygen saturations should be maintained between 88% and 92%, normally with
controlled oxygen via fixed percentage delivery mask.

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 Ensure adequate oxygenation to patients with cyanosis, significant
hypoxemia, severe dyspnea, circulatory disturbance or delirium.
 Intravenous fluids: required in hypotensive patients showing evidence of volume
depletion.
 Thromboprophylaxis if admitted for more than 12 hours subcutaneous low
molecular weight heparin should be prescribed unless contraindications exist.
 Physiotherapy: chest physiotherapy is not needed unless sputum retention is an
issue.
 Nutritional supplementation
 Antipyretics should be given.
 Analgesia: paracetamol or NSAIDs help treat pleuritic pain, thereby reducing the
risk of further complications due to restricted breathing because of pain e.g.
sputum retention, atelectasis or secondary infection.
 Paracetamol 500mg to 1g PO TDS/QID

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COMPLICATIONS OF PNEUMONIA
LOCAL COMPLICATIONS
 Parapneumonic effusion and empyema: early indications of empyema are
ongoing fever and rising or persistently elevated inflammatory markers despite
appropriate antibiotic therapy.
 Thoracentesis should be performed to make a diagnosis.
 Light’s criteria can be applied to assess whether an effusion is transudative
or exudative.

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 If empyema develops the fluid should be urgently drained to prevent further
complications such as development of a thick pleural ring or prolonged
hospital admission. The presence of empyema further increases mortality
risk.
 Lung abscess: severe localized suppuration within the lung associated with cavity
formation visible on the chest X-ray or CT scan, often with a fluid level (which
always indicated an air-liquid interface). Causes include
 Aspiration pneumonia: rare complication, a history of severe alcohol
consumption or impaired swallowing in a patient with pneumonia suggests
aspiration.
 Tuberculosis
 Staph pneumonia or Klebsiella pneumonia
 Foreign body inhalation
 Bronchial obstruction by an endoluminal cancer
 Spread from an amoebic liver abscess in right lower lobe from
transdiaphragmatic spread.
 Septic emboli usually containing Staphylococci: can cause multiple lung
abscesses. The presence of multiple lung abscesses in an injecting drug user
should prompt investigation for infective endocarditis or the tricuspid valves
(or rarely pulmonary). Infarcted areas of lung (due to pulmonary emboli)
occasionally cavitate and become infected.
 Emphysema
DISTANT COMPLICATIONS
 Septic arthritis
 Meningitis
 Pneumonia can progress to sepsis, sometimes with septic shock
 Heart failure (Cor pulmonale)

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HOSPITAL ACQUIRED PNEUMONIA
 This is defined as new onset of cough with purulent sputum along with a
compatible X-ray demonstrating consolidation in patients who are beyond 2 days
(48 hours) of their initial admission to hospital or who have been in a healthcare
setting within the last 3 months.
 Hospital acquire pneumonia (HAP) includes the presence of a new progressive
infiltrate of chest X-ray plus at least 2 of the following:
 Fever> 37.8 oC
 Leukocytosis >10, 000/mm3
 Production of purulent sputum
 Other findings: dyspnea, hypoxemia and chest pain
 Hospital acquired pneumonia is the second most common form of hospital-
acquired infection after urinary tract and carries a significant mortality risk,
particularly in the elderly or those with co-morbidities such as stroke, respiratory
disease or diabetes.
 The causative agents differ from those of community acquired.
 Viral or fungal pathogens are not responsible in immunocompetent host.
 Aerobic Gram-negative bacilli are commonly involved (e.g. P. aeruginosa, E.
coli, Klebsiella and Acinetobacter species).
 Staphylococcus aureus is increasingly recognized in hospital acquired
pneumonia especially methicillin-resistant S. aureus (MRSA).
 HAP due to S. aureus is more common in patients with diabetes mellitus, head
trauma and patients in intensive care units.
 Empirical antimicrobial therapy should be tailored accordingly.
 Other conditions should be excluded including aspiration of gastric contents due
to impaired swallowing or bulbar weakness.
 Treatment:
 Antibiotics: should be initiated empirically which latter on may be modified
based on culture and sensitivity result.
 The selection of drugs should be guided by an understanding of local patterns
of antibiotic resistance.
 Antibiotics should cover at least gram negatives and S. aureus
o Ceftriaxone 1g IV BD daily plus Cloxacillin or methicillin or
o Levofloxacin 500mg IV/day
 When resistant organisms are suspected:
o Cefotaxime 750mg IV TDS plus vancomycin 1g IV BD.

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 Prevention:
 Strict hand washing protocols by health care providers
 Extubate an intubated patient as soon as the patient is stable
 Remove NG tubes when the patient is stable
 Proper aseptic handling of IV lines
PNEUMONIA IN IMMUNOCOMPROMISED
 Immunocompromised patients are at risk of pneumonia from the usual organisms
as well as the opportunistic pathogens which would not be expected to cause
disease.
 Pathogens like Streptococcus pneumonia, which cause pneumonia in
immunocompetent people, are still responsible for the majority of pneumonia
in compromised patient.
 These opportunistic pathogens can be commonly occurring microorganisms or
bacteria, viruses and fungi that are less often.
 The symptom pattern may resemble community acquired pneumonia or may be
more non-specific.
 A high degree of clinical suspicion is therefore necessary when assessing an ill
patient who is immunocompromised.
 Immunocompromised host include patients with AIDS, acute leukemia, cancer
chemotherapy, diabetes, sickle cell disease, Hodgkin’s disease and
corticosteroids treatment.
 Diagnosis:
 Sputum examination and culture are used but they are not specific.
 Transtracheal aspirate, bronchoscopy and biopsy have high accuracy,
however these are done only in specialized hospitals.
 Acutely ill patients who have suspected bacterial infections are often treated with
antibiotics selected on the basis of probability and the findings with sputum gram
stain and culture. Later treatment is adjusted on the basis of more definitive
diagnostic evaluation.
PNEUMOCYSTIS JIROVECI
 Pneumocystis pneumonia (PCP) is one of the most common opportunistic
infections encountered in clinical practice.
 It affects patients on immunosuppressant therapy such as long-term
corticosteroids, monoclonal antibody therapy, or methotrexate for autoimmune
disease, those on anti-rejection medication post-solid organ transplantation or

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following stem cell transplantation and patients infected with HIV (with CD4
counts less than 200/mm3).
 Pneumocystis Jirovercii is found in the air, and pneumonia arises from re-
infection rather than reactivation of persisting organisms acquired in childhood.
 Clinically the pneumonia is associated with a high fever, breathlessness and dry
cough.
 A characteristic feature on examination is rapid desaturation on exercise or
exertion.
 The typical radiographic appearance is of a diffuse bilateral alveolar and
interstitial shadowing beginning in the perihilar regions and spreading out in a
butterfly pattern.
 Other chest X-ray appearances include localized infiltration, nodules, cavitation
or a pneumothorax.
 Empirical treatment is justified in very sick high-risk patients but wherever
possible the diagnosis should be confirmed by indirect immunofluorescence on
induced sputum or Bronchoalveolar lavage fluid.
 First-line treatment of PCP is with high-dose co-trimoxazole (Septrin).
 Cotrimoxazole 960 mg every 12 hours (or 3 tablets 480mg PO QID) for 21
days in combination with a steroid i.e. Prednisolone for PCP starting with
40mg per day and reducing by 5mg every 3 days for adults.
o Co-trimoxazole= (Trimethoprim 1 part + 5 parts sulfamethoxazole)
o (Trimethoprim 160mg/ Sulfamethoxazole 800mg)-960mg
o (Trimethoprim 80mg/Sulfamethoxazole 400mg)- 480mg
o Single-strength tables of TMP-SMX (Septrin) are effective and may be
less toxic than double-strength tablets.
 Alternatively, dapsone +/- pyrimethamine or pentamidine nebulizers or
atovaquone can be used.
 Adjunct therapy: Supplemental oxygen.

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TUBERCULOSIS
 This is a chronic necrotizing  TB can be classified into:
disease caused by Mycobacterium  Primary tuberculosis (PTB):
tuberculosis complex usually 80% of cases
affecting the lungs and sometimes o 75-80% of all PTB cases
some other organs. are smear-positive PTB.
 Tuberculosis is caused by a range o 20-25% of all PTB cases
of mycobacterium including the are smear-negative PTB.
species M. tuberculosis (most  Extra-pulmonary TB (EPTB)-
common), M. bovis (reservoir 20% of cases.
cattle), M. africanum (reservoir
TRANSMISSION
human) and M. microti.
 Adults with smear positive TB such
 M. tuberculosis is an encapsulated
as cavitory TB and laryngeal TB
obligate aerobe, facultative
are the sources of infection.
intracellular pathogen rod-shaped,
non-spore forming, thin bacterium  Patients who are culture-negative
pulmonary TB and extra pulmonary
measuring 0.5m by 3m.
disease are not infectious.
 The mycolic acid in the cell wall
 M. tuberculosis is commonly
and the capsule impede
transmitted from a patient with
phagocytosis.
infectious tuberculosis to a healthy
 They are slow growing with a
individual through:
generation time of 12-18 hours.
 Inhalation of droplets excreted
 Due to high lipid content in the cell
via coughing, sneezing or
wall, they are relatively
speaking.
impermeable and stain only weakly
 Only a small number of
with Gram-stain.
bacteria need to be inhaled to
 The bacterium is demonstrated by develop infection but not all
acid fast staining technique. those who are infected develop
 When stained with a dye combined active disease.
with phenol and washed with acidic  The outcome is dependent on a
organic solvents, they resist number of factors including the
decolorization and therefore are host’s immune response.
termed ‘acid-fast bacilli’-AFB.

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 Drinking non-sterilized infected  Immune suppressive drugs like
cow milk could also transmit M. long-term corticosteroids (e.g.
bovis but the incidence seems to be prednisolone)
decreasing because of health  Old age: decreased immunity
education on boiling or  Malnutrition is a very
pasteurizing milk. important factor for the
 Factors that facilitate transmission development of disease.
of PTB are:  Alcohol
 Presence of a contact
PATHOGENESIS
 Infectivity of the contact
 Transmission is through droplet
(patients with heavy bacterial
infection. Only a small number of
load)
bacteria need to be inhaled to
 Duration of contact (prolonged
develop infection but not all those
exposure)
who are infected develop active
 Intimacy (how close the source
disease.
and the subject are)
 Environment: overcrowding,  M. tuberculosis interacts with host
poor ventilation immune system immediately after
entry. It initiates the recruitment of
 Patients who acquire the infection
macrophages and lymphocytes.
may not develop the disease. The
rate of clinical disease is highest  Activated alveolar macrophages
during late adolescence and early ingest the bacilli, after which they
adulthood but the reasons are not release neutrophil chemo-
clear. attractants and cytokines to activate
other immune system components
 Infections are more common in
and try to control the infection or
young women than men.
multiplication of bacilli.
 Conditions that increase the likely
 This process will recruit cells (cell
hood of developing active TB
mediated immune response).
include:
 HIV (co-infection) due to  Macrophages present the antigen to
suppression of cellular the T-lymphocytes.
immunity.  Macrophages undergo
 Hematologic and other transformation into epithelioid and
malignancies: lymphoma, Langerhans cells which aggregate
leukemia, malignancies. with lymphocytes to form the
 Chronic renal failure classical tuberculous granuloma.
 Diabetes mellitus

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 A delayed hypersensitivity-type (Ghon focus + ipsilateral calcified
reaction occurs resulting in tissue mediastinal nodes).
necrosis and formation of a  If no further complication arises the
granuloma. lesion may eventually be calcified
 Activated cells aggregate around and is clearly seen on X-ray
the lesion and the center becomes  The center however may still
necrotic, soft cheese like material contain live bacteria that become
called caseous necrosis. dormant.
 Granulomatous lesions consist of a  These bacteria will flare up and
central area of necrotic material multiply when the person’s
(caseation), surrounded by immunity is depressed.
epithelioid cells and Langhans’  But if the bacteria inside the
giant cells with multiple nuclei, macrophage multiply rapidly, they
both cells being derived from will kill the macrophage and are
macrophages. Lymphocytes are released but to be taken up by other
present and there is a varying macrophages again. If this process
degree of fibrosis. is not arrested, patients may
 Numerous granulomas aggregate to develop disseminated infection.
form a primary lesion or ‘Ghon  On initial contact with infection
focus’ characteristically situated in <5% of patients develop active
the periphery of the lung. disease. This percentage increases
 Spread of organisms to the hilar to 10% within the first year of
lymph node is followed by a similar exposure.
pathological reaction and the  In the majority of people who are
combination of the Ghon focus and infected by mycobacterium spp, the
regional lymph nodes is referred to immune system contains the
as the ‘Primary complex of Ranke’. infection and the patient develops
 The primary complex is cell mediated immune memory to
encapsulated in a fibrous capsule, the bacteria. This is termed latent
limiting the spread of the bacilli, so tuberculosis.
called latent TB.  The majority of TB cases are due to
 The primary complex of Ranke is reactivation of latent infection. The
seen in ‘healed’ primary pulmonary initial contact usually occurred
tuberculosis and is a later many years or decades earlier. In
manifestation of the ghon complex patients with HIV infection newly
acquired TB infection is also

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common. This is called reactivation CLINICAL
tuberculosis. MANIFESTATIONS
PULMONARY TUBERCULOSIS
 Patients are frequently
symptomatic with a productive
cough and occasionally hemoptysis
along with systemic symptoms of
weight loss, fever and sweats
(commonly at the end of the day
and through the night).
 This can be classified as
 Primary Pulmonary
tuberculosis
 Secondary/ Re-activation
Tuberculosis
 Note: extrapulmonary involvement
is far less common in primary
disease and is usually only seen in
regions of high endemnicity.
PRIMARY PULMONARY
DISEASE
 Clinical illness follows after
primary tuberculosis (no history of
prior TB infection).
 This is common in children <4
years of age, it results from an
initial infection.
 Frequently it involves the middle
and lower lung zones.
 In the majority it heals
spontaneously leaving a healed scar
on the lung called Ghon lesion.

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 It may be contained by immunity  Early in the course patients may
into dormant stage only to flare up have intermittent fever, night
in immunocompromised state (re- sweats, weight loss, anorexia and
activation). weakness. Most patients have
 In children or in immune cough which may be dry at first but
compromised individuals the later becomes productive of whitish
disease is usually rapid involving sputum, it is frequently blood
lungs, pleura and mediastinal streaked.
lymph nodes.  Patients may have exertional
 It may disseminate into the blood dyspnea, and hoarseness of the
stream and cause miliary voice if there is laryngeal
tuberculosis. involvement.
 Characterized by 2-3 weeks of  Physical examination:
fever, night sweats, anorexia,  Chronically sick patient
weight loss and a dry cough.  Pallor
 Finger clubbing
SECONDARY/RE-ACTIVATION  Inspiratory crepitations are
PULMONARY TUBERCULOSIS seen in some cases
 If no clinical disease is developed  Laboratory findings:
after primary infection, dormant  ESR: raised
bacilli may persist for years or  Full blood count: Anemia,
decades before being reactivated Leukocytosis
when this happens, it is called  Sputum examination
secondary (post primary) (microscopy, culture and
tuberculosis. sensitivity) may be positive for
 It is more common in adults and AFB
typically involves the apical lobes,  GeneXpert
where oxygen tension favors  CXR findings are non-specific:
survival of the strictly aerobic o Infiltrations,
organism but any portion of the o Consolidation with or
lungs can be involved. without cavitation
 The disease could extend from o Pleural effusion
small infiltrates to large cavitory o Thickening or widening or
lesions. Patients with cavitory the mediastinum caused
lesion expectorate tuberculosis by hilar or paratracheal
bacilli with sputum. adenopathy

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 Extrathoracic nodes are more
commonly involved than
intrathoracic or mediastinal.
 The commonest sites are cervical
and supraclavicular.
 Other sites include axillary and
inguinal.
 The nodes are usually painless
(non-tender) and initially mobile
but become matted together
overtime, sometimes pus may be
discharging (the overlying skin is
frequently indurated or there can be
sinus tract formation).
 The node becomes necrotic
centrally and can liquefy and be
fluctuant if peripheral.
EXRAPULMONARY  Characteristically there is no
erythema (cold abscess formation)
TUBERCULOSIS
 Half the cases do not have any
 Accounts for about 20% of cases in
constitutional features such as fever
those who are HIV-negative but is
or night sweats.
more common in HIV-positive
 The diagnosis is made by fine
individuals.
needle aspiration (under
 Commonly affected organs are
radiological guidance) and/or
lymph nodes, pleura, meninges,
lymph node biopsy.
genitourinary tract, bones, joints,
Histocytopathological examination
adrenal glands and peritoneum.
as well as culture can be done on
LYMPH NODE the sample.
TUBERCULOSIS (TB  Mediastinal nodal sampling
LYMPHADENITIS) (endobronchial ultrasound
 This is the second most common transbronchial needle aspiration
site of infection. mediastinoscopy/mediastinotomy)
 Seen more in HIV patients.  Nodes typically can be enlarged for
several months prior to diagnosis.

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 On CT imaging, the central area  Dysuria, intermittent hematuria and
appears necrotic. flank pain are common
presentations.
 But it may be asymptomatic for a
long period of time.
 Urinalysis shows pyuria and
hematuria without bacteria in
majority of cases (commonly called
sterile pyuria).
 Diagnosis may be reached by
culturing urine repeatedly for M.
tuberculosis.
 It affects more females and may
PLEURAL TUBERCULOSIS present as infertility or pelvic pain.
 Pleural involvement may be
asymptomatic or patients could SKELETAL TUBERCULOSIS
have fever, pleuritic chest pain and  It is usually reactivation of
dyspnea. hematogenous site or extension
 On physical examination, typically from a nearby lymph node. The
there will be decreased tactile most common sites are spine, hips
fremitus, dullness and decreased and knees.
breath sounds on the affected side.  Spinal tuberculosis is called Pott’s
 Fluid should be aspirated from disease or tuberculous spondylitis.
pleural space (thoracentesis) and In adults, lower thoracic and
analyzed. lumbar vertebrae are commonly
affected. Patients may present with
 Chest X-ray is also helpful in
swelling (Gibbus) and pain on the
diagnosis; it may show
back with or without paraparesis or
homogenous opacity with meniscus
paraplegia due to cord
sign.
compression.
 Empyema (pus in the pleural space)
 Tuberculosis in other bones or
may complicate tuberculosis
joints usually presents with pain
occasionally.
and swelling.
GENITOURINARY  Joint tuberculosis- any joint can be
TUBERCULOSIS affected but weight bearing joints,
 Can involve any part of the system. particularly the hip and knee joints
are commonly involved.

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 Patients present with progressive but joint space reduction and
joint swelling, usually with pain bone destruction develop
and limitation of movement. If left rapidly if treatment is delayed.
untreated, the joint may be  MRI shows the abnormality
destroyed. earlier in the spine and CT-
 TB arthritis occurs as the primary guided biopsy from the affected
disease in children. In adults, it is disc is often necessary to obtain
usually due to hematogenous cultures.
spread from secondary pulmonary  Treatment is as for pulmonary
or renal lesions. tuberculosis with therapy for 9
 The onset is insidious and months. The joint should be
diagnosis often delayed. rested and the spine
 The organism invades the immobilized in the acute phase.
synovium or intervertebral  TB osteomyelitis:
disc.  This is usually due to
 There are caseating granulomas hematogenous spread from a
and rapid destruction of reactivated primary focus in the
cartilage and adjacent bone. lungs or gastrointestinal tract.
 Some patients develop a  The disease starts in intra-
reactive polyarthritis (Poncet’s articular bone.
disease).  The spine is commonly
 The Hip or knee (30%) is quite involved (Pott’s disease), with
commonly affected but around damage to the bodies of two
50% develop spinal disease. neighboring vertebrae leading
 The patient is febrile, has night to vertebral collapse and acute
sweats, is anorexic and loses angulation of the spine
weight. (gibbus).
 The usual risk factors for TB  Pus can tract along tissue
apply- debility, excess alcohol planes and discharge at a point
use or immunosuppression far from the affected vertebrate.
especially with HIV/AIDs.  Symptoms consist of local pain
 Investigations should include and later swelling if pus has
culture of fluid and culture & collected. Systemic symptoms
biopsy of synovium. of malaise, fever and night
 A chest X-ray should be sweats occur.
performed. Initially joint or
spinal X-rays may be normal

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 Treatment is as for pulmonary  Bacteria could reach GI by
tuberculosis but extended to 9 swallowing sputum,
months together with initial hematogenously or by ingesting
immobilization. raw milk. The commonest sites are
terminal ileum and cecum. The
TUBERCULOSIS MENINGITIS
colon can also be affected.
 It is commonly seen in children and
 Patients usually present with
immune-compromised people
Abdominal pain (right iliac fossa
particularly patients with HIV.
pain), anemia, diarrhea, symptoms
 More than half have evidence of
of intestinal obstruction and
disease in the lungs.
hematochezia (frank blood on
 Patients with TB meningitis present
stool) may be presenting
with headache, behavioral changes
symptoms.
and neck rigidity for about two
 One-third of patients present
weeks or more. Patients may have
acutely with intestinal obstruction
cranial nerve paralysis and seizure.
or generalized peritonitis. 50%
 Cerebral spinal fluid (Lumbar
have X-ray evidence of pulmonary
puncture) analysis
TB.
 Increased WBC count
 There could be associated fever,
predominantly lymphocytes
night sweats, weight loss and
and very high protein (usually
anorexia. There could be a palpable
>2-3g/L) and low glucose
mass in the abdomen. Patient could
content (<1/2 blood glucose).
have involvement of the
But any of these could be
peritoneum, liver and spleen.
normal in the presence of the
 Differential diagnosis includes
disease.
Crohn’s disease and cecal
 AFB can be seen in sediment
carcinoma.
CSF in only 20% of cases, this
percentage increases if  A small bowel follow-through may
examined CSF volume is show transverse ulceration, diffuse
increased. Culture may be narrowing of the bowel with
positive in about 80% but it shortening of the cecal pole.
takes 4 to 6 weeks to grow.  Ultrasound or CT shows additional
mesenteric thickening and lymph
GASTROINTESTINAL node enlargement.
TUBERCULOSIS  Histology and culture of tissue is
 TB can affect anywhere from the desirable but not always possible.
mouth to the anus.

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 Specimen can be obtained by  Treatment is as for pulmonary TB
colonoscopy or laparoscopy but but prednisolone 60mg daily for 2-
laparotomy is required in some 6 weeks is added.
cases.
MILIARY TUBERCULOSIS
PERICARDIAL  This is secondary to hematogenous
TUBERCULOSIS (TB dissemination of the bacilli to
PERICARDITIS) multiple sites, including the central
 Arises from ruptured abdominal nervous system in 20% cases.
lymph node or hematogenous  It is more common in children and
dissemination. immune-compromised patients.
 Patients usually present with  Manifestations are nonspecific with
chronic low-grade fever fever, night sweats, anorexia,
(particularly in the evening), weakness and weight loss. Patients
associated with feature of acute may or may not have respiratory
pericarditis, retro-sternal pain, symptoms.
cough, dyspnea and generalized  Physical examination:
edema because of pericardial  Seriously sick patient with
effusion. Cardiac tamponade may hepatomegaly,
appear later.  splenomegaly and
 Constrictive pericarditis may  lymphadenopathy.
develop as a complication of TB  Since symptoms and signs are not
pericarditis even after treatment specific, high index of suspicion is
and patients can present with required for the diagnosis.
symptoms and signs of right sided  Systemic upset is the rule, with
heart failure. respiratory symptoms in the
 Diagnosis is usually reached by majority. Other findings are liver
analyzing the pericardial effusion. and splenic microabscesses with
It may show lymphocytosis but deranged liver enzymes or
yield for AFB is low. cholestasis and GI symptoms.
 Chest X ray may show enlarged  Chest X-ray usually shows miliary
heart shadow which suggests pattern of infiltration bilaterally
effusion. Ultrasound should be (millet seed like lesions)
done when available and it
demonstrates effusion.

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 Diagnosis:  Differential diagnosis for miliary
 Blood cultures TB on X-ray includes:
 Bronchoalveolar lavage fluid  Miliary tuberculosis
(usually smear negative but  Histoplasmosis
culture-positive)  Sarcoidosis
 Lumbar puncture should be  Pneumoconiosis
performed in all cases unless  Pulmonary siderosis
contraindicated to assess for  Bronchoalveolar carcinoma
CNS involvement (affects  Hematogenous metastasis from
treatment duration) primary thyroid cancer, kidney,
 Sampling of other involved trophoblast and some sarcomas.
organs often necessary.
SKIN MANIFESTATIONS OF
TB
 TB can occasionally cause skin
manifestations:
 Lupus vulgaris: usually arises
as a post-primary infection. It
usually presents on the head or
neck with red-brown nodules
that look like apple jelly when
pressed with a glass slide
(‘diascopy’). They heal with
scarring and new lesions slowly
spread out to form chronic
solitary erythematous plaque.
Chronic lesions are at high risk
of developing squamous cell
carcinoma.
 Tuberculosis verrucosa cutis:
arises in people who are
partially immune to TB but
who suffer a further direct
inoculation in the skin. It
presents as warty lesions on a
‘cold’ erythematous base.

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 Scrofuloderma: arises when an o Sputum (more than 2
infected lymph node spreads to samples are taken to
the skin causing ulceration, increase diagnostic yield).
scaring and discharge. Induced sputum (inhale
 The tuberculides: are a group of hypertonic saline which
rashes caused by an immune induces coughing) gives
manifestation of TB rather than more diagnostic yield than
direct infection. Erythema bronchoscopic samples.
nodosum is the commonest. o Bronchoalveolar lavage
Erythema induratum (“Bazin’s fluid if cough
disease) produces similar deep unproductive and induced
red nodules but these are sputum not possible.
usually found on the calves o Aspiration of pleural fluid
rather than the shins and they and pleural biopsy.
often ulcerate. o Gastric aspirates may be
useful in pediatric disease.
DIAGNOSIS o Nasoendoscopic or
 Patients who have suggestive bronchoscopic
symptoms and signs for examination/biopsy of
tuberculosis should undergo further vocal cords with biopsy
tests. for smear/culture and
 AFB microscopy histology in laryngeal
o Specimen: sputum, disease
pleural, peritoneal, CSF  Gene expert: PCR
and body discharges.  Chest X-ray: varies but
o Stains used Ziehl-Neelsen. typically there will be nodular
o Definitive diagnosis infiltrates and cavities in the
depends on detection of upper lobe, pleural effusion is
M. tuberculosis from a also common. Chest X-ray
culture of specimen. Since findings do not confirm
culture routinely takes 4-6 diagnosis of TB.
weeks to grow, the culture  Raise ESR: non-specific, there
is often not available to could also be anemia of chronic
guide initial therapy. It is illness.
also necessary in order to  Do not use PPD testing to
do sensitivity testing. diagnose acute cases of TB.
PPD is relatively insensitive

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and nonspecific with acute levels may be mildly or
illness. moderately high.
 Adenosine deaminase test (ADA)  Urine LAM can also be done
can also be done.  This detects the
 ADA is an enzyme present in lipoarabinomannan (LAM)
the body whose main function antigens in urine samples
is to aid in purine metabolism.  Other important tests:
 It helps in the breakdown of  Full blood count
adenosine from food and  Liver function tests
thereby facilitates the turnover  Kidney function tests (Urea,
of nucleic acids in different electrolytes and creatinine)
body tissues.
 In humans, the primary ANTITUBERCULOSIS
function of ADA is to keep the CHEMOTHERPAY
immunity system developed  Patients with fully sensitive TB
and maintained. It also has require 6 months of treatment
minor function functions such excluding TB meningitis for which
as gestation maintenance, the the recommended duration is at
release of amino acids in the least 12 months.
body, neurotransmission, and  In CNS and pericardial disease,
epithelial cell differentiation. corticosteroids are used as adjunct
 ADA test is done to measure treatment to reduced long-term
the level of ADA in pleural complications. (Prednisolone 60mg
fluid in the diagnosis of TB. In PO for 2-6 weeks then taper)
very rare cases it is done to test  Drugs currently in use include:
other infections. streptomycin (S), Ethambutol (E),
 In rare cases ADA test can also Isoniazid (H), Rifampicin (R) and
be done on cerebrospinal fluid pyrazinamide (Z)
or peritoneal fluid.  The treatment of tuberculosis
 Normal range is less than through drug observed therapy has
40L. 2 phases:
 If levels are increased in pleural  The intensive (initial) phase: 4
fluid the result is indicative of fixed drug combination
Mycobacterium tuberculosis (4FDCs) are given for the first
infection in the pleural. 2 months or until sensitivity
 In sarcoidosis, pulmonary testing is known.
embolus, cancer or lupus ADA

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o Drugs include: dangerous only because it
Rifampicin, Isoniazide, could stain contact lenses and
Pyrazinamide and white underwear.
Ethambutol (given if  Ethambutol is associated with
sensitivity is not known) optic neuritis which can cause
 The continuation phase: 2 color blindness and other visual
drugs are used for the disturbances.
remaining 4 months.  Pyrazinamide can cause benign
o Drugs include Rifampicin hyperuricemia. Don’t treat the
and Isoniazide hyperuricemia unless there are
 The only forms of TB that symptoms of gout associated
definitely must be treated for longer with it, which rarely occurs.
than 6 months are TB meningitis
(12 months), TB in pregnancy (9
months) and osteomyelitis.
 HIV positive persons may be
treated for 6-9 months, there is no
clear evidence that 9 months is
necessary even in HIV positive
persons, 6 months therapy is
effective.
 Isoniazide should be given with
Vitamin B6 (Pyridoxine 10mg OD)
to prevent peripheral neuropathy
that can be a side effect of
isoniazid.
 Side effects:
 All TB medications can cause
liver toxicity except
streptomycin and ethambutol.
Isoniazide also causes
peripheral neuropathy because
of pyridoxine deficiency.
 Rifampicin is associated with
causing a benign change in the
color of all bodily fluids to
orange/red. This color is

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DRUG SIDE EFFECT PREVENTIVE

MEASURE
RIPAMPICIN (inhibits Major: Hepatitis (inducer of P450), acute Stop Rifampicin if
DNA-dependent RNA renal failure, shock, purpura transferases are >3 times
polymerase- transcription (thrombocytopenia) elevated.
inhibitor) Minor: orange, pink or red discoloration of Reassurance and advice
tears, sweat and urine + nausea, abdominal patient to take drugs with
pain a small meal
ISONIAZID: inhibits Major: Jaundice and hepatitis (age Stop isoniazide
mycolic acid synthesis dependent)
(Cell wall synthesis Minor: burning sensation in the feet Give pyridoxine (Vitamin
inhibitor) (peripheral neuropathy), sideroblastic B6) 10mg OD
anemia
PYRAZINAMIDE Major: hepatotoxicity/ jaundice, Stop pyrazinamide
(unknown mode of hyperuricemia
action) Minor: Joint pain (pyrazinamide reduces Analgesics
the renal excretion of urate and may
precipitate hyperuricemia gout)
ETHAMBUTOL Major: optic neuritis: visual impairment Stop ethambutol
(Inhibits the synthesis (dose-related optic retrobulbar neuritis that
arabinogalactan-a cell presents with color blindness for green,
wall component) reduction in visual acuity and a central
scotoma-commoner at doses of 25mg/kg)

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Minor: none
STREPTOMYCIN Major: Ototoxicity: vertigo and hearing Stop streptomycin
(aminoglycoside- protein impairment, neuromuscular blockade (by
synthesis inhibitor) decreasing acetylcholine release)
Minor: mild skin rash, perioral paresthesia symptomatic treatment

 Streptomycin should not be given to pregnant women and patients with renal
failure and ear problems. It should be replaced by ethambutol. Streptomycin dose
should not be more than 750mg if the patient’s age is >50 years.
 Children who are 6 years or below should not be given ethambutol because of
damage to the eyes and children may not complain of it.
 Streptomycin is used only if patients are very ill, have multidrug-resistant TB or
are not responding adequately to therapy.
 Patients should be strictly followed after initiation of the drugs.
 Corticosteroids are added to the anti-TB in meningitis, pericarditis and spinal TB
to reduce long term complications. Adrenal TB patients should have replacement
therapy.
 Close follow-up is needed and frequently children are put on Direct Observed
therapy (DOTS) where nursing staff observe the therapy being given 3 times a
week.
 During the intensive phase the health worker or trained person watches as the
patient swallows the drugs in his presence
 During the continuation phase the patient is issued medicines for one week
in a multi-blister combo-pack of which the first dose is swallowed by the
patient in the presence of the health worker or trained person.
 The consumption of medicines in the continuation phase is also checked by
return of the empty multi-blister combo-pack when the patient comes to
collect medicine for the next week.
 DOTS is required especially for:
o Patients thought unlikely to comply
 History of serious mental illness
 History of non-adherence of TB therapy in past or during current
treatment course
o Street or shelter-dwelling homelessness
o Multi-drug resistant TB

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 Drug resistant TB accounts for possibly only 2% of the million cases of TB in
the world.
 It arises due to incomplete or incorrect drug treatment and can be spread from
person to person.
 Factors associated with an increased risk of drug-resistant TB:
 History of prior drug treatment of TB (particularly if unsupervised, self-
administered treatment)
 Co-infection with advanced HIV and previous TB treatment
 Infection acquired in region with high rates of drugs resistance
 Contact with a known case of resistant TB
 Failure to respond to empiric TB therapy despite documented adherence
 Exposure to multiple courses of fluoroquinolone antibiotics for presumed
community acquired pneumonia
 Healthcare workers exposed to cases of resistant TB.
 Types of drug resistance:
 Primary drug resistance: infected with TB which is already drug resistant
 Secondary (Acquired) drug resistance: drug resistance develops during
treatment
 Drug resistant TB denotes resistance to one of the first line TB drugs (being
Rifampicin or isoniazid)
 Multidrug resistant (MDR) TB denotes resistance to at least 2 main first line TB
drugs i.e. rifampicin and isoniazide.
 Extreme drug resistant (XDR) TB denotes MDR-TB + resistance to any
fluoroquinolone and at least 1 of the 3 injectable second-line drugs (amikacin,
kanamycin or capreomycin)
 The second line drugs include:
 Oral: fluoroquinolones
o Ciprofloxacin
o Levofloxacin
o Movifloxacin
o Gatifloxacin
 Injectables
o Amikacin
o Kanamycin
o Capreomycin
o Streptomycin

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 TB defaulter: this a patient whose treatment is interrupted for more than 2
consecutive months.
 Treatment failure in TB: This is the presence of continued or recurrently positive
cultures during the course of antituberculosis therapy.
 After 3 months of multi-drug therapy for PTB caused by drug susceptible
organisms, 90-95% of patients will have negative cultures and show clinical
improvement.
 All patients with positive cultures after 3 months of appropriate treatment
must be evaluated carefully to identify the cause of the delayed conversion.
 Patients whose sputum culture remains positive after 4 months of treatment
should be classified as treatment failure.
 The reasons for this include:
o Non-adherence
o Drug resistance
o Malabsorption of drugs
o Laboratory errors
o A few patients take a long time to respond as part of extreme biological
variation.
 TB relapse: this is a patient who has become (and remained) culture negative
while receiving therapy but after completion they become culture positive or have
clinical or radiological deterioration that is consistent with active TB.
 Chemoprophylaxis can be offered to reduce the risk of active infection especially
in patients at risk e.g. individuals with TB contact.
 300mg daily for 6 months, alternatively 300mg daily for 3 months, to be
taken in combination with rifampicin.
 The BCG vaccine is a live attenuated vaccine derived from M. bovis that has lost
its virulence. It has variable efficacy but it is still recommended in certain
situations in developed countries. It has been shown to reduce the risk of
disseminated and CNS TB in babies and children and is therefore used
worldwide. There are safety concerns in babies with HIV. Its efficacy in adults is
very variable.

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COMPLICATIONS OF TUBERCULOSIS
 Pulmonary complications:
 Pleurisy
 Pleural effusion
 Empyema
 Pneumothorax
 Aspergillosis
 Endobronchitis
 Bronchiectasis
 Laryngitis
 Cor pulmonale
 Ca bronchus
 Miliary TB

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CHRONIC OBSTRUCTIVE PULMONARY DISORDERS

 COPDs are conditions characterized by chronic partial/complete irreversible
airway obstruction causing an increased resistance to outflow of air.
 The airflow limitation is usually progressive and associated with an abnormal
inflammatory response of the lungs to noxious particles or gases.
 The obstruction can occur at any level (from the trachea to the terminal and
respiratory bronchioles)
 These disorders include: emphysema, chronic bronchitis and asthma (although
changes in asthma are reversible it is therefore not essentially a true COPD)
 COPDs can occur together in the same individual in a variable proportion but the
manifestations of one often predominates the clinical picture.
 The older terms ‘chronic obstructive airway disease’ and ‘chronic obstructive
lung disease’ are synonymous with COPD.
 Previous (before 1979) patients with COPD were often classified by:
 Symptoms:
o Chronic bronchitis
o Chronic asthma
 Pathological changes: emphysema
 Physiological correlates
o Pink Puffers
o Blue bloaters
 Recognition that these entities overlapped and often co-existed led to
introduction of the term COPD.
 COPDs can occur with a number of co-morbidities e.g. ischemic heart disease,
hypertension, diabetes, heart failure and cancer, suggestive that it may be part of
a generalized systemic inflammatory process.
 COPDs are a major health problem especially in Western societies because of the
effect of cigarette smoking and aging.
 Males are affected more than females which could be attributed to the high
prevalence of smoking in males. Nowadays, the incidence of this disease in
females is increasing because of the increasing smoking habit.
 In patients with chronic obstructive pulmonary disorders, forced vital capacity
(FVC) is either normal or slightly decreased while forced expiratory volume in
1second is significantly decreased.
 The FEV1/FVC ratio is characteristically decreased (FEV1/FVC<80%)

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 The residual volume is increased but the total lung capacity may remain normal
or increase (air trapping).
 The condition eventually leads to hypercapnic respiratory failure with pCO2 of
>45mmHg.
 Mechanisms of airflow limitation:
 Loss of elastic recoil: emphysema
 Increased resistance:
o “Large” airways (>2mm): chronic bronchitis
o “Small” airways (<2 mm): small airway disease
EMPHYSEMA
 Pulmonary emphysema is permanent enlargement of the airspaces distal to the
terminal bronchioles, accompanied by destruction of their walls and alveolar
septa without obvious fibrosis.
 Recent evidence suggests that the enlargement of the distal air spaces is a
secondary result of small airway inflammation and destruction.
ETIOLOGY
 Any factor leading to chronic alveolar inflammation would encourage
development of an emphysematous lesions.
 Smoking has adverse effects on lung defenses, leading to emphysematous
change.
 In developed countries, cigarette smoking accounts for over 90% of cases. In
developing countries other factors such as inhalation of smoke from biomass
fuels used in heating and cooking in poorly ventilated areas are also
implicated.
 Only 10-20% of heavy smoker develop COPD indicating individual
susceptibility.
 The development of COPD is proportional to the number of cigarettes
smoked per day. The risk of death from COPD in patients smoking 30
cigarettes daily is 20 times that of a non-smoker.
 Congenital enzyme defects such as alpha-1 antitrypsin deficiency are also risk
factors for the disease.
 10-15% are occupational. Due to many of the same dusts that cause interstitial
lung disease.

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PATHOPHYSIOLOGY
 Emphysema is characterized by destruction of alveolar septa and distension of
alveoli resulting in reduced surface area and loss of vessels, the later causing
reduced perfusion.
 Irritants from cigarette smoke, tobacco smoke or inhaled pollutants induce
an ongoing inflammation. Tumor necrosis factor and IL -8 activate
neutrophils which produce damaging proteases (especially elastase).
 Nicotine also inactivates anti-proteases and produces reactive oxygen species
which inactivate proteases and deplete antioxidants.
 The loss of pulmonary parenchyma causes a loss of elastic recoil when the
patient breathes out the airways collapse, trapping air (hyperinflation)
because of reduced driving pressure (elastic recoil).
 Changes are irreversible.
 In alpha-1 antitrypsin
deficiency there are low
levels of protease inhibitor
(Pi). Liver cirrhosis may
also be present.
 In addition, emphysema
causes mucus production and
airway narrowing with
accompanying reduction in
ventilation. This leads to
retention of carbon dioxide in
the blood and severe dyspnea
from reduced tissue perfusion
 These patients however, do
not suffer from hypoxia and
acidosis and have less chance
of development of pulmonary
hypertension and cor-
pulmonale. However, patients
usually have a mixed picture
of emphysema and chronic
bronchitis.

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TYPES OF EMPHYSEMA
 It is classified according to the site of damage:
 Centri-acinar emphysema: distension and damage of lung tissue is
concentrated around the respiratory bronchioles whilst the more distal
alveolar ducts and alveoli tend to be well preserved. This form is extremely
common. When of modest extent it is
not necessarily associated with
disability. Severe centri-acinar
emphysema is associated with
substantial airflow limitation. It
mostly affects the upper lobes
particularly in the apical segments
and is most commonly seen in
smokers.
 Pan-acinar emphysema: the acini are
uniformly enlarged from the level of
the respiratory bronchioles to the
terminal blind alveoli. it affects the
lower lung zones mostly and is
associated with alpha-1 antitrypsin
deficiency.
 Distal acinar emphysema: proximal
portion is normal but distal part is Figure 43: Types of emphysema
primarily involved. More severe in
upper half of the lungs and may be associated with spontaneous
pneumothorax in young adults.
 Irregular emphysema: acinus is irregularly involved and is almost invariably
associated with scarring such as that resulting from healed inflammatory
disease. Although clinically asymptomatic this may be the most common
form of emphysema.
 Bullous emphysema: this results from any form of emphysema that produces
large sub-pleural spaces more than 1cm in diameter. Such blebs represent
localized accentuations of 1 of the 4 forms of emphysema. Most blebs are
sub-pleural near the apex and on occasion they may rupture leading to
pneumothorax.

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CLINICAL FEATURES
 Dyspnea: usually the first symptoms. It
begins insidiously but is steadily
progressive.
 Patients have prolonged expiration sitting
forward in a hunched-over position,
attempting to squeeze the air out of the
lungs with each expiratory effort
 Rapid respirations with pursed lips.
 Because of prominent dyspnea (frank
cyanosis and hypoxia) and adequate
oxygenation of hemoglobin, there is
secondary eyrthrocytosis (polycythemia)
and these patients appear plethoric and are
sometimes called “Pink puffers”
 Weight loss is common and may be severe
to suggest a hidden malignancy (“Lots of
calories just to breath”)
 On examination they may have:
 Barrel-shaped chest due to
hyperinflation and trapped air. Figure 44: Pink Puffers of Emphysema
 Finger clubbing
 Tachypnea and use of accessory muscles
 Pulsus paradoxus
 Chest is Hyper-resonant to percussion
 Wheeze/Rhonchi
 Prolonged expiration (normally <4 seconds)
 Diminished vesicular breath sounds and distant heart sounds
 In advanced emphysema the chest may be remarkably “quiet”
CHRONIC BRONCHITIS
 Chronic bronchitis is due to chronic excess mucus secretion in the bronchial tree.
 It is defined by the presence of a persistent productive cough for at least 3
consecutive months in at least 2 consecutive years (‘Smoker’s cough’).
 It is common among cigarette smokers and urban dwellers in smog-ridden cities.
 20-25% of men in the 40 to 65-year-old age group have the disease.

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 In the early stages of disease, the productive cough raises mucoid sputum but
airflow is not obstructed.
 Some patients with chronic bronchitis may demonstrate hyperresponsive airways
with intermittent bronchospasms and wheezing.
 A subset of bronchitis patients especially heavy smokers develop chronic
obstruction usually with associated emphysema.
ETIOLOGY
 Sufficient exposure to bronchial irritate particularly cigarette smoke, most
persons develop some degree of chronic bronchitis with signs of inflammation of
the airways.
 In developing countries household smoke from fire wood is said to be a major
contributing factor.
PATHOPHYSIOLOGY
 There is hypersecretion of mucus beginning in the large airways.
 Although the single most important cause is cigarette smoking (chronic
irritation), other air pollutants such as sulfur dioxide and nitrogen dioxide may
contribute.
 Bacterial and viral infections are triggers of acute exacerbation.
 These environmental irritates induce hypertrophy of mucus glands in the trachea
and main bronchi leading to a marked increase in mucin-secreting globlet cells
in the surface epithelium of smaller bronchi and bronchioles.
 The irritants also cause inflammation with infiltration of CD8+ lymphocytes,
macrophages and neutrophils. In contrast to asthma there are no eosinophils in
chronic bronchitis.
 Mucus hypersecretion is primarily a reflection of large bronchial involvement.
Accompanying alterations in small airways leads to bronchiolitis which can
result in earlier manifestations of chronic obstruction.
 Obstruction of airway by mucus leads to bronchiectasis (pathological dilation
airways) or atelectasis (collapse).
 In chronic bronchitis alveoli are often spared and no vessel loss and lung
perfusion remains normal but ventilation is very much reduced. This leads to
abnormal V/Q (arteriovenous shunt) and patients usually suffer from hypoxemia
(manifested with cyanosis) and acidosis which causes pulmonary hypertension
and right heart failure in the long term.

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CLINICAL FEATURES
 Prominent productive cough (for 3month
in past 2 years). Sputum is copious and
purulent.
 Shortness of breath
 Patients tend to be obese
 Hypercapnia, hypoxemia and in severe
cases cyanosis (hence the term ‘blue
bloater’)
 In advanced stages chest may be “noisy”.
 On examination:
 Cyanosis
 Finger clubbing
 Normal RR
 Rhonchi/Wheezing
 With progression chronic bronchitis is
complicated by pulmonary hypertension
and cardiac failure (Cor pulmonale).
 Recurrent infections and respiratory
failure are constant threats Figure 45: Blue bloater of Chronic bronchitis

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Feature Predominant emphysema Predominant chronic bronchitis

Age 60 +/- 50 +/-
Body habitus Thin Obese
Cough After dyspnea Before dyspnea
Sputum Scanty, mucoid Copious, purulent
Appearance Pink, tachypnic (Pink Puffers) Cyanosed, normal RR (blue
bloaters)
Physical  Increased Anteroposterior
examination diameter
 Use of accessory muscles of
respiration
 Silent chest
 Hyper-resonant
 Decreased cardiac dullness
CXR  Long narrowed tubular heart  Enlarged heart
 Low diaphragm (flat  Large pulmonary artery
diaphragm)  Increased bronchovascular
 Dark lung fields markings
(translucent) with loss of
peripheral vascular
markings
Hematology Normal Hct Increased Hct
Blood gasses PaO2= 65-75 mmHg PaO2= 40-60 mmHg
PaCO2= 35-40mmHg PaCO2=50-60 mmHg
Complications  Less bronchial infection  Frequent bronchial infection
 Terminal respiratory  Repeated respiratory
insufficiency +/- cor- insufficiency
pulmonale  Frequent cor-pulmonale

 Distinction from asthma:

 Suggest COPD: smoker, cough, older (>35 years old), chronic productive
cough, progressive SOB.
 Suggest asthma: nocturnal symptoms. Significant diurnal or day to day
variability in symptoms.

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DIAGNOSIS
 Diagnosis is based on history and spirometry.
 History of chronic productive cough and/or exertional dyspnea of unknown
etiology, or whose physical examination reveals evidence of prolonged forced
expiration.
INVESTIGATIONS
 Pulmonary spirometry: FEV1/FVC <0.7, decreased FEV1 and decreased TLC.
 Classification by % of FEV1 predicted
o Mild: ≥80%. Symptoms must be present for diagnosis
o Moderate: <80% (50-79%)
o Severe: <50% (30-49%)
o Very severe: <30%
 Chest X-ray: findings are very variable. In the early stages it is normal.
 Hyperinflation: >6 anterior ribs and flat/tented diaphragm, generalized
radio-lucency of the lung fields is common usually late in the disease
process.
 In patients with recurrent chest infections, a variety of non-descriptive
post-inflammatory abnormalities (referred to as ‘dirty lung’) may be noted
on the film.
 Other findings: large pulmonary arteries, bullae, loss of lung markings
(emphysema) and cardiomegaly (cor pulmonale)
 Sputum for microscopy, culture and sensitivity
 ECG: RVH, may show P pulmonale (Tall P waves of pulmonary hypotension),
Right bundle branch block.
 Bloods:
 Full blood count: increased RBC and elevated hematocrit in chronic
hypoxemic patients.
 Baselines:
o U+Es: for Kidney function
o Liver function tests and liver enzymes for alpha-1 antitrypsin
deficiency
 Alpha-1 antitrypsin levels.
 Arterial blood gasses: decreased oxygen and increased carbon dioxide.

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 Other investigations:
 CT: not needed for diagnosis but emphysema may be incidental finding
which prompts consideration for COPD
MANAGEMENT
 There is no curative treatment.
 Therapy is direct at relieving symptoms, controlling potentially fatal
exacerbation, and slowing of the progression of the disorder.
 Avoidance of bronchial irritants especially cessation of smoking is of
primary importance.
 Vaccination: one-off pneumococcal and annual flu.
 Hydration with oral fluids.
 Stepwise medical treatment
 SOB or exercise limitation: PRN inhalers, either one of:
o Short acting Beta 2 agonists e.g. salbutamol (200g every 4-6 hours)
which is continued at all stages
o Short acting muscarinic antagonist e.g. ipratropium (40 g QID)
 Persistent SOB or exacerbations: regular inhalers either one of:
o Combination of long acting muscarinic antagonist e.g. tiotropium
(17g BD) (an M3 antagonist) + Long acting beta 2 agonist e.g.
salmeterol (50 g BD), formoterol (12g BD). First line for most.
o Combination of Long acting beta 2 agonist + inhaled corticosteroid
e.g. Seretide (salmeterol + Beclometasone-40g) or Symbicort
(formoterol + budesonide)
 Consider if there are asthmatic features such as prior
diagnosis of asthma or atopy, eosinophilia or substantial
FEV1 or peak flow variability.
 Inhaled corticosteroids increase the risk of pneumonia in
COPD but does not affect (or even reduces) mortality risk.
 Still persist: triple therapy
o Long acting antimuscarinic e.g. tiotropium + Long acting beta 2
agonist e.g. salmeterol + Inhaled corticosteroid e.g. beclometasone
 Further options in severe disease:
o Home nebulizers
o Oral immunomodulators:

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 Prednisolone 30mg should be given for 2 weeks, with
measurements of lung function before and after the period of
treatment.
 Roflumilast (PDE 4 inhibitor)
o Antibiotics: to treat infections
 Co-trimoxazole 980mg PO BD or TTC or Ampicillin 250-
500mg QID for 10days for infections
 Cefaclor 500mg 8 hourly or Cefixime 400mg OD. Co-
amoxiclav can be used as an alternative.
 Long-term treatment with antibiotics remain controversial.
o Oxygen therapy: 2L/min via nasal prongs
o Theophylline PO if inhaled therapy not possible
o Diuretic therapy for all edematous patients with daily weighing.
o Carbocisteine (2.25g daily) a mucolytic if there is no chronic
productive cough
 Surgical treatment
 Lung volume reduction
surgery (LVRS) namely
upper lobe resection. Offer
if SOB and severe COPD
but well enough for surgery
(6-minute walk test
>140m).
 Bullectomy like LVRS
removes areas of dead air
space but is more limited.
Offer if SOB and bulla
>1/3 of hemithorax
 Transplant if nothing else
works in severe disease.
COMPLICATIONS
 Exacerbations
Figure 46: COPD management algorithm
 Chronic type 2 respiratory failure:
respiratory acidosis is
compensated for with raised bicarbonate ion and hence normal pH but this can
decompensate in exacerbations

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 Pulmonary hypertension and right heart failure (cor pulmonale)
 Anxiety and depression
 Bullae: dilated air spaces in lung which may require surgical excision due to
compression of surrounding lung.
ACUTE EXACERBATION OF COPD
 Causes:
 Upper or lower respiratory tract infections due to viruses or bacteria such
as S. pneumoniae, H. influenzae or Moraxella catarrhalis.
 Pollution
 Drug changes
 Co-morbidities: Heart failure, pulmonary embolism
 Indications for admission
 Severe SOB
 Oxygen saturation <90%
 Cyanosis
 Generally unwell, reduced activity or altered mental status
 Not coping especially if living alone
 Worsening edema
 On long term oxygen therapy
 Investigate fully
 Bloods: FBC, U +E, arterial blood gasses
 Imaging: ECG, CXR and consider Echo
 Microbiology: sputum microscopy/culture/Sensitivity and blood culture if
fever
 Treatment: ‘A VENTS’
 A-antibiotics i.e. Erythromycin 500mg while awaiting sputum results.
 Ve- ventilation with 24-28% oxygen through venturi mask if stats <90%.
(target O2 stats=88-92%). Suction any fluid from the airway.
 N- nebulize with short acting beta 2 agonist +/- short acting antimuscarinic
agent. Stop long acting antimuscarinic agent when using short acting
antimuscarinic agent.
 T- Theophylline IV if there is poor response
 S-Steroids, ideally prednisolone PO 1-2 weeks
o Hydrocortisone 200mg 4 hourly for 24 hours and maintain on oral
prednisolone 30mg on alternate days.
 At discharge arrange 6 week follow up.

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ASTHMA
 This is a chronic inflammatory condition of the airways characterized by:
 Airflow limitation: which is usually reversible, spontaneously or with
treatment.
 Airway hyperresponsiveness to a wide range of stimuli
 Bronchial inflammation with T lymphocytes, mast cells, eosinophils with
associated plasma exudation, edema, smooth muscle hypertrophy, matrix
deposition, mucus plugging and epithelial damage.
 Note: In chronic asthma, inflammation may be accompanied by irreversible
airflow limitation as a result of airway wall remodeling that may involve large
and small airways and mucus impaction.
 Symptoms include wheeze, chest tightness, cough and shortness of breath often
worse at night.
 Asthma commonly starts in childhood (it affects 15% of children) between the
ages of 3 to 5 years and may either worsen or improve during adolescence.
 It is not usually diagnosed in those under 2 years old due to the difficulty of
distinguishing from viral-induced wheeze and frequent upper respiratory
tract infections.
 Asthma can occur at any age but it usually starts early in life. About 50% of
patients develop asthma before the age of 10 and another 35% before the age of
40.
 Males are affected twice as common as females in early life, this sex difference
equalizes by age 30. Most causes of asthma are associated with personal or family
history of allergic disease such as eczema, rhinitis and urticarial.
CLASSIFICATION
 Can be classified as:
 Extrinsic asthma
 Intrinsic asthma
 Previously it was classified as:
 Allergic (Atopic)
 Non-allergic (idiosyncratic)
 Mixed

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EXTRINSIC ASTHMA
 Occurs most frequently in atopic individuals (i.e. those with positive skin-prick
reactions to common inhalant allergens such as dust mite, animal danders, pollens
and fungi)
 90% of children and 70% of adults with persistent asthma have positive skin prick
tests to inhalant allergens.
 Childhood asthma is often accompanied by eczema (Atopic dermatitis).
 Sensitization to chemicals or biological products in work place is a frequently
overlooked cause of late-onset asthma in adults.
INTRINSIC ASTHMA
 Often starts in the middle age
 Many patients with adult-onset asthma show positive allergen skin test and on
close questioning some of these will give a history of childhood respiratory
symptoms suggesting they have extrinsic asthma.
 Non-atopic individuals may develop asthma in middle age from extrinsic causes
such as:
 Sensitization to occupational agents e.g. toluene diisocyanate
 Intolerance to NSAIDs e.g. aspirin or because they were given a Beta blocker
for concurrent hypertension or angina that block the protective effect of
endogenous adrenergic agonists.
 Viral infection which causes epithelial damage and mucosal inflammation
 Emotional upset which mediates excess parasympathetic input
 Exercise which causes water and heat loss from the airways
 Cold weather
 Extrinsic causes must be considered in all cases of asthma and where possible
avoided.
ETIOLOGY AND TRIGGERS
 The 2 main causes of asthma symptoms are:
 Hyperreponsiveness: this is an increased tendency of the airway to react to
stimuli or triggers to cause an asthma attack.
 Bronchoconstriction: narrowing of the airways that causes airflow
obstruction.
 Asthma has a strong genetic predisposition or familial tendency.

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 Triggers:
 Allergens: seasonal allergens such as pollen green. Non-seasonal animal
feathers, dust mites, molds.
 Pharmacologic stimuli: Tatrazin (coloring agent), beta blockers such as
propranolol etc.
 Environmental and air pollution: in industrial and heavily populated areas.
The common pollutants are ozone, nitrogen dioxide and sulfur oxide.
 Infections: respiratory infections are the most common of stimuli that evoke
acute exacerbation of asthma. Respiratory viruses are the major factors.
 Exercise: this is a very common precipitant of acute episodes of asthma
 Emotional stress: psychological factors can worsen or ameliorate asthma
PATHOPHYSIOLOGY
 Asthma results from a state of persistent subacute inflammation of the airways.
 The hallmark of this is an IgE type 1 hypersensitivity reaction.
 Exposure to an antigen or allergen leads to sensitization and production of IgM.
With subsequent exposure to the same antigen or allergen IgE is produced.
 IgE via its Fc portion can bind to the surface of mast cells and basophils via the
Fc receptors (FcR1). Cross-linkage of adjacent bound antibodies provides the
signal to cause mast cell degranulation (histamine and heparin are release) and
release of chemical mediators of inflammation resulting in vasodilation,
increased pulmonary capillary permeability, viscous mucus production and
severe constriction of bronchioles.
 In an acute attack there are 2 phases:
 Early phase characterized by bronchospasm. This phase lasts 2 to 3 hours.
This is due to interaction of mast cells and trigger leading to release of
preformed mediators of inflammation, bronchospasms and increased mucus
production.
 Late phase associated with inflammation. This phase lasts 4 to 8 hours. It is
due to infiltration of T lymphocytes, monocytes and eosinophil. There is
airway hyperactivity.
 The airway obstruction in asthma is due to a combination of factors.
 The cells thought to play important part in the inflammatory response are mast
cells, eosinophils, lymphocytes and airway epithelial cells.
 The mediators involved include histamine, prostaglandins, platelet activating
factors and leukotrienes.

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 These inflammatory mediators cause:
 Bronchoconstriction (spasm of airways smooth muscle)
 Vascular congestion and edema of airway mucosa
 Increased mucus production
 Injury and desquamation of the airways epithelium and impaired muco-
ciliary transport.
 The epithelium lining the airway can become damaged and smooth muscle can
undergo hypertrophy.
 In chronic state this can lead to airway remodeling.
CLINICAL FEATURES
 Attacks vary greatly in frequency and duration. Some patients only have 1 or 2
attacks a year that last for a few hours while others have attacks lasting for weeks.
 Some patients have chronic persistent symptoms, on top of which there are
fluctuations.
 An attack usually begins acutely with paroxysms of wheezing, coughing, and
shortness of breath or insidiously with slow increasing manifestations of
respiratory distress.
 The asthmatic first notices dyspnea, tachypnea, cough, and tightness in the chest
and may even notice audible wheezes.
 Symptoms:
 Episodic shortness of breath
 Wheezing
 Chest tightness
 Dry cough
 Symptoms are usually worst during the night and early morning, especially in
uncontrolled disease.
 Cough is a frequent symptom that sometimes predominates especially in children
in whom nocturnal cough can be a presenting feature.
 Signs:
 Varying degrees of respiratory distress: tachypnea, tachycardia, and audible
wheezes (or can be heard with a stethoscope as a rhonchi) are often present.
 Dehydration may be present because of sweating and tachypnea
 In more severe episodes, patients may be unable to speak more than a few
words without stopping for breath.
 Cyanosis is a late sign of hypoxia

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 Confusion and lethargy may indicate the onset of progressive respiratory
failure
 Pulsus paradoxus in a severe attack (An exaggeration in the normal variation
in pulse pressure seen with inspiration such that there is drop in systolic blood
pressure of greater than 10mmHg)
 Chest examination:
o Prolonged expiratory phase with relatively high pitched wheeze
throughout inspiration and most of expiration.
o Reduced air entry due to mucous plug in attack
o Less wheezing (silent chest) might indicate mucous plug or patient
fatigue with less airflow and is a sign of impending respiratory failure.
o The presence, absence or prominence of wheezes does not correlate
precisely with the severity of the attack.
 The most reliable clinical signs which can be confirmed by arterial blood gas
analysis are:
o Degree of dyspnea at rest
o Cyanosis
o Difficult in speaking
o Use of accessory muscles
INVESTIGATIONS
 Spirometry: FEV1/FVC ratio <0.7 confirms obstructive airway disease. Then do
bronchodilator reversibility (BDR) test with more than 12% improvement in
FEV1 is positive for asthma.
 Chest X-ray: varies from normal to hyperinflation. Atelectasis and pneumothorax
may be seen in complicated cases.
 Full blood count: eosinophilia
 Sputum: is tenacious, rubbery and whitish or may be yellowish, eosinophils are
present in sputum.

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DIAGNOSIS
 Asthma should be considered in anyone who wheezes. A family history of
allergy, rhinitis or asthma can be elicited in most asthmatics.
 Differential diagnosis:
 In children
o Foreign body obstruction
o Viral upper respiratory tract infection (URTI) including epiglottis
(croup) and bronchiolitis (RSV infection)
 In adults: (physical examination should search for heart failure signs and
signs of chronic hypoxemia (clubbing), unilateral wheezes indicate
obstruction by foreign bodies or tumors)
o COPD
o Heart failure
o Endobronchial TB
o Malignancies
MANAGEMENT
 General principles:
 Assessing the severity of the attack is paramount in deciding management
 Bronchodilators should be used in orderly progression
 Decide when to start corticosteroids. Inhaled corticosteroids reduce nocturnal
symptoms quickly but wider effects take months so users need to know to be
patient
 Teach inhaler technique as many patients have trouble
 General measures: Remove any identifiable trigger, stop smoking. Routine
antibiotics are not recommended.
 Mild cases: no acute distress, pulse rate <100 b/min, no cyanosis or dehydration
 Salbutamol 2-4mg PO TDS
 Salbutamol inhaler 2 puffs stat. Followed by 1 puff 4-6 hourly
 Note: inhaled corticosteroids e.g. beclomethasone, 2 puffs given 10 minutes
after salbutamol inhaler may be used.
 The patient must be taught how to use the inhaler. Check that he can use it
correctly. If he/she cannot learn, use oral salbutamol 4mg TDS daily though
it may cause extrapyramidal symptoms.

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 Stepwise medical therapy:
 Principles
o Most people are at steps 1-2
o Start at a level appropriate to disease severity
o Remember you can move down as well as up!
 Step 1: Inhaled short acting Beta agonist (SABA) as required
o Salbutamol 100g/puff. Use 2 puffs before exercise if likely to bring on
symptoms
o Salbutamol tablets (4mg PO TDS/QID) can be used as an alternative.
o Move to step 2 if using >3 times/week, waking at night or has acute
asthma exacerbation
 Step 2: SABA + Inhaled corticosteroid (ICS)
o Fluticasone, beclometasone or budesonide.
o Start at low dose
 Step 3: SABA + ICS + leukotriene receptor antagonist (LTRA)
o Monteleukast or Zafirlukast
 Step 4: add long acting beta agonist (LABA)
o Salmeterol or formoterol in combination in combination inhaler with
ICS.
o Continue LTRA if felt to be effective
 Step 5: increase ICS dose until effective or trial further drug (theophylline or
long-acting muscarinic antagonist)
 Step 6: refer to specialist for consideration of systemic immunomodulators
such as prednisolone PO and monoclonal antibodies: Omalizumab (anti IgE)
and Reslizumab (anti-IL5)
USE OF INHALERS
 Basics:
 First ask what they broadly know about asthma and inhaler use.
 Detach metal canister to show and check the date on the drug.
 Ensure lips and teeth are around mouthpiece.
 Ensure slow breath
 Praise correct behavior
 Advise them to follow a steroid inhaler with mouth wash (e.g. Canestan-
Fluconazole) to prevent thrush

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 Metered dose inhaler:
 Remove inhaler cap and shake inhaler
 Breath out gently
 Place mouthpiece in mouth, start breathing in then press canister and continue
slow, deep inhalation.
 Hold breath 10 seconds then breath out slowly
 Wait 30 seconds then repeat all steps including the shake.
ACUTE SEVERE ASTHMA
 This is a term used to describe an exacerbation of asthma that has not been
controlled by the use of standard medication.
 Patients with acute severe asthma typically have:
 Inability to complete a sentence in one breath
 Respiratory rate ≥25breaths/min
 Tachycardia ≥110beats/min (pulsus paradoxus is not useful as it is only
present in 45% of cases)
 Use of accessory muscles of respiration
 Paradoxical movement of the chest and the abdomen
 PEFR <50% of predicted normal or best

 Features of life-threatening attacks are:

 A silent chest, cyanosis or feeble respiratory effort
 Exhaustion, confusion or coma
 Bradycardia or hypotension
 Presence of complications: pneumothorax, atelectasis
 PEFR <30% of predicted normal or best (approximately 150L/min in adults)

 Features of a very severe life threatening attack:

 A high PaCO2 >42mmHg
 Severe hypoxemia (PaO2<60mmHg) despite treatment with oxygen, SaO2 <
90%
 A low and falling arterial pH

 Arterial blood gases should always be measured in asthmatic patients requiring

admission to hospital, with particular attention paid to the PaCO2. Pulse oximetry
is useful in monitoring oxygen saturation during the admission and can reduce
the need for repeated arterial puncture.

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MANAGEMENT
 Assess the patient and admit patient
 Humidified Oxygen100%-3L/min is given through a Management of a severe
mask (Aim for SpO2 94-98%) asthmatic attack ‘O SHIT’
 Fluid and electrolyte balance. Avoid over hydration.
O-oxygen
 3L/day (1-liter NS and 2L 5% Dextrose)
 20 mmol potassium chloride added to 1L of any of S-salbutamol
above fluids in 24 hours
H-hydrocortisone
 Calm patient and reassure the patient.
 Measure oxygen saturation with a pulse oximeter. I-Ipratropium
 Nebulized Salbutamol 5mg or Terbutaline 10mg stat T-Theophylline/Aminophylline
followed by Salbutamol 2.5mg 4-hourly
 Add nebulized ipratropium bromide 0.5mg to nebulized salbutamol/terbutaline
 Hydrocortisone 200mg (4mg/kg) IV is given 4-hourly for 24 hours
 Prednisolone is continued at 60mg orally daily for 2 weeks then taper
 Aminophylline in doses of 1mg/kg/hr in a continuous IV infusion should be
given.
 Aminophylline 250mg IV over 5-10mins followed by maintenance dose of
100mg (less than 500mg over 24 hours)
 If the patient has heart disease, liver disease or is taking beta blockers reduce
the dose.
 Always give oxygen with aminophylline. Patients who have taken oral
aminophylline in the last 8 hours should not be given the loading dose.
 Respiratory tract infections precipitate acute asthmatic attacks are predominantly
viral, but if patient expectorate yellowish, green or brown sputum antibacterial
therapy is indicated. Ampicillin is first line, alternative TTC, erythromycin or
Cotrimoxazole. CXR should be taken if there is suspicion of pneumonia or
complications
 If patient does not improve consider endotracheal intubation and mechanical
ventilation, they should be admitted to ICU
 One of the following IV infusion is given if no improvement is seen:
 Salbutamol 3-20 mg/min or
 Terbutaline 1.5-5.0 mg/min or
 Magnesium sulphate 1.2-2g over 20 min

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COMPLICATIONS DURING AN ACUTE ATTACK OF ASTHMA
 Pneumothorax
 Mediastinal and subcutaneous emphysema due to alveolar rupture
 Atelectasis due to obstruction
 Dilated right chamber (Cor pulmonale) from chronic hypoxemia and pulmonary
hypertension
 Respiratory failure

INTERSTITIAL LUNG DISEASES

PNEUMOCONIOSIS
 These are occupational lung disease in which inhalation of certain mineral dust
that initiates an inflammatory process (tissue reaction) that eventually leads to
lung fibrosis excluding bronchitis and emphysema.
 They are environmental disease caused by inhalation of inorganic dust particles.
 They usually appear 20-30 years after constant exposure to offending agents but
can develop in less than 10 years when dust exposure is extremely high.
 History is of primary importance in assessing possible occupational lung
diseases.
 Not all dusts are pathogenic. For example, silica is highly fibrogenic whereas iron
(siderosis), tin (stannosis) and barium (baritosis) are almost inert.
 Coal dust has an intermediate fibrogenic effect. Exposure to silica or asbestos
leads to extensive fibrosis and disability.
 The most important pneumoconiosis includes:
 Coal miner’s lung/coal worker’s pneumoconiosis (CWP)
 Asbestosis
 Silicosis
 Berylliosis: causes interstitial granulomatous disease similar to sarcoidosis.
 Alveolar macrophages engulf offending agents, causing inflammation and
fibrosis of the lung parenchyma in pneumoconiosis. Respiratory insufficiency is
the ultimate consequence of silicosis and the other pneumoconiosis.
 They are characterized by dyspnea, shortness of breath, cough, sputum
production, cor pulmonale and clubbing.
 The hallmark of these restrictive lung diseases is an increase in the FEV1/FVC
ratio (FEV1: FVC >80%)

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 This is because there is a decrease in Forced expiratory volume in 1 second
(FEV 1) however, this decrease is not less than the decrease in Forced vital
capacity (FVC)
 There is also a decrease in Total lung capacity (TLC)
 Recall in COPDs FEV1/FVC <80%
 Hypoxemia is evident with an increased atmospheric-alveolar partial pressure
gradient.
 In many types of pneumoconiosis, a long period of dust exposure is required
before radiological changes appear and these may precede clinical symptoms.
 Chest X-ray findings include: small irregular opacities, interstitial densities,
ground glass appearance and honeycombing.
COAL MINER’S LUNG/COAL WORKER’S PNEUMOCONIOSIS
 This is caused by inhalation of coal dust which contains both carbon and silica.
 The risk of development and progression of CWP is related to the amount of coal
dust exposure, higher rank (hardness) of coals and increased silica content of
inhaled dust.
 The disease is caused by dust particles approximately 2-5 m in diameter that are
retained in the small airways and alveoli of the lung.
 The incidence of the disease is related to total dust exposure which is highest at
the coal face, particularly if ventilation and dust suppression are poor.
 Clinical features: dyspnea, shortness of breath, cough, sputum production, cor
pulmonale and clubbing
 2 different syndromes result from the inhalation of coal
 Simple pneumoconiosis:
o This is deposition of coal dust in the lung.
o It is the most common type of pneumoconiosis.
o It is marked by coal macules around the bronchioles formed by ingestion
of coal dust particles by macrophages. In most cases it is inconsequential
and produces no disability.
o It produces fine micronodular shadowing on the chest X-ray. It is graded
on the Chest-X-ray appearance:
 1- small round opacities definitely present but few in number
 2- small round opacities numerous but normal lung markings still
visible
 3- small round opacities very numerous and normal lung markings
partly or totally obscured

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o Simple pneumoconiosis can progress to development of progressive
massive fibrosis. It almost never occurs with category 1 but occurs with
7% of patients in category 2 and 30% of patients in category 3.
o Miners with category 1 pneumoconiosis are unlikely to receive
compensation unless they have evidence of COPD. Those with more
extensive radiographic changes are compensated solely on basis of their
X-ray appearances.

 Progressive massive fibrosis:

o This is marked by fibrotic nodules filled with necrotic black fluid.
o Patients develop round fibrotic masses several centimeters in diameter,
almost invariably in the upper lobes and sometimes having necrotic
central cavities.
o Pathogenesis still not understood though some fibrogenic promoting
factors in individuals developing the disease lead to formation of
immune complexes, analogous to the development of large fibrotic
nodules in coal miners with rheumatoid arthritis (Caplan’s syndrome).
o Pathologically there is apical destruction and disruption of the lung
resulting in emphysema and airway damage.
o Lung function tests show a mixed restrictive and obstructive ventilator
defect with loss of lung volume, irreversible airflow limitation and
reduced gas transfer.
o The patient with PMF suffer considerable effort dyspnea usually with
cough. The sputum may be black (melanoptysis).
o The chest X-ray appearance may be confused with lung cancer,
tuberculosis and granulomatosis with polyangiitis.
o The disease can result in bronchiectasis, pulmonary hypertension or
death from respiratory failure or right sided heart failure.
 Chest X-ray: small round densities are seen in the parenchyma usually involving
the upper half of the lungs. Complicated or progressive massive fibrosis is
diagnosed by the presence of larger densities from 1 cm in diameter to the entire
lobe.
 Associated immunologic abnormalities: increased levels of IgA, IgG, C3,
antinuclear antibodies (ANA) and rheumatoid factor.

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 In Caplan syndrome there are rheumatoid nodules (rounded fibrotic nodules 0.5-
5cm in diameter) in the periphery of the lung in a patient with rheumatoid arthritis
and coexisting pneumoconiosis.
 The rheumatoid nodules show central necrosis, palisading histiocytes and a
peripheral rim of lymphocytes and plasma cells.
 This syndrome may also occur in other types of pneumoconiosis.

ASBESTOSIS
 This is caused by inhalation of asbestos
fibers.
 Its fibers may be classified as either:
 Chrysotile (white asbestos)-90% of
the world’s production
 Serpentine (crocidolite or blue
asbestos, and amosite or brown
asbestos)
 Asbestos fiber exposure maybe seen in
mining, milling, foundry work, Figure 47: Ferruginuous (asbestos) bodies. These asbestos
shipyards, or application of asbestos fiber inclusions are coated with protein and iron and will
products to pipes, brake lining, appear blue when stained with Prussian blue.
insulation and boilers.
 Previously some roofing of houses were built using asbestos material.
 History of exposure to asbestos is needed to consider the diagnosis.

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 This disease is initiated by uptake of asbestos
fibers by alveolar macrophages. A fibroblastic
response occurs probably from release of
fibroblast-stimulating growth factors by
macrophages and leads to diffuse interstitial
fibrosis, mainly in the lower lobes.
 Clinical features: exertional dyspnea and
reduced exercise tolerance, cough and
wheezing (especially among smokers), chest
wall pain, and ultimately respiratory failure.
 On examination there may be finger clubbing
and bilateral basal end inspiratory crackles.
 It is characterized by ferruginous bodies,
yellow-brown, rod-shaped bodies with clubbed
ends that stain positively with Prussian blue,
these arise from iron and protein coating on
fibers.
 Dense hyalinized fibrocalcific plaques of the
parietal pleura are also present.
 On chest x-ray diffuse or local pleural thickening, pleural plaques and
calcifications at the level of the diaphragm are seen. Pleural effusions are
commonly seen, and the interstitial lung process associated with asbestosis
usually involves the lower lung fields.
 Asbestosis results in marked predisposition to bronchogenic carcinoma
(adenocarcinoma or squamous cell carcinoma) and to malignant mesothelioma
of the pleura or peritoneum.
 Cigarette smoking further increases the risk of bronchogenic carcinoma.
 A lung biopsy is usually necessary for the diagnosis in which the classic barbell-
shaped asbestos fiber is found.
 No specific treatment is offered, though corticosteroids are often prescribed. It is
important that patients with asbestos exposure stop smoking since the risk of lung
cancer is 75 times higher than that of the normal population.
SILICOSIS
 This is a chronic occupational lung disease caused by exposure to free silica dust,
it is seen in miners, quarry workers, glass and pottery manufacturers, sandblasting
workers and stone cutters.

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 The dust is highly fibrogenic. For example, a coal miner can remain healthy with
30g of coal dust in his lungs but 3g of silica is sufficient to kill.
 This disease is initiated by ingestion of silica dust by alveolar macrophages,
damage to macrophages initiates an inflammatory response mediated by
lysosomal enzymes and various chemical mediators.
 These reactions cause susceptibility to tuberculosis.
 Silicosis will cause similar symptoms to asbestosis (or any other
pneumoconiosis) except the acute form of silicosis, which is caused by massive
exposure that causes lung failure in months.
 Silicotic nodules that enlarge and eventually obstruct the airways and blood
vessels are characteristics.
 Silicosis is associated with increased susceptibility to tuberculosis, the frequent
concurrence is referred to as silicotuberculsos.
 Chest X-ray findings: in silicosis there are nodules (1-10mm) seen throughout
the lungs that are most prominent in the upper lobes. A characteristic finding is
eggshell calcifications (rare). In progressive massive fibrosis, densities are 10mm
or more and coalesce in large masses.
 There is no effective therapy for silicosis. Death occurs usually because of
progressive respiratory insufficiency.
BERYLLIOSIS
 Beryllium-copper alloy has a high tensile strength and is resistant to metal
fatigue, high temperature and corrosion.
 It is used in the aerospace industry, in atomic reactors and in many electrical
devices.
 When beryllium is inhaled, it can cause a systemic illness with a clinical picture
similar to sarcoidosis.
 Clinically there is progressive dyspnea with pulmonary fibrosis. However, strict
control of levels in the working atmosphere has made this disease a rarity.

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PLEURISY AND PLEURAL EFFUSION

 Pleural effusion is the presence of excess fluid in the pleural space.
 The visceral pleura: covers the lung parenchyma including the fissures
 The parietal pleura: lines the inside of the thoracic cavity
 Normally 10-20ml of fluid is spread in a thin layer between the 2 layers of
pleurae. It acts as a lubricant allowing smooth movement of the lung during
respiration.
 The pleural fluid is from different sources include: Pleurisy is pain arising from any
o Pleural capillaries disease of the pleura. The
o Interstitial spaces of the lungs localizaed inflammation produces
o Intrathoracic lymphatics/blood vessels: sharp localized pain which is
disruption of the thoracic duct, injury to the worse on deep inspiration,
blood vessel etc. coughing and occasionally on
o Peritoneal cavity: requires there to be free twisting and bending movements.
fluid in the abdomen and openings in the
diaphragm Common causes are pneumonia,
 Hydrostatic and oncotic pressure balance the pulmonary infarct and carcinoma.
movement of fluid into the pleural space. Pleural Rarer causes include rheumatoid
fluid is reabsorbed normally by pleural arthritis and SLE
lymphatics.
 Pleural effusions are as a result of excess production of pleural fluid or less
commonly due to reduced clearance e.g. in lymphatic obstruction due to TB or
cancer.
 Pleural effusions are classified based on laboratory analysis as (see common
procedure chapter 13-Thoracentesis):
 Transudates
 Exudates

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Transudative effusion Exudative effusion
 Results from elevation in  Due to pleural inflammation
hydrostatic pressure or decrease in (pleurisy) with increased
oncotic pressure permeability of the pleural surface
to protein.
 Pleurisy is seen in infections such as
pneumonia, infections of the
esophagus, mediastinum or sub-
diaphragmatic areas, traumatic
injuries and extension of infections
from adjacent organs.
 Initially pleurisy tends to be dry but
fluid starts to collect subsequently.
 Heart failure  Infection (Parapneumonic, TB,
 Cirrhosis of the liver fungal, empyema)
 Nephrotic syndrome  Esophageal rupture
 Myxedema (hypothyroidism)  Pulmonary embolism
 Hypoproteinemia  Neoplasms e.g. mesothelioma
 Constrictive pericarditis  Autoimmune (Systemic lupus
 Ovarian tumors producing right erythematosus)
sided pleural effusion- Meigs’  Rheumatoid pleural effusion
syndrome  Esophageal rupture
 Sub-diaphragmatic abscess
 Pancreatitis
 Uremic pleural effusion
 Hemothorax
 Chylothorax (thoracic duct injury)
 Radiation and drugs

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CLINICAL FINDINGS AND DIAGNOSIS
 Underlying causes should be suspected from the history.
 Shortness of breath (dyspnea), Pleuritic chest pain and dry non-productive
cough are the most common symptoms but many pleural effusions are
asymptomatic and discovered on physical examination or chest X-ray.
 Physical examination:
 Decreased chest motion on affected side
 Tracheal deviation (if effusion is large)
 Decreased/Absent tactile fremitus
 Stony Dullness to percussion
 Decreased or absent breath sounds
 Reduced or absent vocal resonance
 At the superior border of the fluid, there may be bronchial breath sounds-
may be secondary to increased conductance of breath sounds through a
partially collapsed lung
 Pleural rub
 There may be signs of underlying e.g. raised JVP in heart failure, clubbing in
lung cancer
 Clinically it can be detected when 500ml or more of pleural fluid is present.
INVESTIGATIONS
 Chest X-ray:
 Homogenous opacity with a meniscus sign and obliteration of the
costophrenic angle.
 Large pleural effusions may result in complete opacification of the
hemithorax and mediastinal shift to the opposite side.
 An air-fluid level indicates bronchopleural fistula, pneumothorax, rupture of
the esophagus into pleural space, gas forming organisms.
 At least 200ml of fluid needs to be present for the lateral costophrenic angle
to be blunted on a CXR. Ultrasound is more sensitive than CXR in detecting
pleural effusions
 The best way to identify and localize a loculated pleural effusion (when there
are adhesions between the visceral and parietal pleural and the pleural fluid
becomes encapsulated especially when there is pleural
inflammation/pleurisy) is with ultrasonography

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 Pleural thoracentesis (aspiration of fluid):

 Should be performed to confirm the presence of fluid and to determine its
characteristics including color and consistency.
o Clear yellow fluid is described as serous
o Bloody or blood-tinged fluid as sanguineous or serosanguineous. Some
of the causes include pulmonary infarction and pleural carcinomatosis
o Translucent or opaque, thick fluid as purulent.
 Microscopic examination of the fluid is important including Gram stain and
culture (if possible)
 Total and differential cell counts should be obtained.
o Predominance of Polymorphonuclear leukocytes suggests an underlying
pneumonia with a Parapneumonic effusion.
o The presence of small mature lymphocytes, particularly with few
mesothelial cells strongly suggests tuberculosis
 It is important to determine where the fluid is a transudate or exudate (using
Light’s criteria)

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Light’s Criteria: Exudate if any of the 3 are found
Transudate Exudate
Protein (Pleural/Serum) ≤0.5 >0.5
Lactate dehydrogenase ≤0.6 >0.6
(Pleural/Serum) Pleural LDH ≤ two thirds Pleural LDH > two-thirds
of upper limit of serum of upper limit of serum
LDH LDH
Common causes  Hypoalbuminemia  Infection
(Cirrhosis, Nephrotic (Parapneumonic, TB,
syndrome) fungal, empyema)
 Congestive heart Esophageal rupture
failure  Pulmonary embolism
 Constrictive  Neoplasms
pericarditis  Autoimmune
 Myxedema (Systemic lupus
(hypothyroidism) erythematosus)
 Ovarian tumors  Rheumatoid pleural
producing right sided effusion
pleural effusion- Esophageal rupture
Meigs’ syndrome  Sub-diaphragmatic
abscess
 Pancreatitis
 Uremic pleural
effusion
 Hemothorax
 Chylothorax (thoracic
duct injury)
 Radiation and drugs
Note: in resource limited setting where LDH is often not available: Total protein
effusion >30g/L is often used to indicate an exudate effusion whilst that <30g/L is a
transudate.
 Full blood count: for infection
 Total Serum protein
 Serum Lactate dehydrogenase
 Liver function tests and U + Es

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Etiology Appearance WBC RBC pH Glucose Comments
CHF Clear, straw <1000 <5000 Normal Normal Bilateral,
cardiomegaly
Parapneumonic Turbid 5-40, 000 <5000 Normal/low Normal
Neutrophils
Empyema Pus 25-100,000 <5000 <7.2 Low Needs
Neutrophils drainage!
TB Serosangeous 5-10, 000 <10,000 Normal Normal + AFB
Lymphocytes or low
Malignancy Bloody 1-100, 000 <100,000 Normal Normal + Cytology
Lymphocytes
Pulmonary Sometimes 1-50, 000 <100,000 Normal Normal
embolism bloody Neutrophils
Hemothorax Bloody 1-50,000 >100,000 Normal Normal Hct ratio
Esophageal Turbid 5-50, 000 <10,000 Very low Low High
rupture amylase

TREATMENT
 Therapeutic thoracentesis should be done in massive effusion to relieve
respiratory distress.
 Removal should be limited to 1200 to 1500ml at a time.
 Definitive treatment of pleural effusion requires identifying the underlying
condition and administration of specific therapy.
 TB effusion should be treated with anti-TB drugs
 Parapneumonic effusions and other bacterial infections in the pleural space
should be treatment with long course of antibiotics
 Empyema (purulent fluid in the pleural cavity) is treated with high dose of
parenteral antibiotics coupled with surgical drainage (chest tube insertion).
 Malignant pleural effusions that reaccumulate and are symptomatic can be
aspirated to dryness followed by the instillation of a sclerosing agent such as
tetracycline or talc. Effusions should be drained slowly since rapid shift of the
mediastinum causes severe pain and occasionally shock. The treatment produces
only temporary relief.

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PNEUMOTHORAX

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LUNG NEOPLASMS
 Lung cancer is one of most common cause of cancer mortality.
 Metastatic tumors are more common than primary tumors of the lungs with the
commonest primary sites being the breast, thyroid, stomach, colon carcinoma,
prostate and ovary.
 Present as multiple ‘Cannon-ball nodules on imaging’
 90-95% of primary lung tumors are malignant epithelial tumors collectively
called bronchogenic carcinomas.
 The remaining are bronchial carcinoids, mesenchymal tumors (lymphomas,
sarcomas, leiomyomas, lipomas, fibromas and liomyosarcomas), and bronchial
hamartomas, the last being benign tumors with aberrant differentiation of the
bronchial tissues.
 Neoplasms are common between the age range of 65-75 years and affect men
more than women (2:1)
ETIOLOGY AND RISK FACTORS
 Cigarette smoking- cigarettes contain at least 55 carcinogens and the risk of lung
cancer increases to 20 fold for people who smoke more than 40 cigarettes/day.
 Exposure to Radon (from radioactive decay of Uranium) in underground
Uranium miners (occupational) or indoors (in basements as a colorless odorless
gas).
 Exposure to other carcinogens:
 Asbestos
 Polycyclic aromatic hydrocarbons (these are mutagenic and present in
cigarette smoke and arsenic)
 Ni, Co, Cr
 Silica
 Mustard gas (World war I)

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PATHOLOGICAL FEATURES OF BRONCHOGENIC
CARCINOMAS
 Classic division of lung carcinoma:
 Small cell carcinoma/Oat cell (15%)
 Non-Small cell carcinoma (85%): Adenocarcinoma, squamous carcinoma,
large cell carcinoma and carcinoid tumor
 These originate from the bronchial epithelium and have 4 main histological types:
 Adenocarcinoma including the bronchoalveolar carcinoma (30-35%)
 Squamous cell carcinoma (25-30%)
 Small (Oat cell) carcinoma (15-25%)
 Large cell carcinoma (10-15%)
 Others include:
 Mixed cell type (squamous and small cell or squamous cell and
adenocarcinoma) 5-10%
 Pleomorphic carcinoma (mixed carcinoma and sarcomatoid pattern) 0.5%
 Note: Differentiating between small cell and non-small cell carcinoma
(Adenocarcinoma, squamous cell carcinoma and large cell carcinoma) is very
important because small cell carcinoma is responsive (At least initially) to
chemotherapy.
 All lung neoplasms are very aggressive, invasive and widely metastasizing
commonly to liver, adrenals, brain and bones. They also produce bioactive
hormones and other products.

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Adenocarcinoma Squamous cell Small cell Large cell
carcinoma carcinoma carcinoma
 Glands or mucin production  Keratin pearls or  Poorly  Anaplastic
 Common in women than intercellular bridges differentiated (undifferentiated)
men (desmosomal small cells tumors and occur
 Develops in the periphery of connections between arising from in smokers
the lung squamous cells) on neuroendocrine  No keratin
 Commonest lung cancer in histology (Kulchitsky) pearls,
non-smokers  More common in cells intercellular
 Some adenocarcinomas arise males than females  Very bridges, glands
from area of pulmonary  Strongly associated aggressive or mucin
fibrosis/scar (old infarcts, with cigarette  Early mets  Central or
asbestosis, or on healed TB smoking  Strongly peripheral
scars) which are referred to  Arise centrally in the associated with locations
as scar cancers major or segmental cigarette  Metastasizes
 Located peripherally bronchi and spread smoking very rapidly and
 Distant organ metastases to hilar lymph nodes  Centrally widely
occur in 50% especially to in 70-90% of cases located  Poor prognosis
the brain or distant mets in  Commonly
 Poor prognosis (5 year 50-60% or to viscera associated with
survival is 10-12%)  May produce paraneoplastic
parathyroid hormone syndromes
related peptide (ADH or
(leading to ACTH or
hypercalcemia) cause Eaton-
 Poor prognosis (5 Lambert
year survival 5-8%) syndrome)
 Poor prognosis
(5 year
survival 5-8%)
 Bronchoalveolar carcinoma:
 Columnar cells that grow along pre-existing bronchioles and alveoli. It arises
from Clara cells.
 Not related to smoking
 Located peripherally
 May present with pneumonia-like consolidation on imaging, excellent
prognosis

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 Carcinoid tumor:
 Tumor of well-differentiated neuroendocrine cells,
 Chromogranin positive,
 Not related to smoking
 Central or peripheral location, classically forms a polyp-like mass in the
bronchus.
 Low grade malignancy, rarely can cause carcinoid syndrome
CLINICAL FEATURES
 Clinical features are variable.
 Presentations:
 Local pulmonary symptoms:
o Depend on location of the tumor
o When tumors are endobronchial cough, hemoptysis, stridor, wheezes,
dyspnea and non-resolving pneumonia may predominate.
o Pleuritic chest pain is common with peripheral tumors.
o Local tumor invasion and obstruction:
 Recurrent laryngeal nerve palsy causing hoarseness of voice
 Phrenic nerve paralysis with diaphragm paralysis
 Esophageal obstruction causing dysphagia
 Superior vena cava obstruction presenting with edema
 Pancoast syndrome is said to exist when apical lung tumors infiltrate
spinal nerves (C8-T1) and cause shoulder pain and cervical
sympathetic nerves causing Horner’s syndrome (anhidrosis-
absence of sweating, ptosis- eyelid drooping and miosis on the
affected side)
 Pericardial or pleural effusions and bronchial obstruction leading to
atelectasis, pneumonia and lung abscess
 Metastatic symptoms
 Ectopic hormone secretions (paraneoplastic syndromes):
o Occur in 10-15% of bronchogenic carcinoma and manifestations are
related to ectopic hormone secretions by tumors.
o The manifestations can be systemic or related to different systems.
o Systemic symptoms: anorexia, cachexia, weight loss and fever in 30%
of cases.
o Another 1/3 of patients may present with endocrine manifestations like
hypercalcemia or hypocalcemia (from ectopic secretion of parathyroid

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hormone or calcitonin), Cushing’s syndrome (from ectopic secretion of
ACTH), gynecomastia (from ectopic secretion of gonadotrophins) and
inappropriate release of ADH (SIADH) causes sodium and water
retention.
o Additionally, patients may present with clubbing, migratory
thrombophlebitis, cerebellar degeneration, neuropathies, and
myopathies such as Eaton-Lambert myasthenic syndrome (this is an
autoimmune condition characterized by the production of
autoantibodies against the presynaptic voltage gated calcium channels
thus impairing the release of acetylcholine at the neuromuscular junction
resulting in proximal muscle weakness, and depressed tendon reflexes),
Myasthenia gravis (autoantibodies against Nicotinic Acetylcholine
receptors on post-synaptic membrane at the neuromuscular junction
resulting in muscle weakness), anemia and thrombocytopenic purpura.
 About 10-15% of lung tumors are detected by chance (a coin shaped lesion on
chest X-ray)
 Benign lesions (e.g. in the young can also present as a coin lesion):
Granuloma (TB, Histoplasma) and bronchial hamartoma (often calcified)
DIAGNOSIS
 Screening
 For all men over 45 years and those smoking more than 40 cigarettes/day/
 Can be done by:
o Cytology (to detect malignant cells)-50% sensitivity
o CXR:
 Solitary pulmonary nodule (Coin shaped lesion 2-5cm) and about
35% of such cases are due to bronchogenic carcinoma
 Compare with past X-rays if coin lesion has not changed it is
most likely a benign entity, however if it has changed or is
new there is a possibility of bronchogenic carcinoma that
would warrant a biopsy to confirm.
 Effusion, lobar collapse or mediastinal/hilar lymphadenopathy may
be seen
 Other investigations for diagnosis and staging (TMN staging):
 Blood investigations:
o Basics: FBC, U+Es, LFT

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o LDH may be raised especially in small cell lung carcinoma due to tissue
necrosis
o Calcium may be increased (squamous) or reduced
o Tumor markers
 Lung biopsy
 Lymph node biopsy from enlarged or supraclavicular lymph node to detect
mets
 Bronchoscopy with biopsy or lavage if CT shows an accessible lesion or
node.
 Thoracentesis to collect fluid for cytology
 Pleural biopsy
 Mediastinoscopy
MANAGEMENT
 Prevention: cessation of smoking
 Non-small cell carcinoma
 Surgical excision is curative for patient with ipsilateral lymph node
involvement but without local/distant spread or contralateral lymph node
involvement
 Intrathoracic disease- radiotherapy is palliative
 Pancoast syndrome (tumor in the lung apices)- radiotherapy/chemotherapy
 Extrathoracic disease- analgesics, radiotherapy, dexamethasone, obliteration
of the pleural cavity
 Small cell carcinoma
 By the time of diagnosis 95% of tumors have metastasized.
 Responsive for chemotherapy +/- radiotherapy
 Bronchial adenomas, carcinoids need surgical resection

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GASTROINTESTINAL CONDITIONS
GASTROINTESTINAL PHYSICAL EXAMINATION
 Before starting:
 Introduce yourself to the patient.
 Explain the procedure to the patient and ask the patient for permission to
examine his/her abdomen (Gain consent).
 Wash hands and say to the examiner that you would normally expose the
patient from nipples to knees, but for modesty sake you are going to limit
yourself to exposing the patient to the groins.
 Position the patient so that they are lying flat on the couch, with their arms at
side and head supported by a pillow (Anatomical position).
 Ensure that the patient is comfortable.
GENERAL INSPECTION
 From the foot-end of the bed, inspect and make general comments about the
surrounding (Drains/ vomit/ NG tube).
 Observe and make comments on:
 The patient’s general appearance: Healthy/ Obese/ Cachexic
 Are they comfortable or in any respiratory distress
 Age, state of health (is the general condition of the patient stable or unstable),
nutritional status (Good, fair or poor) and any other obvious signs (such as
jaundice- indicating hepatic/ biliary disease).
 Abdomen- is abdomen distended and are there are obvious scars, markings,
or masses observed from the foot end of the bed.
INSPECTION AND EXAMINATION OF THE HANDS
 From the right side of the bed, take both hands, looking for:
 Finger Clubbing (Inflammatory bowel disease)
 Palmar erythema (Chronic liver disease)
 Dupuytren’s contracture (Liver cirrhosis)
 Nail signs (leukonychia- hypoalbuminemia, koilonychias- iron deficiency)

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 Test for Asterixis or “liver flap” (hepatic failure- hepatic encephalopathy) by
showing the patient how to extend both arms with the wrists dorsiflexed and the
palms facing forwards.
 Check for any needle track marks (Hepatitis B/C), Bruising/ Petechiae
(Thrombocytopenia)
 Feel for the epitrochlear lymph nodes
 Check axilla for acanthosis nigricans (GI malignancy)
INSPECTION AND EXAMINATION OF THE HEAD, NECK AND
UPPER BODY
 Inspect the sclera and conjunctivae for signs of jaundice or anemia.
 Inspect the mouth, looking for
 Ulcers (Crohn’s disease),
 Angular stomatitis (nutritional deficiency),
 Atrophic glossitis (iron deficiency, vitamin B12 deficiency, folate
deficiency),
 Furring of the tongue (loss of appetite)
 State of the dentition
 Purple lesions on the palate (Kaposi sarcoma)
 Palpate cervical lymph nodes (lymphadenopathy- Infection/ malignancy),
Virchow’s node (gastric malignancy) and check for parotid swelling
(paratomegaly-in alcoholic liver disease).
 Examine the upper body for:
 Gynecomastia: (Chronic liver disease)
 Spider naevi- (>5 chronic liver disease)
 Caput medusa (Portal hypertension)
 Stretch marks
 Stomas (Ileostomy vs Colostomy)
INSPECTION OF THE ABDOMEN
 Inspect the abdomen for its contours and any obvious distension (Ascites/
organomegaly), localized masses, scars and skin changes. Ask the patient to lift
his head to tense the abdominal muscles. When inspecting the abdomen, you
should crouch down to be at the same level as the abdomen.
 Comment on any distension (Causes of abdominal distension -5Fs- Fluid,
Fat, Fetus, Flatus and Fecal matter). Measure abdominal girth with measuring
tape if abdomen is distended.

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 Comment on presence of flank fullness
 Comment on symmetry
 Comment on movement with respiration

PALPATION OF THE ABDOMEN

 Ask the patient if he has any abdominal pain (Always start furthest from this
region) and fix upon his face as you palpate his abdomen.
 Palpate with the palmar surface of your fingers whilst sitting or kneeling beside
the patient.
 Light palpation- Begin by examining the segment furthest away from any pain or
discomfort and systematically palpate the four quadrants and the umbilical area.
Look for tenderness, guarding and any masses.
 Deep palpation- for greater precision. Describe and localize any masses
 On deep palpation ask the patient to take deep breaths.
 Assess masses for size, shape and consistency.

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PALPATION OF THE ORGANS
 Liver- ask the patient to breathe in and out, starting in the right lower quadrant,
feel for the liver edge leading with the index finger. The liver edge, if felt, can be
described in terms of regularity, nodularity and tenderness. Note the degree of
extension below the costal margin (cm)
 Gallbladder- palpate for tenderness over the gallbladder region that is at the tip
of the right ninth rib.
 Spleen- palpate for the spleen as for the liver, again starting in the right lower
quadrant feel for the splenic edge moving towards your index finger during
inspiration.
 Kidneys- Position the patient close to the edge of the bed and ballot each kidney
using the technique of deep bimanual palpation.
 Aorta- palpate the descending aorta between the thumb and the index of your
right hand at a point midway between the xiphisternum and the umbilicus.
PERCUSSION
 Percuss the liver area, also remembering to detect its upper border (usually found
in the fourth intercostal space). This is to estimate the size (liver span).
 Percuss the spleen to assess splenomegaly starting from the right iliac fossa
ascending diagonally.
 Percuss the suprapubic area for undue dullness (bladder distention). Start in the
midline and descend.
 If the abdomen appears distended, test for shifting dullness (ascites). Shifting
dulling can be tested for by percussing down the right side of the abdomen. If an
area of dullness is detected, keep two fingers on it and ask the patient to roll over
to his left. Re-percuss the area which should now sound tympanic.
 Check for fluid thrills.
AUSCULTATION
 Auscultate in the mid-abdomen for abdominal sounds. Listen for 60 seconds
before concluding that they are normal, hyperactive, hypoactive or absent.
 Hypoactive bowel sound: constipation, drugs such as anticholinergics &
opiates, General anesthesia, abdominal surgery, Paralytic ileus (absent bowel
sounds)
 Hyperactive bowel sounds: diarrhea of any cause, inflammatory bowel
disease, GI bleeding, Mechanical bowel obstruction (high pitched bowel
sounds)

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 Normally there are 5 to 30 bowel sounds in a minute.
 Listen over the abdominal aorta for aortic bruits suggestive of arteriosclerosis or
an aneurysm.
 Listen for renal artery bruits 2.5 cm above and lateral to the umbilicus- a bruit
suggests renal artery stenosis.
 Inspect for pedal edema.

 The following are not usually performed in an abdominal examination station,

but they should nevertheless be mentioned at this stage.
 Examination of the groins and genitals
 Assess hernia orifices
 Perform a Rectal examination (PR)

 After the examination

 Cover the patient up.
 Thank the patient.
 Ask the patient if he/she has any questions or concerns.
 State that you would test the urine and order some key investigations e.g.
ultrasound scan, FBC, LFTs, U&Es, and clotting screen.
 Summarize your findings and offer a differential diagnosis.

 Most common conditions likely to appear on an abdominal examination station:

 Chronic liver disease
 Splenomegaly
 Polycystic kidney
 Renal transplant
 Scars
 Hernias

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DIARRHEAL DISEASES
 Diarrhea is an increase in stool frequency (>3 stools per day) and volume (>200-
250grams/day).
 Normal stool volume is 100-200grams/day.
 Normal bowel habits= 3 times/day to 3 times/week.
 Stool weight is affected by fiber contents of diet, gender (higher in males),
medications, possibly exercise and stress.
 About 9 liters of fluid is presented to the GIT daily (7L from the secretion
and 2 liters from diet). Of this only 100-200ml of fluid is excreted with feces
and the rest will be reabsorbed.
 Fluid absorption follows sodium absorption which is co-transported with
chloride ion, glucose and amino acids and through sodium channels.
 Sodium-glucose co-transport is unaffected by many diarrhea diseases.
 Sudden onset of bowel frequency associated with crampy abdominal pains and a
fever will point to an infective cause, bowel frequency with loose blood-stained
stools to an inflammatory basis and the passage of pale offensive stools that float
often accompanied by loss of appetite and weight loss, to steatorrhea.
 Nocturnal bowel frequency usually points to an organic cause. Passage of
frequent small-volume (often formed) points to a functional cause.
CLASSIFICATION OF DIARRHEA
 Diarrhea can be classified according to:
 Duration of symptoms
 Etiology
 Pathophysiological mechanism of diarrhea

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BASED ON DURATION
ACUTE DIARRHEA
 Tis is diarrhea of sudden onset, it is very common, often short-lived and requires
no investigation or treatment.
 Occurs within 14 days (2 weeks).
 It is usually infectious in origin.
 Bacterial: E. coli (enteropathogenic, enteroaggregative, 014:H1,
Enteroinvasive, Enterotoxigenic and enterohemorrhagic), Campylobacter
(associated with Guillain-Barre syndrome), Salmonella, Shigella, C. difficile
(due to antibiotic use), C. perfringes, C. botulinum, Bacillus cereus, Vibrio
cholerae, Yersinia, Aeromonas.
 Viral: Adenovirus, Rotavirus, Norwalk virus
 Parasitic: Entamoeba histolytica (associated with liver abscess), Giardia
lamblia, Cryptosporidium parvum, Isospora belli, Microsporidium and
Mycobacterium avium complex in those with AIDS.
 Other causes include: antibiotics, NSAIDs, quinine, beta blockers, magnesium
based antacids, Proton pump inhibitors, colchicine, theophylline, acarbose, and
food allergies.
 Although dietary causes should be considered, diarrhea due to viral agents may
also last 24-48 hours.
 Symptoms/Exam:
 Diarrhea accompanied by urgency, tenesmus, abdominal bloating, pain and
vomiting
 Exam may reveal tachycardia, orthostasis, decreased skin turgor with
dehydration, abdominal pain and distention.
o Alarming features: fever >38.5oC, severe abdominal pain, bloody
diarrhea, immune compromise, age >70 years or severe dehydration
o No alarming features (short duration, non-bloody diarrhea, nontoxic
exam): treat with oral rehydration and symptomatic therapy. It no
improvement is seen, evaluation is indicated.
 Resolves with or without intervention.
 If diarrhea is particularly severe, dehydration can be a problem particularly in the
very young and very old.
 Investigations are necessary if diarrhea lasts more than 1 week:
 Stool for microscopy, culture and sensitivity
 Stool for Ova, cysts and parasites

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 Full blood count
 Viral and bacterial infective diarrheas do not last more than 2 weeks.
CHRONIC DIARRHEA
 Diarrhea has an insidious onset and lasts more than 2 weeks (14 days).
 Common causes include malabsorption, inflammatory bowel disease (ulcerative
colitis), irritable bowel syndrome, pancreatic insufficiency, colonic cancer and
HIV/AIDS.
 Infectious causes are not common causes of chronic diarrhea (excluding HIV GI
OIs).
 Symptoms/Exam:
 Presents with diarrhea accompanied by abdominal bloating and pain,
 Exam reveals tachycardia, orthostasis, decreased skin turgor with
dehydration, abdominal pain and distension.
PERSISTENT DIARRHEA
 Diarrhea starts off as acute and lasts more than 14 days.
BASED ON ETIOLOGY
INFECTIOUS
 Bacterial
 Vibrio cholerae
 E. coli: enterotoxigenic, enteroinvasive, enterohemorrhagic*
 Shigella*
 Clostridium perfringens
 Clostridium difficle
 Salmonella typhi and paratyphi
 Campylobacter jejuni*
 Viral
 Norwalk and Rota virus
o Invade and damage villous epithelial cells.
o Causes diarrhea by interfering with absorption through selective
destruction of absorptive villous tip cells with sparing of secretory crypt
cells.
o Stool is usually water and its content resembles those of non-invasive
diarrhea, with few inflammatory cells, probably because of absence of
colonic damage

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 Cytomegalovirus*
 Enteric adenovirus
 Astrovirus
 Coronavirus
 Picornavirus
 HIV
 Parasitic
 Giardia lamblia
o Few organisms need for infection
o Multiples in small intestines and attaches to it and occasionally invades
the mucosal cells.
o Clinical features: acute diarrheal illness, chronic diarrhea associated
with malabsorption and weight loss.
o Diagnosis based on identification of organisms either in stool or
duodenal mucus or by small intestine biopsy.
o Cysts or trophozoites can be identified in the stool and treatment should
be given in both cases.
 Entamoeba histolytica*
o Symptoms range from Mild diarrhea to fulminant amoebic colitis with
multiple bloody stools, fever and severe abdominal pain.
 Cryptosporidium parvum and Isospora belli
o Occasionally causes self-limited acute diarrheal illness in otherwise
healthy individuals. They may cause voluminous life threatening
diarrheal diseases in patients with AIDS. Modified acid fast staining of
the stool will identify both organisms.
 NOTE ‘*’ denotes causative agents that cause bloody diarrhea
NON-INFECTIOUS
 Include:
 Drugs: antibiotics (erythromycin)
 Food allergy
 Surgical conditions: Appendicitis
 Inflammatory bowel disease*
 Hyperthyroidism
 Diabetes mellitus
 Malabsorption syndromes: celiac disease, lactose intolerance

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PATHOPHYSIOLOGY OF DIARRHEA
TYPE OF DIARRHEA MECHANISM
SECRETORY DIARRHEA  Occurs due to the secretion of fluid and electrolytes or
decrease in normal absorptive capacity of the bowel.
 It usually follows stimulation by mediators like enteric
hormones, bacterial enterotoxins (e.g. cholera, heat labile E.
coli toxin, Salmonella enterotoxin), vasoactive intestinal
peptide (VIP) or laxatives. These agents activate the
adenylyl-cyclase cAMP system.
 The mediators block sodium chloride absorption and induce
chloride secretion. These events can result in massive
diarrhea, without evidence of cell injury as shown by the
ability of the cell to absorb sodium if coupled to nutrients
(sodium to glucose, sodium to amino acids) that is why
cholera and other forms of diarrhea can be treated with oral
solutions containing sodium and glucose.
 Diarrhea of secretory type persists even if the patient fasts
OSMOTIC DIARRHEA  It is due to presence of poorly absorbed or non-absorbable
substances in the intestine which are osmotically active,
resulting in secondary accumulation of fluid and electrolytes,
 Such non-absorbable substances include lactose in patients
with lactase deficiency.
 This type of diarrhea is usually caused by malabsorption and
disappears when patient fast for 48-72 hours.
EXUDATIVE DIARRHEA  Inflammations or infectious conditions that result in damage
to the intestinal mucosa cause diarrhea by several
mechanisms.
 There is loss of blood, mucous proteins and serum proteins
 Mucosal damage can interfere with absorption, induce
secretion and affect motility all of which contribute to
diarrhea.
ABNORMAL  Causes or contributes to diarrhea seen in diabetes mellitus,
INTESTINAL MOTILITY irritable bowel syndrome, postvagotomy states, carcinoid
syndrome and hyperthyroidism.
 If small bowel peristalsis is too rapid, an abnormal large
amount of fluid and partially digested foodstuffs may be
delivered to the colon.

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 Extremely slow peristalsis may allow bacterial overgrowth to
occur and bile salts deconjugation to cause secondary
malabsorption.
 Rapid colonic motility may not allow adequate time for the
colon to absorb fluid delivered to the cecum (normally 90%
of the fluid is absorbed)

PATHOPHYSIOLOGY OF INFECTIOUS DIARRHEA

 Microbes cause diarrhea either directly by invasion of gut mucosa or indirectly
through elaboration of different types of toxins: secretory enterotoxins,
cytotoxins and inflammatory mediators.
Type of diarrhea Comments Examples
Secretory toxin  Patients seldom have fever or  Vibrio cholerae: produces
induced major systemic symptoms enterotoxins which stimulate
diarrhea  Little or no inflammatory response adenylate cyclase which results in
 The organisms colonize the massive intestinal secretion
intestinal mucosa but do not  Enterotoxigenic E. coli is the
invade the intestinal wall major cause of Traveler’s
diarrhea
 Non- typhoidal salmonella like S.
typhimarium
 Shigella dysenterae may initially
cause secretory diarrhea
Cytotoxin  Cytotoxins are soluble factors that  Shigella dysentrae produces
induced directly destroy mucosal epithelial Shiga toxin which causes
diarrhea cells destructive colitis
 Enterohemorrhagic E.coli
 Clostridium perfringens, Vibrio
parahemolyticus
 Clostridium difficle causes
pseudomembranous colitis in
individuals treated with
antibiotics
Diarrhea cause  Characterized by fever and other  Acute shigellosis
by invasive systemic symptoms like headache  Acute salmonellosis
pathogens and myalgia.  Campylobacter jejuni:
Responsible for up to 10% of

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 The diarrhea is frequent but small acute diarrhea worldwide. It
in volume. It is associated with invades both the small and large
crampy abdominal pain and intestines.
tenesmus.  Enterohemorrhagic E. coli: it
 These pathogens induce marked produces bloody diarrhea without
inflammatory response and stool evidence of mucosal
usually contains pus cells, proteins inflammation (grossly bloody
and often gross blood. stool with few or no leucocytes)

EVALUATION OF A PATIENT WITH DIARRHEA

HISTORY
 History should include:
 Duration of diarrhea
o <2 weeks is acute and suggests an infectious causes and resolves with
or without intervention
o >2 weeks consider chronic diarrhea disease and infectious causes are
unlikely (also consider HIV status). In most cases cause includes
malabsorption, inflammatory Bowel disease (ulcerative colitis), Irritable
Bowel syndrome, Colonic cancer, and immunosuppression like AIDS
 Number of stool per day
o Large volume indicates small bowel or proximal colonic disease
o Scanty, frequent stools associated with urgency suggests left colon or
rectal diseases
 Diurnal variation
o Nocturnal- organic causes
o Non-nocturnal- functional causes like irritable bowel syndrome
 Nature of diarrhea- Watery or blood?
o Bloody diarrhea is usually inflammatory or ischemic in origin and
causes by invasive organisms, ulcerative colitis or neoplasms
 Association with specific meal
o Fat diet- due to fatty intolerance
o Sweet diet- it is due to osmotic diarrhea
o Milk and milk products- due to lactase deficiency
 History of drug intake
o Penicillin may be associated with pseudomembranous colitis
o Laxatives

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o Chemotherapeutic agents
 Presence of co-morbidities: diabetes mellitus
PHYSICAL EXAMINATION
 Physical examination:
 Assess severity of dehydration
 Weight loss and other associated signs in patients with chronic diarrhea
 Digital rectal examination
INVESTIGATIONS
1. Stool microscopy, culture and sensitivity for:
 Ova and parasites
 Pathogenic bacterial strains
2. Stool for occult blood test
3. Full blood count, Urea, Electrolytes, Creatinine and liver enzymes
4. Proctosidmoidoscopy to exclude or confirm the diagnosis of inflammatory bowel
diseases.
MANAGEMENT
 Rehydration
 IV fluids: Ringer’s lactate or normal saline for patients with massive diarrhea
and vomiting with hypotension.
 For patients without hypotension oral fluid containing sodium, glucose,
potassium and chloride ions (ORS) are preferred.
 Antimicrobial therapy
 Antibiotics
o Most acute infectious diarrheal diseases do not require antibiotic therapy
because the majority of them are self-limited and viral in nature.
o Of the non-invasive bacterial diarrhea, antibiotics decrease the volume
only in cholera. Doxycycline 300mg single dose is the drug of choice.
o For invasive bacterial diarrhea causes by E. coli and Shigella (bacillary
dysentery) Ciprofloxacin 500mg or Norfloxacin 400mg TDS for 3-5
days is indicated.
 Anti-protozoal
o Entamoeba histolytica: metronidazole 500 mg PO TDS for 7 days.
o Giardia lamblia: Metronidazole 250mg TDS for 5 days or Tinidazole
2g once

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o Isospora belli: Co-trimoxazole 960mg QID for 10 days then 960mg BD
for additional 3 weeks. In immunocompromised patients continue
maintenance dose of the same drug three times a week.
o Nitazoxanide for Cryptosporidiosis
 When no specific therapy is available or no cause is identified it’s appropriate to
give empirical therapy e.g.
 Antibiotics for possible bacterial overgrowth or Metronidazole for Giardia,
Cholestyramine for bile acid malabsorption
o Metronidazole 500mg TDS for 7 days
o Ciprofloxacin 500mg TDS for 5 days
 Non-specific therapy with constipating agents such as loperamide,
diphenoxylate and in more severe cases codeine or long acting somatostatin
analogue
o Loperamide 4mg initially and then 2mg after each stool (maximum 8
mg/day)

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ENTERIC FEVER
 Enteric fever is an acute illness characterized by fever, headache and abdominal
discomfort caused by Salmonella typhi.
 This is a member of the family Enterobacteriacae.
 It is an encapsulated facultative anaerobic non-spore forming gram negative
bacilli.
 Like other organisms in the family the bacterium has:
o Somatic antigen (O antigen)
o Flagella antigen (H antigen)
o Capsular antigen: Vi (K)
 The disease was initially called typhoid fever because of its clinical similarity to
typhus. The name enteric fever was proposed as an alternative designation to
distinguish typhoid fever from typhus however, to this day the two designations
are used interchangeably.
 The term enteric fever is a misnomer, in that the hallmark features of this disease-
fever and abdominal pain are variable.
 Infection by S. paratyphi A, B or C also causes illness although it is less severe.
 Man is the only natural host for S. typhi.
PATHOGENESIS
 Transmission: ingestion of contaminated food or water (Fecal-oral route).
 Incubation period is 3-21 days.
 After ingestion, the bacteria invade the small bowel wall via Peyer’s patches
(specifically the mononuclear phagocytes- M cells in the terminal part of the
ileum) from where they spread to the regional lymph nodes (especially the
mesenteric lymph nodes) and then to the blood (bacteremia).
 Gastric acid is protective so for infection to happen its either there is low
gastric acid, immunocompromise or a large inoculum.
 The Vi antigen is important in preventing antibody mediated opsonization
and complement mediated lysis.
 The bacteria also spread to the phagocytes of the liver, gallbladder and spleen.
 The usual site of carriage is the gallbladder (chronic carrier is associated with gall
stones).
 In some areas endemic for urinary schistosomiasis chronic carriage is in the
urinary bladder.
 The pathogen can be excreted into bile and feces further transmitting the disease.

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CLINICAL FEATURES
 Infection begins in the small intestine but few gastrointestinal symptoms occur.
 A prodrome of non-specific symptoms often precedes fever and include:
 Chills
 Headache
 Anorexia
 Cough
 Weakness
 Sore throat
 Dizziness
 Muscle pain
 The onset of illness is insidious (causing harm without showing any obvious
signs) and nonspecific with persistent step-ladder fever (lasting more than 1 week
caused by endotoxins), headache, asthenia (severe weakness), insomnia,
anorexia, epistaxis and abdominal pain.
 Fever and constipation (due to hypertrophy of Peyers patches) rather than
vomiting and diarrhea predominate.
 Diarrhea may occur early but usually disappears by the time the fever and
bacteremia occur.
 After the first week, as the bacteremia becomes sustained, high fever, delirium,
tender abdomen and enlarged spleen occur.
 Rose spots i.e. rose-colored macules on the abdomen are associated with typhoid
fever but occur only rarely.
 Physical findings in the early stages include:
 Abdominal tenderness
 Hepatosplenomegaly
 Lymphadenopathy
 Scanty maculopapular rash (‘rose spots’)
 Within 3 weeks without treatment serious complications can arise:
 Meningitis and encephalitis
 Coma
 Bronchitis and Lobar pneumonia
 Hepatitis
 Myocarditis
 Intestinal perforation and peritonitis
 Intestinal hemorrhage

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 Nephritis
 Osteomyelitis and arthritis
 Parotitis and orchitis
 The 4th weeks of illness is characterized by gradual improvement but 30% of
infected will die and 10% of untreated will relapse.
 After clinical recovery 5-10% of patients will continue to excrete the pathogen
for several months (convalescent carriers)
 1-4% will carry organisms for more than 1 year (chronic carriage) in the gall
bladder and urinary bladder.
DIAGNOSIS
 Diagnosis can be suggested by the presence of:
 Persistent fever
 Relative bradycardia
 Rose spots
 Leucopenia
 The definitive diagnosis requires culture of S. typhi or S. paratyphi from the
patient.
 Blood culture is positive in most cases in the first 2 weeks Use the mnemonic
 Culture of intestinal secretions, feces and urine is also used, “BUS” to help
although care must be taken to distinguish acute infection from remember the
chronic carriage. specimen to take
 Bone marrow culture is more sensitive than blood culture but is for culture during
rarely required except in patients who have already received the first 3 weeks
antibiotics
 Full blood count: Leukopenia and anemia are often seen. B- blood/bone
st
 Liver function tests (LFTs) are often abnormal indicating hepatic marrow in 1 week
involvement U- urine in 2nd
 Chest X-ray to rule out pneumonia Week
 Serological tests such as the Widal antigen tests are of little
S- stool in 3rd week
practical value, are easily misinterpreted and should not be used.
They check for the somatic O and flagella H antigens.
 Widal antigen could be positive due to infection by other Salmonellae, recent
vaccination for typhoid, past typhoid (already treated)
DIFFERENTIAL DIAGNOSIS
 Malaria

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 Urinary tract infection
 Lower respiratory tract infection
 Dengue fever

MANAGEMENT AND PREVENTION

 Increasing antibiotic resistance has been noted.
 Chloramphenicol, Cotrimoxazole, and amoxicillin may all still be effective in
some cases but quinolones (e.g. ciprofloxacin 500 mg twice daily) are now the
treatment of choice.
 Antibiotic therapy is curative. The drugs are given either orally or intravenous
depending on the patient condition (able to take orally or not), severity of the
disease.
 First line: Quinolones and third generation cephalosporin
 Ciprofloxacillin PO 500mg BD for 10 days or
 Ceftriaxone 1-2gm IM or IV for 10-14 days or
 Cefixime PO 1g/day in 2 divided doses for 10-14 days
 Alternatives
 Azithromycin 1gm PO daily for 5 days
 Chloramphenicol 500mg PO QID for 14 days (initial doses of 3-4g/day for
adults with clinical response observed in 24-48 hours after initiation. Dose
should be reduced to 2g/day when fever starts to decrease usually after 5-6
days and continued to complete 2 weeks treatment)
 Norfloxacin 400mg BD for 14 days
 IV drugs are recommended for critically sick patients who are admitted or for
patients who are unable to take oral drugs.
 Ceftriaxone 2-4g OD for 3 days and then 1-2 g IV/IM for a total of 10-14
days
 IV chloramphenicol 1g IV QID for 2-3 days then start PO medication as soon
as the patient can take oral medication.
 Quinolones are not recommended for use in children and pregnant women
because of their observed potential damaging effect on cartilage of the growing

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animals. However, in severe infections especially by MDR strains, we have to
outweigh the benefits and the potential risks.
 With resistance to quinolones azithromycin may be effective.
 The patient’s temperature may remain elevated for several days (4-6 days) after
starting antibiotics and this alone is not a sign of treatment failure.
 Prolonged antibiotic therapy may eliminate the carrier state but in the presence
of gall bladder disease it is rarely effective.
 Cholecystectomy may be necessary to abolish the chronic carrier state.
 Prevention is mainly through improved sanitation and clean water.
 Vaccination with either injectable inactivated or oral live attenuated vaccines
give partial protection.

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CHOLERA
 Cholera is an illness characterized excessive diarrhea and vomiting.
 It is caused by the curved, flagellated Gram-negative bacillus, Vibrio cholerae.
 The organism is killed by temperatures of 100oC in a few seconds but can survive
in ice for up to 6 weeks
 1 major pathogenic serogroup possess a somatic antigen (O1) with 2 biotypes
 Classical
 El tor: infection causes milder symptoms but can still cause severe and life-
threatening disease.
PATHOGENESIS
 Transmission is by fecal-oral route
 Contaminated water plays a major role in the dissemination of cholera,
although contaminated foodstuffs and contacts carriers may contribute in
epidemics.
 Achlorrhydria or hypochlorhydria facilitates passage of cholera bacilli into the
intestines
 In the intestines they proliferate, elaborating an exotoxin which produces massive
secretion of isotonic fluid into the intestinal lumen
 The toxin has an alpha and beta subunit
 The cholera toxin binds to its receptor (monosialoganglioside Gi) via fimbria
(toxin co-regulated pilus) on its beta-subunit
 This activates the alpha stimulatory subunit (or the Gs protein) which
activates the cAMP cascade.
 This in turn activates protein kinase and there is an influx of calcium into the
cytosol which then acts on the apical membrane causing chloride secretion
(with water) and inhibition of sodium and chloride absorption.
 Cholera toxin also releases serotonin (5-HT) from enterochromaffin cells in the
gut, which activates a neural secretory reflex in the enteric nervous system. This
may account for at least 50% of cholera toxin’s secretory activity.
 V. cholerae also produces other toxins (zona occcludens toxins, ZOT and
accessory cholera toxin, ACT) which contribute to its pathogenic effect.
CLINICAL FEATURES
 The incubation period is from a few hours to 6 days.
 Cholera may present as a mild illness indistinguishable from diarrhea due to other
causes.

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 Classically it has 3 phases
 Evacuation phase: characterized by abrupt onset of painless, profuse watery
diarrhea associated with vomiting in severe forms. Stools may be rice-water,
flecked with mucus.
 Collapse phase: is reached if appropriate treatment is not given. It is
characterized by features of circulatory shock (cold clammy skin,
tachycardia, hypotension and peripheral cyanosis) and dehydration (sunken
eyes, hollow cheeks and diminished urine output). There may also be muscle
cramps. Children may also have convulsions due to hypoglycemia.
Complications such as renal failure and aspiration of vomitus may occur.
 Recovery phase: occurs if the patient survives the collapse phase. With
adequate treatment the prognosis is
good, with a gradual return to normal
clinical and biochemical parameters in
1-3 days.
DIAGNOSIS
 Largely clinical.
 Examination of freshly passed stools may
demonstrate rapidly motile organisms
(although this is not diagnostic, as
Campylobacter jejuni may give a similar
appearance).
 A rapid dipstick test is now also available.
 Stool and rectal swabs should be taken for
culture to confirm the diagnosis and to
establish antibiotic sensitivity.
 Cholera should always be reported to
appropriate public health authority
MANAGEMENT
 Mainstay of treatment is rehydration. Give
Oral rehydration salts (ORS) solution or
any fluids after each loose stool. ORS and
other fluids should be continued until
diarrhea stops.
 Assess dehydration

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o Mild dehydration: give ORS 50ml/kg in first 4 hours then
100ml/Kg/day until diarrhea stops.
o Moderate dehydration: give ORS 100ml/kg in first 4 hours then 10-
15ml/kg/hour until improvement then give 100ml/kg/day until diarrhea
stops
o Severe dehydration: intravenous fluid (Ringer’s lactate or normal saline
if RL is not available): 100ml/kg in 3 hours and reassess if no
improvement repeat, if improvement is seen give 10-15ml/kg/hr ORS
until improvement then give 100ml/kg/day ORS till diarrhea stops
 Monitor the patient frequently
 Reassess the patient after 4 hours using the classification of dehydration. If
signs of dehydration are present repeat the same management. If patient shows
signs of severe dehydration change management of that severe dehydration
 Patients should be encouraged to eat and drink as much as they want.
 Drugs only given according to sensitivity patterns
 Doxycycline 300 mg single dose (drug of choice except in pregnant
women)
 Azithromycin 1g single dose
 Tetracycline 500mg QID for 3 days
 Erythromycin QID for 3 days (Dose depends on age): this is recommended
when other recommended antibiotics are not available or where V. cholerae
is resistant to them.
 Immunization is now recommended by the WHO in potential or actual outbreak
situations. Live attenuated and killed vaccine (both oral) are available: neither
protect against the O139 strain.
 The best preventive measures are good hygiene and improved sanitation.

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DYSENTERY
 Dysentery is the passage of bloody diarrhea or mucus or both in stool.
 There are two types of dysentery:
 Bacillary dysentery
 Amoebic dysentery
BACILLARY DYSENTERY
 Bacillary dysentery is caused by the bacteria Shigella which has a short
incubation period usually being 2 days.
 Shigella are enteroinvasive bacteria, which cause classical bacillary dysentery.
 The principle species are:
 S. dysenteriae
 S. flexneri
 S. sonnei
 They all cause a similar syndrome, as a result of damage to the intestinal mucosa.
Some strains of S. dysenteriae also secrete a Cytotoxin affecting vascular
endothelium.
 Initially it multiples in the small intestine causing secretory diarrhea later it
invades colonic epithelium causing bloody diarrhea
 Transmission is strongly associated with poor hygiene. The organism is spread
from person to person and only small numbers need to be ingested to cause illness
(<200 compared with 104 for campylobacter and >105 for salmonella).
 The illness is usually self-limiting in 7-10 days but in children in developing
countries mortality may be as high as 20%.
CLINICAL FEATURES
 Acute onset (symptoms start 24-48 hours after ingestion and typically consist of
frequent small-volume stools containing blood and mucus)
 Malaise
 Fever
 Watery diarrhea
 Bloody diarrhea with mucus
 Fecal urgency
 Severe cramping abdominal pain
 Nausea
 Vomiting

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 Headache
 Convulsions (in children)
 Tenesmus
 Mild or moderate dehydration: dehydration is not as significant as in the secretory
diarrheas but systemic symptoms and intestinal complications are worse.
DIAGNOSIS
 Stool microscopy may show leukocytes
 Stool culture and susceptibility test
MANAGEMENT
 Antibiotics relieve symptoms, shorten illness, reduce mortality in children and
decrease transmission.
 The first drug of choice is Ciprofloxacillin 500mg BD for 3 days
 Alternatives
o Ampicillin 500mg PO QID
o Azithromycin 500mg PO OD
o Co-trimoxazole 960 mg PO BD
 Nalidixic acid 1g PO QID for 7 days is no longer the preferred drug of choice
due to increased resistance
 Prevention:
 Drink clean, boiled/chlorinated water
 Good sanitation
 Good personal hygiene
COMPLICATIONS
 Shigella type 1:
 Encephalopathy
 Conjunctivitis
 Hemolytic uremic syndrome
 Metabolic disorders
 Septicemia
 Arthritis
 Colonic perforation
 Toxic mega colon
 Rectal prolapse in children

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AMOEBIC DYSENTRY
 This is caused by the parasite Entamoeba histolytica.
CLINICAL FEATURES
 Bloody diarrhea with mucus
 Low grade fever
 Dehydration is unusual
DIAGNOSIS
 Stool microscopy
 Sero diagnosis
MANAGEMENT
 Metronidazole 800mg PO TDS for 5 days followed by diloxanide furoate
500mg TDS for 10 days (for eradication of cysts) or
 Tinidazole 2g PO daily 2-3 days
 Avoid use of anti-diarrhea agents
 Supportive
 Fluid replacement
 Analgesics
COMPLICATIONS
 Fulminant colitis
 Colon perforation
 Peritonitis
 Chronic infection
 Stricture formation
 Severe hemorrhage
 Amoebic liver abscess
 Amoeboma
PREVENTION
 Good disposal of excreta-good pit latrine, flush toilets
 Provision of clean water
 Boiling water. This kills amoeba cysts if water is boiled for at least 10 minutes.
 Chlorination of water- effects variable on amoeba

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 Personal hygiene- washing of hands after use of toilet, when preparing food and
before eating.
DIFFERENCES BETWEEN BACILLARY AND AMOEBIC DYSENTRY
Feature Bacillary dysentery Amoebic dysentery
Causative organism Usually Shigella but can Entamoeba histolytic
also be caused by
enterohemorrhagic
E.coli, Vibrio
parahemolyticus,
Campylobacter jejuni
Onset Acute Chronic
Fever High grade Low grade
Dehydration Frequent Moderate
Number of stools Over 10 motions per day 6-8 motions per day
Amount Small Relatively copious
Odor Odorless Offensive
Color Bright red Dark red
Nature Blood and mucus no Blood and mucus mixed
feces with feces
Nature of lesion Suppurative due to Necrotic due to
diffusible toxins proteolytic ferment
Depth of ulcer Shallow Deep
Margin of ulcer Uniform, clear-cut Ragged and undermined
(sharp)
Intervening mucosa Inflamed Normal
Type of necrosis Karyolysis (Ghost cell Pyknotic (Pyknotic body
(cellular level) and ring nucleus) and mouse eaten cell)
Liver abscess Rare Common
Cellular response Polymorphonuclear Mononuclear

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GIT BLEEDING
UPPER GIT BLEEDING
 This is bleeding from the upper gastrointestinal tract proximal to the ligament of
Treitz which anatomically separates the duodenum from the jejunum.
 Mortality is 10% and usually results from complications of underlying disease
rather than from exsanguination.
 The risk of re-bleeding is low if bleeding occurred more than 48 hours before
presentation.
ETIOLOGY
 Peptic ulcer disease (50%) (H. pylori and
NSAIDs)-ulcer erosion into blood
vessel. Commonly posterior duodenal
ulcer.
 Gastroesophageal varices (15%) (either
due to cirrhosis or schistosomiasis)
 Mallory-Weiss tear (5%) following
severe vomiting
 Gastroesophageal reflux disease
 Drugs: Aspirin and NSAIDs
 Inflammation:
 Esophagitis (25%)
 Gastritis (25%)
 Erosive gastritis (in HIV patients
consider CMV, HSV, candida)
 Duodenitis (15%)
 Gastric cancer (5%)
 Gastric vascular ectasia
 Cameron’s ulcer
 Dieulafoy’s lesion (submucosal artery)
 Aortoenteric fistula
 Hemobilia (mixture of blood and bile due to surgical and non-surgical trauma)

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CLINICAL FEATURES
 History:
 Nausea
 Retching prior to hematesis (Mallory-Weiss tear)
 Hematemesis (bright red blood or “coffee ground” emesis due to stasis of
blood in the stomach)
 Dyspepsia
 Abdominal pain
 Melena: dark tar like stool (as little as 50ml of blood in the GIT can cause
melena)
 Hematochezia (from rapid upper GI bleeding or massive bleeding with
shock)
 Orthostasis (orthostatic hypotension)
 Chronic slow upper GI bleeding can present with occult blood positive brown
stool and chronic iron deficiency anemia.
 General features: nausea, epigastric pain, syncope, lightheadedness,
dizziness, fatigue
 History of alcohol use are usually found among those with variceal
hemorrhage, esophagitis, and Mallory-Weiss tear
 History of NSAID use (peptic ulcer)
 History of prior abdominal aortic graft (aortoenteric fistula)
 History of chronic GERD (esophagitis)
 History of weight loss/iron deficiency (malignancy)
 Physical examination
 Melena or hematochezia
 Pallor
 Hypotension and orthostatic hypotension (>10-point rise in pulse when the
patient goes from the supine to the standing or sitting position or >20-point
drop in systolic blood pressure on change in position)- there should be at least
a minute in between the position change and the measurement of pulse and
blood pressure to allow time for the normal autonomic discharge to
accommodate to the position change. Orthostasis indicates a 15 to 20% blood
loss.
 Tachycardia
 Stigmata of chronic liver disease (spider angioma, ascites, jaundice)

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DIAGNOSIS AND INVESTIGATIONS
 First determine if the bleed is acute or chronic.
 Ask about the number of bleeding episodes, most recent episode, abdominal
pain, weight loss, use of ASA, NSAIDs, alcohol, cirrhosis, risk factors of
schistosomiasis.
 If the bleed is acute, first evaluate hemodynamic stability. Check blood
pressure and heart rate. Ask about lightheadedness, syncope, dizziness.
Check for orthostatic vital signs, they will be positive in patients with
significant blood loss.
 Do a rectal exam to look for bright red blood or melena.
 Investigations:
 Full blood count: chronic or subacute bleeding leads to anemia but
hemoglobin concentration may be normal after sudden, major bleeding until
hemodilution occurs. Thrombocytopenia may be a clue to the presence of
Hypersplenism in chronic liver.
 Stool for occult blood
 Urea, electrolytes and creatinine: this may show evidence of renal failure.
The blood urea rises as the absorbed products of luminal blood are
metabolized by the liver, an elevated blood urea with normal creatinine
concentration implies severe bleeding.
 Liver enzymes: for chronic liver disease
 PT/PTT/INR for coagulopathy
 Cross-matching- at least 2 units of blood should be cross-matched.
 NG tube lavage: useful if positive (red blood, coffee grounds), if negative
(clear or bilious), does not exclude upper GIT bleeding. 10% of Upper GIT
bleeding cases have a negative lavage.
o If you pull out fresh blood (acute and active upper GI bleed)
o If you pull out coffee ground like material (recent upper GI bleed)
o If you pull out non-blood bilious material (this does not exclude an upper
GI bleed, the bleed may be lower)
 H. pylori testing: perform on all patients with ulcers. (Stool for H. Pylori)
 Endoscopy: perform after stabilization and resuscitation, often done <12
hours from admission. Diagnostic, prognostic and therapeutic.

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MANAGEMENT
 Stabilization:
 Oxygen given by facemask
 Nil per oral, consider an NG tube and place two large-bore IVs.
 If the patient is in shock, treat with aggressive IV fluids (normal saline or
Ringer’s lactate) and cross-matched blood with a hematocrit goal of 25-30%
or above in older patients and in those who may have coronary artery disease.
(if you suspect esophageal variceal bleed, start normal saline cautiously)
 Cross match blood and administer packed red blood cells if needed.
 In the presence of active bleeding and platelets <50 000/L or if there is
known impaired function (uremia, aspirin), transfuse platelets or
desmopressin. With active bleeding, increased PT time, and INR> 1.5
transfuse fresh frozen plasma (FFP).
 Place a Foley catheter to closely monitor urine output, decreased urine output
is a sign of hypoperfusion and bleeding.
 Hourly measurement of pulse, blood pressure and urine output.
 Medical therapy:
 Give high dose oral proton pump inhibitors twice daily upon presentation.
(Omeprazole 40mg BD)
 Initiate an IV proton pump inhibitor drip (8mg/h for 72 hours) if
esophagogastroduodenoscopy (EGD) suggests a high risk of re-bleeding (i.e.
active bleeding, visible vessel, adherent clot). This reduces the relative risk
of bleeding by 50%.
 IV octreotide for suspected variceal hemorrhage continue for 3 days if
verified by EGD. This is meant to decrease portal hypertension.
 Correct any coagulopathies, consider giving vitamin K if signs of liver
disease. For severe bleeding give vitamin K 5mg IV stat.
 Propranolol is a non-selective beta blocker that used in the long-term
management of portal hypertension to decrease the frequency of bleeding.
Everyone with varices from portal hypertension and cirrhosis should be on a
beta-blocker.
 Broad-spectrum antibiotics in patients with suspected liver disease.
 Endoscopy: should be carried out after adequate resuscitation, ideally within 24
hours and will yield a diagnosis in 80% of cases.
 Patients can be effectively treated with banding (band ligation for varices),
thermal coagulation (heater probe) sclerosant, epinephrine and/or

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electrocautery. Predictors of re-bleeding include significant comorbidities,
size of lesion and high risk stigmata (visible vessel, adherent clot).
 Refractory or recurrent upper GIT bleeding:
 Esophageal balloon tamponade (Minnesota or Sengstaken-Blakemore tubes)
for varices as a bridge to TIPS
(transjugular intrahepatic portosystemic
shunting)- a catheter is placed into the
jugular vein and guided radiographically
through the liver to form a shunt between
the systemic circulation in the hepatic
vein and the portal circulation through
the portal vein. TIPS has largely replaced
the need to surgically place the shunt.
The most common, long-term
complication of TIPS is worsening of
hepatic encephalopathy.
 Angiogram with intra-arterial
embolization or surgery for refractory
non-variceal bleeding
 H. pylori eradication: for all peptic
ulcer causing upper GIT bleeding with
(H. pylori testing).
 Surgery is indicated when endoscopic
hemostasis fails to stop active
bleeding and if re-bleeding occurs on
one occasion in an elderly or frail
patient or twice in a younger fitter
patient. If available, angiographic
embolization is an effective
alternative to surgery in frail patients.
The choice of operation depends on the site and diagnosis of the bleeding lesion.
 Discharge: The patient’s age, diagnosis on endoscopy, co-morbidity and the
presence or absence of shock and the availability of support in the community
should be taken into consideration. In general, all patients who are
hemodynamically stable and have no stigmata of recent hemorrhage on
endoscopy can be discharged from hospital within 24 hours. All shocked patients
and patients with co-morbidity need longer inpatient observation.

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LOWER GASTROINTESTINAL BLEEDING
 This is bleeding from a source distal to the ligament of Treitz.
 More 95% of cases are from a colonic source and more than 85% are self-limited.
 It may be due to hemorrhage from the colon, anal canal or small bowel.
 It useful to distinguish those patients who present with profuse, acute bleeding
from those who present with chronic or subacute bleeding of less severity.
ETIOLOGY
 Diverticulosis (40%)
 Diverticular disease
 Meckel’s disease
 Angiodysplasia
 Vascular ectasia
 Neoplasm (carcinoma)
 Fissure
 Inflammatory bowel disease
 Ischemic colitis
 Hemorrhoids
 Infectious e.g. hookworms
 Postpolypectomy
 NSAID ulcers
 Radiation colitis
 Rectal varices
 Solitary rectal ulcer syndrome
CLINICAL FEATURES
 Symptoms:
 Usually asymptomatic but may present with
abdominal cramps and to a less extent pain.
 Orthostasis is seen in severe cases.
 Signs:
 Hematochezia (bright red blood, maroon stool)
 Melena
 Pallor, chronic bleeding tends to present with anemia (iron deficiency)
 Abdominal distension with mild tenderness
 Hypotension and Tachycardia

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DIAGNOSIS AND INVESTIGATIONS
 Demographics and history
 Age group: distinguish elderly, asymptomatic patients (diverticular/vascular
ectasias) from young patients who present with pain (infectious,
inflammatory).
 Description of first blood seen by patient: bright red indicates a distal or rapid
proximal source, black or marron blood points to a more proximal source.
 Rectal examination
 Investigations:
 Full blood count: chronic or subacute bleeding leads to anemia but
hemoglobin concentration may be normal after sudden, major bleeding until
hemodiluation occurs. Thrombocytopenia may be a clue to the presence of
hypersplenism in chronic liver.
 Stool for occult blood
 Stool microscopy, cultures and sensitivity if infection is suspected.
 Urea, electrolytes and creatinine: this may show evidence of renal failure.
The blood urea rises as the absorbed products of luminal blood are
metabolized by the liver, an elevated blood urea with normal creatinine
concentration implies severe bleeding.
 Liver enzymes: for chronic liver disease
 PT/PTT/INR for coagulopathy
 Cross-matching- at least 2 units of blood should be cross-matched.
 Anoscopy to exclude an anal source
 Mild to moderate bleeding: consider nasogastric lavage. Urgent colonic
purge (over 4-6 hours then colonoscopy)
 Massive bleeding
o Endoscopy to rule out upper GI bleeding.
o Technetium-labelled RBC scan and/or mesenteric angiography: if >6
units of blood are transfused, consider surgical intervention.
o Minimum bleeding rates: tagged RBC scan, 0.1-0.5ml/min, mesenteric
angiogram, 1.0 ml/min
 Diagnostic colonoscopy: typically performed 12-48 hours after presentation
and stabilization.
 Proctoscopy for anorectal disease particularly hemorrhoids
 Flexible sigmoidoscopy or colonoscopy for IBD, cancer, ischemic colitis,
diverticular disease, angiodysplasia

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 Angiography- vascular abnormality (angiodysplasia): the yield of
angiography is low so it is a test of last resort
 If gastroscopy, colonoscopy and duodenal biopsy have not revealed the
cause, investigation of the small bowel is necessary. Capsule endoscopy is
the diagnostic investigation of choice but currently has no therapeutic ability.
(A capsule with a camera is swallowed and it takes pictures along the GIT)
MANAGEMENT
 Stabilization:
 Oxygen given by facemask
 Nil per oral, consider an NG tube and place two large-bore IVs.
 If the patient is in shock, treat with aggressive IV fluids (normal saline or
Ringer’s lactate) and cross-matched blood with a hematocrit goal of 25-30%
or above in older patients and in those who may have coronary artery disease.
(if you suspect esophageal variceal bleed, start normal saline cautiously)
 Cross match blood and administer packed red blood cells if needed.
 In the presence of active bleeding and platelets <50 000/L or if there is
known impaired function (uremia, aspirin), transfuse platelets or
desmopressin. With active bleeding, increased PT time, and INR> 1.5
transfuse fresh frozen plasma (FFP).
 Place a Foley catheter to closely monitor urine output, decreased urine output
is a sign of hypoperfusion and bleeding.
 Hourly measurement of pulse, blood pressure and urine output.
 Medical therapy: H2 receptor antagonists and PPIs have no role in the treatment
of lower GI bleeding. Discontinue ASA and NSAIDs. Oral iron is given to treat
anemia.
 Urgent therapeutic colonoscopy:
 Large volume purge >6L, cautery or injection of epinephrine or clipping.
 Colonoscopy is technically challenging with brisk Lower GI bleeding (urgent
colonic purge requires sedation; visualization is often poor)
 Mesenteric angiography/embolization: the intervention of choice for brisk lower
GI bleeding. Associated with 80-90% cessation rates for those with diverticular
or vascular ectasia etiology though 50% experience re-bleeding.
 Surgery: indicated with active lower GI bleeding involve >4-6 units of blood in
24 hours or >10 units in total. If the site is well localized, consider
hemicolectomy, otherwise perform total abdominal colectomy.

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THE STOMACH AND DUODENUM

 The stomach is a muscular pouch continuous from the esophagus (the cardia) to
the pylorus.
 It consists of the cardia, an upper region (the fundus, under the left diaphragm),
the mid-region or body and the antrum, which extends to the pylorus.
 The cardia is lined by mucin-
secreting foveolar cells that form
shallow glands.
 The fundus contains parietal cells
and chief cells.
 The body also contains parietal and
chief cells.
 The antrum contains G-cells and D-
cells.
 The pylorus has a sphincter
separating the stomach from the
duodenum.
 It serves as a reservoir where food can be retained (Stomach capacity=1500-
3000ml) and broken up before being actively expelled into the proximal small
intestine.
 The stomach is innervated by the vagus nerve.
 The smooth muscle of the wall of the stomach has 3 layers:
 Outer longitudinal
 Inner circular
 Innermost oblique
 There are 2 sphincters, the gastro-esophageal sphincter and the pyloric sphincter.
 The pyloric sphincter is largely made up of a thickening of the circular muscle
layer and controls the exit of gastric contents into the duodenum.
 The duodenum has outer longitudinal and inner smooth muscle layers, it is C-
shaped and the pancreas sites in the concavity. It terminates at the duodenojejunal
flexure where it joins the duodenum.
 The mucosal lining of the stomach can stretch in size with feeding. The greater
curvature of the undistended stomach has thick fold or rugae.
 The mucosa of the upper 2/3 of the stomach contains:
 Parietal cells which secrete hydrochloric acid and intrinsic factor.
 Chief cells these secrete pepsinogen (which initiates proteolysis)

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 There is a color change at the junction between the body and the antrum of the
stomach that can be seen macroscopically and confirmed by measuring surface
pH.
 The antral mucosa contains
 G- cells which secretes gastrin which stimulates acid production. There are 2
major forms of gastrin G17 and G34, depending on the number of amino acid
residues. G17 is the major form found in the antrum.
 D-cells which secrete somatostatin, a suppressant of acid secretion.
 Mucus secreting cells which produce mucus and bicarbonate. The mucus is
made of glycoproteins called mucins.
 The wall of the stomach also contains enterochromaffin cells which produce
histamine that promotes acid secretion.
 The ‘mucosal barrier’ made up of the plasma membrane of mucosal cells and the
mucus layer protects the gastric epithelium from damage by acid and for
example, alcohol, aspirin, NSAIDs and bile salts. Prostaglandins stimulate
secretion of mucus and their synthesis is inhibited by aspirin and NSAIDs which
inhibit cyclo-oxygenase
 The duodenal mucosa has villi like the rest of the small bowel and also contains
Brunner’s glands that secrete alkaline mucus. This along with pancreatic and
biliary secretions, helps to neutralize the acid secretion from the stomach when it
reaches the duodenum.
 Gastric acid secretion:
 The apical membrane contains H+-K+ ATPase as well as Chloride channels.
 The basolateral membrane contains Na+-K+ ATPase and Cl—HCO-3
exchanger
 The parietal cell also contains the enzyme carbonic anhydrate.
 Carbon dioxide in the cell reacts with water in the presence of carbonic
anhydrase to form carbonic acid which dissociates into hydrogen and
bicarbonate ions.
 The hydrogen ions are secreted along with chloride ions into the lumen of the
stomach while the bicarbonate is absorbed into the blood.
 At the apical membrane hydrogen ions are exchanged for potassium ions.
 Potassium ions leave via a potassium channel found on the apical membrane.
 At the basolateral side of the cells chloride is exchanged for bicarbonate ions
(Responsible for the alkaline tide observed in gastric venous blood after a
meal)

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 Acid is not essential for digestion but

does prevent some food-born infectious.
It is under neural and hormonal control
and both stimulate acid secretion through
the direct action of histamine on the
parietal cell. Acetylcholine and gastrin
also release histamine via the
enterochromaffin cells.
 Somatostatin inhibits both histamine and
gastrin release therefore acid secretion.
 Other major functions are:
 Reservoir for food
 Emulsification of fat and mixing of
gastric contents
 Secretion of intrinsic factor
 Absorption (of only minimal
importance)
 Gastric emptying depends on many factors. There are osmoreceptors in the
duodenal mucosa that control gastric emptying by local reflexes and the release
of gut hormones. In particular, intraduodenal fat delays gastric emptying by
negative feedback through duodenal receptors.

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GASTRITIS
 This is inflammation of the gastric
mucosa (although the term is often used
loosely by endoscopists to describe
‘redness’).
 Note the word gastritis is not
synonymous with dyspepsia or gastric
erythema seen during endoscopy.
 In gastritis there is a disruption of
mucous layer, stimulation of acid
secretion and decreased production of
bicarbonate which eventually cause
direct damage to the epithelium.
 It is classified into:
 Acute gastritis
 Chronic gastritis
ACUTE GASTRITIS
 This is commonly caused by
Helicobacter pylori.
 Other causes:
 Drugs e.g. ASA, NSAIDs
 Alcohol in high doses
 Severe stress
 Other infections e.g. virus (CMV, Herpes simplex), mycobacterium and
syphilis
 Patients are usually asymptomatic but at times may present with sudden onset of
epigastric pain, nausea & vomiting (with or without diarrhea), upper GIT
bleeding (melena and hematesis), indigestion with neutrophilic infiltration,
edema and hyperemia of the gastric mucosa.
 If not treated, H. pylori gastritis may progress to one of the chronic gastritis. No
specific treatment of acute gastritis is indicated. Removal of the offending agents
may be adequate.

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CHRONIC GASTRITIS
 This is defined as a histological demonstration of lymphocytic and plasma cell
infiltration of gastric mucosa.
 Course: Superficial gastritis is followed by atrophic gastritis (characterized by
distortion and destruction of gastric glands) progressing to gastric atrophy (with
loss of gastric glands) which then undergo intestinal metaplasia (replacement of
gastric mucosal cells by intestinal cells) and finally progressing to gastric
carcinoma.
 Chronic gastritis is classified into 3 types:
 Type A (autoimmune) gastritis (chronic fundal gastritis)
o The inflammation is limited to the gastric fundus and body with antral
sparing.
o Associated with pernicious anemia, with circulating autoantibodies to
parietal cells (AKA Autoimmune gastritis)
 Type B (bacterial) gastritis (chronic antral gastritis)
o It is the more common type
o It commonly involves the antrum and mostly associated with H. pylori
infection. However, the inflammation may progress to involve the gastric
fundus and body causing pangastritis usually after 15-20 years.
o Histology improves with eradication of H. pylori.
 Type C (chemical) gastritis
o Is due to repeated injury with bile reflux (duodenal-gastric reflex) or
chronic ingestion of NSAIDs
 Most chronic gastritis is asymptomatic.
 Treatment:
 Lifelong parenteral Vitamin B12 is recommended for patients with
pernicious anemia.
 There is no need to treat H. pylori unless there is ulcer or MALT Lymphoma.

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PEPTIC ULCER DISEASE
 A peptic ulcer is a break in the superficial cells (Mucosal surface) penetrating
down to the muscularis mucosa (found in the submucosa) of either the stomach
or the duodenum.
 An erosion by contrast are superficial breaks in the mucosa alone.
 Recall the layers of the GIT include: mucosa, submucosa, muscularis and
serosa
 Peptic ulcers are caused by discrete tissue destruction caused by acid and pepsin.
 Most duodenal ulcers are found in the duodenal cap, the surrounding mucosa
appears inflamed, hemorrhagic or friable (duodenitis).
 Gastric ulcers are most commonly seen on the lesser curve near the incisura but
can be found in any part of the stomach.
 Duodenal ulcers affect approximately 10% of the adult population and are 2 to 3
times more common than gastric ulcers.
 Peptic ulcer disease occurs more commonly in males than females. They are
common in adults between 25 and 64 years.
 About 90-100% of all duodenal ulcers and 75-85% of gastric ulcers are associated
with H. pylori infection.
 Ulcers occur when there is an imbalance between the protective forces of the GIT
and aggressive ones.
 Protective forces:
o Surface mucus
o Presence of bicarbonate
o Rapid epithelial regeneration
o Normal mucosal blood flow
o Normal mucosal prostaglandin secretion
 Aggressive forces:
o H. pylori
o NSAIDs
o Corticosteroids
o ASA
o Smoking
o Alcohol
o Psychological stress
o Zollinger-Ellison syndrome

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ETIOLOGY
 H. pylori
 This is a slow-growing spiral Gram-negative flagellate urease-producing
bacterium.
 It is acquired through fecal-oral or oral-oral route
 It colonizes the mucous layer in the gastric antrum but is also found in the
duodenum in areas of gastric metaplasia.
 It is found in greatest numbers under the mucous layer in gastric pits, where
it adheres specifically to gastric epithelial cells.
 It is protected from gastric acid by the juxtamucosal mucous layer which
traps bicarbonate secreted by antral cells and ammonia produced by bacterial
urease.
 Mechanisms by which H. pylori damages mucosa:
o Induction of IL-8 which recruits neutrophils
o Production of urease which cleaves urea to ammonia and carbon dioxide
creating a buffer against the HCL.
o Enhancement of gastric acid secretion and impairment of duodenal
bicarbonate production
o Adheres to surface epithelial cells and secretes phospholipase, adhesins,
platelet activating factors and protease enzymes (catalase, lipase)
o Production of a passive urea transporter (VacA) that causes cell injury
(vacuolization)

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o CagA (cytotoxic-associated protein) and VacA (vacuolating toxin) genes
have also been implicated in the development of ulcers.
 NSAIDs, ASA, Corticosteroids: these drugs inhibit prostaglandin synthesis
which leads to decreased mucus production, bicarbonate secretion and an
impaired blood flow. It commonly causes gastric ulcers as opposed to duodenal
ulcers.
 Alcohol and smoking
 Uremia and radiation therapy
 Severe burns (Curling ulcer)- hypovolemia and dehydration leads to decreased
blood supply and so acid that infiltrates into the mucosa is not carried away.
 Cushing ulcer- increased intracranial pressure and increased stimulation of Vagus
nerve leads to increased acid production. This is seen with head injury.
 Sever physiological Stress
CLINICAL FEATURES
 Manifestation is dependent on ulcer location and patient age.
 Course is usually chronic and recurrent.
 Pain is the most common symptom it is described as burning, gnawing or felt as
hunger often localized to epigastrium and relieved by food or antacids.
 Gastric ulcers:
 Symptoms often do not follow a consistent pattern, especially when ulcer is
located in pyloric channel where symptoms of obstruction may predominate
(bloating, nausea, vomiting due to edema and scarring).
 Duodenal ulcers:
 Pain tends to be consistent usually absent when patient wakes up but appears
in the morning, and relieved by food but recurs again 2-3 hours after a meal.
 Pain may be severe enough to awaken patient at night.
 Note: the relationship of the pain to food is variable and on the whole not helpful
in diagnosis. The pain of a duodenal ulcer classically occurs at night (as well as
during the day) and is worse when the patient is hungry but this is not reliable.
The pain of both gastric and duodenal ulcers may be relieved by antacids.
 Nausea may accompany the pain, vomiting is infrequent but can relieve the pain.
Anorexia and weight loss may occur particularly with gastric ulcers. Persistent
and severe pain suggests complications such as penetration into other organs.
 Duodenal ulcer pain that becomes constant is no longer relieve by food or
antacids or radiates to the back or to either upper quadrant may signal
penetration of the ulcer to the pancreas.

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 Duodenal ulcer pain accentuated rather than relieved by food and/or
accompanied by vomiting often indicates gastric outlet obstruction
 Abrupt severe or generalized abdominal pain is characteristic of free ulcer
perforation into the peritoneal cavity.
 Back pain suggests a penetrating posterior ulcer.
 Severe ulceration can occasionally be symptomless, as many who present with
acute ulcer bleeding or perforation have no preceding ulcer symptoms.
 Physical findings:
 Epigastric tenderness
 Signs of peritonitis may be found in ulcer perforation
 Succussion splash is often detected in gastric outlet obstruction
Duodenal ulcer Gastric ulcer
Age Uncommon before 16 years May develop in children as young
as 5 years but peak incidence is
later than duodenal ulcer
Relation of pain to Pain is relieved by food or Pain aggravated by ingestion of
food/antacids antacids food
Relation of pain to food The pain characteristically The pain comes within 30
timing comes 2 to 3 hours after minutes of ingestion of food
ingestions of food (hunger
pain)
Nausea and vomiting Not common Common
Weight loss Uncommon Common because of fear to eat
Perforation More common Less common
Bleeding Less common More common
INVESTIGATIONS
 Endoscopy: this is the most sensitive and specific method for the diagnosis of
PUD.
 Direct visualization and photographic documentation of the ulcer is possible
 Permits mucosal biopsy for detection of H. pylori infection
 Provides baseline reference for the assessment of ulcer healing
 H. pylori tests: stop Proton pump inhibitors 2 week before.
 13C-Urea breath test- simple, rapid, useful for early follow up, false negative
with recent therapy. The measurement of 13CO2 in the breath after ingestion
of 13C urea requires as mass spectrometer. The test is sensitive (90%) and
specific (96%) but the sensitivity can be improved by insuring the patient has

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not taken antibiotics in the 4 weeks prior and proton pump inhibitors in the 2
weeks before the test.
 Stool antigen test: it is 97.6% sensitive and 96% specific.
 Barium studies (Barium meal and Barium follow through): sensitivity of this
investigation to detect ulcers ranges from 70-90%.
 Full blood count may show iron deficiency anemia.
MANAGEMENT
 Remove any offending drug
 Stop smoking.
 Avoid coffee, and foods that cause or aggravate their symptoms
 Drugs:
 For indigestion/dyspepsia, to relieve symptoms given then between meals
and at bedtime:
o Magnesium trisilicate compound 250-500mg to chew PRN.
o Aluminium hydroxide 500mg-1g to chew PRN
 For acid reflux: Omeprazole 20mg PO daily BD.
 No single agent is effective for eradication of H. pylori hence a combination
of multiple drugs is essential. Proton pump inhibitors are added to antibiotics
o Triple therapy:
 Omeprazole 20mg BD (or 40mg OD), Clarithromycin 250mg
or 500 mg BD and Metronidazole/Amoxicillin 500mg BD/1g
BD for 14 days.
 Omeprazole 20mg BD (or 40 mg OD), Metronidazole 400mg
TDS, Amoxicillin 500mg TDS
 Omeprazole 20 mg BD (or 40 mg OD), Metronidazole 400mg
(or Tinidazole 500mg) BD and Clarithromycin 500mg BD for
14 days.
o Quadruple therapy: Bismuth subsalicylate 2 tabs QID, Omeprazole 20mg
BD, Metronidazole 400mg TDS, Tetracycline 500mg QID
 This is used for eradication failures
 Surgical treatment is indicated for:
 Perforation
 Obstruction not responding to medical therapy
 Uncontrolled/recurrent bleeding
 Suspected malignancy
 Symptoms refractory to medical management

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COMPLICATIONS
 Hemorrhage
 Anemia
 Penetration to other organs e.g. pancreas, liver
 Perforation
 Gastric outlet obstruction, Pyloric stenosis
 Stomach cancer

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LIVER AND BILIARY TRACT DISEASE

THE LIVER
 In many countries, alcohol is the major cause of liver disease, followed by
hepatitis C virus infection.
 Hepatitis B virus is still a significant factor but widespread vaccination will
reduce its prevalence.
 Non-alcoholic fatty liver disease is associated with the metabolic syndrome and
is increasing in affluent (wealthy) countries.
 Imaging techniques enable the liver, biliary tree and pancreas to be visualized
with precision, resulting in earlier
diagnosis.
 The liver is one of the largest internal
organ (1.2-1.5kg) and is situated in the
right hypochondrium.
 A functional division into the larger
right lobe (containing caudate and
quadrate lobes) and the left lobe is made
by the middle hepatic vein.
 The liver is further subdivided into 8
segments by divisions of the right middle
and left hepatic veins. Each segment has
its own portal pedicle permitting
individual segment resection at surgery.
 The hepatic blood supply constitutes
25% of the resting cardiac output and is
delivered via two main vessels, entering via the liver hilum (portal hepatis):
 Hepatic artery: A branch of the coeliac axis, supplied 25% of the hepatic
blood flow. The hepatic artery auto-regulates flow ensuring a constant total
blood flow.

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 Portal vein: drain most of the GIT and spleen. It supplies 75% of hepatic
blood flow. The normal portal pressure is 5-8mmHg, flow increases after
meals
 Blood from these vessels is distributed to the segments and flows into the
sinusoids via the portal tracts. Blood leaves the sinusoids, entering branches of
the hepatic vein which joint into 3 main branches before entering the inferior
vena cava.
 The caudate lobe is an autonomous segment as it receives an independent blood
supply from the portal vein and hepatic artery and its hepatic vein drains directly
into the inferior vena cava.
 Lymph, formed mainly in the
perisinusoidal space is collected in
lymphatics which are present in the portal
tracts. These small lymphatics enter larger
vessels which eventually drain into the
hepatic ducts.
 The acinus is the functional hepatic unit.
It consists of parenchyma supplied by the
smallest portal tract containing portal vein
radicles, hepatic arterioles and bile
ductules.
 The hepatocytes near this triad (zone 1)
are well supplied with oxygenated blood
and are more resistant to damage than the
cells near the terminal hepatic (central
veins (zone 3).
 The sinusoids lack a basement membrane
and are loosely surrounded by specialist
fenestrated endothelial cells and Kupffer
cells (phagocytic cells).
 Sinusoids are separated by plates of liver cells (hepatocytes). The subendothelial
space between the sinusoids and hepatocytes is the space of Disse, which contains
a matrix of basement membrane constituents and stellate cells.
 Stellate cells store retinoids in their resting state and contain the intermediate
filament, desmin. When activate (to Myofibroblast) they are contractile and
probably regulate sinusoidal blood flow.

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 Endothelin and nitric oxide play a major role in modulating stellate cell
contractility.
 Activated stellate cells produce signal proteins for synthesis or inhibition of
degradation of extracellular matrix components, including collagen as well as
cytokines and chemotactic signals.
 Functions of the liver include:
 Protein metabolism
o Synthesis and storage: all serum proteins (albumin and fibrinogen except
gamma-globulins are synthesized by the liver).
o It also synthesizes other proteins such as transferrin, ceruloplasmin,
acute-phase reactive protein, alpha-1 antitrypsin and alpha-fetoprotein as
well as clotting factors: fibrinogen, prothrombin, V, VII, IX, X and XII,
proteins C, S and anti-thrombin as well as proteins of complement
system.
 Carbohydrate metabolism: gluconeogenesis, glycolysis, glycogenesis,
glycogenolysis
 Lipid metabolism: synthesis and transport of lipids via lipoproteins.
 Storage of vitamins: A, D, B12, K, folate and other minerals such as iron in
ferritin & hemosiderin, and copper
 Synthesis and secretion of bile
 Detoxification and inactivation of endogenous and exogenous substances
 Immunological function: complement proteins.

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LIVER DISEASE
 Liver disease is classified according to duration:
 Acute: <6 months
 Chronic: >6 months

SYMPTOMS AND SIGNS OF LIVER DISEASE

1. Signs of cirrhosis (i.e. signs of liver dysfunction): Jaundice, Spider naevi,
gynecomastia, loss of body hair, palmar erythema, Asterixis, easy bruising and
testicular atrophy
2. Signs of portal hypertension: splenomegaly, ascites, caput medussae (distended
abdominal veins)
 Note: cirrhosis will present with both signs of cirrhosis & portal hypertension
whereas schistosomiasis will present only with signs of portal hypertension.
SYMPTOMS OF LIVER DISEASE
ACUTE LIVER DISEASE
 This may be asymptomatic and anicteric (without jaundice).
 Symptomatic disease which is often viral, produces generalized symptoms of
malaise, anorexia and fever. Jaundice may appear as the illness progresses.
CHRONIC LIVER DISEASE
 Patients may be asymptomatic or complain of nonspecific symptoms, particularly
fatigue.
 Specific symptoms include:
 Right hypochondrial pain due to liver distension
 Abdominal distension due to ascites
 Ankle swelling due to fluid retention
 Hematemesis and melena from GIT hemorrhage
 Pruritus due to cholestasis-this is often an early symptom of primary biliary
cirrhosis.
 Breast swelling (gynecomastia), loss of libido and amenorrhea- due to
endocrine dysfunction (increased estrogen in the body because most of it is
not broken down by the liver).

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SIGNS OF LIVER DISEASE
ACUTE LIVER DISEASE
 There may be few signs apart from jaundice and an enlarged liver.
 Jaundice is a yellow coloration of the skin and mucous membranes and is best
seen in the conjunctivae and sclerae.
 In the cholestatic phase of the illness, pale stools and dark urine are present.
 Spider naevi and palmar erythema usually indicated chronic disease but they can
occur in severe acute disease.
CHRONIC LIVER DISEASE
 The physical signs include:
 Skin
o The chest and upper body may show spider naevi. These are
telangiectasia (widened venules) that consist of a central arteriole with
radiating small vessels. They are found in the distribution of the superior
vena cava (i.e. above the nipple line)- commonly more than five is taken
as diagnostic. They are also found in pregnancy.
o In hemochromatosis the skin may have a slate-grey appearance.
o The hands may show palmar erythema, which is a nonspecific change
indicative of hyper-dynamic circulation, i.e. it is also seen in pregnancy,
thyrotoxicosis or rheumatoid arthritis.
o Clubbing occasionally occurs and a Dupuytren’s contracture is often seen
in alcoholic cirrhosis.
o Xanthomas (cholesterol deposits) are seen in the palmar creases or above
the eye in primary biliary cirrhosis.
 Abdomen:
o Initially hepatomegaly will be followed by a small liver in well-
established cirrhosis.
o Splenomegaly is seen with portal hypertension.
 Endocrine system:
o Gynecomastia (usually unilateral) and testicular atrophy may be found in
males. The cause of gynecomastia is complex but it is probably related
to altered estrogen metabolism or to treatment with spironolactone.

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 In decompensated cirrhosis, additional signs include:
 Neurological (Hepatic encephalopathy) i.e. disorientation, drowsy coma,
hepatic flap, fetor hepaticus (also known as breath of the dead or hepatic
fetor, a condition seen in portal hypertension where portosystemic shunting
allows thiols to pass directly into the lungs, the breath becomes strong and
musty)
 Ascites
 Edema
 Loss of proximal muscle bulk
 Dilated veins on abdomen

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 Sometimes the physical examination is sometimes normal in patients with

advanced chronic liver disease.
 Additional signs of acute and chronic liver disease include:
 Hepatomegaly: a smooth tender liver is seen in hepatitis and with
extrahepatic obstruction but a knobby irregular liver suggests metastases.
 Splenomegaly: indicates portal hypertension in patients when signs of
chronic liver disease are present. The spleen can also be “tipped”
occasionally in viral hepatitis.
 Ascites: this is found in cirrhosis but can also be due to carcinoma
(particularly ovarian) and many other causes.
 A palpable gall bladder occurs with a carcinoma of the pancreas obstructing the
bile duct.
 Generalized lymphadenopathy suggests a lymphoma.
 Cold sores are seen with a herpes simplex virus hepatitis.

EXAMINATION OF THE LIVER

 Size: normal size is 12cm. Upper border defined by percussion which is normally
at the 5th intercostal space and lower border below the costal margin in the
midclavicular space.
 Edge: regular or irregular
 Surface: smooth or nodular
 Consistency- hard or soft or firm
 Pulsatile or not
 Bruit- present or not and position
 If a mass is identified within the liver, define its margins, is it fluctuant?

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LABORATORY EVALUATION
 These tests used to determine the following: if the liver disease is primary or
secondary, due to parenchymal or extrahepatic biliary obstruction and how
progressed the disease has become.
 Due to large reserve, test may be normal in early liver disease
 Liver synthetic function tests: Albumin, bilirubin, PT/PTT
 Albumin: this is a marker for liver protein synthesis. It decreases in chronic
liver disease.
 Bilirubin: This is a product of heme metabolism in liver. Direct/conjugated
bilirubin is high in obstruction. Indirect/unconjugated bilirubin is high in
hemolysis and decreased conjugation by the liver.
 Prothrombin time (PT): depends on synthesis of coagulation factors.
Increased levels found in severe acute injury or chronic injury. Best guide to
the prognosis in acute hepatitis. Because of its short half-life, it is a sensitive
indicator of both acute and chronic liver disease. Vitamin K deficiency
should be excluded as the cause of a prolonged PT by giving an intravenous
bolus (10mg) of vitamin K.
o This is the time taken by blood to clot after adding tissue thromboplastin
to it.
o Normal prothrombin time= 11-16s.
o It is a marker of the extrinsic pathway.
o Since PT varies in different laboratories depending upon the
thromboplastin used in the assay, the international normalized ratio
(INR) was developed to standardize anticoagulation with coumarin
derivatives but is very variable in liver disease.
 Partial thromboplastin time/activated partial thromboplastin time: this is the
time taken for blood to clot after adding an activator such as phospholipid
along with calcium to it.
o Normal PTT = 40s
o It is a marker of the intrinsic pathway.
 Inflammatory/injury tests (liver enzymes): AST/ ALT
 These are intracellular enzymes released secondary to
necrosis/inflammation.
 AST is primarily a mitochondrial enzyme (80%, 20% in cytoplasm)
 ALT is a cytosol enzyme more specific to the liver so that a rise only occurs
with liver disease.

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 ALT is more specific for the liver than AST (also found in heart, skeletal
muscles, brain and kidney).
 ALT> AST more likely viral hepatitis or fatty liver.
 AST: ALT > 2.1 suggests alcoholic hepatitis
 Increased LDH suggests ischemic or toxic hepatitis.
 Alkaline phosphatase: Enzyme bound in hepatic canicular and sinusoidal
membrane. Also in bone and intestines. If from liver GGT (Gamma glutamyl
transferase, a microsomal enzyme present in the liver and many other tissues)
will also be increased. High alkaline phosphatase is seen in biliary obstruction or
intrahepatic cholestasis.
 Viral markers: can be used to detect multiple viral diseases especially hepatitis
viruses.
 Urine tests- for bilirubin and urobilinogen
 Alpha 1 antitrypsin- a deficiency of this enzyme can produce cirrhosis
 Alpha fetoprotein- this is normally produced by the fetal liver, its reappearance
in increasing and high concentrations in adults indicates hepatocellular
carcinoma. Increased concentrations in pregnancy in blood and amniotic fluid
suggests fetal neural tube defects. Blood levels are also slightly raised with
regenerative liver tissue in patients with hepatitis, chronic liver disease and also
in teratomas.
 Imaging technique- to define gross anatomy
 Ultrasound
 Abdominal X-ray
 Upper GI endoscopy
 CT scan
 MRI
 Liver biopsy- for histology

PATTERNS OF LIVER INJURY

 Hepatocellular: marked increase in AST and ALT +/- increased bilirubin
(indirect ++) in severe forms. AST and ALT >1, 000 is indicative of severe viral
hepatitis, acetaminophen toxicity or ischemic hepatitis
 Cholestasis: increased alkaline phosphatase and direct bilirubin +/- mild
increases in AST and ALT
 Jaundice: a clinical sign when bilirubin levels are high >2.5 mg/dl, if
hyperbilirubinemia is conjugated, should see increase in urine bilirubin.

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 Fulminant liver failure: high AST/ALT, alkaline phosphatase, bilirubin, PT with
hepatic encephalopathy

TYPES OF LIVER INJURY

Pre-haptic causes Hepatic causes Post-hepatic (biliary origin)
 Falciparum malaria  Viral hepatitis  Primary biliary cirrhosis
 Hemolytic uremic  Alcoholic hepatitis
syndrome  Vascular hepatitis
 Sepsis  Toxin-induced
 Pneumococcal hepatitis
pneumonia  Genetic causes of
 Sickle cell disease liver disease:
 Hemochromatosis
 Wilson’s disease

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HEPATITIS
 This is inflammation of the liver due to viral, toxic, pharmacologic or immune
mediated damage to the liver.
 Hepatocellular necrosis and inflammatory cell infiltration of the liver are
common pathologic features.
 There are 2 types of hepatitis:
 Acute hepatitis: lasts for about 6 months or less.
 Chronic hepatitis: sustained inflammatory response for over 6 months.
HEPATITIS
 Ranges from asymptomatic to fulminant liver failure.
 When encephalopathy is seen within 8 weeks the prognosis is poor.
ETIOLOGY
 Viral: hepatitis A, E, G, EBV and CMV viruses. (note even B, C, and D have the
propensity to cause acute hepatitis but most often cause chronic hepatitis)
 Toxins: amanita phylloides in mushroom poisoning, carbon tetrachloride.
 Drugs: acetaminophen, Isoniazide, halothane, chlorpromazine, erythromycin,
heavy alcohol intake.
 Others: Wilson’s disease, herbs.
VIRAL HEPATITIS
 Viral hepatitis is the most common form of acute hepatitis.
 Viral hepatitis can be self-limiting or can progress to fibrosis, cirrhosis or liver
cancer.
 Most of viral hepatitis cases are caused by one of the following:
 Hepatitis A (HAV) virus (infectious hepatitis)
 Hepatitis B (HBV) virus (serum hepatitis)
 Hepatitis C (HCV) virus (was the most common cause of post-transfusion
hepatitis)
 Hepatitis D (HDV) virus (defective virus dependent on co infection with
HBV)
 Hepatitis E virus (HEV) (enterically transmitted hepatitis)
 Note: acute viral hepatitis is caused by hepatitis viruses HAV, HEV and HGV
(non A, non B virus) all of which are RNA viruses (remember HBV, HCV and
HDV have propensity to cause acute viral hepatitis but are more associated with
chronic hepatitis, HBV is a DNA virus).

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 HDV is an incomplete RNA virus and requires the presence of HBV to cause
infection, thus it causes hepatitis when HDV infection occurs at the same time as
HBV infection (HDV co-infection) or in patients with chronic hepatitis B
infection (super infection- it may present as an acute infection superimposed on
a chronic infection).
 Superinfection is much more severe than co-infection.
 Type A and E are typically caused by ingestion of contaminated food or water.
 Hepatitis B, C and D usually occur as a result of parenteral contact with infected
body fluids.
 Clinical features:
 Swelling and tenderness of the liver
 Jaundice, fever, nausea, vomiting, anorexia and dark urine.
 Transaminase, alkaline phosphatase levels increase.
HEPATITIS A
 This is a non-enveloped (naked) single
stranded positive sense linear RNA virus
with icosahedral symmetry belonging to the
picornavirus family.
 Although it was first provisionally
classified as enterovirus 72. It is now
assigned to the genus hepatovirus.
 It has only one known serotype.
 The Virus resists inactivation and is stable
at -20oC with low pH.
 Its genome is divided into 3 coding regions:
 P1 region which encodes structural
proteins.
 P2 and P3 which encodes non-structural proteins.
PATHOGENESIS
 It is transmitted via the fecal-oral route.
 The largest known modern epidemic of HAV was from consumption of
contaminated seafood as well following consumption of contaminated
lettuce, ice slush beverages, frozen strawberries and salad food items.
 The virus is hardy, surviving on human hands and inanimate objects
(fomites).

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 Incubation period is 2-6 weeks (on average 30 days).
 HAV is ingested and probably enters the bloodstream (viremia) through the
oropharynx or the epithelial lining of the intestines to reach its target, the
parenchymal cells of the liver.
 It interacts with -macroglobulin receptors on target cells (liver cells and a
few other cell types on enteric mucosa).
 The response to replication in the liver is followed by lymphoid infiltration,
necrosis of the liver parenchymal cell and proliferation of Kupffer cells.
 The virus is produced in these cells and is released into bile and from the stool.
 The virus is shed in large quantity into the stool approximately 10 days (1-2
weeks) before symptoms of jaundice appear or antibody can be detected.
 There is no chronic carrier stage. Except in rare instances of acute hepatic
necrosis, the infection is cleared and the liver damage is reversed.
CLINICAL FEATURES
 Disease in children is generally milder than in adults and is usually
asymptomatic.
 The clinical disease has 2 stages:
 Prodromal or preicteric stage: onset may be acute with fever, malaise,
anorexia, nausea, arthralgia (joint pain), myalgia, upper respiratory
symptoms, vomiting and liver tenderness. Patients will have aversion to
smell of food and cigarette with mild fever and flu-like symptoms.
 Icteric or jaundice stage: 1-2 weeks dark urine and pale stool is common in
cholestasis, jaundice, mild pruritus (itch) and slight liver enlargement
(hepatomegaly +/- splenomegaly), lymphadenopathy (less likely to occur if
patient is <30 years) and tenderness (right upper quadrant pain).
o The hyperbilirubinemia is due to both conjugated and unconjugated
bilirubin. Damage to the bile ductules causes conjugated bile to leak into
the blood while damage to the hepatocytes renders conjugation in the
liver inefficient resulting in a rise in unconjugated bilirubin.
 Recovery is slow over a period of 4-6 weeks.

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INVESTIGATIONS
 Liver enzymes: damage to hepatocytes causes release of
Note: to convert
intracellular enzymes like AST and ALT. Normal levels range
mg/dl tomol/L
between 0-35U/L. In acute hepatitis. They often rise to 20 fold
multiply by 17.1
or more. In viral hepatitis ALT rises more than AST.
 Serum bilirubin usually peaks after transaminase levels but
usually remains less than 10mg/dl. Normal levels range between 0.3 and 1mg/dl
(5.1-17.1mol/L). When levels go above 2.5-3.0mg/dl (42.8-51.3 mol/L)
jaundice appears (Called icteric hepatitis).
 Alkaline phosphatase: may be increased by about 3 fold except in cholestatic
hepatitis, in which the increment is very much higher.
 Full blood count: leucopenia with atypical lymphocytes (relative lymphocytosis)
is common.
 Serology: Diagnosis requires the presence of serum HAV IgM.
 IgM antibodies present for 3-6 months after onset of symptoms.
 IgG is not diagnostic. IgG is an indication of recovery or immunization
(vaccination).
 IgG confers lifelong immunity.

TREATMENT
 Alcohol should be avoided until serum transaminases normalize.
 Supportive:
 Rest to limit fatigue
 Maintain hydration
 Adequate dietary intake (adequate nutrition)
 Vitamin supplementation has no proven value but vitamin K can be given if
there is prolonged cholestasis.
 Metoclopramide (plasil) for nausea.
o More than 60kg: 10mg PO daily in 3 divided doses (when administered
by slow intravenous injection to be given over at least 3 minutes)
o Less than 60kg: 500micrograms/kg PO daily in 3 divided doses (when
given as slow intravenous injection to be given over at least 3 minutes)
 Admission:
 Patients with severe nausea and vomiting
 Patients with deteriorating liver function, especially those with
encephalopathy or prolonged prothrombin time.

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 In general, HAV may be regarded as non-infectious after 2-3 weeks.
 It usually resolves in 2-6 weeks.
PROPHYLAXIS
 Good hygiene.
 For close contracts of HAV infected people:
 Immune serum globulin (IgG) as soon as possible but no later than 6 weeks
after exposure. Manufactured immune serum globulin (ISG) is protective if
given before or during incubation period of disease. When clinical symptoms
have appeared ISG administration is not indicated as the person is already
producing antibodies. ISG should be administered to household and intimate
contacts of hepatitis A patient, those in contact with food handled by HAV
infected people.
 Active immunization: Formalin-killed HAV grown in human cells. Induces
antibody titers similar to those of wild type virus Infection. Two doses are
given at 6 and 12 months apart.

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HEPATITIS B
 This is the most widespread and most important type of viral hepatitis. It can
cause both acute and chronic disease.
 It infects the liver and to a lesser extent the kidneys and pancreas of only humans
and chimpanzees.
 HBV is an encapsulated DNA virus with circular double stranded DNA
belonging to the Hepadnaviridae family.
 The nucleocapsid encloses the viral genome consisting of 2 linear strands of DNA
held in circular configuration. 1 strand (the plus strand) is incomplete so that
DNA appears partially double stranded and partially single stranded. Viral DNA
polymerase is associated with the plus
strand. It has both DNA-Dependent
polymerase as well as RNA dependent
reverse transcriptase functions.
 Although it is a DNA virus, it encodes a
reverse transcriptase and replicates through
an RNA intermediate. This polymerase can
repair the gap in the plus strand and render
the genome fully double stranded.
 The complete HBV consists of several
antigenetically distinct components
including:
 a surface coat (Hepatitis B surface
antigen- HBsAg) and
 a core of circular DNA, DNA polymerase, hepatitis B core antigen (HBcAg)
and hepatitis B envelope antigen (HBeAg)
 The HBsAg is expressed on the surface of the virion. It is encoded by the S region
of DNA. The body’s immune response produces antibodies against these
antigens. Antibodies against HBsAg are called anti-HBs.
 HBsAg appears 1-2 weeks (late to 11-12 weeks) after exposure and persists
for 1-6 weeks (even 5 months) in acute hepatitis B.
 In chronic patients/carriers HBsAg persists many years.
 HBsAg can be found in body fluids: saliva, urine, semen, tears, sweat and
breast milk.
 It has 10 subtypes with the major being adr, adw, ayr and ayw.

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 Anti-HBs appear after HBsAg disappear several weeks (or months) anti-HBs
the protective antibody, can persist for many years.
 The HBcAg is expressed on the core. HBcAg can be found in the nuclei of liver
cells, no free HBcAg in serum. HBcAG is the marker of replication of HBV.
 The stage in which both HBsAg and Anti HBs levels are equal in blood and
so they both cannot be detected is called the window period (Anti-HBc is
then used).
 Anti-HBc IgM is a marker of acute infection and acute attack of chronic
infection of HBV.
 Anti-HBc IgG is a marker of past infection, high titer means low levels of
replication of HBV, it is important in disease resolution. It does not develop
in response to vaccine.
 The HBeAg is a soluble non-particulate nucleocapsid protein. It is a reliable
indicator of active replication of HBV. Anti-HBe is a marker of reduced
infectivity. If it exists long, it may be a marker of integration of HBV into the
liver cells.

 The main antigens that induce antibodies include HBsAg, HBcAg and
HBeAg.
 With the exception of HBcAg all other antigens and antibodies together
with the viral DNA polymerase can be detected in the blood at various
times after infection and are referred to as “markers”
 HBcAg is readily detectably only in the hepatocyte nuclei.
 HBsAg stimulates protective antibodies and is a marker for current
infection
 HBcAg localized within the liver cells indicates acute infection, anti-
HBcAg persists for life and is a marker of past infection.
 Anti-HBc IgM is a marker of acute infection and acute attack of
chronic infection of HBV
 Anti-HBc IgG is a marker of past infection. High titers indicate low
levels of replication
 HBeAg is a marker of active replication and infectivity.
 Anti-HBe is a marker of reduced infectivity

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PATHOGENESIS
 Transmissions occurs parenterally via blood, saliva, menstrual and vaginal
discharges, semen and breast milk as well as through sexual contact. It can also
occur perinatally from mother to child.
 HBV is found in highest concentrations in blood and in lower concentrations
in other body fluids (e.g. semen, vaginal secretion and wound exudates)
 The incubation period is 6weeks to 6 months.
 The factors determining the clinical manifestations of acute hepatitis B are
largely unknown however some appear to involve immunologic response of host
(cell mediated and humoral immunity)
 Antibody to HBsAg is protective and associated with resolution of disease.
 Defects in cellular immunity results in high incidence of chronic infection.
 Chronic infection leads to progressive fibrosis and cirrhosis.
 HBV infection may not cause hepatitis but may lead to carrier state.
 There are 2 types of carriers:
 Super carriers: they have HBeAg, high titers of HBsAg and DNA polymerase
in their blood. HBV may also be demonstrated in blood. Very minute amount
of serum or blood can transmit infection.
 Simple carriers: these are more common types of carriers who have low titer
of HBsAg in blood with negative HBeAg, HBV and DNA polymerase. They
transmit the infection only when large volumes of blood are transferred as in
blood transfusion.
CLINICAL MANIFESTATION
ACUTE INFECTION
 Preicteric phase: long incubation (1-6 months) and an insidious onset. Symptoms
include arthralgia, urticaria, fever, malaise, anorexia, vomiting, abdominal
discomfort, chills, joint pain, cholestasis in some patients (clay-colored stool).
 Arthritis and urticarial may be present particularly in HBV which are
attributed to immune complex deposition.
 Icteric phase: jaundice, dark urine, pale stool. Right upper quadrant pain, hepato
± splenomegaly
 Convalescent (recovery) phase: 90-95% of adults with acute HBV recover within
1-2 months of onset and eliminate the virus from the body within about 6 months,
remaining immune thereafter.

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CHRONIC INFECTION
 1-10% remain chronically infected.
 There may be asymptomatic carriers or may progress to recurrent or chronic
liver disease or cirrhosis.
 A few of them develop hepatocellular carcinoma after many decades.
 Fulminant hepatitis leading to liver necrosis and death develops in less than 1%
of the cases.
DIAGNOSIS
 Liver enzymes: increase in AST and ALT. Normal range between 0 to 35U/L. In
acute hepatitis, they often rise to 20 fold or more. The rise in ALT is greater than
that in AST.
 Serum bilirubin: normal levels between 0.3 to 1mg/dl when levels go above 2.5-
3.0mg/dl jaundice appears (called icteric hepatitis)
 Alkaline phosphatase: may increase about 3 fold except in cholestatic hepatitis
when rise is much higher.
 Full blood count: leucopenia with atypical lymphocytes (relative lymphocytosis)
is common.
 Serodiagnosis: Serodiagnosis involves antigen/antibody detection.
 Diagnosis of HBV
o Antigens
- HBsAg- First marker to appear (2-6 weeks), usually cleared within
3 months. It may persist in some patients for 6 months to one year
without complications. Its clearance from the blood precedes the
appearance of anti-HBs antibody with a time gap in between
(known as the window period) during which the only evidence of
HBV infection may be anti-HBc antibody.
- HBeAg- indicates HBV replication and high chance of infectivity
to others
o Antibodies
- Anti HBs antibody- confers long term immunity
- Anti HBc- IgM indicates recent infection, IgG indicates remote
infection, do not provide immunity.
- Anti HBe- active infection, do not provide immunity.

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 Incubation: HBs Ag and HBeAg present and neither is

detectable (=infective)
 Acute infection: HBs Ag, HBc IgM, HBc IgG, HBe Ag
(=infective), ↑↑ LFTs
 Chronic infection: HBs Ag, HBc IgG, ↑LFTs. Sometimes
HBe Ag (=infective), HBc IgM (acute insult)
 Recovered: Hbs Ag, HBc IgG
 Vaccinated: HBs Ig

TREATMENT
 For acute infection there is no specific medication. Treatment is supportive (high
caloric diet is desirable).
 HBV antibodies may be administered with a week of exposure and to newborn
infants with HBs Ag positive mothers.
 Acute infection:
 Alcohol should be avoided until serum transaminases normalize.
 Supportive:
o Rest to limit fatigue
o Maintain hydration
o Adequate dietary intake (adequate nutrition)
o Vitamin supplementation has no proven value but vitamin K can be given
if there is prolonged cholestasis.
o Metoclopramide (plasil) for nausea.
 More than 60kg: 10mg PO daily in 3 divided doses (when
administered by slow intravenous injection to be given over at
least 3 minutes)
 Less than 60kg: 500micrograms/kg PO daily in 3 divided doses
(when given as slow intravenous injection to be given over at
least 3 minutes)
 Admission:
o Patients with severe nausea and vomiting
o Patients with deteriorating liver function, especially those with
encephalopathy or prolonged prothrombin time.
 Lamivudine (3TC), tenofovir (TDF/TAF), or entecavir can be used if acute
liver failure develops in acute HBV.

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 Chronic infection:
 Advice and support:
o Avoid alcohol
o Prevent transmission: avoid unprotected sex and toothbrush sharing
 Monitoring for complications:
o Hepatocellular carcinoma screening: 6 monthly Ultrasound and AFP in
hepatitis B cirrhosis
o Cirrhosis detection: 2-yearly
o Varices detection: 3 yearly
 Medication
o Overview
- Start treatment if LFTs changes, HBV DNA rises or cirrhosis
develops
- Rarely cures but lower complications risk
- Aims for seroconversion from HBe Ag positive to negative and
HBe Ab negative to positive
o Options
- Lamivudine, Tenofovir or entecavir: PO once-daily until 6 months
after seroconversion
- Peginterferon alpha 2a, subcutaneous once weekly for 48weeks.
PROPHYLAXIS
 HBV vaccine
 Contains Recombinant inactive HBsAg
 Indications: sexual and household contacts, children of affected mothers,
men who have sex with men, HIV positive individuals, healthcare workers,
and those with chronic liver disease.
 Efficacy ranges from 80-100%
 Duration of immunity 20 or more years
 Immunologic memory established following vaccination
 Dose of HBV vaccine: 3 dose series (0, 1, 6 months) or for the new vaccines
1 month apart.
o 2.5g for <11 years (when mother is HBsAg negative)
o 5g for 11-19 year and children <11 years born to HBsAg positive
mother
o 10g for immunocompetent adults.

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 Post-exposure prophylaxis within 48hours, even if already immunized. May
be given to healthcare workers, babes or sexual contacts. Add HBV Ig
(HBIG) if non-immune.
HEPATITIS C
 HCV resembles Flaviviruses in structure and organization.
 It is a linear single stranded positive sense RNA genome enclosed within an
envelope, carrying glycoprotein spikes and E1 + E2 envelope glycoproteins.
 It consists of 6 genotypes.
 It replicates in liver cells, lymphocytes and monocytes.
 The virus mutates rapidly (error prone RNA polymerase) and it also down
regulates stimulatory receptors on NK cells as well as increasing inhibitory
receptors on NK and CD8+ killer cells.
 In addition to this the virus produces TGF-beta which blocks activation of T-cells
and inhibits production of IFN-gamma.
 HCV disease is mainly immune mediated. Cytokines cause inflammation in HCV
infection.
 There is no cure for hepatitis C.
 Transmission is through:
 Intravenous drug uses
 Contaminated equipment
 Perinatal
 Sexual
 Blood transfusions and other blood products although blood is now routinely
checked for HCV

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CLINICAL FEATURES
 Incubation period is 15 to 60 days.
 HCV causes 3 type:
 Acute hepatitis with resolution of
infection and recovery in 15% of
cases.
 Chronic hepatitis infection with
possible progression to disease
much later in life-85%
 Severe rapid progression to
cirrhosis in 20% patients- many
patients develop cirrhosis and are
at high risk of hepatocellular
carcinoma (25%) decades later.
DIAGNOSIS
 60-70% of persons newly infected with HCV typically are usually asymptomatic
or have a mild clinical illness.
 HCV RNA can be detected in blood within 1-3 weeks after exposure.
 The average time for exposure to antibody to HCV (anti-HCV) seroconversion is
8-9 weeks. Anti-HCV can be detected in more than 97% of persons by 6 months
after exposure.
TREATMENT AND PROPHYLAXIS
 Screening of blood and blood products prior to transfusion.
 No specific active or passive immunizing agent is available.
 Treatment:
 Recombinant interferon-alpha alone or with ribavirin
 Goals in treatment of chronic HCV infection
o Achieve sustained eradication of HCV: persistent absence of HCV RNA
in serum 6 months or more after completing antiviral treatment.
o Preventing progression to cirrhosis, hepatocellular carcinoma (HCC) and
decompensated liver disease requiring liver transplantation.

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HEPATITIS D
 This is also known as a delta virus. It is a single stranded negative sense circular
RNA virus structurally unrelated to the other hepatitis viruses.
 HDV is an incomplete virus that requires the helper of HBV to replicate and only
occurs among people infected with HBV.
PATHOGENESIS
 Its mode of transmission is the same as HBV. It is spread through blood, semen
and vaginal secretion. It can replicate and cause disease only in people with active
HBV infections.
 The virus uses HBsAg for transmission and assembly.
 Replication of HDV is complex and unique.
 Transcription and replication of HDV occurs in the nucleus using host cell RNA
polymerase.
 Types of infection:
 Co-infection: HDV + HBV are transmitted together at the same time.
 Super-infection: HBV infection and then HDV infection. No association with
hepatocellular carcinoma.
DIAGNOSIS
 Detecting presence of Delta antigens and antibodies (ELISA and
radioimmunoassay).
TREATMENT AND PROPHYLAXIS
 No specific treatment
 Vaccination against HBV covers HDV infection

HEPATITIS E
 This is a spherical non-enveloped single stranded positive sense RNA virus
belonging to the genus Hepevirus.
 HEV usually results in an acute infection. It does not lead to a chronic infection.
 It is transmitted through fecal oral route and outbreaks are usually associated with
contaminated water supplies in countries with poor sanitation.
 Symptoms similar to HAV: abdominal pain, anorexia, dark urine, fever,
hepatomegaly, nausea, vomiting, malaise and jaundice.

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 HEV infection is especially serious in pregnant women and during pregnancy
may cause a high rate of abortion, intrauterine death and increased perinatal
mortality in babies born to women with fulminant hepatitis.
DIAGNOSIS
 Serology
 IgM or IgG in serum (mainly IgM because there is no chronic stage)
 PCR for HEV RNA
TREATMENT AND PROPHYLAXIS
 No specific treatment
 ISG (immune serum globulin) does not provide any protection
 Safe hygiene measures reduce risks of transmission (washing with soap)
 Good sanitation
HEPATITIS G
 Resembles HCV (flavivirus), enveloped positive sense RNA.
 Transmitted through blood and blood products
 Role in human disease is currently uncertain but it is associated with chronic
hepatitis disease.
 HGV and HIV infection may prolong survival of AIDS patient HGV may inhibit
HIV replication.
 HGV frequently results in chronic viremia.
 May be associated with acute, fulminant and chronic hepatitis.
 It often subsides after several years and anti HG env antibody develops.
 Diagnosis:
 PCR to detect HGV
 Immunoassay to detect anti-HG env antibodies (Serum HGV RNA indicate
viremia and anti-HG env is associated with recovery).

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FEATURE HAV HBV HCV HDV HEV

FAMILY Picornavirus Hepadnavirus Flavivirus Delta virus Hepevirus
(Hepatovirus) (encapsulate) (Enveloped) (naked) (naked)
(naked)
GENOME SS (+) RNA Circular SS (+) RNA SS (-) RNA SS (+)
linear dsDNA linear circular RNA

ONSET Acute Often Insidious Acute on Acute

insidious chronic
AGE Children, young Any age Any age but Any age Children,
PREFERENCE adults more young
common in adults
adults
TRANSMISSION Fecal oral Parenteral Parenteral Parenteral Fecal oral
SEVERITY Mild Often severe Variable Often severe Mild, but
with severe in
superinfection pregnancy
PROGNOSIS Generally good Worse with Moderate Worse with Fair
age, debility age, debility
CHRONICITY None Occasional (5 Frequent Occasional None
to 10%) (65-85%)
PROPHYLAXIS Immunoglobulin/ Standard Ig, None Protection None
HAV vaccine HBIg, HB against HBV
vaccine
CARRIER None 0.1 to 30% Exists but None None
prevalence
unknown

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COMPLICATIONS  Persistent HBV infection

(1) Cholestatic hepatitis (persistence of HBsAg)
 Occurs mostly with HAV and without evidence of liver
HEV infection damage resulting in
 Self-limited asymptomatic or ‘healthy’
 Pruritus is a common symptom HBV carriers.
 Marked conjugated
hyperbilirubinemia presenting
with dark urine and pale stool
 Increased alkaline phosphatase

(2) Fulminant hepatitis

 About 1% cases
 Defined as the onset of
encephalopathy occurring
within 8 weeks in a patient with
acute liver disease
 Associated with massive
hepatocellular necrosis
 Commonly follows HAV,
HBV (usually superinfection of
HBV infection by HDV), HCV
and HEV (in pregnancy)

(3) Chronic hepatitis

 Occurs in HBV and HCV
infection
 Manifests with persistently
increased AST and ALT for
over 6 months
 Slowly resolving HBV
infection may persist for 6-12
months with eventual complete
resolution

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HEPATITIS DUE TO intranuclear inclusions and giant

cells.
OTHER INFECTIOUS
 Herpes simplex: Very occasionally
AGENTS the herpes simplex virus causes a
 Abnormal liver biochemistry is generalized acute infection,
frequently found in a number of particularly in the
acute infections. The abnormalities immunosuppressed and
are usually mild and have no occasionally in pregnancy.
clinical significance. Aminotransferases are usually
 Infectious mononucleosis: This is massively elevated. Liver biopsy
due to Epstein-Barr virus (EBV). shows extensive necrosis.
Mild jaundice associated with Acyclovir is used for treatment.
minor abnormalities of liver  Toxoplasmosis: The clinical
biochemistry is extremely common picture is similar to infectious
but ‘clinical’ hepatitis is rare. mononucleosis, with abnormal
Hepatic histological changes occur liver biochemistry but Paul-
within 5 days of onset, the Bunnell test is negative.
sinusoids and portal tracts are  Yellow fever: This viral infection is
infiltrated with large mononuclear carried by the mosquito Aedes
cells but the liver architecture is aegypti and can cause acute hepatic
preserved. A Paul-Bunnell or necrosis. There is no specific
Mono-spot test is usually positive, treatment.
and atypical lymphocytes are
present in the peripheral blood. AUTOIMMUNE
Treatment is symptomatic. HEPATITIS
 Cytomegalovirus (CMV): This can  Autoimmune hepatitis is most
cause acute hepatitis, usually a frequent in women
glandular fever type syndrome in  It has 2 types
healthy individuals but is more  Type 1: associated with other
severe in those with an impaired autoimmune disease e.g.
immune response. Only the latter pernicious anemia, thyroiditis,
need treatment with valganciclovir coeliac disease and Coomb’s
or ganciclovir. CMV DNA is positive hemolytic anemia.
positive in blood; CMV IgM is also  Type 2: not associated with
positive but there are false-positive other autoimmune diseases
reactions. The liver biopsy shows

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 Pathogenesis unknown but though  There are rare overlap
to occur in genetically predisposed syndromes with primary biliary
people in response to cirrhosis and primary
environmental agents e.g. a virus sclerosing cholangitis existing
that causes a sequence of T cell concomitantly or developing
mediated events against liver consecutively
antigens, producing a progressive  Investigations:
necroinflammatory process which  Liver biochemistry: high serum
results in fibrosis and cirrhosis. aminotransferases with lesser
 Clinical features: elevations in the ALP and
 2 peak presentations bilirubin. Serum gamma-
 In peri- and post-menopausal globulins are high, frequently
group, patients may be twice normal particularly the
asymptomatic or present with IgG.
fatigue, the disease being  Blood:
discovered by abnormalities in o Mild normochromic
liver biochemistry or because normocytic anemia with
of signs of chronic liver disease thrombocytopenia and
on routine examination. leucopenia even before
 In teens and early 20s the portal hypertension and
disease (often type II) presents splenomegaly.
as an acute hepatitis with o Prothrombin time is often
jaundice and very high high
aminotransferases which do not  Autoantibodies:
improve with time. Clinical o Type 1: anti-nuclear
features in this age group: (ANA), Anti-smooth
hepatosplenomegaly, muscle (anti-actin), soluble
cutaneous striae, acne, hirsutes, liver antigen (anti SLA/LP)
bruises and sometimes ascites. o Type 2: anti-liver/Kidney
 An ill patient can also have microsomal (anti-LKM1).
features of autoimmune disease The main target is
with a fever, migratory cytochrome P450 2D6
polyarthritis, (CYP2D6) on liver cell
glomerulonephritis, pleurisy, plasma membranes.
pulmonary infiltration or lung  Liver biopsy: shows changes of
fibrosis. chronic hepatitis. The amount
of interface hepatitis is

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variable, but tends to be high in Hepatocellular carcinoma
untreated patients. Lymphoid occurs less frequently than with
follicles are less often seen than viral-induced cirrhosis.
in HCV, and plasma cell
infiltration is frequent. 1/3 of DRUG INDUCED
patients have cirrhosis at CHRONIC HEPATITIS
presentation.  Several drugs can cause a chronic
 Treatment: hepatitis which clinically bears
 Steroids: many similarities to autoimmune
o Budesonide 3mg BD or hepatitis.
TDS (has fewer side effects  Patients are often female, present
than prednisolone) or with jaundice and hepatomegaly,
o Prednisolone 30mg daily have raised serum
for at least 2 weeks aminotransferases and globulin
followed by a slow levels and LE cells and anti-LKM1
reduction and a antibodies may be detected
maintenance dose of 10-  Improvement follows drug
15mg daily withdrawal but exacerbations can
o Response to steroids forms occur with drug reintroduction.
part of the diagnostic  Isoniazid, amiodarone and
criteria for autoimmune methotrexate can lead to chronic
hepatitis. 80% of cases histological changes.
remit with steroids and  With rare exceptions patients with
azathioprine. pre-existing chronic liver disease
 Azathioprine should be added are not more susceptible to drug
1-2mg/kg daily, as a steroid injury.
sparing agent and in some  Chronic alcoholic liver disease can
patients as sole long-term occasionally have histological
maintenance therapy. Levels of appearances more like a chronic
thiopurine methyltransferase hepatitis.
should be obtained.
 Mycophenolate, cyclosporine
and tacrolimus have been used
in resistant cases.
 Liver transplantation is
performed if treatment fails,
although the disease may recur.

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ALCOHOL AND THE ALCOHOLIC HEPATITIS

LIVER  This is severe and prognostically
ominous lesion and characterized
 Alcohol abuse is the most common
by the following pathologic triads:
cause of liver disease.
 Mallory bodies (intracellular
 Patients at risk include those
eosinophilic aggregates of
exceeding the critical intake
cytokeratins) usually seen near
threshold (80g/day in men and
or around nuclei.
20g/day in women), females,
 Infiltration by
blacks, those with poor nutritional
polymorpnuclear leukocytes
status, and those with HBV or HCV
 A network of interlobular
infection.
connective tissue surrounding
 3 major pathologic lesions resulting
hepatocytes and central veins
from alcohol abuse and appearing
(spider fibrosis)
as stages/spectrum of the disease
are: CLINICAL
 Fatty liver (Alcoholic MANIFESTATION
Steatosis)  Symptoms: Fever, Weight loss,
 Acute Alcoholic hepatitis anorexia, nausea, vomiting and
 Alcoholic (Laennee’s) abdominal pain (RUQ pain) are
Cirrhosis common presenting symptoms.
 Note: Alcoholic hepatitis is not a  Signs:
prerequisite to alcoholic cirrhosis.  Hepatomegaly is found in 80%
ALCOHOLIC FATTY LIVER and splenomegaly is often
 Patients may be asymptomatic or present.
 Jaundice, spider
present with
 Right upper quadrant (RUQ) angioma/telangiectasia, parotid
pain enlargement gynecomastia,
 Incidentally discovered as loss of body hair, Dupuytren’s
tender hepatomegaly contractures and palmar
 Jaundice is rare, transaminases erythema, and testicular
are mildly elevated (<5times atrophy.
normal)  Ascites and encephalopathy may be
present and indicate severe disease.
 There is completely reversible on
cessation of alcohol.  Full blood count strikingly elevated
white blood cells (leukocytosis).

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 Transaminases modestly increased  Modest elevation of AST>ALT
(200-400IU/L). in a 2:1 ratio,
 The ratio of AST to ALT frequently  Liver biopsy shows small
exceeds one in contrast to viral (microvesicular) and large
hepatitis in which the ratio is (macrovesicular) fat droplets in
approximately one. the cytoplasm
 AST: ALT ratio >2:1  Alcoholic hepatitis:
 Prolonged prothrombin time,  Marked leukocytosis
hypoalbuminemia and  Modest elevation of AST>ALT
hyperglobulinemia may be found. in a 2:1 ratio
 Alcoholic hepatitis can reverse with  Markedly elevated serum
cessation of alcohol but more bilirubin
commonly progresses to cirrhosis.  Liver biopsy shows steatosis,
hepatocellular necrosis,
ALCOHOLIC CIRRHOSIS Mallory bodies (eosinophilic
 Patients may be asymptomatic or hyaline deposits), ballooned
may present with anorexia, fatigue hepatocytes and lobular PMN
and decreased libido. inflammatory infiltrate.
 There is associated increased risk  Alcoholic cirrhosis:
of variceal hemorrhage.  Liver biopsy shows micro- or
macronodular cirrhosis and
DIFFERENTIAL DIAGNOSIS
perivenular fibrosis that is not
 Nonalcoholic fatty liver disease
usually seen in other types of
 Non-alcoholic steatoheatitis
cirrhosis.
 Autoimmune hepatitis
 Viral hepatitis TREATMENT
 Hemochromatosis  Stop alcohol
 Alpha-1 antitrypsin deficiency  Alcoholic steatosis: can resolve
 Wilson’s disease with abstinence and improved
 Toxic or drug induced hepatitis nutrition.
 Alcoholic hepatitis:
DIAGNOSIS AND  Corticosteroids: improve
INVESTIGATIONS survival when discriminant
 History of habitual alcohol function (DF) is >32 and there
consumption. are no contraindications (active
 Alcoholic steatosis: GI bleeding, active infection,
serum creatinine >2.3)

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o DF is a function of PT/INR NONALCOHOLIC
and total bilirubin
o DF= [4.6 x (patient’s PT-
FATTY LIVER DISEASE
control PT)] + serum  The spectrum of disease ranges
bilirubin from benign steatosis (Fatty liver)
o A DF >32 predicts 1-month to steatohepatitis (hepatic
mortality as high as 50%. inflammation).
o If severe injury with  Disease is generally benign and
hepatic encephalopathy indolent but can progress to
patients can be treated with cirrhosis in 15-20%.
steroids for one month with  Nonalcoholic fatty liver disease is
taper. the third most common cause of
 Other therapies under study: abnormal LFTs in adult outpatients
Medium-chain triglycerides after medication and alcohol.
and pentoxifylline.  Risk factors:
Pentoxifylline has anti-TNF  Female gender
effects but s less effective than  Age> 45 years
corticosteroids when DF is  Body mass index (BMI)>30
>32.  AST/ALT >1
 Long term therapy:  Type 2 DM
antioxidants, S- CLINICAL FEATURES
adenosylmethionine (SAMe),
 Patients are asymptomatic in >50%
silymarin, Vitamins A and E.
of cases, Symptoms:
 Alcoholic cirrhosis: hepatic  Fatigue, malaise and to a lesser
function can significantly improve
extent RUQ fullness or pain
with abstinence and improved
 Signs:
nutrition
 Hepatomegaly is common but
 Liver transplant is often precluded examination may be limited in
by active or recent alcohol abuse or
the obese
use. Recidivism rates are high.
 Stigmata of chronic liver
Most transplant centers require at
disease.
least 6 months of documented
abstinence prior to listing for liver
transplant.

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DIFFERENTIAL DIAGNOSIS o Normal AST and ALT
 Alcoholic liver disease cannot exclude non-
 Nutrition: TPN, kwashiorkor, rapid alcoholic fatty liver
weight loss disease.
 Drugs: Estrogens, corticosteroids,  BMI is an independent
chloroquine predictor of the degree of
 Metabolic: Wilson’s disease, hepatocellular fatty infiltration.
abetaliproproteinemia  Ultrasound or CT scan
 Liver biopsy is the gold
 Iatrogenic: weight reduction
standard. The grade of
surgery with jejunoileal bypass,
inflammation and stage of
gastroplasty or small bowel
fibrosis predict disease course
resection.
and response to therapeutic
DIAGNOSIS intervention.
 Diagnosis as follows:
TREATMENT
 Exclude causes of liver disease,
 Gradual weight loss. Rapid weight
specifically alcoholic liver
loss may increase inflammation and
disease
fibrosis.
 Aminotransmiases:
o Typically, ALT>AST (x2-  Treat hyperlipidemia and diabetes
4) (vs alcoholic liver  No FDA-approved therapy is
disease in which available
AST>ALT), poor  Therapeutic agents under study
correlation with the include metformin, rosiglitazone,
presence and extent of urosodeoxycholic acid and vitamin
inflammation E.

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METABOLIC LIVER DISEASE

HEREDITARY HEMOCHROMATOSIS
 This is an autosomal-recessive disease.
 It is associated with a major mutation on the short arm of chromosome 6, the HFE
genes.
 Patients have a normal life expectancy if there is no cirrhosis and the patient is
adherent to treatment. Survival is lower if the patient has cirrhosis at the time of
diagnosis.
 Cirrhosis with Hereditary hemochromatosis (HH) carries a high risk of
hepatocellular carcinoma (200 times that of the control population).
 The condition results in decreased hepcidin synthesis resulting in increased iron
absorption and increased release from erythrophagocytosis (iron levels 10 times
normal).
 It results in damage to the liver, joints, anterior pituitary, pancreas, heart and
thyroid.
CLINICAL FEATURES
 Symptom onset usually in middle-age for men, but 10 years later and less likely
in women.
 10-25% are often asymptomatic.
 Symptoms: arthritis (Pseudogout), skin color change, Right upper quadrant pain,
symptoms of chronic liver disease (fatigue, anorexia, muscle wasting), loss of
libido, impotence and dysmenorrhea, heart failure, DM.
 Signs: hepatomegaly, skin hyperpigmentation (bronze skin), stigmata of chronic
liver disease, hypogonadism
 Clinical features can be remembered using A-J mnemonic:
 A- anterior pituitary damage (hypogonadism- loss of libido, impotence, and
dysmenorrhea)
 B-bone disease: osteoporosis
 C-chronic liver disease: hepatomegaly, cirrhosis, fatigue, anorexia, muscle
wasting. Liver disease later contributes to hypogonadism
 D-dilated or restrictive cardiomyopathy
 E-excess iron
 F-fatigue
 G-grey skin - though initially may be bronze
 H- hypothyroidism

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 I-insulin decrease: Diabetes mellitus
 J-joint pain, Arthritis (Pseudogout)- due to chondrocalcinosis. Especially
affects 2nd/3rd metacarpophalangeal and Proximal interphalangeal joints
DIAGNOSIS
 Iron studies:
 Increased ferritin, increased iron, and decreased total iron binding capacity
(TIBC).
 Recall: TIBC is a proximal measure of transferrin and is decreased as most
is already bound.
 Rule out other causes of increased ferritin: inflammation (CRP), alcoholism,
metabolic syndrome (BP, BM, lipids, glucose), anemia.
𝐼𝑟𝑜𝑛
 Transferrin saturation (TSAT)= × 100
𝑇𝐼𝐵𝐶
 TSAT>45% is seen in HH and may also be raised in asymptomatic carriers.
 If TSAT>45% and ferritin is elevated, hereditary hemochromatosis is
suggested check HFE genotype.
 A TSAT<45% and normal ferritin exclude hereditary hemochromatosis.
 HFE genotyping:
 Homozygote is diagnostic only if (1) age <40 years, (2) ferritin <1000 and
(3) transaminases are normal. Otherwise, confirmation with liver biopsy is
necessary.
 If positive, screen first degree relatives
 If negative but suspicion remains high, consider liver MRI and/or liver biopsy
to assess iron content and fibrosis.
 Liver biopsy: the best means of making a definitive diagnosis, a hepatic Prussian
blue stain with iron index >1.9 is diagnostic. Also used for disease staging
(influences prognosis: hepatocellular carcinoma screening is needed if the patient
is cirrhotic).
 Bloods:
 Liver function tests
 Glucose
 Thyroid function tests
 Imaging:
 Liver MRI
 Joint X-ray
 DEXA
 ECG

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 ECHO
DIFFERENTIAL DIAGNOSIS
 Chronic liver disease: HBV, HCV, alcoholic liver disease, non-alcoholic fatty
liver disease, Wilson’s disease, alpha-1 antitrypsin deficiency, autoimmune
hepatitis.
 Secondary iron overload disease: Homozygous alpha thalassemia, multiple
previous blood transfusions.
MANAGEMENT
 Conservative treatment if normal serum ferritin and asymptomatic:
 Lifestyle changes: avoid iron and vitamin C supplements, minimize alcohol.
 Annual monitoring with serum ferritin and transferrin saturation
 Hepatitis A and B vaccination.
 Iron reduction if increased serum ferritin or symptomatic:
 Remove 1 unit (approximately 450ml) per week until ferritin is mildly low,
then maintain with less frequent venesection e.g. 1 unit every 3-6 month for
life. Note that this may lead to falsely low HbA1c levels.
 Second line: iron chelation with desferrioxamine
 Screen first degree family members
 In the setting of cirrhosis, screen for hepatocellular carcinoma.
 Liver transplantation for those with decompensation.
COMPLICATIONS AND PROGNOSIS
 Normal life expectancy if no cirrhosis or diabetes at diagnosis.
 Complications:
 Cardiomyopathy (dilated or restrictive cardiomyopathy)
 Joint disease (chondrocalcinosis, degenerative arthritis, Pseudogout)
 Diabetes mellitus
 Hepatocellular carcinoma
 Increased incidence of bacterial infection (especially Vibrio, Yersinia and
Listeria spp)

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ALPHA-1 ANTITRYPSIN DEFICENCY
 Alpha-1 antitrypsin is a serine protease inhibitor which is synthesized in the liver
and controls inflammatory cascades. It protects tissues from protease-related
degradation.
 In the lung, alpha 1 antitrypsin inhibits neutrophil elastase preventing breakdown
of elastin and thus maintaining lung elasticity.
 The alpha -1 antitrypsin gene on chromosome 14 has 3 possible alleles:
 M (medium)
 S (slow)
 Z (very slow)
 The deficiency has an autosomal-codominant transmission with the Z allele being
most commonly deficient.
 Healthy individuals have an MM genotype (aka PiMM) while symptomatic
individuals are usually ZZ (aka PiZZ)
 Those with MS and MZ genotypes are just carriers, while SS and SZ genotypes
may cause a mild clinical picture.
 There is a high incidence of hepatocellular carcinoma in those with cirrhosis. A
high prevalence of HBV and HCV markers suggests synergistic liver injury.
CLINICAL FEATURES
 Neonatal cholestasis, neonatal jaundice, occult cirrhosis, shortness of
breath/dyspnea on exertion, panniculitis (inflammation of the panniculus
adiposus-a layer of fat underneath the skin producing tender swellings on the
thighs and breasts).
 Usually presents as early-onset COPD (age 30-50) especially if they are smokers.
 Liver disease is less common. Presents as hepatitis, cirrhosis and/or liver failure
 Examination reveals:
 Signs of cirrhosis: spider angiomata, palmar erythema, gynecomastia
o Abnormal alpha 1 anti-trypsin accumulates in the hepatocyte
endoplasmic reticulum causing cell damage.
 Panacinar Emphysema: clubbing, barrel chest
 Consider alpha 1 antitrypsin deficiency in any adult who presents with chronic
hepatitis or cirrhosis of unclear etiology.
 Alpha 1 antitrypsin deficiency is associated with bilateral basilar pulmonary
emphysema.

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DIAGNOSIS
 Serum alpha-1 antitrypsin concentration: for screening, alpha-1 antitrypsin is an
acute phase reactant. False positive may be obtained with inflammation (even if
PiZZ)
 Serum alpha 1 antitrypsin phenotyping: the screening and diagnostic test of
choice. Genotype is only needed if phenotype does not match the clinical picture.
 Screen family members
 COPDs and liver tests:
 Chest X-ray
 Pancreatic function tests
 Liver function tests
 Liver ultrasound
 Liver biopsy: characteristic eosinophilic alpha-1 antitrypsin globules are seen
in the endoplasmic reticulum of periportal hepatocytes
MANAGEMENT
 COPD:
 Manage as usual with smoking cessation, flu and pneumococcal vaccines and
stepwise medical therapy
 Alpha-1 antitrypsin augmentation therapy: consider pooled alpha-antitrypsin
from human plasma for those with at least moderate COPD. However, not
recommended due to lack of strong evidence for survival benefit.
 Liver disease:
 Prevention and monitoring for all: Hep A and B vaccine plus LFT +/-
coagulation monitoring.
 If liver disease alcohol cessation, monitoring alpha-fetoprotein and consider
transplantation in liver failure.

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WILSON’S DISEASE (PROGRESSIVE HEPATOLENTICULAR
DEGENERATION)
 This is an uncommon autosomal recessive disease.
 It usually presents between ages 3 and 40 and is associated with mutations in the
WD gene on chromosome 13.
 Decreased biliary copper excretion results in toxic copper deposition in tissues.
 Dietary copper is normally absorbed from the stomach and upper small intestine.
Copper is transported to the liver loosely bound to albumin where it is
incorporated into apoceruloplasmin forming ceruloplasmin a glycoprotein
synthesized in the liver and secreted into the blood.
 The remaining copper is normally excreted in the bile and excreted in feces.
 Copper then deposits in various organs including the liver, basal ganglia of the
brain and the cornea.
CLINICAL FEATURES
 Symptoms:
 Presents with abnormal behavior, personality change, psychosis, tremor,
dyskinesia, athropathy (Pseudogout) and jaundice.
 Clinical presentation may be acute, subacute or chronic.
 Organ involvement (in descending order of frequency): Hepatic, neurologic,
psychiatric, hematologic, renal (Fanconi’s syndrome), other
(ophthalmologic, cardiac, skeletal, endocrinologic, dermatologic)
 The mean age at onset of hepatic symptoms is 8-12 years.
 Signs:
 Exam reveals Kayser-Fleischer rings (a greenish-brown ring
on the outer edge of the cornea which is a diagnostic sign of
hepatolenticular degeneration and deposition of copper in the
Descemet’s membrane of the cornea), icterus, slowed
mentation, hypophonia and tremor
 Clinical stigmata of cirrhosis are associated with chronic
disease.
DIAGNOSIS
 Suspect Wilson’s disease in patients 3-40 years of age with
unexplained LFTs or liver disease associated with neurologic or
psychiatric changes, Kayser-Fleischer rings, hemolytic anemia
and a positive family history.

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 Liver biochemistry:
 Low Alkaline phosphatase
 Marked hyperbilirubinemia
 Modest aminotransaminase elevation (AST>ALT)
 Ceruloplasmin (CP): typically, low in Wilson’s disease but a low CP is both
insensitive (15% have normal CP, since CP is an acute phase reactant) and
nonspecific (CP is also low in nephrotic syndrome, protein-losing enteropathy
and malabsorption).
 Urinary copper excretion: high if symptomatic (100-1000 g/24 hours, level may
indicate disease severity). Normal excretion is <40 g/24 hours.
 Liver biopsy: shows high hepatic copper concentration (>250 g/g) may also be
seen in primary biliary cirrhosis, primary sclerosing cholangitis, fibrosis or
cirrhosis.
 Other: Serum copper concentration, slit lamp examination.

TREATMENT
 D-penicillamine: improvement lags 6-12 months following treatment,
maintenance is typically required.
 Other: trientine, zinc, ammonium
 Liver transplantation: for acute hepatic or medically refractory Wilson’s disease,
reverses metabolic defect and induces copper excretion.

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JAUNDICE
 Jaundice (icterus) is detectable  Biliverdin is converted by
clinically when the serum bilirubin biliverdin reductase to bilirubin
is more than 3mg/dl (50  Bilirubin is toxic to tissue
micromol/L). therefore; it is transported to the
 In neonates it is more than liver as it binds to albumin.
5mg/dl (85 micromol/L)  Bilirubin is taken up by hepatocytes
at their sinusoidal surface. This
METABOLISM OF
uptake is very rapid.
BILIRUBIN  In the hepatocytes bilirubin is
 Bilirubin is as a result of hemolysis bound to cytoplasmic proteins:
of RBCs. ligandins and Z protein.
 Recall, RBCs have the pigment  Ligandins are a group of
hemoglobin which consists of enzymes that represent 2% of
Heme (with iron) and the globin cytosolic proteins
part.  Z proteins bind fatty acids.
 RBCs after 120 days are broken  The primary function of these
down in the reticuloendothelial proteins is that of avoiding the
system (spleen) by macrophages. reflux of free bilirubin into the
 Hemoglobin is broken down to the blood because the time lapse
heme part and the globin part. between uptake of bilirubin and
 The globin part is broken down conjugation is relatively long.
to amino acids that are  In the hepatocytes bilirubin is
recycled. conjugated as it is bound to
 The heme part is broken down glucuronic acid. Conjugated
by heme oxygenase to oxy- bilirubin is also called Direct
heme (a closed tetrapyrrolic bilirubin, while unconjugated
ring with iron) bilirubin is called indirect bilirubin.
 Oxy-heme is further converted The enzyme important for
by heme reductase to biliverdin glucuronidation is Glucuronyl
(an open tetrapyrrolic ring transferase.
without iron)  Conjugated bilirubin is then
 The iron removed from the secreted into bile which is stored
heme binds to transferrin and is and concentrated in the gall
transported to the liver to be bladder.
stored where it binds to ferritin.

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 Bile is then secreted into the first either an intrinsic defect of
part of the duodenum from the RBCs or Extrinsic causes
common bile duct. external to RBCs.
 In the intestines bilirubin is  Hepatic/ hepatocellular:
deconjugated by bacterial/intestinal o The pathology is located
enzyme Beta-glucuronidase to within the liver due to
form free bilirubin. disease of parenchymal
 Bilirubin is converted by bacterial cells of liver.
dehydrogenase to urobilinogen (a  Post-hepatic/
colorless substance) Cholestatic/obstructive/surgica
 The bulk of urobilinogen, bilirubin l jaundice:
and urobilin is excreted in feces (by o The pathology is located
conversion to stercobilinogen and after the conjugation of
stercobilin which gives feces their bilirubin in the liver caused
characteristic orange-yellow color). due to obstruction of biliary
 Small amounts of bilirubin and passage.
urobilinogen are reabsorbed into PRE-HEPATIC/
the blood stream.
HEMOLYTIC JAUNDICE
 The reabsorbed urobilinogen is
 Increased breakdown of red cells
excreted in the urine (about
leads to an increase in production of
4mg/day).
bilirubin.
 Urobilinogen is converted to  Red blood cells have a life span
urobilin (orange-yellow pigment) of 120 days; they are broken
by dehydrogenase down by the macrophages of
CLASSIFICATION OF the reticuloendothelial system
JAUNDICE (especially in the spleen)
 Hemoglobin is split into a
 Jaundice is divided into 3
globin part and a heme part.
categories, depending on which
 The globin part is a protein that
part of the physiological
is broken down to amino acids
mechanism the pathology affects:
 Pre-hepatic/ Hemolytic that are recycled.
 The heme part is broken down
jaundice:
to iron and protoporphyrin
o Increased bilirubin load for
 The iron is recycled and stored
the liver cells.
o The pathology is occurring  The protoporphyrin is broken
prior to the liver due to down to unconjugated bilirubin

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which then binds to serum o Red cell membrane defects
albumin and is transported to (membranopathies):
the liver. In the liver bilirubin is hereditary spherocytosis,
conjugated and deposited into hereditary elliptocytosis
the bile canaliculi and o Hemoglobin abnormalities
eventually stored in bile in the (hemoglobinopathies):
gall bladder. thalassemia, sickle cell
 The bile from the gall bladder disease
is excreted into the duodenum o Metabolic defects
following a meal and the (enzymopathies): glucose-
conjugated bilirubin is 6 phosphate dehydrogenase
converted by intestinal deficiency, pyruvate kinase
bacterial normal flora into deficiency, pyrimidine
urobilinogen (which makes kinase deficiency
stool brown) and some is  Acquired: Immune
partially reabsorbed and (autoimmune, transfusion
filtered by the kidneys (making reactions), drug induced (e.g.
urine yellow). sulphonamides, penicillins),
 The resulting jaundice from non-immune (systemic disease
excessive breakdown of RBCs is e.g. renal and liver failure,
mild (serum bilirubin of 4-6mg/dl malaria)
or 68-102micromol/L) as the  The clinical features depend on the
normal liver can handle the cause:
increased bilirubin derived from  Anemia
excess hemolysis.  Jaundice
 Unconjugated bilirubin is not water  Splenomegaly
soluble and therefore does not pass  Gallstones (there is an
into urine, hence the term increased risk for pigmented
“acholuric jaundice”. bilirubin gallstones)
 Urinary urobilinogen is increased  Leg ulcers may be seen
(due to increased hemolysis and (especially with Sickle cell
production of conjugated bilirubin disease).
excreted in bile).  Urine is dark because of increase
 The causes of hemolytic jaundice urine urobilinogen.
are those of hemolytic anemia.  Investigations show features of
 Inherited: hemolysis.

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 There is increased level of  It is characterized by increase in
unconjugated bilirubin but serum unconjugated bilirubin.
normal serum ALP,  It is asymptomatic and is usually
transferases and albumin. detected as an incidental finding of
 Serum haptoglobulins are low a slightly raised bilirubin on a
 In urine there is increased urine routine check, all other liver
urobilinogen but no bilirubin. biochemistry is normal and there
 The differential diagnosis is from are no signs of liver disease.
other forms of jaundice.  Jaundice may manifest during
stress (e.g. severe infection) but
INTRAHEPATIC JAUNDICE
otherwise it is not clinically
 It can be caused by acute or chronic
significant.
hepatitis, hepatotoxicity, cirrhosis,
 The reticulocyte count is normal,
drug induced hepatitis and
excluding hemolysis and no
alcoholic liver disease.
treatment is necessary.
 Cell necrosis reduces the liver’s
ability to metabolize and excrete CRIGLER-NAJJAR SYNDROME
bilirubin leading to a buildup of
 Divided into 2 types:
unconjugated bilirubin in the blood.
 Type 1 (autosomal recessive)-
 Other causes include primary absolute deficiency of UGT
biliary cirrhosis leading to increase  Type 2 (autosomal dominant)-
in plasma conjugated bilirubin decreased UGT
because there is impairment of
 Liver histology is normal but there
excretion of conjugated bilirubin
is increased unconjugated serum
into bile
bilirubin.
 Thus intrahepatic jaundice can be
 It manifests as kernicterus and is
further divided into:
usually fatal.
a. Unconjugated
 Transplantation is the only
b. Conjugated
effective treatment.
UNCONJUGATED
CONJUGATED
GILBERT’S SYNDROME
DUBIN JOHNSON AND ROTOR
 This is due to mildly low UDP- SYNDROME
glucuronosyl transferase (UGT)
 Dubin-johnson is a deficiency of
activity. It is an autosomal
bilirubin canicular transport
recessive disease.

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protein, it is an autosomal recessive o Inflammatory bowel
disorder. disease- ulcerative colitis
 There is increased conjugated o Poisons: amanita
bilirubin (due to lack of regulation phylloides (mushrooms),
of bilirubin transport) aflatoxin, carbon
 It presents with a dark liver tetrachloride
(owning to melanin deposition) but
POST-HEPATIC
is also otherwise not clinically
significant. (OBSTRUCTIVE) JAUNDICE
 Rotor syndrome is similar to  This is caused by an interruption to
Dubin-Johnson syndrome but the the drainage of bile containing
liver lacks dark discoloration. conjugated bilirubin in the biliary
system.
 The most common causes are
 Other causes of intrahepatic gallstones in the common bile duct,
jaundice are due to hepatitis, that pancreatic carcinoma of the head of
cause parenchymal damage: the pancreas, liver flukes.
 Alcoholic hepatitis  Other causes include: stricture to
 Nonalcoholic hepatitis the common bile duct, biliary
o Infectious: atresia, cholangiocarcinoma,
 Viral hepatitis: HAV, pancreatitis, cholestasis of
HBV, HDV, HCV, pregnancy and pancreatic
CMV, EBV, Yellow pseudocysts.
fever virus  In complete obstruction of the bile
 Non-viral: Toxoplasma duct, no urobilinogen is found in
gondii, Coxiella the urine, since bilirubin has no
burnetti (Q fever), access to the intestine and it is in the
Leptospira intestine that it is converted to
icterohaemorrhagiae urobilinogen by micro-organisms,
o Autoimmune hepatitis with the urobilinogen partly being
o Drugs: paracetamol, absorbed from the intestine into the
methyldopa, isoniazid, general circulation and then
ketoconazole, excreted into the urine.
nitrofurantoin  In this case, presence of bilirubin
o Wilson’s disease: defect in (conjugated) in the urine without
metabolism of copper urine-urobilinogen suggests

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obstructive jaundice, either intra-  The presence of pale stool and dark
hepatic of post-hepatic. urine suggests an obstructive or
 Intra-hepatic: occurs due to post-hepatic cause as normal feces
failure of bile secretion due to get their color from bile pigments.
either inhibition of the  However, although pale stools and
sodium/potassium ATPase dark urine are a feature of biliary
pump on the basolateral obstruction, they can occur in many
membranes, decreased fluidity intra-hepatic illnesses and are
of the sinusoidal plasma therefore not a reliable clinical
membrane, disruption of the feature to distinguish obstructive
microfilaments responsible for from hepatic causes of jaundice.
canalicular tone and damage to
the tight junction. in addition,
inflammatory change in
ductular cells interferes with
bile flow.
 Extra-hepatic: due to large duct
obstruction of bile flow at any
point in the biliary tract distal to
the bile canaliculi.
 Clinically in both types, there is
jaundice with pale stools and dark
urine and the serum bilirubin is
conjugated.
 This type of jaundice presents also
with pruritus due to increased
plasma bile acids,
hypercholesterolemia and
Xanthomas.
 Steatorrhea is also present and is
due to malabsorption of fat soluble
vitamins.
 However, intrahepatic and
extrahepatic cholestatic jaundice
must be differentiated as their
clinical management is entirely
different.

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PHYSIOLOGICAL JAUNDICE OF THE NEWBORN

 Newborn liver has low conjugation ability due to low UGT and so there is
increase serum unconjugated bilirubin.
 Unconjugated bilirubin is fat soluble and can deposit in the basal ganglia
(kernicterus) leading to neurological deficits and death.
 Treatment is phototherapy (makes unconjugated bilirubin more water soluble).

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FUNCTION PRE-HEPATIC INTRAHEPATIC POST-HEPATIC

TEST JAUNDICE JAUNDICE JAUNNDICE
Total bilirubin Normal/ increased Increased Increased
Conjugated Normal Increased Increased
bilirubin
Unconjugated Normal/increased Increased Normal
bilirubin
Urobilinogen Normal/increased Decreased Decreased/negative
Urine color Normal Dark Dark (conjugated
(urobilinogen + bilirubin)
conjugated
bilirubin)
Stool color Normal Slight pale Pale
Alkaline Normal Increased Increased
phosphatase
levels
ALT and AST Normal Increased Normal/slightly
levels increased
Conjugated Not present Present Present
bilirubin in urine
Large spleen Present Present Absent

DIFFERENTIAL DIAGNOSIS OF JAUNDICE

 The history often gives a clue to the diagnosis.
 Certain causes of jaundice are more likely in particular categories of people e.g.
a young person is more likely to have hepatitis, so questions should be asked
about drug and alcohol use and sexual behavior. An elderly person with gross
weight loss is more likely to have a carcinoma.
 All patients may complain of malaise. Abdominal pain occurs in patients with
biliary obstruction by gallstones and sometimes with an enlarged liver there is
pain resulting from distension of the capsule.
 Questions should be appropriate to the particular situation:
 Country of origin: HBV infection is increased in many parts of the world
 Duration of illness: a history of jaundice with prolonged weight loss in an
older patient suggest malignancy. A short history with a prodromal illness of
malaise points towards hepatitis.

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 Recent outbreak of jaundice: HAV
 Recent consumption of shellfish: HAV
 Men having sex with men: HBV
 Female sex workers: HBV
 Blood transfusion or infusion of pooled blood products: HBV and HCV
 Alcohol consumption
 Drugs taken (in previous 2-3 months): many drugs cause jaundice
 Travel: HAV, HEV
 Recent anesthetic: Halothane and occasionally isoflurane and sevoflurane.
 Family history: Gilbert’s disease
 Recent surgery on the biliary tract or for carcinoma
 Environment: HEV, exposure to chemicals and people at risk for
leptospirosis.
 Fevers or rigors: suggestive of cholangitis or possibly a liver abscess,
infections (malaria).
INVESTIGATIONS
 Jaundice is not itself a diagnosis and the cause should always be sought.
 Investigations include:
 Blood investigations:
o Liver enzymes: AST and ALT (extent of liver damage)
o Serum ALP: demonstrates extrahepatic obstruction
o Serum albumin: usually low
o Prothrombin time
o Hepatitis profile
o Peripheral smear
o Full blood count: leukocytosis (indicating infections), leucopenia often
occurs. In viral hepatitis, while abnormal mononuclear cells suggest
infectious mononucleosis and a monospot test should be performed
o Hepatitis profile
o Others: anti-mitochondrial antibody (AMA) for primary biliary cirrhosis,
HIV status.
 Imaging
o Abdominal ultrasound: to exclude an extrahepatic obstruction.
 Ultrasound demonstrates the size of the bile ducts (which are dilated
in extrahepatic obstruction), level of obstruction, cause of obstruction
(tumors, gallstones).

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APPROACH OF THE JAUNDICE PATIENT

MANAGEMENT
 Dependent on the cause

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FULMINANT HEPATIC FAILURE

 This is severe hepatic failure in which
encephalopathy develops in under 2 weeks
in a patient with a previously normal liver
(occasionally in some patients with previous
liver damage e.g. D virus superinfection in a
previous carrier of HBsAg, Budd-Chiari
syndrome or Wilson’s disease).
 Cases which evolve at a slower pace (2-12
weeks) are called subacute or subfulminant
hepatic failure.
 This is a rare but life-threatening syndrome
that is due to acute hepatitis from many
causes.
 Most cases are due to viral hepatitis but
paracetamol overdose is common.
 Histologically, there is multiacinar necrosis involving a substantial part of the
liver. Severe fatty change is seen in pregnancy, Reye’s syndrome or following
tetracycline administration intravenously.
CLINICAL FEATURES
 Examination shows a jaundiced patient with a small liver and signs of hepatic
encephalopathy.
 The mental state varies from slight drowsiness, confusion and disorientation
(grades I and II) to unresponsive coma (grade IV) with convulsions.
 Fetor hepaticus is common but ascites and splenomegaly are rare.
 Fever, vomiting, hypotension and hypoglycemia occur.
 Neurological examination shows spasticity and hyperreflexia; plantar responses
remain flexor until late.
 Cerebral edema develops in 80% of patients with fulminant hepatic failure but is
far less common with subacute failure and its consequences of intracranial
hypertension and brain herniation account for about 25% of the causes of death.
 Other complications: bacterial and fungal infections, gastrointestinal bleeding,
respiratory arrest, kidney failure (Hepatorenal syndrome and acute tubular
necrosis) and pancreatitis.

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INVESTIGATIONS
 Blood:
 Serum bilirubin: hyperbilirubinemia
 Serum aminotransferases: high serum aminotransferases. Aminotransferases
are not useful indicators of the course of the disease as they tend to fall along
with the albumin with progressive liver damage.
 Coagulation factors: low, including prothrombin and factor V
 Imagining:
 Ultrasound: to define liver size and indicate underlying pathology
 EEG can be helpful in grading encephalopathy
MANAGEMENT
 No specific treatment
 Transfer to specialized unit if:
 INR >3.0
 Presence of hepatic encephalopathy
 Hypotension after resuscitation with fluid
 Metabolic acidosis
 Prothrombin time (seconds) > interval (hours) from overdose (paracetamol
cases)
 For signs of increased intracranial pressure give 20% mannitol (1g/kg
bodyweight) infused intravenously, this dose may need to be repeated.
 Dexamethasone is of no value
 Hypoglycemia, hypokalemia, hypomagnesemia, hypophosphatemia, and
hypocalcemia should be anticipated and corrected with 10% dextrose infusion
(checked by 2hourly dipstick testing), potassium, calcium, phosphate and
magnesium supplements.
 Hyponatremia should be corrected with hypertonic saline.
 Coagulopathy is managed with intravenous vitamin K, platelets, blood or fresh
frozen plasma.
 Hemorrhage may be a problem and patients are given a proton pump inhibitor
(PPI) to prevent gastrointestinal bleeding.
 Prophylaxis against bacterial and fungal infection is routine as infection is a
frequent cause of death and may preclude liver transplantation.
 Suspected infection should be treated immediately with suitable antibiotics.
 Renal and respiratory failure should be treated as necessary.

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 Liver transplantation has been a major advance for patients with fulminant
hepatic failure. It is difficult to judge the timing or the necessity for
transplantation.

CHRONIC LIVER DISEASE AND LIVER CIRRHOSIS

 Chronic liver diseases include:
 Chronic hepatitis
 Liver cirrhosis
 Hepatocellular carcinoma (hepatoma)
CHRONIC HEPATITIS
 This is a hepatic inflammatory process that fails to resolve after 6 months.
ETIOLOGY
 Infectious: Viral (HBV, HCV, HDV)
 Non-infectious
 Drug induced hepatitis (e.g. methyldopa, isoniazid, ketoconazole,
nitrofurantoin)
 Hereditary: Wilson’s disease
 Autoimmune disorders
 Others:
o Inflammatory bowel disease- ulcerative colitis
o Alcohol (rarely)
 Idiopathic causes
PATHOLOGY
 Chronic inflammatory cells infiltrates comprising of lymphocytes, plasma cells
and sometimes lymphoid follicles are usually present in the portal tracts.
 The amount of inflammation varies from mild to severe.
 The overall severity of the hepatitis is judged by the degree of hepatitis and
inflammation (grading) and the severity of the fibrosis or cirrhosis (staging).
 In chronic viral hepatitis there are various scoring systems e.g. Knodell scoring
system (histological activity index) uses the sum of 4 factors (periportal or
bridging necrosis, intralobular degeneration and focal necrosis, portal
inflammation and fibrosis). The Lshak score stages fibrosis from 0 (none) to 6
(cirrhosis). The METAVIR system has 4 stages. Scoring systems are used for
drug trials and for assessing progression of disease, but are descriptions of
architectural changes and no quantitative measures of fibrosis.

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 Liver changes seen include:
 Loss of definition of the portal/periportal limiting plate (interface hepatitis)
damage is due to apoptosis rather than necrosis
 Lobular change, focal lytic necrosis, apoptosis and focal inflammation
 Confluent necrosis
 Fibrosis which may be mild, bridging (across portal tracts) or severe
cirrhosis.
PATHOLOGICAL CLASSIFICATION
 Chronic persistent hepatitis- inflammatory activity is confined to portal areas.
 Chronic lobular hepatitis-
 Inflammatory activity and necrosis are scattered throughout the lobule.
 Limiting plates of periportal hepatocytes are intact and no periportal
 Chronic active hepatitis-
 Inflammatory activity in portal areas spills out into the lobule (periportal
hepatitis, piecemeal necrosis) in association with necrosis and fibrosis
 Though to have a significant risk for progression to cirrhosis and hepatic
failure.
CHRONIC VIRAL HEPATITIS
 Chronic viral hepatitis is the principal cause of chronic liver disease, cirrhosis
and hepatocellular carcinoma.
 It Complicates about 1% of acute hepatitis B (young, immunocompetent) and 85-
90% of acute hepatitis C will develop chronic hepatitis.
 About 20% of the later will develop cirrhosis in 10-20 years.
 Subjects with either HBV or HCV infection have greater risk of developing
hepatocellular carcinoma.
 Treatment:
 Can suppress hepatic inflammatory activity in 30-40%.
 Hepatitis B- therapy is indicated for patients positive for HBsAg and HBcAg
(high replicative phase). Treat with interferon alpha and lamivudine or
Tenofovir and Lamivudine (TDF + 3TC).
o Note only give TDF when creatinine clearance >50.
 Hepatitis C can be treated with interferon alpha and ribavirin

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LIVER CIRRHOSIS
 Cirrhosis results from necrosis of liver cells followed by fibrosis and nodule
formation.
 It is the common pathway of many liver diseases that cause hepatocellular injury
and lead to fibrosis and nodular regeneration.
 Reversal may occur with treatment of some chronic liver diseases (e.g. HBV,
HCV)
 The liver architecture is diffusely abnormal and this interferes with liver blood
flow and function. This derangement produces the clinical features of portal
hypertension and impaired liver cell function.
 Common causes of cirrhosis include:
 Alcohol
 Viral infection: HBV, HDV, HCV
 Non-alcoholic fatty liver disease
 Other causes include:
 Biliary cirrhosis: primary and secondary.
 Autoimmune hepatitis
 Hereditary hemochromatosis
 Hepatic venous congestion
 Budd-Chiari syndrome
 Wilson’s disease
 Drugs e.g. methotrexate, amiodarone, nitrofurantoin
 Sarcoidosis
 Hypervitaminosis A
 antitrypsin deficiency
 Cystic fibrosis
 Galactosaemia
 Glycogen storage disease
 Veno-occlusive disease
 Idiopathic (cryptogenic)
 other viruses
 Young patients with cirrhosis must be investigated to exclude treatable causes
(e.g. Wilson’s disease).

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PATHOGENESIS
 Chronic injury to the liver results in inflammation, necrosis and eventually
fibrosis.
 Fibrosis is initiated by activation of the stellate cells.
 Kupffer cells, damaged hepatocytes and activated platelets are probably
involved.
 In the space of Disse, the normal matrix is replaced by collagens, predominantly
type 1 and 3 and fibronectin.
 Subendothelial fibrosis leads to loss of the endothelial fenestrations (openings)
and this impairs liver function.
 Collagenases (matrix metalloproteinases, MMPs) are able to degrade this
collagen but are inhibited by tissue inhibitors of metalloproteinases (TIMPs)
which are increased in human liver fibrosis.
 There is accumulating evidence that liver fibrosis is reversible, particularly when
inflammation is reduced on a long-term basis e.g. by suppressing or eliminating
viruses.
PATHOLOGY
 3 types of cirrhosis have been described which give clues to the underlying cause:
 Micronodular cirrhosis: regenerating nodules are usually less than 3mm in
size and the liver is involved uniformly. This type is often caused by ongoing
alcohol damage or biliary tract disease.
 Macronodular cirrhosis: The nodules are of variable size and normal acini
may be seen within the larger nodules. This type is often seen following
chronic viral hepatitis.
 Mixed: small and large nodules is sometimes seen.
CLINICAL FEATURES
SYMPTOMS
 Patients may be asymptomatic or complain of nonspecific symptoms, particularly
fatigue, anorexia, muscles wasting, loss of libido, impotence, dysmenorrhea,
gynecomastia.
 Decompensation is associated with:
 Confusion and drowsiness due to neuropsychiatric complications
(portosystemic/hepatic encephalopathy)
 Abdominal distention due to ascites
 Hematemesis and melena from gastrointestinal hemorrhage

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 Ankle swelling due to fluid retention
 Pruritus due to cholestasis- this is often an early symptom of primary biliary
cirrhosis
 Platypnea (dyspnea induced by sitting upright and relived by recumbence)
and orthodeoxia (Low PaO2 when sitting upright that is relieved by
recumbence).
SIGNS
 Confusion, drowsiness and coma
 Hepatic flap/ asterixis
 Fetor hepaticus (breath of death): in portal hypertension there is portosystemic
shunting which allows thiols to pass directly into the lungs. The breath smells
like rotten eggs and garlic.
 Bilateral Parotid enlargement
 Skin:
 The chest and upper body may
show spider naevi. These are
Telangiectases that consist of a
central arteriole with radiating
small vessels. They are found in
the distribution of the superior
vena cava (i.e. above nipple line)-
commonly more than 5 is taken as
diagnostic. They are also found in
pregnancy.
 Caput medusae
 In hemochromatosis the skin may
have a slate-grey appearance.
 The hands may show palmar
erythema which is non-specific
change indicative of a
hyperdynamic circulation, it is also
seen in pregnancy, thyrotoxicosis
or rheumatoid arthritis.
 Clubbing occasionally occurs and a Dupuytren’s contracture is often seen in
alcoholic cirrhosis. As well as Terry’s nails (white, obscure nails)

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 Xanthomas (cholesterol deposits) are seen in the palmar creases or above the
eyes in primary biliary cirrhosis.
 Abdomen: initial hepatomegaly will be followed by a small liver in well-
established cirrhosis, splenomegaly is seen with portal hypertension.
 Endocrine:
 Gynecomastia (occasionally unilateral) and testicular atrophy may be found
in males. The cause of gynecomastia is complex but it is probably related to
altered estrogen metabolism or to treatment with spironolactone.
 In decompensated cirrhosis there are additional signs.
INVESTIGATIONS
 These are performed to assess the severity and type of liver disease.
SEVERITY
 FBC: indicates thrombocytopenia (splenic sequestration)
 Liver function:
 Serum albumin: there is low albumin due to decreased synthetic function.
outlook is poor with albumin level below 28g/L.
 Prothrombin time: this is prolonged corresponding with the severity of the
liver disease (decreased coagulation factors)
 INR is elevated
 Liver biochemistry: these can be normal depending on severity of cirrhosis. In
most cases there may be a slight elevation in serum ALP, GGT (cholestasis) and
serum aminotransferases. In decompensated cirrhosis all biochemistry is
deranged.
 Serum bilirubin: hyperbilirubinemia
 Serum electrolytes: low sodium indicates severe liver disease due to defect in free
water clearance or to excess diuretic therapy.
 Serum creatinine: an elevated concentration >130 mol/L is a marker of worse
prognosis.
 Serum alpha fetoprotein: if >200ng/ml is strongly suggestive of the presence of
a hepatocellular carcinoma.

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 The Modified Child-Pugh classification is used in scoring cirrhosis to provide a

1 year, 5 year and 10 year survival:
SCORE 1 2 3
Ascites None Mild Moderate/severe
Encephalopathy None Mild Marked
Bilirubin (mol/L) <34 34-50 >50
Albumin (g/l) >35 28-35 <28
Prothrombin time (seconds over <4 4-6 >6
normal)
Add above scores for your patient for survival figures below
Grade (scores) % survival
1 year 5 years 10 years
Child’s A (<7) 82 45 25
Child’s B (7-9) 62 20 7
Child’s C (10+) 42 20 0
TYPE
 Viral markers
 Serum autoantibodies and immunoglobulins
 Iron indices and ferritin
 Copper, ceruloplasmin
 Alpha-1 antitrypsin
 Note: Serum copper and serum alpha-1 antitrypsin should be measured in young
cirrhotics. Total iron-binding capacity (TIBC) and ferritin should be measured to
exclude hereditary haemochromatosis, genetic markers are also available
IMAGING
 Ultrasound: can demonstrated changes in size and shape of the liver. Fatty change
and fibrosis produce a diffuse increased echogenicity. In established cirrhosis
there may be marginal nodularity of the liver surface and distortion of the arterial
vascular architecture. The patency of the portal and hepatic veins can be
evaluated. It is also useful in detecting HCC. Elastography is being used in
diagnosis and follow-up to avoid liver biopsy.
 Endoscopy: performed for the detection and treatment of varices and portal
hypertensive gastropathy. Colonoscopy is occasionally performed for colopathy.

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 CT scan: shows hepatosplenomegaly and dilated collaterals are seen in chronic
liver disease. Arterial phase-contrast enhanced scans are useful in the detection
of HCC.
 MRI scan: this is useful in the diagnosis of both malignant and benign tumors
such as hemangiomas. MR angiography can demonstrate the vascular anatomy
and MR cholangiography the biliary tree.
LIVER BIOPSY
 This is the gold-standard. It confirms the type and severity of liver disease.
 The core of liver often fragments and sampling errors may occur in macronodular
cirrhosis.
MANAGEMENT
 Management is that of complications seen in decompensated cirrhosis.
 Patients should have 6 monthly ultrasounds and serum AFP to detect the early
development of a HCC.
 Treatment of the underlying cause may arrest or occasionally reverse cirrhotic
changes.
 Patients with compensated cirrhosis should lead a normal life. The only dietary
restriction is to reduce salt intake.
 Aspirin, Iron supplements (except in iron deficiency), NSAIDs, benzodiazepines
should be avoided.
 Minimize narcotics and limit acetaminophen to <2g/day
 Alcohol should be avoided although if the cirrhosis is not due to alcohol and not
due to viral hepatitis, small amounts not taken on a regular basis are probably not
harmful.
 Administer pneumococcal and influenza vaccines
 Prophylactic measures:
 Primary prophylaxis: HAV and HBV vaccination, nonselective Beta blockers
for documented esophageal varices
 Secondary prophylaxis: Antibiotics for spontaneous bacterial peritonitis
(SBP), esophageal variceal banding or nonselective beta-blockers +/- long
acting nitrates. Patients typically show low adherence/tolerance to beta-
blockers/nitrates

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 Liver transplant
 Indications:
o Acute liver disease: patients with fulminant hepatic failure of any cause
including acute viral hepatitis
o Chronic liver disease: the indications of transplantation are usually for
complications of cirrhosis, no longer responsive to therapy. Extrahepatic
complications of cirrhosis, even with preserved liver function such as
hepatopulmonary syndrome (shunting in the lung leading to hypoxia) and
porto-pulmonary hypertension can be reversed by liver transplantation.
 Primary biliary cirrhosis
 Chronic HBV if HBV DNA negative
 Chronic hepatitis C
 Autoimmune hepatitis
 Alcoholic liver disease
 Primary metabolic disorders: Wilson’s disease, hereditary
hemochromatosis
 Others: primary sclerosing cholangitis, Polycystic liver
disease, NASH and metabolic diseases in which the defect is
in the liver e.g. primary oxaluria
 Contraindications:
o Absolute:
 Active sepsis outside the hepatobiliary tree,
 Malignancy outside the liver,
 Liver metastases (except neuroendocrine) and
 If the patient is not psychologically committed.
o Relative: mainly anatomical considerations that would make surgery
more difficult, such as extensive splanchnic venous thrombosis. With
exceptions patients aged 70 years or over are not usually transplanted. In
hepatocellular carcinoma the recurrence rate is high unless there are
fewer than 3 small (<3cm) lesions or a solitary nodule of <5cm.
COURSE AND PROGNOSIS
 Extremely variable and depends on many factors, including the etiology and
presence of complications.
 Presence of complications usually worsens the prognosis.
 In general, 5-year survival is about 50% but this also varies depending on the
etiology and stage at which the diagnosis was made.

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 Poor indicators in cirrhosis:
 Clinical:
o Persistent jaundice
o Failure to respond to therapy
o Ascites
o Hemorrhage from varices, particularly with poor liver function
o Neuropsychiatric complications developing with progressive liver failure
o Small liver
o Persistent hypotension
o Etiology (e.g. alcoholic cirrhosis if the patient continues drinking)
 Blood tests:
o Low albumin (<28g/L)
o Low serum sodium (<125mmol/L)
o Prolonged prothrombin time >6s above normal value
o Raised creatinine >130mol/L
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
 These include:
 Hepatic encephalopathy (portosystemic encephalopathy)
 Hepatopulmonary syndrome
 Porto-pulmonary hypertension
 Portal hypotension and gastrointestinal hemorrhage
 Ascites
 Bacteremia, infections and spontaneous bacterial peritonitis
 Renal failure (Hepatorenal syndrome)
 Primary hepatocellular carcinoma

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HEPATIC ENCEPHALOPATHY (PORTOSYSTEMIC
ENCEPHALOPATHY/ HEPATIC COMA)
 This is a chronic neuropsychiatric syndrome due to cirrhosis.
 It manifests in 2 forms:
 Acute hepatic encephalopathy:
o Occurs in the setting of fulminant hepatitis (within 2 weeks)
o Cerebral edema plays a more important role
o Mortality rate is very high
 Chronic hepatic encephalopathy:
o Occurs in chronic liver disease
o Often reversible
 Hepatic encephalopathy can occur in portal hypertensive patients due to
spontaneous ‘shunting’ or in those with surgical or TIPS shunts (Transjugular
intrahepatic portocaval shunt).
 Encephalopathy is potentially reversible.
 Neuropsychiatric changes in the setting of liver disease constitute hepatic
encephalopathy until proven otherwise.
PATHOGENESIS
 The mechanism is unknown but several factors are involved.
 The hepatocellular dysfunction and portosystemic shunt leads to inadequate
removal of nitrogenous compounds and toxins ingested or produced in the
gastrointestinal tract getting access to the brain and causing hepatic
encephalopathy.
 Many ‘toxic’ substances may be causative factors namely:
 Ammonia (very well-known and studied)
 Short chain Fatty acids
 Mercaptans- a cause of fetor hepaticus in Chronic liver disease
 Accumulation of false neurotransmitters (octopamine) or activation of the
GABA (gamma aminobutyric acid) inhibitory neurotransmitter system.
 Increased blood levels of aromatic amino acids (tyrosine and phenylalanine) and
reduced branched amino acids (valine, leucine and isoleucine) also occurs.
 Ammonia has a major role, ammonia-induced alteration of brain neurotransmitter
balance-especially at the astrocyte-neuron interface is the leading
pathophysiological mechanism.
 Ammonia is absorbed by astrocytes and is converted to glutamine. Glutamine
increases intracellular osmotic pressure causing swelling and cerebral edema.

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 Ammonia is produced by intestinal bacterial breaking down protein.
 Predisposing factors/triggers to hepatic encephalopathy:
 High dietary protein
 Gastrointestinal hemorrhage
 Constipation/ileus
 Alkalosis
 Infection including spontaneous bacterial peritonitis
 Fluid and electrolyte disturbance due to diuretic therapy
o Hypovolemia
o Dehydration
o Hypokalemia
 Paracentesis
 Azotemia
 Hypoxia
 Hypoglycemia
 Drugs e.g. any CNS depressant (narcotics, benzodiazepines,
anticholinergics)
 Porstosystemic shunt operations, TIPS (Transjugular intrahepatic
portocaval shunt)
 Any surgical procedure
 Progressive liver damage
 Development of hepatocellular carcinoma
 Non-compliance with hepatic encephalopathy treatment
CLINICAL FEATURES
 Acutely the patient becomes increasingly drowsy and comatose.
 Chronically there is disorder of personality, mood and intellect with a reversal
of normal sleep rhythm
 These changes may fluctuate and a history from a relative must be obtained.
 The patient is:
 Irritable
 Confused
 Disoriented
 Slow slurred speech
 General features:
 Nausea
 Vomiting

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 Weakness
 Coma occurs as the encephalopathy becomes more marked but there is
always hyperreflexia and increasing tone.
 Convulsions are so very rare that other causes must be looked for
 Signs include:
 Fetor hepaticus (breath of death)
 Course flapping tremor when the hands are outstretched and the wrist is
hyperextended (asterixis)
 Constructional apraxia with the patient being unable to write or draw e.g. a
five-pointed star
 Decreased mental function: can be assessed by using the serial-sevens test.
 The manifestation depends on the stage/grade of hepatic encephalopathy.
STAGE CLINICAL MANIFESTATION
I Mildly altered mental status: apathy, restlessness, reversal of sleep
rhythm, slowed intellect, impaired computing ability, impaired
handwriting
II Disorientation, drowsiness lethargy, and Asterixis
III Stupor (arousable) and Upper motor neuron signs (hyperreflexia and
extensor plantar responses, increase in tone),
IV Coma

DIAGNOSIS
 Diagnosis is clinical.
 Routine liver biochemistry merely confirms the presence of liver disease not the
presence of encephalopathy.
MANAGEMENT
 Identify and remove the possible precipitating cause, such as drugs with cerebral
depressant properties, constipation or electrolyte imbalance due to over-diuresis.
 Triggers: High dietary protein, Gastrointestinal hemorrhage, Constipation,
Alkalosis, Infection including spontaneous bacterial peritonitis, Fluid and
electrolyte disturbance (hypokalemia) due to diuretic therapy (hypovolemia),
Paracentesis, Azotemia, Drugs e.g. any CNS depressant, Porstosystemic
shunt operations, TIPS (Transjugular intrahepatic portocaval shunt), Any
surgical procedure, Progressive liver damage, and Development of
hepatocellular carcinoma

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 Reduce and eliminate substrates for the generation of nitrogenous compound:
 Maintain nutrition with adequate calories, given if necessary via a fine-bore
nasogastric tube, and do not restrict protein for more than 48h.
 Restrict dietary protein
o For non-comatose patients restriction of protein to 40-60g/day
o For patients in coma, no protein should be given
 Cleanse the bowel with enema in patients with gastrointestinal hemorrhage
o Give purgatives and enemas to empty the bowels of nitrogenous
substances.
o Oral/NG tube or rectally administered lactulose (adverse effects include
dehydration and hypokalemia).
o Lactulose (10-30ml TDS) is an osmotic purgative that reduces the
colonic pH and limits ammonia absorption.
o Lactilol (beta-galactoside sorbital 30g daily) is metabolized by colonic
bacteria and is comparable in efficacy to lactulose.
o Lactose can be given to patient deficient for lactase.
o Lactulose, lactilol and lactose are all fermented by bacterial to organic
acids and reduce stool pH. The hydrogen ion produced traps ammonia in
the colon and changes it to non-diffusable ammonium (NH+4) ions.
o Additionally, the laxative effect increases excretion of ammonia.
 Increase protein in the diet to the limit of tolerance as the encephalopathy
improves.
 Reduce colonic bacteria that generate ammonia.
 Give antibiotics. Rifaximin is main unabsorbed and well tolerated long term
and prevents further episodes of hepatic encephalopathy.
 Metronidazole 200mg QID is also effective in the acute situation (adverse
effect: neuropathy)
 Neomycin should be avoided (adverse effects: ototoxicity and renal toxicity)
 Stop or reduce diuretic therapy
 Treat any infection.
 Give intravenous fluids as necessary (beware of too much sodium).
 Zinc, short-term protein restriction, branched-chain amino acids-enriched diet
should be instituted.

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HEPATOPULMONARY SYNDROME
 This is characterized by abnormal arterial oxygenation in a patient with cirrhosis
and/or portal hypertension
 Pathogenesis is thought to be due to intrapulmonary vasodilation leading to
impaired oxygen transfer that improves with 100% Oxygen. There is no evidence
of primary pulmonary disease.
 Clinical features:
 Range from subclinical abnormalities in gas exchange to profound
hypoxemia causing dyspnea at rest.
 The patient may have features of cirrhosis with spider naevi and clubbing as
well as cyanosis.
 Most patients have no respiratory symptoms but with more severe disease
patients are breathless on standing.
 Transthoracic ECHO shows intrapulmonary shunting and arterial blood gasses
confirm the arterial oxygen desaturation.
 It is a functional disorder that reverses with liver transplantation.

PORTO-PULMONARY HYPERTENSION
 This must be distinguished from hepatopulmonary syndrome as in this group
there is pulmonary hypertension.
 It occurs in 1-2% of patients with cirrhosis related to portal hypertension.
 It may respond to medical therapy.
 Severe pulmonary hypertension is a contraindication for liver transplantation.

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PORTAL HYPERTENSION
 The portal vein is formed by the union of the superior mesenteric and splenic
veins.
 The pressure within it is normally 5-8mmHg with only a small gradient across
the liver to the hepatic vein in which blood is returned to the heart via the inferior
vena cava.
 Portal hypertension can be classified as:
 Prehepatic: due to blockage of the
portal vein before the liver. This is
due to portal vein thrombosis.
 Intrahepatic: due to distortion of the
liver architecture which can be:
o Presinusoidal: Increased
resistance to portal blood flow
into the liver (e.g. in
schistosomiasis due to
periportal fibrosis and
perisinusoidal portal HTN) or
o Sinusoidal: The resistance is in the sinusoids of the liver. It is the
commonest cause (e.g. found in cirrhosis i.e. alcoholic.)
o Post-sinusoidal: increased resistance to hepatic venous outflow from the
liver causes include veno-occlusive disease, Budd-Chiari syndrome
 Post-hepatic: due to venous blockage outside the liver (rare) e.g. right heart
failure, constrictive pericarditis and IVC obstruction
 As portal pressure rises above 10-12mmHg, the compliant venous system dilates
and collaterals occur within the venous system.
 The main sites of the collaterals are at the gastro-esophageal junction, rectum,
left renal vein, diaphragm, retroperitoneum, and the anterior abdominal wall via
the umbilical vein.
 The collaterals at the gastro-esophageal junction (varices) are superficial in
position and tend to rupture.
 Portosystemic anastomoses at other sites seldom give rise to symptoms. Rectal
varices are found frequently (30%) if carefully looked for and can be
differentiated from hemorrhoids which are lower in the anal canal.

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CLINICAL FEATURES
 Often asymptomatic and only clinical evidence of portal hypertension is
splenomegaly.
 Clinical features of chronic liver disease are usually present.
 Presenting features include:
 Hematemesis or melena from rupture of gastroesophageal varices or portal
hypertensive gastropathy
 Ascites
 Encephalopathy
 Breathlessness due to porto-pulmonary hypertension or hepatopulmonary
syndrome (rare)
VARICEAL HEMORRHAGE
 90% of patients with cirrhosis will develop gastro-esophageal varices over 10
years but only one third of these will bleed from them.
 Bleeding is likely to occur with large varices, red signs on varices (diagnosed at
endoscopy) and in severe liver disease.
 It may present with painless hematemesis, melena, hematochezia.
MANAGEMENT
 Depends on the speed and volume of bleeding.
 Management can be divided into:

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 Active bleeding episode
 Prevention of re-bleeding
 Prophylactic measures to prevent the
first hemorrhage
ACTIVE BLEEDING EPISODE
 Nurse in high dependency/intensive care
nursing.
 Stabilization and resuscitation:
 Assess the general condition of the
patient-pulse and blood pressure.
 Nil per oral, consider an NG tube and
place two large-bore IVs. Obtain blood
for grouping and crossmatching,
hemoglobin, PT/INR, urea,
electrolytes, creatinine, liver
biochemistry and blood cultures.
 Cross match blood and administer packed red blood cells if needed.
 If the patient is in shock, treat with aggressive IV fluids (normal saline), start
it cautiously, prompt correction but not over correction of hypovolemia is
necessary in patients with cirrhosis as their baroreceptor reflexes are
diminished. Restore blood volume with plasma expanders or if possible
blood transfusions. Target hemoglobin only needs to be 8g/dl as this lessens
the likelihood of early rebleeding.
 In the presence of active bleeding and platelets <50 000/L or if there is
known impaired function (uremia, aspirin), transfuse platelets or
desmopressin. With active bleeding, increased PT time, and INR> 1.5
transfuse fresh frozen plasma (FFP).
 Oxygen given by facemask
 Place a Foley catheter to closely monitor urine output, decreased urine output
is a sign of hypoperfusion and bleeding.
 Hourly measurement of pulse, blood pressure and urine output.
 Ascitic tap
 Monitor for alcohol withdrawal. Give thiamine IV
 Start prophylactic antibiotics- third-generation cephalosporins e.g. cefotaxime.
These treat and prevent infection and early rebleeding and reduce mortality.

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 Give PPI as it lessens the risk of C. difficile infection. Sucralfate 1g QID can
reduce esophageal ulceration following endoscopic therapy.
 Medical therapy:
 Vasocontrictor therapy: to control bleeding while waiting for endoscopy. The
main aim is to restrict portal inflow by splanchnic arterial constriction
o Somatostatin (or octreotide) reduces splanchnic blood pressure when
given intravenously. An infusion of 250-500 g/hour appears to reduce
bleeding but has no effect on mortality. It should be used if there are
contraindications to terlipressin. It has few side effects.
o Vasopressin (terlipressin) with nitroglycerin help to minimize systemic
vasoconstriction.
 Terlipressin is the only vasoconstrictor shown to reduce mortality.
The dose is 2mg 6 hourly, reducing to 1mg 4-hourly after 48 hours if
a prolonged dosage regimen is used. It should not be given to patients
with ischemic heart disease. The patient will complain of abdominal
colic, will defecate and have facial pallor owing to the generalized
vasoconstriction.

 Urgent endoscopy to confirm the diagnosis of varices. It also excludes bleeding

from other sites e.g. gastric ulceration or portal hypertensive (or congestive)
gastropathy. The latter term is used for chronic gastric congestion, punctate
erythema and gastric erosions. It is a source of bleeding but varices may or may
not be present. Propranolol is the best treatment for this gastropathy.
 Balloon tamponade (with Four-lumen Sengstaken-Blakemore balloon tube)-
compressing bleeding varices temporarily. It should be left in place for no more
than 12 hours and removed in the endoscopy room prior to the endoscopic
procedure. The tube is passed into the stomach and the gastric balloon is inflated
with air and pulled back. It should be positioned in close apposition to the
gastroesophageal junction to prevent the cephalad variceal blood flow to the
bleeding point. The esophageal balloon should be inflated only if bleeding is not
controlled by the gastric balloon alone.
 Endoscopic therapy include injection of sclerosing agent and/or band ligation of
varices
 The use of repeated courses of banding at 2 weekly intervals leads to
obliteration of varices. This markedly reduces rebleeding most instances

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occurring before the varices have been fully obliterated. Banding is superior
to sclerotherapy and should be used combined with beta blockers.
 Although a reduction in bleeding episodes occurs, the effect on survival is
controversial and probably small. Complications include esophageal
ulceration, mediastinitis and rarely strictures.
 Refractory or recurrent upper GIT bleeding:
 Esophageal balloon tamponade (Minnesota or Sengstaken-Blakemore tubes)
for varices as a bridge to TIPS (transjugular intrahepatic portosystemic
shunting)- a catheter is placed into the jugular vein and guided
radiographically through the liver to form a shunt between the systemic
circulation in the hepatic vein and the portal circulation through the portal
vein. TIPS has largely replaced the need to surgically place the shunt. The
most common, long-term complication of TIPS is worsening of hepatic
encephalopathy.
 Angiogram with intra-arterial embolization or surgery for refractory non-
variceal bleeding
 Surgery: portosystemic shunt
 Prevention of variceal hemorrhage:
 Non-selective beta-blockers (propranolol and nadolol): in a dose sufficient to
reduce resting pulse rate by 25% has been shown to decrease portal pressure.
Portal inflow is reduced by 2 mechanisms: by decreased in cardiac output
(beta 1) and blockade of beta 2 vasodilator receptors on the splanchnic
arteries leaving an unopposed vasoconstrictor effect. This decreases the
frequency of rebleeding and is as effective as sclerotherapy and ligation as it
also prevents bleeding from portal hypertensive gastropathy. It is the
treatment of first choice combined with endoscopic ligation but a substantial
number of patients either have contraindications or are intolerant of beta-
blockers.
 Mononitrates (isosorbide mononitrate) decrease portal blood flow and
pressure

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ASCITES
 This is fluid within the peritoneal cavity and is a common complication of
cirrhosis.
 The pathogenesis of ascites in liver disease is secondary to renal sodium and
water retention.
 Implicated factors:
 Sodium and water retention: this is due to peripheral vasodilation and
consequent reduction in the
effective blood volume caused
by portal hypertension. Nitric
oxide and other substances
(e.g. atrial natriuretic peptide
and prostaglandins) act as
vasodilators. The reduction in
effective blood volume
activates the Renin-
angiotensin aldosterone
system.
 Portal hypertension: increased
local hydrostatic pressure
leads to increased hepatic and
splanchnic production of
lymph and transudation of
fluid into the peritoneal cavity.
 Low serum albumin: as a
consequence of poor synthetic
liver function may further
contribute to ascites by
reduction in plasma oncotic pressure.
CLINICAL FEATURES
 Mild generalized abdominal pain and discomfort but if more severe should raise
the suspicion of spontaneous bacterial peritonitis.
 Respiratory distress accompanies tense ascites, and also causes difficulty in
eating.

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 The presence of fluid is confirmed by demonstrating shifting dullness. It is
clinically detectable when larger than 500ml. Subclinical ascites can be detected
by ultrasound examination.
 Many patients also have peripheral edema.
 A pleural effusion (usually on the right side) may infrequently be found and arises
from the passage of ascitic fluid through congenital diaphragmatic defects.
INVESTIGATIONS
 A diagnostic aspiration of 10-20ml of fluid should be obtained and the following
performed:
 Cell count: a neutrophil count above 250 cells/mm3 is indicative of an
underlying (usually spontaneous) bacterial peritonitis.
 Gram stain and culture: for bacteria and acid-fast bacilli
 Protein: a high serum ascites albumin gradient (SAAG criteria) of >1.1g/dL
suggests portal hypertension and a low gradient <1.1g/dL is associated with
abnormalities of the peritoneum e.g. inflammation, infection, neoplasia.
 Cytology for malignant cells
 Amylase- to exclude pancreatic ascites
MANAGEMENT
 Check serum electrolytes, creatinine and eGFR at the start and every other day,
weigh patient and measure urinary output daily
 Bed rest to promote diuresis
 Salt restriction to less than 2g/day
 Fluid restriction if serum sodium level is below 120mEq/L
 Drugs that may contain significant amounts of sodium (up to 50mmol daily) e.g.
antacids, antibiotics (especially penicillins and cephalosporins) and effervescent
tablets. Sodium retaining drugs (NSAIDs, corticosteroids) should be avoided
 The maximum rate at which ascites can be mobilized is 500-700ml in 24 hours.
 The diuretic of first choice is spironolactone starting at 100mg daily. Chronic
administration produces gynecomastia. Eplerenone 25mg OD does not cause
gynecomastia.
 Spironolactone can be increased gradually to 400mg daily providing there is no
hyperkalemia.
 Spironolactone is an aldosterone antagonist is often effective when given with
loop diuretics. A loop diuretic such as furosemide 20-40mg or bumetanide 0.5mg
or 1mg can be added is response is poor.

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 Side effects of loop diuretics: hyponatremia, hypokalemia and volume
depletion
 Diuresis should be monitored because vigorous diuresis leads to hypovolemia
and hypokalemia and precipitate hepatic encephalopathy. The goal of diuresis
should be dependent on the extent of edema and be monitored by daily body
weight measurement i.e.
 Decrease weight by 0.5-0.7kg/day if no peripheral edema
 Decrease weight by 1kg/day if peripheral edema is present
 Diuretics should be temporarily discontinued if a rise in serum creatinine level
occurs representing over-diuresis and hypovolemia or if there is hyperkalemia or
the development of pre-coma.
 Refractory ascites: persistent tense ascites despite maximal diuretic therapy
(Spironolactone 400mg/d, Furosemide 160mg/d) or if azotemia develops
(creatinine >2mg/dl) while the patients is receiving submaximal doses.
 It occurs in 10% of ascites of chronic liver disease (CLD) origin.
 Repeated large volume paracentesis (with IV albumin replacement if
available) should be done
o The main complication is hypovolemia and renal dysfunction (post-
paracentesis circulatory dysfunction) as the ascites reaccumulates at the
expense of the circulating volume, this is more likely with >5L removal
and worse liver function. In patients with normal renal function and
without hyponatremia this is overcome by infusing albumin (8g/L of
ascitic fluid removed).
o In practice up to 20L can be removed over 4-6 hours with albumin
infusion.
 Surgical treatment: Portal systemic shunt
 Liver transplantation
COMPLICATIONS OF ASCITES
 Spontaneous bacterial peritonitis
 Hepatopulmonary syndrome
 Hepatorenal syndrome
 Rupture of the umbilicus

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SPONTANEOUS BACTERIAL PERITONITIS
 This is a complication of ascites and in turn increases the risk of hepatorenal
syndrome.
 This is usually due to enterobacteriacae e.g. E.coli, Klebsiella, enterococci or
pneumococci.
 It is due to portal hypertension which causes a weakened gut mucosal defence
and infection of ascitic fluid usually with E. coli.
 The condition should be suspected in any patient with ascites who clinically
deteriorates.
 Spontaneous bacterial peritonitis may be asymptomatic or may present with:
 Fever
 Abdominal pain/tenderness
 Vomiting
 Diagnosis is suspected when ascitic polyymorphonuclear cell count is >250/L.
 It is confirmed by ascitic fluid culture.
 Management:
 Antibiotics (third generation cephalosporins e.g. cefotaxime or Ceftazidime
for 5-7 days) modified on the basis of culture.
 If severe consider lifelong prophylactic antibiotics (with oral
fluoroquinolones).
 Indications: previous history of SBP, patient admitted with gastrointestinal
hemorrhage, ascitic protein less than 1g/dl and candidates of liver transplant
o Co-trimoxazole 960mg/day for 5 days (Monday-Friday)
o Ciprofloxacin- 750mg OD weekly
o Norfloxacin- 400mg/day
 Refer for possible liver transplant.

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HEPATORENAL SYNDROME
 This is functional renal failure in the presence of cirrhosis.
 It accounts for 25% of AKI in cirrhosis patients.
 It can also be defined as kidney failure without known causes in the presence of
severe liver disease, the latter defined as ascitic cirrhosis or acute liver failure.
 A diagnosis is made after prerenal causes of renal failure are excluded.
 The urine output is low with a low urinary sodium concentration (<10mg/l), a
maintained capacity to concentrate urine (i.e. tubular function is intact) and
almost normal renal histology.
 There are normal urinary sediments and azotemia occurs often with
disproportionately high levels of blood urea nitrogen and creatinine.
 Two- month mortality rate from hepatorenal syndrome is 90% (prognosis is grave
with a 10-14 days median survival rate)
PATHOPHYSIOLOGY
 Hepatorenal syndrome occurs typically in a patient with advanced cirrhosis,
portal hypertension with jaundice and ascites.
 Vigorous diuresis, NSAIDs, diarrhea, paracentesis without volume expansion,
variceal bleeding and sepsis (spontaneous bacterial peritonitis) may predispose
to hepatorenal syndrome.
 The initiating factor is thought to be extreme peripheral vasodilation, possibly
due to nitric oxide leading to an extreme decrease in effective blood volume and
hypotension.
 The Renin-angiotensin response leads to regional vasoconstriction (cortical
vasoconstriction), causing renal hypoperfusion.
 There is an increased preglomerular vascular resistance causing the blood flow
to be directed away from the renal cortex. This leads to a reduced glomerular
filtration rate and plasma renin remains high.
 Salt and water retention occur with reabsorption of sodium from the renal tubules.
 There is also a decrease in cardiac output inappropriate to the degree of systemic
vasodilation which further exacerbates the hemodynamic abnormalities.

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MANAGEMENT
 Identify and treat precipitants
 Discontinue diuretics
 Volume expansion to rule out volume depletion: 1.5L IV normal saline or 5% IV
albumin. If serum creatinine is decreased suspect another diagnosis.
 Restrict sodium to <2g/day if serum Na <125mEq/L the restrict fluids to <1.5
L/day
 Treat infection
 Low dose vasopressin, octreotide or norepinephrine may be given.
 Terlipressin a splanchnic vasoconstrictor plus human albumin solution can
be given.
 Liver transplantation is the accepted management. Renal failure from hepatorenal
syndrome reverses with liver transplant.

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LIVER TUMORS
 Tumors of the liver can either be:
 Primary: these may be benign or malignant, but the most common are
malignant.
 Secondary (metastatic): these are the most common liver tumors, particularly
from the gastrointestinal tract (From the distribution of the portal blood
supply), breast or bronchus.

PRIMARY BENIGN TUMORS

 The most common benign tumor is a hemangioma. It is usually small and single
but can be multiple and large.
 Hemagiomas are usually found incidentally on ultrasound, CT or MRI
and have characteristic appearances. They require no treatment.
 Hepatic adenomas are associated with oral contraceptives. They can present
with abdominal pain or intraperitoneal bleeding.
 Resection is only required for symptomatic patients, those with tumors
>5cm diameter or in those in whom discontinuation of oral contraception
does not result in shrinkage of the tumor.
 Immunohistochemical characteristics are helpful in indicating malignant
potential which is far more common in men

PRIMARY MALIGNANT TUMORS

HEPATOCELLULAR CARCINOMA (HEPATOMA)
 Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide.
 Males are affected more than females (4:1 to 8:1).
ETOLOGY
 Carriers of HBV and HCV have extremely high risk of developing HCC.
 Cirrhosis is present in approximately 80% of patients with HBV.
 The development of HCC is related to the integration of viral HBV DNA into
the genome of the host hepatocyte and degree of viral replication (>10 000
copies/ ml)
 The risk of HCC is higher in HCV than HBV (even higher with both HBV
and HCV) despite no viral integration.
 Unlike HBV infection, cirrhosis is always present in HIV infection.

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 Primary liver cancer is also associated with other forms of cirrhosis including:
 Alcoholic cirrhosis
 Non-alcoholic fatty liver disease associated cirrhosis
 Hemochromatosis
 Other etiological factors:
 Aflatoxin (a metabolite of a fungus found in groundnuts)
 Androgenic steroids
 Contraceptive pill (weak association)
PATHOLOGY
 The tumor is either single or occurs as multiple nodules throughout the liver.
 Histologically it consists of cells resembling hepatocytes.
 It can metastasize via the hepatic or portal veins to the lymph nodes, bones and
lungs.
CLINCAL FEATURES
 Common symptoms & findings: Weight loss, anorexia,
fever, an ache in the right hypochrondrium, abdominal
mass and ascites.
 The rapid development of these features in a
cirrhotic patient is suggestive of HCC.
 On examination an enlarged irregular tender liver may
be felt. Sometimes HCC is found without symptoms in
cirrhotics.
 Unusual manifestations: bloody ascites, tumor emboli,
jaundice, gynecomastia, hepatic bruit or friction rub,
metabolic effect (erythrocytosis, hypercholesterolemia,
hypoglycemia, hypercalcemia, acquired porphyria)
INVESTIGATIONS
 Serum alpha-fetoprotein: may be raised but normal in
at least 1/3 of patients.
 Ultrasound scan: shows filling defects in 90% of cases
 Enhanced CT scans: identifies HCC but it is difficult to
confirm diagnosis in lesions <1cm
 MRI: helps further delineate lesions.

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 Tumor biopsy under ultrasonic guidance is used for diagnosis but is employed
less frequent as imaging techniques show characteristic appearances
(hypervascularity of the nodule and lack of portal vein wash out) and because
seeding along the biopsy tract can occur.
TREATMENT AND PROGNOSIS
 Surgical resection of isolated lesions <5cm diameter or up to 3 lesions <3cm
diameter is associated with a median survival of 5 years although the remaining
liver remains at risk of further recurrence.
 Liver transplantation offers the only opportunity for cure for patients with a
small primary but is limited often by the underlying causes of hepatitis and
cirrhosis.
 Conventional chemotherapy and radiotherapy are unsuccessful but
transarterial embolization or radiofrequency ablation in patients with small
primaries as above and adequate liver function prolongs survival though less
successful than surgery.
 Antiangiogenic compounds are being evaluated: sorafenib prolongs survival in
patients with non-resectable tumors to 10 months.
PREVENTION
 Widespread vaccination against HBV
 Alcohol abstinence
CHOLANGIOCARCINOMA
 These are increasing in incidence and can be extrahepatic or intrahepatic.
 Intrahepatic adenocarcinomas arising from the bile ducts account for
approximately 10% of primary tumors. They are not associated with cirrhosis or
hepatitis.
 In the Far East, they may be associated with infection with Clonorchis sinensis
or Opisthorchis viverrini.
 Clinical features are similar to primary HCC except that jaundice is frequent with
hilar tumors and cholangitis is more frequent.
 Surgical resection is rarely possible and patients usually die within 6 months.
 Transplantation is contraindicated outside of specialized protocols.

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SECONDARY LIVER TUMORS
 The most common liver tumors are secondary (metastatic) tumor.
 They spread from the gastrointestinal tract (from the distribution of the portal
blood supply), breast or bronchus.
 They are usually multiple.
CLINICAL FEATURES
 Clinical features are variable but usually include weight loss, malaise, upper
abdominal pain and hepatomegaly with or without jaundice.
DIAGNOSIS
 Ultrasound is the primary investigation, with CT or MRI to define metastases and
look for a primary.
 The serum alkaline phosphatase is almost invariable raised.
TREATMENT
 This will depend on the site of the primary and the burden of liver metastases.
 The best results are obtained in colorectal cancer in patients with few hepatic
metastases.
 If the primary tumor is removed and hepatic resection is performed, reasonable
survival rates are possible.
 Chemotherapy is used, particularly with breast cancer.
 Radiofrequency ablation of the metastases is an alternative to surgery.
 Thermal and cryotherapy is also used.

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BUDD-CHIARI SYNDROME
 There is obstruction to the venous outflow of the liver owning to occlusion of the
hepatic vein.
 Cause is unknown in 1/3 of patients but specific causes including
hypercoagulability states (e.g. paroxysmal nocturnal hemoglobinuria,
polycythemia vera) or thrombophilia taking the contraceptive pill, or leukemia.
 Other causes include occlusion of the hepatic vein owing to posterior abdominal
wall sarcomas, renal or adrenal tumors, hepatocellular carcinoma, hepatic
infections (e.g. hydatid cyst), congenital venous webs, radiotherapy or trauma of
the liver.
 The acute form presents with:
 Abdominal pain
 Nausea
 Vomiting
 Tender hepatomegaly and ascites (a fulminant form occurs particularly in
pregnant women)
 In the chronic form there is enlargement of the liver (particularly the caudate
lobe), mild jaundice, ascites, a negative hepatojugular reflux, and splenomegaly
with portal hypertension.
 Investigations:
 High protein content in the ascitic fluid
 Ultrasound, CT or MRI will demonstrate hepatic vein occlusion with diffuse
abnormal parenchyma on contrast enhancement
 Liver biopsy: centrizonal congestion, hemorrhage, fibrosis and cirrhosis
 Thrombophilia screening is mandatory
 Differential diagnosis:
 Inferior vena caval obstruction
 Right sided cardiac failure
 Constrictive pericarditis
 Treatment:
 Thrombolytic therapy
 Ascites should be treated as should any underlying cause e.g. polycythemia.
 Transjugular intrahepatic portosystemic shunt (TIPS) is the first treatment of
choice as caval conmpression does not prejudice theefficacy of TIPS.
 Liver transplantation is the treatment of choice for chronic Budd-Chiari
syndrome and for fulminant form.

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 Lifelong anticoagulation is mandatory following TIPS and transplantation.

THE BILIARY SYSTEM AND PANCREAS

 Bile canaliculi form a network between the hepatocytes. These join to form thin
bile ductules near the portal tract, which in turn enter the bile ducts in the portal
tract.
 These then combine to form the right and left hepatic ducts that leave each liver
lobe.
 The hepatic ducts join at the porta hepatis to form the common hepatic duct.
 The cystic duct connects the gall bladder to the lower end of the common hepatic
duct.
 The gall bladder lies under the right lobe of the liver and stores and concentrates
hepatic bile, its capacity is approximately 50mL.
 The common bile duct is formed at the junction of the cystic and common duct
and is 8mm in diameter or less, passing through the head of the pancreas,
narrowing at its lower end to pass into the duodenum.
 The common bile duct and pancreatic duct open into the second part of the
duodenum most often through a common channel at the ampulla of Vater which
contains the muscular sphincter of Oddi.
 This contracts rhythmically and prevents all of the bile from entering the
duodenum, by maintaining a higher pressure than the gall bladder in the fasting
state.
PANCREATITIS

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RENAL CONDITIONS
 Patients with renal disease may  Urine for laboratory analysis must
have a variety of different clinical be transferred quickly and at the
presentations. correct temperature otherwise it is
 Some have symptoms that are becomes a breeding ground for
directly referable to the kidney contaminants.
(gross hematuria, flank pain) or to
BEDSIDE URINALYSIS
associated external symptoms
(edema, hypertension, signs of  Always wear gloves whilst
uremia) handling urine and ensure that the
dipsticks are functional and not
 Many patients, however, are
expired.
asymptomatic and are noted on
routine examination to have an  Before beginning the test assess the
elevated creatinine concentration or urine for appearance (color,
an abnormal urinalysis. presence or sediments), smell and
consistency.
 Specific disorders are more likely
to be acute or chronic. COLOUR
 Normal urine color is often
URINE EXAMINATION described as straw, yellow or
(URINALYSIS) amber. This color may be altered by
 Indications: medications, food sources or
 Metabolic disorders (Diabetes disease.
and DKA)  Vitamin tablets often result in a
 Renal dysfunction (e.g. bright yellow urine, as does the
nephrotic syndrome, nephritic presence of bilirubin (a bile
syndrome) pigment).
 Urinary tract infections  Red urine may be due to blood,
 Hematuria hemoglobin or beetroot.
 Urine may be assessed both at the  Iron supplements may cause a dark
bedside (dipstick) and in the brown specimen, as might amounts
laboratory (microscopy, culture, of urobilin (a chemical produced in
sensitivity and urinary the intestines).
electrolytes).

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 Normal urine is also transparent.  Compare the colors with the
Turbid or cloudy urine may result parameters shown on the urinalysis
from infection, the presence of container.
blood cells, bacteria or yeast (e.g.
Candida).
PARAMATERS OF
 Foamy urine may indicate either MEASURED
the presence of glucose or protein.  These include:
 Leucocytes (white cell count)
SMELL  Nitrites
 The normal smell of urine can be  Proteins
described as urinoid.  pH
 Other smells include:  Blood
 Fecal smell: gastrointestinal-  Specific gravity
bladder fistula.  Ketones
 Fruity or sweet smell: diabetic  Bilirubin
ketoacidosis.  Glucose
 Smell of ammonia: alkaline
fermentation. LEUCOCYTES (WHITE
 Smell of asparagus: eating a lot CELL COUNT)
of asparagus.  Determines the presence of whole
or lysed white cells in the urine
CONSISTENCY (pyuria) by detecting leucocyte
 Check for any urine sediments esterase activity.
 Check for any visible blood  A positive leucocyte esterase test
correlates well with pyuria.
However, the diagnosis may be
 When doing the test ensure the missed in up to 20% of cases if a
dipstick is completely immersed in negative urinalysis dipstick is used
the specimen of fresh urine. to exclude UTI.
Withdraw immediately, drawing or  False positive: contaminated
gently tapping edge along rim of specimen, trichomonas vaginalis,
container to remove excess. drugs or foods that color the urine
 Take your time. Some of the red.
reactions can take up to 2 minutes  False negative: intercurrent or
to cook. recent antibiotic therapy (especially
gentamicin, tetracycline and
cephalosporins), glycosuria,

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proteinuria, high specific gravity. glomerulonephritis, malignant
Low bacteria count UTI (especially hypertension
in women)  CVS disease: benign
hypertension, congestive
NITRITES cardiac failure
 Nitrates in the urine are converted  Drug intake: aminoglycosides,
to nitrates in the presence of Gram- gold, amphotericin, NSAIDs,
negative bacteria e.g. E.coli and sulphonamides, penicillins.
Klebsiella.  Other: fever, cold exposure,
 A positive nitrate test is a surrogate stress, pregnancy, shock,
marker of bacteruria. severe exercise, orthostatic
 Positive test strongly suggests proteinuria, electric current
infection but negative test does not injury, hypokalemia, Cushing’s
exclude it. syndrome
 False negative: drugs or foods that  Note: Bence Jones globulin
color the urine. Certain bacteria associated with multiple myeloma,
such as S. saprophyticus, lymphoma and macroglobulinemia
acinetobacter and most is not detected by dipstick.
enterococci.
pH
PROTEIN  Normal urine pH is 5.5-6.5 but it
 Normal daily protein excretion may vary from as low as 4.5 to as
should not exceed 150mg per day high as 8.0. Recall the kidneys play
or 10mg/100ml. Proteinuria is an important role in acid-base
defined by production of balance.
>150mg/day with nephrotic  Causes of high urinary pH (alkali
syndrome producing >3.5g/day. urine):
 Dipstick urinalysis detects proteins  Systemic alkalosis
and is most sensitive to albumin  Renal tubular necrosis
and less sensitive to Bence-Jones  Fanconi syndrome
proteins and globulins.  UTI
 Trace positive results are  Drugs: Amphotericin B,
equivalent to about 150mg/day (the carbonic anhydrase inhibitor
upper limit) (acetazolamide), sodium
 Proteinuria may be seen in: bicarbonate, ASA
 Renal disease: nephrotic  Stale ammoniacal sample (left
syndrome, nephritic syndrome, standing)

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 Vegetarian diet, low  The presence of myoglobin
carbohydrate diet or ingestion (myoglobinuria) after muscle
of citrus fruits injury will also cause there the
 Causes of low urinary pH (acidic reagent strip to indicate blood.
urine):
SPECIFIC GRAVITY
 Systemic acidosis
 Diabetes mellitus  Urine specific gravity is a measure
 Starvation of the weight of dissolved particles
 Diarrhea in urine, whereas urine osmolality
 Malabsoprtion reflects the number of such
 High protein diet or fruits such particles.
as cranberries  Normal specific gravity: 1.002-
1.035
BLOOD  Decrease in specific gravity:
 Dipstick urinalysis is able to detect  Inability to concentrate urine or
hemolyzed and non-hemolyzed excess hydration
blood in the urine.  Nephrogenic diabetes
 Hematuria is classified: insipidus, acute
 Microscopic: blood is not glomerulonephritis,
visible with the naked eye. pyelonephritis, acute tubular
 Macroscopic necrosis
 Blood may be present in the urine  Increase in specific gravity
following trauma, smoking,  Dehydration (fever, vomiting,
infection, inflammation, neoplasia, diarrhea)
clotting disorders, renal calculi or  SIADH, adrenal insufficiency,
strenuous exercise. pre-renal failure, hyponatremia
 It may also be present with: with edema, liver failure,
 Urinary tract infections, congestive cardiac faiulure,
 Damage to glomerulus or nephrotic syndrome, dibetes
tumors which erode the urinary mellitus
tract,  Specific gravity is usually fixed at
 Acute tubular necrosis, 1.010 in CKD or acute tubular
 Traumatic catheterization necrosis as compared to pre-renal
 Damage caused by passage of acute kidney injury and
kidney stones inappropriate ADH secretion where
 Contamination from the vagina specific gravity is very high- close
during menstruation to 1.025.

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KETONES test for urine bilirubin confirms
 Ketones (acetone, aceto-acetic conjugated hyperbilirubinaemia.
acid, beta-hydroxybutyric acid) are  Raised conjugated bilirubinemia
the end-point of incomplete fat (with bilirubinuria) is associated
metabolism. They accumulate in with hepatocellular disease,
plasma and are excreted in urine. cirrhosis, viral and drug induced
 Ketonuria is seen in: hepatitis, biliary tract obstruction
 Diabetic ketoacidosis (e.g. choledocholithiasis),
 Low carbohydrate (high pancreatic causes of obstructive
fat/protein) diet jaundice (e.g. carcinoma of the
 Starvation head of the pancreas) and recurrent
 Alcoholism idiopathic jaundice of pregnancy.
 Eclampsia  False positive: phenothiazines.
 Hyerthyroidism  False negative: ascorbic acid
(Vitamin C), aged sample
BILIRUBIN (conjugated bilirubin hydrolses to
 Bilirubin is not present in the urine unconjugated bilirubin at room
of normal healthy individuals. The temperature), rifampicin and
presence of bilirubinuria may be an exposure to UV light (converts
early indicator of liver disease and bilirubin to biliverdin)
occur before the clinical signs of
jaundice develop. UROBILINOGEN
 Bilirubin is formed as a by-product  Urobilinogen is normally present in
of red blood cell degradation in the the urine in low concentrations
liver, and then conjugated with the (0.2-1.0mg/dl or <17 mol/L).
solubilizing sugar, glucoronic acid  Bilirubin is converted to
and excreted in bile. Within the urobilinogen by intestinal bacteria
intestine, the bilirubin is converted in the duodenum. Most
into stercobilin (excreted in feces) urobilinogen is excreted in feces or
and urobilinogen (excreted by the transported back to the liver and
kidneys). converted into bile. The remaining
 Failure of conjugated bilirubin to urobilinogen (<1%) is excreted in
reach the intestines (e.g. biliary the urine.
obstruction) will result in  Urobilinogen is present in
bilirubinuria. Note: only increased concentrations in the
conjugated bilirubin can be urine in patients with cirrhosis,
excreted as bilirubinuria. A positive infective hepatitis, extravascular

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hemolysis, hemolytic anemia,  Urobilinogen levels are decreased
pernicious anemia, malaria and or absent in obstructive jaundice
hepatitis secondary to infectious and elevated in bilirubinuria.
mononucleosis.

Dipstick Normal Biliary Hepatic Hemolytic

urinalysis obstruction disease disease
Bilirubin Negative Positive Positive Negative
Urobilinogen Positive Negative/decreased Increased Increased

GLUCOSE
 Glucose is not normally present in
the urine with <0.1% of glucose
normally filtered by the glomerulus
appears in urine (<130mg/day)
 Glycosuria indicates as rise in
serum glucose levels.
 It may be seen in:
 Diabetes mellitus
 Renal tubular
 Pregnancy
 Drugs: cephalopsorins,
penicillins, nitrofurantoin,
methyldopa, tetracycline,
lithium, carbamazepine,
phenothiazines, steroids, and
thiazides.

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ACUTE KIDNEY INJURY (AKI)

 Acute kidney injury is an abrupt deterioration in parenchymal renal function,
which is usually but not invariably, reversible over a period of days or weeks.
 It is a rapid reduction in kidney function over hours to days, as measured by
serum urea and creatinine and leading to failure to maintain fluid, electrolyte and
acid-base homeostasis.
 In clinical practice such deterioration in renal function is sufficiently severe to
results in uremia.
 Acute renal failure is a syndrome characterized by: Normal urine output=
 Rapid decline in glomerular filtration rate (hours to days) 0.5-1 ml/kg/hr
 Retention of nitrogenous wastes due to failure of excretion
 Disturbance in extracellular fluid volume and
Normal Creatinine
 Disturbance in electrolyte and acid base homeostasis.
 The hallmark of acute renal failure is azotemia, often with Male= 53-106 mol/L
oliguria (0.6-1.2mg/dl
 Azotemia: increase in nitrogenous waste products in the
Female= 44-97 mol/L
blood (Blood urea nitrogen and creatinine) without
(0.5-11mg/dl)
symptoms (GFR is about 20-35% of normal).
 Uremia implies a deterioration of renal function associated
with symptoms (GFR <20% of normal)
 Oliguria is a condition in which a person does not produce Normal Urea
enough urine.
 Oliguria is usually but not invariably, a feature. 2.5 to 7.2 mmol/L (7 to
20mg/dl)
 Based on the amount of urine output acute renal failure may
be classified as:
 Anuric: if urine volume is less than 100ml/day
 Oliguric- if urine volume is less than 400ml/day Normal BUN
 Non-oliguric- if urine volume is greater than or equal to
400ml/day 3.6 to 7.1 mmol/L (10 to
 AKI may cause sudden life-threatening biochemical 20mg/dl)
disturbances and is a medical emergency.
 AKI can also be defined as any 1 of the following:
 Urine output <0.5 ml/kg/hr for 6 hours or 8 hours consecutive in kids
 Creatinine x 1.5 from baseline in 1 week
 Creatinine increase greater than 26 mol/L in 48 hours

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 Decrease in GFR 25% in children over 7 days
 The distinction between acute and CKD or even acute-on chronic kidney disease
cannot be readily apparent in a patient presenting with uremia.
 In view of these difficulties, the Acute Dialysis Quality initiative group proposed
the RIFLE (Risk, Injury, Failure, Loss, End-stage renal disease) criteria utilizing
either increases in serum creatinine or decreases in urine output.
 It characterizes 3 levels of renal dysfunction (R, I, F) and 2 outcome measures
(L, E). These criteria indicate an increasing degree of renal damage and have a
predictive value for mortality. (See the table below for RIFLE classification for
acute kidney injury)

Grade GFR criteria Urine output

Risk (KDIGO Stage 1) Serum creatinine x 1.5 baseline or Urine output <0.5ml/kg/h for
increase >26mol/L in 48 hours 6 hours
Injury (KDIGO Stage 2) Serum creatinine x 2-2.9 baseline Urine output <0.5 ml/kg/h for
12 hours
Failure (KDIGO Stage 3) Serum creatinine x 3 or Serum Urine output <0.3 ml/kg/h for
creatinine >350 m with an acute 24 hours or anuria for 12
rise >40 mol/L or dialyzed hours
Loss Persistent AKI >4 weeks (1 month)
ESKD (end stage Kidney Persistent renal failure >3 months
disease)
 Note: KDIGO (Kidney Disease Improving Global Outcome)
 Risk factors for developing AKI
 Age>75
 Chronic kidney disease
 Cardiac failure
 Peripheral vascular disease
 Chronic liver disease
 Diabetes
 Drugs (especially newly started)
 Sepsis
 Poor fluid intake/increased losses
 History of urinary symptoms

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 Signs and symptoms of uremia include:
 General: Nausea and vomiting, fatigue, weight loss, anorexia (loss of
appetite), fetor uremicus (urine like odor of the breath), metallic taste,
hiccups, pruritus, uremic frost, muscle cramps, metabolic flap/asterexis
 Neurologic: encephalopathy (change in mental status, Intellectual clouding,
confusion, drowsiness, fits, coma, decreased memory and attention),
seizures, neuropathy.
 Cardiovascular: Pericarditis, hypertension, volume overload, CHF,
cardiomyopathy, hyperlipidemia, accelerated atherosclerosis
 Hematologic: Anemia, and bleeding (due to platelet dysfunction)
 Metabolic: hyperkalemia, hyperphosphatemia, acidosis, hypocalcemia,
secondary hyperparathyroidism, osteodystrophy
CLASSIFICATION OF ACUTE KIDNEY INJURY
 Renal failure results in reduced excretion of nitrogenous waste products, of which
urea is the most commonly measured. A raised serum urea concentration
(Uremia) is classified as:
 Pre-renal (40-70%)
 Renal (10-50%)
 Post-renal (10-25%)
 More than one category may be present in an individual patient.
 Other causes of altered serum urea and creatinine concentration include:

Decreased concentration Increased concentration

Urea  Low protein intake  Corticosteroid treatment
 Liver failure  Tetracycline treatment
 Sodium valproate treatment  Gastrointestinal bleeding
Creatinine  Low muscle mass  High muscle mass
 Red meat ingestion
 Muscle damage (rhabdomyolysis)
 Decreased tubular secretion e.g.
Cimetidine, trimethoprim therapy

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PRE-RENAL UREMIA
 This accounts for nearly 55% of all cases of acute renal kidney.
 It is also known as pre-renal azotemia.
 There is impaired perfusion of the kidneys with blood.
 Usually the kidney is able to maintain glomerular filtration close to normal
despite wide variations in renal perfusion pressure and volume status- so called
‘autoregulation’. Further depression of renal perfusion leads to a drop in the
glomerular filtration and development of pre-renal uremia.
 Renal hypoperfusion leads to a decrease in GFR as an appropriate response to
retain Na+/H2O. There is no renal cell injury and restoration of perfusion restores
function.
 Prolonged hypoperfusion can lead to acute tubular necrosis, thus ischemic AKI
is a spectrum from pre-renal to intrinsic AKI, differentiated by presence of renal
cell injury.
CAUSES OF PRE-RENAL UREMIA
 This results either from
 Hypovolemia: hemorrhage, severe diarrhea, severe vomiting, burns
dehydration, renal fluid loss (diuretics, osmotic diuresis e.g. diabetes
mellitus), hypoadrenalism, third spacing (pancreatitis, peritonitis, trauma,
burns, severe hypoalbuminemia).
 Low cardiac output and hypotension: diseases of myocardium (dilated
cardiomyopathy), valves, and pericardium, arrhythmias, tamponade,
congestive heart failure, others (pulmonary hypertension, massive pulmonary
embolism)
 Altered renal systemic vascular resistance ratio: systemic vasodilatation
(sepsis, anaphylaxis, renal hypoperfusion with impairment of renal
autoregulatory response e.g. with NSAIDs, ACE inhibitors. NSAIDs
constrict the afferent arterioles while ACEi and ARBs dilate efferent
arterioles than afferent arterioles)
 Vascular disease limiting renal blood flow
CLINICAL FEATURES
 Pre-renal failure is suggested by clinical signs of:
 Intravascular volume depletion (e.g. orthostatic hypotension, rapid pulse and
poor skin turgor).

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 Congestive heart failure e.g. raised JVP, S3, dependent edema and pulmonary
rales.
DIAGNOSIS
 Careful history is essential:
 Exposure to nephrotoxins and drugs
 Anuria may indicate post-renal causes
 Skin rashes may indicate allergic nephritis
 Evidence of volume depletion: diarrhea, bleeding
 Pelvic and per-rectal examination: look for evidence of abortion
 Ischemia or trauma to the legs or arms may indicate rhabdomyolysis
 Recent surgical or radiologic procedures
 Past and present use of medications
 Family history of renal disease
 Physical examination should be focused to rule out possible differential
diagnosis.
 In pre-renal uremia:
 There is decrease in GFR (due to decreased blood flow), azotemia and
oliguria.
 Urine sodium (<20mmol/L) is low if there is avid (eager) tubular
reabsorption, but may be increased by diuretics or dopamine.
 The urine osmolarity is also >500mOsm/kg also indicating there is no
damage to the tubules yet.
 The urine specific gravity is >1.020
 The serum BUN: Cr increases (20mg/dl) and is more than 15mg/dl (normal)
o Recall BUN and Creatinine are both filtered by the glomerulus but only
BUN is reabsorbed and creatinine is not.

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o In pre-renal uremia because of decreased renal perfusion the renin
angiotensin system is activated resulting in release of aldosterone from
the adrenal glands causing resorption of sodium and water. Resorption of
water will also result in resorption of some filtered BUN, this increased
the BUN: Cr ratio.
 The fractional excretion sodium
(FENa) i.e. a ratio of sodium
clearance to creatinine clearance, is
less than 1% indicating there is no
damage to the tubules yet. It may
remain low in some ‘intrinsic’ renal
disease, including contrast
nephropathy and myoglobinuria.
 Laboratory tests, however are no
substitute for clinical assessment. A
history of blood or fluid loss, sepsis potentially leading to vasodilatation or of
cardiac disease may be helpful.
 Hypotension (especially postural), a weak rapid pulse and a low jugular venous
pressure will suggest that the uremia is pre-renal
 In doubtful cases, measurement of central venous pressure is often invaluable,
particularly with fluid challenge.

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MANAGEMENT
 Treat the underlying cause. There is no specific treatment indicated for AKI, it is
just supportive.
 If the pre-renal uremia is a result of hypovolemia and hypotension, prompt
replacement with appropriate fluid is essential to correct the problem and prevent
development of ischemic renal injury and acute kidney disease.
 Severe hypovolemia due to hemorrhage should be corrected with packed red
blood cells, whereas normal saline is usually
Management box: Pre-renal failure
appropriate replacement for mild to moderate
hemorrhage or plasma loss (e.g. burns,  Treat underlying cause
pancreatitis).  Fluid replacement: Pack red blood
 Urinary and gastrointestinal fluids can vary cells and normal saline
greatly in composition but are usually  Monitoring blood pressure
hypotonic. Hypotonic solution (e.g. 0.45% (input/output chart).
saline) are usually recommended as initial  Monitoring serum potassium and
replacement in patient with Pre-renal failure acid base status
due to increased urinary or GI fluid losses,  Antibiotics to treat sepsis,
although normal saline may be more Antiemetics for vomiting
appropriate in severe cases.  Stop Nephrotoxic drugs: NSAIDs,
 If difficult balance with risk of fluid overload, ACEi, ARBs and Diuretics
consider titrating input hourly by matching  Adjust meds to GFR.
previous hours output + 25ml/h for insensible
 Dialysis
losses. If Euvolemic review balance daily
over 24 hour period aim to match input to loss
+ 500ml for insensible loss.
 Consider fluid boluses if you think the patient is dehydrated and has pre-renal
AKI.
o Fluid challenge if patient dehydrated: give 250-500ml of saline over 30
minutes. Repeat challenge if still dehydrated (give fluids until JVP and
systolic BP >100mmHg) caution in patients with cardiac dysfunction
o Once fluid replete continue fluids at 20ml + Previous hour’s urine output
per hour
 For bleeding is still in shock despite 2L crystalloid then cross-match blood
and transfuse FFP alongside packed red cells (1:1 ratio) and aim for platelets
>100 and fibrinogen >1.

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 Listen to lungs to assess for fluid overload. Signs of fluid overload: increased
BP, increased JVP, lung crepitations, peripheral edema, gallop rhythm on
cardiac auscultation.
 Since pre-renal and renal uremia may co-exist and fluid challenge in the latter
situation may lead to volume overload with pulmonary edema, careful clinical
monitoring is vital.
 Blood pressure should be checked regularly and signs of elevated jugular venous
pressure and of pulmonary edema sought frequently.
 Central venous pressure monitoring is usually advisable. If the problem relates to
cardiac pump insufficiency or occlusion of the renal vasculature, appropriate
measures- albeit often unsuccessful need to be taken.
 Serum potassium and acid-base status should be monitored carefully.
 Antibiotics should also be given to treat any infection (Sepsis).
 Give Antiemetics for patients vomiting
 Stop NSAIDs, ACE inhibitors, angiotensin receptor antagonists and Diuretics.
 The role of Furosemide is uncertain. Some advocate it for fluid overload but
NICE doesn’t and there is no good trial evidence.
 Dialysis can be done in refractory cases.
INTRARENAL/ INTRINSIC UREMIA
 This accounts for nearly 40% of all Acute renal failure cases.
ETIOLOGY
 Causes include:
 Acute tubular interstitial necrosis (most common cause): can either be
ischemic (common) or nephrotoxic
o Ischemic: prolonged pre-renal
 Hemorrhage
 Burns
 Diarrhea and vomiting, fluid loss from fistulae
 Pancreatitis, Diuretics
 Myocardial infarction, Congestive cardiac failure, Endotoxic shock,
Snake bite
 Hepatorenal syndrome
 Pre-eclampsia and eclampsia
o Nephrotoxic:
 Myoglobinemia

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 Hemoglobinemia (due to hemolysis e.g. in Falciparum malaria,
‘blackwater fever’)
 Radiological contrast
 Drugs e.g. aminoglycosides, platinum derivatives, heavy metals,
Lithium
 Acute Interstitial nephritis (AIN): glomerulonephritis, including rapidly
progressive glomerulonephritis (RPGN)
o Allergic: sulfa, beta lactams, NSAIDs, traditional meds
o Infection: pyelonephritis
o Infiltrative: sarcoid, lymphoma, leukemia
 Disease of glomeruli or renal microvasculature (renovascular):
o Renal artery stenosis,
o Vasculitis, accelerated/malignant hypertension,
o Cholesterol embolism,
o Microangiopathy: hemolytic uremic syndrome, thrombotic
thrombocytopenic purpura, pre-eclampsia and DIC
o Crescentic glomerulonephritis
ACUTE TUBUOINTERSTITIAL NECROSIS
 This is the most common cause of AKI.
 This is injury and necrosis of tubular epithelial cells.
 Etiology may be ischemic or nephrotoxic:
 Ischemic- decreased blood supply results in necrosis of tubules.
o Often preceded by pre-renal azotemia (Hypovolemia, low cardiac output,
renal vasoconstriction, systemic vasodilatation).
o Other causes include obstetric complications (abruptio placentae,
postpartum hemorrhage).
o Proximal tubule and medullary segment of the thick ascending limb are
particularly susceptible to ischemic damage.
 Nephrotoxic- toxic agents result in necrosis of tubules.
o Proximal tubule is particularly susceptible.
o Causes include aminoglycosides (most common), heavy metals (e.g. lead
and platinum derivative), lithium, myoglobiuria (e.g. from crush injury
to muscle, rhabdomyolysis, electric burns), ethylene glycol (associated
with oxalate crystals in urine), radiocontrast dye and urate (e.g. tumor
lysis syndrome)

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o Hydration and allopurinol are used prior to initiation of chemotherapy to
decrease risk of urate-induced acute tubular necrosis.
 Necrotic cells plug tubules, obstruction decreases GFR.
 Brown, granular casts are seen in the urine in 75% of cases.
 Dysfunctional tubular epithelium results in decreased reabsorption of BUN
(serum BUN:Cr <15mg/dl), decreased reabsorption of sodium (FENa> 2%) and
inability to concentrate urine (urine osm< 350mOsm/kg).
PATHOGENESIS
 Factors implicated in the development of Acute tubulointestitial necrosis include:
 Intrarenal microvascular vasoconstriction:
o Vasoconstriction is increased in response to endothelin, adenosine,
thromboxane A2, leukotrienes and sympathetic nerve activity.
o Vasodilation is impaired due to reduced sensitivity in response to nitric
oxide, prostaglandins (PGE2), acetylcholine and bradykinin. There is also
increased endothelial and vascular smooth muscle cell structural damage
o Increased leucocyte-endothalial adhesion, vascular congestion and
obstruction, leucocyte activation and inflammation.
 Tubular cell injury: ischemic injury results in rapid depletion of intracellular
ATP stores resulting in cell death by necrosis or apoptosis due to:
o Entry of calcium into the cells
o Induction by hypoxia of inducible nitric oxide synthase with increased
production of nitric oxide causing cell death
o Increased production of intracellular proteases such as calpain which
causes proteolysis of cytoskeleton protein and cell wall collapse
o Activation of phospholipase A2 with increased production of free fatty
acids particularly arachidonic acid, due to its action on the lipid layer of
cell membranes.
o Cell injury resulting from reperfusion with blood after initial ischemia
causing excessive free radical generation.
o Tubular obstruction by desquamated viable or necrotic cells and casts
o Loss of cell polarity i.e. integrins located on the basolateral side of the
cell are translocated to the apical surface when combined with other
desquamated cells forms casts, with tubular obstruction and back leak of
tubular fluid.

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 Tubular cellular recovery: tubular cells have the capacity to regenerate
rapidly and to reform the disrupted tubular basement membrane, which
explains the reversibility of ATN.
 In established ATN, renal blood flow is much reduced, particularly blood flow to
the renal cortex. Ischemic tubular damage contributes to a reduction in
glomerular filtration by the following mechanisms:
 Glomerular contraction: reducing the surface area available for filtration due
to reflex afferent arteriolar spasm mediated by increased solute delivery to
the macula densa. Increased solute delivery is due to impaired sodium
absorption in the proximal tubular cells because of loss of cell polarity with
mislocalization of the Na/K-ATPase and impaired tight junction integrity,
resulting in decreased apical-to-basal transcellular sodium absorption.
 ‘Back leak’ of filtrate: in the proximal tubule owing to loss of function of the
tubular cells
 Obstruction of the tubules: by debris shed from ischemic tubular cells, these
appear on renal biopsy as flat rather than the normal tall appearance.
COURSE
 Stages: acute kidney injury due to ATN typically occurs in 3 stages: Azotemic,
Diuretic and recovery phases. The initial azotemic stage can either be oliguric or
non-oliguric type.
 Oliguria is common in the early stages.
 Non-oliguric AKI is usually a result of less severe renal insult.
 Morbidity and mortality are affected by the presence of oliguria:
 GI bleeding, septicemia, metabolic acidosis and neurologic abnormalities are
common in oliguric patients than non-oliguric patients.
 The mortality rate for oliguric patients is 50% where as that of non-oliguric
patients is only 26%.
 Recovery of renal function typically occurs after 7-21 days, although recovery is
delayed by continuing sepsis.
 In the recovery phase GFR may remain low while urine output increases
sometimes to many liters a day owing to defective tubular reabsorption of
filtrates.
 Clinical course is variable and ATN may last for up to 6 weeks even after a
relatively short lived initial insult.
 Eventually renal function usually returns to almost normal or normal (except in
renal cortical necrosis).

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 No treatment is currently available to reduce the duration of ATN once it has
occurred.
 The used of IV mannitol, furosemide or ‘renal-dose’ dopamine (1-5mcg/kg/min)
is not supported by controlled trial evidence and none of these treatments is
without risk.
 Note: in the polyuric (aka diuretic) phase of kidney injury as the kidney heals
from AKI, tubules regenerate but water concentration is last function to return.
There may also be increased osmotic load from renal toxin accumulation and this
leads to massive polyuria. Treatment is with IV fluids to replace the loss.
CLINICAL FEATURES
 Clinical features:
 Oliguria with brown, granular casts.
 Elevated BUN and creatinine.
 Hyperkalemia (Due to decreased renal excretion, particularly following
trauma to muscle and in hemolytic states) with metabolic acidosis (decreased
excretion of organic acids).
 Hyponatremia (due to water overload if patients have continued to drink in
the face of oliguria or overenthusiastic fluid replacement with 5% glucose
has been carried out)
 Fluid overload:
o Pulmonary edema (due to salt and water retention, particularly after
inappropriate attempts to initiate diuresis by infusion of normal saline
without adequate monitoring of patient’s volume status)
o Orthopnea, Paroxysmal nocturnal dyspnea, peripheral edema
 Hypocalcemia (due to reduce renal production of 1,25-
dihydroxycholecalciferol)
 Hyperphosphatemia (due to phosphate retention)
 Signs: Symptoms of uremia
o Intellectual clouding, confusion, drowsiness, fits, coma,
o Uremic frost, hiccups, metallic tast
o Hemorrhagic episodes (Epistaxis and GIT bleeding)
o Metabolic flap/Asterexis
o Anorexia, Nausea and vomiting
o Fatigue
o Pruritus

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 Severe infection may have initiated the AKI or have complicated it owing to
the impaired immune defenses of the uremic patient or ill-considered
management such as the insertion and retention of an unnecessary bladder
catheter with complicating UTI and bacteremia.
 Reversible but often requires supportive dialysis since electrolyte imbalances can
be fatal.
 Oliguria can persist for 2-3 weeks before recovery, tubular cells (stable cells)
take time to reenter the cell cycle and regenerate.
 See management section for details on management.
ACUTE INTERSTITIAL NEPHRITIS
 Drug-induced hypersensitivity involving the interstitium and tubules results in
acute renal failure (intrarenal azotemia).
 Causes include NSAIDs, penicillin and diuretics.
 Presents as oliguria, fever and rash days to weeks after starting a drug,
eosinophils may be seen in urine.
 Resolves with cessation of drug.
 May progress to renal papillary necrosis.
RENAL PAPILLARY NECROSIS
 Necrosis of renal papillae.
 Presents with gross hematuria and flank pain.
 Causes include:
 Chronic analgesic abuse (e.g. long term phenacetin or aspirin use)
 Diabetes mellitus
 Sickle cell trait or disease
 Severe acute pyelonephritis
POST-RENAL UREMIA (OBSTRUCTION)
 Accounts for 5% of all acute renal failure cases.
 Uremia results from obstruction of the urinary tract at any point from the calyces
to the external urethral orifice (meatus). This results in dilation of the tract above
the obstruction. Dilation of the renal pelvis is known as hydronephrosis.
ETIOLOGY
 Causes can be

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 Within the lumen: calculus, blood clot, sloughed papilla (diabetes, analgesia
abuse, sickle cell disease or trait), schistosomiasis, tumor of renal pelvis or
ureter bladder tumor
 Within the wall: pelviuretetic neuromuscular dysfunction (congenital, 10%
bilateral), ureteric stricture (TB, especially after treatment, calculus, after
surgery), ureterovesical stricture (congenital, ureterocele, calculus,
schistosomiasis), congenital megaureter, congenital bladder neck
obstruction, neuropathic bladder, urethral stricture (calculus, gonococcal,
after instrumentation), congenital urethral valve, pin-hole meatus.
 Pressure from outside: pelviureteric compression (bands, aberrant vessels),
tumors, diverticulitis, aortic aneurysm, retroperitoneal fibrosis, accidental
ligation of ureter, retrocaval ureter (right sided obstruction), prostatic
obstruction (CA prostate, BPH), phimosis.
 Screening for urinary obstruction may present in an acute fashion (if obstruction
of a single functioning kidney e.g. a calculus) but typically is of insidious onset.
PATHOPHYSIOLOGY
 Obstruction which may be intra renal i.e. tubules including collecting ducts or
extra-renal i.e. renal calyces to uretheral meatus causes a back flow of filtrate and
resultant pressure on the glomerulus thus reducing the GFR.
 Lower urinary tract obstruction may be suggested by suprapubic or flank mass or
symptoms of bladder dysfunction (e.g. hesitancy, urgency)
 Decreased outflow results in decreased GFR, azotemia and oliguria.
 During early stage of obstruction, increased tubular pressure “forces” BUN into
the blood (Serum BUN:Cr ratio >15), tubular function remains intact (FENa <1%
and urine osm> 500mOsm/kg)
 With longstanding obstruction, tubular damage ensues, resulting in decreased
reabsorption of BUN (serum BUN:Cr ratio <15), decreased reabsorption of
sodium (FENa>2%) and inability to concentrate urine (Urine osm <350
mOsm/Kg)
MANAGEMENT
 Management of post-renal ARF requires close collaboration between
nephrologist, urologist and radiologist.
 Obstruction of urethra or bladder neck is usually managed initially by
transurethral or suprapubic placement of a bladder catheter which provides
temporary relief while the obstructing lesion is identified and treated definitively.

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 Similarly, ureteric obstruction may be treated initially by percutaneous
catheterization of the dilated renal pelvis or ureter.
DIAGNOSTIC APPROACH
 Investigations are aimed at:
 Determining whether the patient has acute or chronic uremia
 Determining the cause of uremia i.e. pre-renal, renal or post-renal
 Determining the underlying cause
ACUTE OR CHRONIC UREMIA
 This depends on:
 History and Duration of symptoms
 Examination
 Previous urinalysis or measurements of renal function
 History:
 Consider these things for all patients. Remember, Kidney injury in the
hospital is often tied into another problem (infection, heart failure,
medications).
 Decreased or no urine output, flank pain, edema, hypertension or discolored
urine? Hesitancy, Frequency?
 Weakness and easy fatigability (from anemia), anorexia, vomiting, diarrhea,
mental status changes or seizures and edema?
 Fever, cough, dysuria? Bleeding (i.e. melena, blood per rectum)?
New/changed doses in medications?
 Does the patient have medical problems that pre-dispose to CKD (i.e. HIV,
diabetes, HTN)
 Examination: vital signs (including orthostatics), Tenderness, Prostate exam
 A rapid rate of change of serum urea and creatinine with time suggests an acute
process.
 A normochromic normocytic anemia suggests chronic disease but anemia may
complicate many diseases that cause AKI owing to a combination of hemolysis,
hemorrhage and deficient erythropoietin production.
 Ultrasound assessment of renal echogenicity and size is helpful. Small kidneys
of increased echogenicity are diagnostic of a chronic process, although the
reverse is not true the kidney may remain normal in size in diabetes and
amyloidosis for instance.

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 Evidence of renal osteodystrophy (e.g. digital subperiosteal erosions due to
hyperparathyroid bone disease) is indicative of CKD
PRE-RENAL, RENAL OR POST RENAL UREMIA
 Bladder outflow obstruction is ruled out by insertion of a urethral catheter or
flushing of an existing catheter which should be removed unless a large volume
of urine is obtained.
 Absence of upper tract dilation on
renal ultrasound will with very rare
exceptions rule out urinary tract
obstruction.
 The distinction between pre-renal
and renal uremia may be difficult.

INVESTIGATIONS
 Urinalysis and microscopy
 Urinalysis
o Trace or no proteinuria with pre-renal and post-renal acute failure
o Mild to moderate proteinuria with acute tubulointerstitial necrosis.
o Moderate to severe proteinuria with glomerular diseases.
o WBCs (pyuria): UTI, Acute interstitial nephritis
o Blood (hematuria) and protein (albuminuria): Glomerulonephritis,
stones, UTI, tumor, trauma. Blood is microscopic in Acute interstitial
nephritis.
 Microscopy
o RBCs and RBC casts in glomerular disease (glomerulonephritis, Rapid
progressive glomerulonephritis)

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o Presence of a few formed elements or hyaline casts is suggestive of
prerenal or postrenal failure.
o Crystal RBCs and WBCs in post-renal failure.
o Many RBCs may suggest calculi, trauma, infection or tumor
o Eosinophilia (with Eosinophil casts): occurs in 95% of patients with
acute allergic nephritis. Neutrophils may also be seen.
o Brownish pigmented granular or tubular epithelial cellular casts and
many renal epithelia cells are seen in patients with acute tubular necrosis.
 Urine culture if there are signs of infection.
 Urine chemistry: Urine Sodium: <1% in prerenal, as the kidneys retain their
function. >2% in renal causes
 Bloods:
 Full blood count: decreased Hemoglobin (CKD), increased WBC (infection,
eosinophilia in AIN), decreased platelets (hemolytic uremic syndrome,
Thrombotic thrombocytopenic purpura)
 Serum urea, creatinine and electrolytes (Sodium, potassium, chloride,
phosphate, calcium, bicarbonate)
 Liver function test and Liver enzymes: hepatorenal syndrome
o Serum albumin
o PT, PTT, INR: DIC in sepsis, altered clotting in CKD.
 Serum Creatinine Kinase: rhabdomyolysis
 C reactive protein: infection
 Arterial blood gasses: metabolic acidosis
 Blood culture in sepsis
 Radiography/imaging
 Ultrasound of kidneys: kidney size & shape, and for detecting
hydronephrosis (dilated calyces) or hydroureter. It also helps to seen renal
calculi and renal vein thrombosis
 Retrograde pyelography: done when obstructive uropathy is suspected.
 Abdominal X-ray
 ECG: increased potassium
 Chest X-ray: pulmonary edema, systemic disease
 Abdominal CT
 Renal biopsy
 Indications
o Any suspicion of rapid progressive glomerulonephritis
o Prolonged ATN (not recovered <3 weeks)

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o No cause found for AKI.
MANAGEMENT
 General measures:
 Exclude reversible causes: obstruction should be relieved; infection should
be treated.
 Good nursing and physiotherapy
 Regular oral toilet and chest physiotherapy
 Fluid input and output chart
 Monitoring and maintenance urine output: although the prognostic
importance of oliguria is debated, management of non-oliguric patients is
easier. Loop diuretics may be useful to convert the oliguric form of ATN to
the non-oliguric form. High doses of loop diuretics such as Furosemide (up
to 200 to 400mg IV) may promote diuresis in patients who fail to respond to
conventional doses.
 Daily weighing
 The patient should be confined to bed only if essential
 Avoid drugs which may cause damage to the kidneys e.g. loop diuretics, beta
blockers, ACE inhibitors, ARBs, aminoglycosides (gentamicin,
streptomycin), amphotericin B, Penicillins, Sulphonamides, NSAIDs,
corticosteroids, and penicillamine
 Avoid intravenous cannulae, bladder catheters and other invasive devices to
avoid infection.
 Diet:
o Adequate calorie intake is essential in patients with AKI.
o Diet should be reduced in protein but contain carbohydrates
o Routes of administration, in preferred order are enteral by mouth, enteral
by NG tube and parenteral. The last of these is however only necessary
if vomiting or bowel dysfunction render the enteral route inappropriate.
o Vitamin supplementation.
 Fluid and electrolyte balance (potassium, phosphate, calcium)
 Management of complications: Pulmonary edema, anemia, sepsis, metabolic
acidosis, electrolyte imbalances and GIT bleeding

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 Dialysis: dialysis replaces renal function until regeneration and repair takes place
to restore renal function. Hemodialysis and peritoneal dialysis appears equally
effective for management of AKI. INDICATIONS OF DIALYSIS
 Absolute indications
A- acid-base imbalance
o Symptoms or signs of uremic syndrome (Acidosis)
o Refractory hypervolemia
E-electrolyte imbalance
o Severe hyperkalemia (Hyperkalemia)
o Metabolic acidosis
I- intoxication (methanol,
EMERGENCY MEASURES ethylene glycol, lithium,
salicylates)
FLUID AND ELECTROLYTE BALANCE
O-overload of volume
 Twice daily clinical assessment is needed. In general, (pulmonary edema)
once the patient is euvolemic.
U-uremia (pericarditis,
 Daily fluid intake should equal urine output plus losses encephalopathy, severe bleeding)
from fistulae and from vomiting, plus an allowance of
500ml daily for insensible loss. Febrile patients will require an additional
allowance.
 Sodium and potassium intake should be minimized.
 If abnormal loss of fluid occurs e.g. in diarrhea, additional fluid and electrolytes
will be required.
 The development of signs of salt and water overload (peripheral edema, basal
crackles, elevation of jugular venous pressure) or of hypovolemia should
prompt reappraisal of fluid intake.
 Large changes in daily weight reflecting change in fluid balance status should
also prompt a reappraisal of volume status.
 Hypervolemia can usually be managed by restriction of salt and water intake
and diuretics.

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HYPERKALEMIA
 Cardiac (cardiac dysrhythmias i.e. ventricular fibrillation) and neurologic
complications may occur if serum potassium level is >6.5mEq/L ECG findings in
 Management: hyperkalemia
 Restrict dietary potassium intake  Peaked T-waves
 Give calcium gluconate 10ml of 10% solution over 5 minutes best seen in
 Glucose solution 50ml of 50% glucose plus insulin 10 units IV precordial leads,
 Shortened QT
 Give potassium binding ion exchange resin (Kayexalate) interval
 Dialysis: if medical therapy fails or the patient is very toxic  sometimes ST
segment
PULMONARY EDEMA depression
 Salt and water restriction  Widened QRS
complex
 Diuretics (IV furosemide)
 Dialysis or hemofiltration
SEPSIS
 Infections, when detected, should be treated promptly, bearing in mind the need
to avoid nephrotoxic drugs and to use drugs with appropriate monitoring and
drug levels (e.g. gentamicin, vancomycin).
 Prophylactic antibiotics or barrier nursing is not recommended in all cases.
HYPERPHOSPHATEMIA
 Is usually controlled by restriction of dietary phosphate and by oral aluminium
hydroxide or calcium carbonate which reduce gastrointestinal absorption of
phosphate.
HYPOCALCEMIA
 Does not usually require treatment.
METABOLIC ACIDOSIS
 Is not treated unless serum bicarbonate concentration fall below 15mmol/L or
arterial pH falls below 7.2.
 More severe acidosis is corrected by oral or intravenous sodium bicarbonate.
Initial rates of replacement are guided by estimates of bicarbonate deficit and
adjusted thereafter according to serum levels.
 Patients are monitored for complications of bicarbonate administration e.g.
hypervolemia, metabolic alkalosis, hypocalcemia and hypokalemia.

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 From a practical point of view most patients requiring sodium bicarbonate need
emergency dialysis within days.
ANEMIA
 Blood transfusion if severe or if recovery is delayed
GI BLEEDING
 Regular doses of antacids appear to reduce the incidence of GIT hemorrhage
significantly and may be more effective in this regard than H2 antagonists or
proton pump inhibitors.
COMPLICATIONS OF ACUTE RENAL FAILURE
 Intravascular overload: may be recognized by weight gain, hypertension,
elevated central venous pressure (raise JVP), pulmonary edema.
 Electrolyte disturbances:
 Hyperkalaemia (serum potassium> 5.5mEq/L): develops as a result of
decreased renal excretion combined with tissue necrosis or hemolysis.
 Hyponatremia (serum sodium <135mEq/L): results from excessive water
intake in the face of excretory failure (dilution)
 Hyperphosphotemia (serum phosphate >5.5mg/dl): results from failure of
excretion or tissue necrosis
 Hypocalcemia (Serum calcium <8.5 mg/dl) results from decreased active
Vit-D, hyperphosphatemia or hypoalbuminemia (as necrosis is taking place
remember calcium is needed and is used up)
 Hypercalcemia (Serum calcium> 10.5mg/dl) may occur during the recovery
phase following rhabdomyolysis induced acute renal failure.
 Metabolic acidosis (arterial blood pH< 7.35) is associated with sepsis or severe
heart failure
 Hyperuricemia: due to decreased uric acid excretion
 Bleeding tendency: may be due to platelet dysfunction and coagulopathy
associated with sepsis.
 Seizure: may occur related to uremia
 Chronic renal failure
PROGNOSIS
 Mortality rate among patients with AKI approximates 50. It should be stressed
however, that patients usually die from sequelae of the primary illness that
induced AKI and not from AKI itself.

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 Mortality is affected by severity of the underlying disease and the clinical setting
in which acute renal failure occurs. E.g. the mortality of ATN is 60% when it
results from surgery or trauma, 30% when it occurs as a complication of medical
illnesses, and 10-15% when pregnancy is involved.
 Mortality rates are higher in older debilitated patients and in those with multiple
organ failure.
 Patients with no complicating factors who survive an episode of acute renal
failure have 90% chance of complete recovery of kidney function.

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GLOMERULAR DISEASES
 A glomerulus consists of a collection
of capillaries which come from the
afferent arteriole and are confined
within the urinary space (Bowman’s
capsule), this is continuous with the
proximal tubule.
 The capillaries are partially attached to
mesangium, a continuation of the
arteriolar wall consisting of mesangial
cells and matrix.
 The free wall of glomerular capillaries
(across which filtration takes place)
consists of basement membrane
covered by visceral epithelial cells
with individual foot processes and
lined by endothelial cells.
 The basement membrane has a normal Figure 48: Filtration membrane

thickness of 250-300nm.
 The spaces between the foot processes are known as filtration pores they are 20-
60nm in diameter. Filtered fluid passes through these pores to reach the urinary
space.
 The endothelial cells on the luminal aspect of the basement membrane are
fenestrated (diameter 70-100nm)
 The basement membrane is arranged in 3 zones and is composed of type IV
collagen and negatively charged proteoglycans (heparin sulphate).
 The glomerular filtration barrier consists of the fenestrated endothelium, the
glomerular basement membrane and the terminally differentiated visceral
epithelial cells known as podocytes.
 Podocytes dictate the size-selective nature of the filtration barrier.
 Glomerular disease include:
 Glomerulopathies: there is no evidence of inflammation
 Glomerulonephritis: inflammation of the glomeruli
 There is an overlap between glomerulopathies and glomerulonephritis.

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GLOMERULOPATHIES
 These are the third most common cause of end-stage kidney disease (after
diabetes and hypertension).
 Glomerulopathy is a general term for a group of disorders characterized by:
 Primary immunologically mediated injury to glomeruli, although renal
interstitial damage is a regular accompaniment.
 Bilateral symmetrical involvement of the kidney.
 Secondary mechanisms of glomerular injury come into play following an
initial immune insult such as fibrin deposition, platelet aggregation,
neutrophil infiltration and free radical-induced damage.
 Renal lesions may be part of a generalized disease (e.g. SLE)
PATHOGENESIS
 Glomerulopathies are considered to be an immunologically mediated disorder
with involvement of cellular immunity (T-cells, macrophages/ dendritic cells),
humoral immunity (antibodies, immune complexes and complement) and
inflammatory mediators (cytokines, chemokines and the coagulation cascade).
 The immune response can be directed against known target antigens, particularly
when glomerulopathy complicates infections, neoplasms or drugs.
 Primary glomerulopathy may occur in genetically susceptible individuals
following an environmental insult.
 Genes involved HLA-A1, B8, DR2, DR3.
 Environmental factors: drugs e.g. hydralazine, chemicals e.g. gold, silica,
hydrocarbons or infectious agents
PATHOLOGICAL TERMS IN GLOMERULAR DISEASE
 The most commonly used terms are:
 Focal: some, but not all glomeruli show the lesion.
 Diffuse (global): most of the glomeruli (>75%) contain the lesion.
 Segmental: Only a part of the glomerulus is affected (most focal lesions are
also segmental e.g. focal segmental glomerulosclerosis)
 Proliferative: an increase in cell numbers due to hyperplasia of one or more
of the resident glomerular cells with or without inflammation.
 Membrane alterations: capillary wall thickening due to deposition of immune
deposits or alterations in basement membrane.
 Crescent formation: epithelial cell proliferation with mononuclear cell
infiltration in Bowman’s space.

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CLASSIFICATION OF GLOMERULOPATHIES
 There is no correlation between histopathological types of glomerulopathies and
the clinical features of disease.
 The four major glomerular syndromes include:
 Nephrotic syndrome- massive proteinuria (>3.5g/day), hypoalbuminaemia,
edema, hyperlipidemia and lipiduria.
 Acute glomerulonephritis (acute nephritic syndrome)- abrupt onset of
glomerular hematuria (RBC casts or dysmorphic RBC), non-nephrotic range
proteinuria, edema, hypertension and transient renal impairment.
 Rapidly progressive glomerulonephritis- features of acute nephritis, focal
necrosis with or without crescents and rapidly progressive renal failure over
weeks.
 Asymptomatic hematuria, proteinuria or both

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NEPHROTIC SYNDROME
 In healthy individuals, urine protein excretion is usually <150mg/day
(0.15g/day).
 2/3 of these proteins are Tamm-Horsfall proteins (also known as uromodulin
is a glycoprotein produced excessively by the renal tubular epithelial cells of
the distal loop of Henle).
 1/3 are albumin.
 With 24 hours:
 Albumin Protein loss <30 mg is normal
 Protein loss between 30-300mg (not detectable on dipstick) is termed
microalbuminuria
 Protein loss between 300-3000mg is termed macroalbuminuria.
 Protein loss > 3.5g is termed a nephrotic syndrome.
State Protein loss in 24
hours
Normal <30 mg
Microalbuminuria 30-300mg
Macroalbuminuria 300-3000mg
Nephrotic syndrome >3.5g

 Nephrotic syndrome is a clinical complex characterized by:

 Significant proteinuria of >3.5g per 24h (most important clinical feature).
 Hypoalbuminemia-pitting edema (lower extremities, periorbital, ascites,
pleural effusion) (decreased oncotic pressure).
 Hypogammaglobinemia- increased risk of infection.
 Hyperlipidemia and lipiduria (fat casts in urine) and hypercholesterolemia
 Hypercoagulability- due to loss of anti-thrombin III.
 Proteinuria is a marker of intrinsic kidney disease, including glomerular
basement membrane leak or tubule damage.
 Recall the filtration membrane in the kidney consists of:
 Endothelial cells
 Basement membrane
 Epithelial cells with podocytes

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Figure 49: The glomerular filtration barrier

ETIOLOGY
 Can be divided into
 Primary nephrotic syndrome
 Secondary nephrotic syndrome
PRIMARY NEPHROTIC SYNDROME
 Primary glomerulopathies (idiopathic): account for 30-50% of adult nephrotic
syndrome.
 These are not a consequence of systemic disease.
 They include:
 Minimal change disease/nephropathy
 Focal segmental glomerulosclerosis
 Membranous glomerulonephritis
 Membranoproliferative glomerulonephritis

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SECONDARY NEPHROTIC SYNDROME
 Multisystem disease: accounts for 50-70% of adult nephrotic syndrome
 Causes include:
 Endocrine disorders: Diabetes mellitus (diabetic nephropathy)
 Cardiovascular diseases: Hypertension, Pre-eclampsia
 Autoimmune: Systemic lupus erythematosus, vasculitis
 Infiltrative: Amyloidosis, sarcoidosis, myeloma, light chain deposition and
fibrillary immunotactoid disease
 Collagen vascular diseases
 Infectious: infectious endocarditis, HBV, HCV, HIV, Malaria, EBV, leprosy,
syphilis
 Drugs
 Neoplasms: leukemias, lymphomas and solid tumors
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION
 Clinical features include:
 Peri-orbital edema which is mostly seen early morning, may also present with
a puffy face or generalized edema or scrotal swelling.
o Differential diagnosis for generalized edema includes: chronic liver
disease, Right ventricular heart failure, Adult malnutrition
 Production of frothy urine (protein in urine)
 Accelerated atherosclerosis
 Recurrent infections especially with pneumococcus (due loss of C3b
complement)
 Iron deficiency anemia (loss of transferrin in urine)
 DVT (hypercoagulable state- loss of antithrombin III and over production of
fibrinogen).
 Note: most patients are normotensive however patients can develop
hypertension (from fluid retention, this is much commoner in nephritic
syndrome) or hypotension (due to fluid loss from vessels, commoner in kids)

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PROTEINURIA
 The mechanism is complex. And occurs partly because of structural damage to
glomerular basement membrane leading to an increase in size and number of
pores, allowing passage of more and larger molecules.
 Fixed negatively charged components are present in the glomerular capillary wall
which repel negatively charged protein molecules. Reduction of this fixed charge
occurs in glomerular disease and appears to be a key factor in the genesis of heavy
proteinuria.
 The urine produced is froathy due to the presence of proteins.
 Hypercoagulabilty-
 Is multifactorial: some of the mechanisms are due to loss of anti-thrombin III
in the urine, increased fibrinogen production by the liver, increased platelet
aggregation.
 Spontaneous peripheral arterial or venous thrombosis, renal vein thrombosis
and pulmonary embolism may occur.
 Clinical features that suggest acute renal vein thrombosis include sudden
onset of flank or abdominal pain, gross hematuria, a left-sided varicocele (the
left testicular vein drains into the renal vein), increased proteinuria and an
acute decline in GFR.
 Chronic renal vein thrombosis is usually asymptomatic.
 Loss of transferrin in urine results in iron deficiency anemia.
 Loss of low molecular weight complement and immunoglobulin predisposes
patients to infections e.g. pneumococcal infection (especially with loss of
complement C3b).
HYPOALBUMINEMIA
 In general, the greater the proteinuria, the lower the serum albumin level.
 The normal dietary protein intake is around 70g daily and the liver can synthesize
albumin at a rate of 10-12g daily. How then does a urinary protein loss of the
order of 3.5g daily result in hypoproteinemia?
 There is increased catabolism of reabsorbed albumin in the proximal tubules
during nephrotic syndrome even though there is an actual increase in the
albumin synthesized. The loss of protein is thus more and only 3.5g is seen
in urine causing the liver to fail to match up the synthesis.

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 Edema- common sites for edema formation in early stage include: dependent
areas, face, peri-orbital areas and scrotum.
 Hypoalbuminemia (Decrease in oncotic pressure) and primary water and salt
retention by kidneys (due to activation of the RAAS as the kidneys are under-
perfused) are the postulated mechanisms for edema formation.
 Edema is initially seen around the eyes because the skin in this area is loosely
attached to the underlying tissue so it can easily accommodate fluid by easily
expanding.
 In later stage the edema tends to occur in dependent areas e.g. feet, sacrum,
abdomen. There is anasarca (generalized edema). The patient may wake up
with a puffy face that goes down as the day progresses due to redistribution
of fluid by gravity.
HYPERLIPIDEMIA
 Hyperlipidemia- is believed to be a consequence of increased hepatic lipoprotein
synthesis and decreased clearance. Hyperlipidemia may accelerate
atherosclerosis and progression of renal disease.
 There is an increase in LDL, IDL and triglycerides but no change or decrease in
HDL.
 There is an increase in the LDL/HDL cholesterol ratio.
 Lipids are also passed in urine. Urine may contain fat oval bodies (which are
proximal convoluted cells filled with fats).
COMPLICATIONS OF NEPHROTIC SYNDROME
1. Recurrent infections: loss of globulins and low molecular weight complements.
2. Thrombosis: most commonly in renal artery (may present as acute abdomen)
 Loss of anticoagulant proteins e.g. anti-thrombin III
 Hyperlipidemia-disturbs platelet membrane as well as endothelium cause
platelet activation and aggregation
 Stasis of blood: since it is concentrated as vascular compartment cannot hold
water due to low oncotic pressure caused by hypoproteinemia.
 Over production of fibrinogen by the liver
3. Iron deficiency anemia: due to loss of transferrin
4. Protein malnutrition
5. Hypocalcemia: Vitamin D deficiency due to enhanced urinary excretion of
cholecalciferol-binding protein.

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HISTOLOGIC SUBTYPES AND ETIOLOGY
MINIMAL CHANGE DISEASE/NEPHROPATHY
 Most common cause of nephrotic syndrome in children.
 Usually idiopathic or secondary to infection, may be associated with Hodgkin
lymphoma (Due to release of cytokines by Reed-Steinburg cells).
 Many implicated drugs include NSAIDs, Lithium, antibiotics
(Cephalosporins, rifampicin, ampicillin), bisphosphonates and sulfasalazine.
 Atopy is present in 30% of cases and allergic reactions can trigger nephrotic
syndrome.
 Infections e.g. HCV, HIV and TB are rarer causes.
 Normal glomeruli can be seen under light microscopy on H & E stain, lipids may
be seen in proximal tubule cells.
 Effacement (flattening) of foot processes is seen on electron microscopy.
 Recall the glomerular filtration membranes consists of the endothelial cells,
basement membrane and the foot processes of the podocytes (epithelial
cells).
 No immune complex deposits are seen (negative immunofluorescence (IF))
 Presentation:
 Selective proteinuria (loss of albumin but not immunoglobulin).
 Edema is present and in children it may be facial.
 It carries an excellent response to steroids (damage is mediated by cytokines from
T-cells) and cytotoxic drugs. It often relapses.
 High dose corticosteroid therapy with prednisolone 60mg/m2 daily (up to a
maximum of 80mg/day) for a maximum of 4-6 weeks followed by 40 mg/m2
every other day for a further 4-6 weeks
 When there is relapse on steroid withdrawal, cyclophosphamide should be
added after repeat induction with steroids. A course of cyclophosphamide
1.5-2.0 mg/kg daily is given for 8-12 weeks with concomitant prednisolone
7.5-15 mg/day.
 Steroid unresponsive patient may also respond to cyclophosphamide. No
more than two courses of cyclophosphamide should be prescribed in children
because of the risk of side-effects which include azoospermia.
 An alternative to cyclophosphamide is ciclosporin 3-5mg/kg per day.
 It is often regarded as a condition that does not lead to CKD.

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FOCAL SEGMENTAL GLOMERUOSCLEROSIS
 Most common cause of nephrotic syndrome in Hispanics and African Americans.
 All age groups are affected.
 Usually idiopathic, may be associated with HIV, heroin use and sickle cell
disease.
 It also recurs in transplanted kidneys, sometimes within days of transplantation,
particularly in patients with aggressive renal disease.
 Focal (some glomeruli) and segmental (involving only part of the glomerulus)
sclerosis (thickening-deposition of collagen) on H&E stain.
 Damage tends to occur at junction between the cortex and medulla.
 Glomerulosclerosis-deposition of collagen
 Effacement of foot process is seen on electron microscopy.
 No immune complex deposits (negative IF).
 Presentation:
 Massive proteinuria (non-selective)
 Hematuria
 Hypertension
 Renal impairment
 Treatment: steroids, cyclosporine A; cyclophosphamide.
 Poor response to steroids, progresses to chronic renal failure
MEMBRANOUS NEPHROPATHY
 Most common cause of nephrotic syndrome in Caucasian adults. Occurs more in
males.
 May present as asymptomatic proteinuria or frank nephrotic syndrome.
 Microscopic hematuria, hypertension and/or renal impairment may accompany
the nephrotic syndrome. There is a predilection to clotting (Renal vein
thrombosis)
 Usually idiopathic, may be associated with hepatitis B or C, solid tumors, SLE
or drugs e.g. NSAIDs and penicillamine
 Thick glomerular basement membrane is seen on H & E.
 Due to immune complex deposition (granular IF), sub-epithelial deposits with
‘spike and dome’ appearance on EM.
 Treatment: Observation if slow progression. Steroids alternating with either
cyclophosphamide or chlorambucil.

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 Poor response to steroids, progresses slowly to chronic renal failure. 25%
spontaneously remit.
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
 This can present with either nephritic or nephrotic syndrome or both.
 Thick glomerular basement membrane on H&E often with ‘tram-track’
appearance.
 Due to immune complex deposition (granular IF).
 Electron-microscopy shows sub-endothelial deposits
 Divided into 2 types based on location of deposits:
 Type I- subendothelial, associated with HBV and HCV. Is more often
associated with the formation of tram-tracks.
 Type II (dense deposit disease)- intramembranous associated with C3
nephritic factor (autoantibody that stabilizes C3 convertase, leading to
overactivation of complement, inflammation and low levels of circulating
C3).
 Treatment:
 Non-nephrotic: observe
 Nephrotic or worsening renal function: steroids.
 Poor response to steroids, progresses to chronic renal failure. 50% die within 5
years of renal biopsy.
DISEASE PRESENTATION CLINICAL PATHOLOGY TREATMENT
COURSE
Minimal  Selective Responds to  Normal light Steroids
change disease proteinuria steroids but often microscopy
(albumin not relapses. Rarely  Lipids may be seen
immunoglobulin) progresses to in cells of proximal
 Edema CKD convoluted tubule.
 Common in  Effacement of foot
children processes on
 May be idiopathic electron microscopy
or associated with  Negative
drugs or infection immunofluorescenc
e
Focal  Massive Poor response to  Focal segmental Steroids,
segmental proteinuria (non- steroids. glomerulosclerosis cyclosporine A;
selective)

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glomeruloscler Hematuria Progresses to end  Effacement of foot cyclophospham
osis Hypertension stage renal processes on ide
Renal impairment disease electron microscopy
Common in  Negative
African Americans immunofluorescenc
and Hispanics e
 May be idiopathic
of associated with
infection
 Affects all age
groups
Membranous  Asymptomatic 25%  Thick glomerular Observation if
nephropathy proteinuria or spontaneously basement membrane slow
frank nephrotic remit. Slow is seen on H & E. progression.
syndrome. progression to  Due to immune Steroids
 Microscopic renal failure complex deposition alternating with
hematuria (granular IF), sub- either
 Hypertension epithelial deposits cyclophospham
 Renal impairment with ‘spike and ide or
 Clotting (Renal dome’ appearance chlorambucil.
vein thrombosis) on EM.
 Common among  Granular
Caucasians Immunofluorescenc
 Can be idiopathic e
or associated with
infection
Membranoproli Can present with 50% die or  Thick glomerular Non-nephrotic:
ferative either nephritic or progress to end basement observation
glomeruloneph nephrotic syndrome stage renal membrane on H&E
ritis or both disease within 5 (‘tram-track’ Nephrotic or
years of renal appearance). worsening
biopsy  EM shows sub- renal function:
endothelial deposits steroids
 Granular
Immunofluorescenc
e

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DIABETES MELLITUS
 This is one of the common systemic causes of nephrotic syndrome
 High serum glucose leads to non-enzymatic glycosylation of the vascular
basement membrane resulting in hyaline arteriolosclerosis (microvascular
damage).
 Glomerular efferent arteriole is more affected than the afferent arteriole, leading
to high glomerular filtration pressure.
 Hyperfiltration injury leads to microalbuminuria.
 Eventually progresses to nephrotic syndrome
 Characterized by sclerosis of the mesangium with formation of Kimmelstiel-
Wilson nodules.
 Retinopathy should be present as eyes are usually affected before kidneys.
 It can definitively be diagnosed by biopsy though rarely needed.
 ACE inhibitors slow progression of hyperfiltration induced damage.
SYSTEMIC AMYLOIDOSIS
 Kidney is the most commonly involved organ in systemic amyloidosis.
 Amyloid deposits in the mesangium, resulting in nephrotic syndrome.
 Characterized by apple-green birefringence under polarize light after staining
with Congo red.

 Glomerular deposition diseases include: multiple myeloma (in adults),

amyloidosis (common because of HIV and infection)
DIAGNOSIS AND INVESTIGATIONS
CONFIRMING SIGNIFICANT PROTEINURIA
 Confirming significant proteinuria
 If protein detected on dipstick rule out benign temporary causes e.g. orthostatic,
fever, exercise. Dipstick only detects albumin >100mg/L so in patient with CKD,
ACR (Urine albumin to creatinine ratio) is used to screen for proteinuria.
 If persistent, quantify proteinuria and do bloods.
 If nephrotic syndrome is confirmed, renal biopsy may be needed to find or
confirm the cause. Not required if specific diagnosis is very likely e.g. minimal
change disease in kids.

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 If significant proteinuria but not nephrotic just arrange regular review.
 Renal biopsy (if available): to identify the underlying histopathologic
abnormality
 Minimal change disease: account for 80% nephrotic syndrome in children
<10 years
 Focal segmental glomerulosclerosis
 Membranous glomerulopathy: accounts for 60-70% of nephrotic syndrome
in adults.
 Membranoproliferative glomerulonephritis
INVESTIGATIONS
1. Urinalysis: (To quantify proteinuria)
 4+ protein in urine
 Microscopy, culture and sensitivity to exclude UTIs
 Look for cell casts
 Protein electrophoresis
2. 24-hour urine collection (proteins >3.5g/day)- rarely done and instead a spot
sample is taken ideally in the morning for ACR or PCR.
3. Urine Albumin-creatinine ratio (ACR):
 Microalbuminuria: >2.5mg/mmol (men) and >3mg/mmol (women)
 Proteinuria >30mg/mmol
 Nephrotic syndrome >250mg/mmol
 Note: ACR is more sensitive than PCR at lower protein levels (ACR<70
mg/mmol)
4. Urine protein-creatinine ratio (PCR)
 Proteinuria >45mg/mmol
 Nephrotic syndrome >300mg/mol
5. Bloods
 Serum albumin (decreased)
 Serum cholesterol (increased)
 Glucose: to rule out diabetes mellitus
 U and E to assess renal function
 LFTs: may show other causes of decreased albumin or fluid retention
 Clotting panel: for clotting abnormalities
 C-reactive protein: may be elevated in autoimmune disease.
 Immunological: complement, dsDNA, ANCA, RF
 Serum Ig and electrophoresis

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 Microbiology: Syphilis, HBV, HCV and HIV tests
6. Imaging:
 Kidney ultrasound is often useful, especially if there is abnormal kidney
function. It is needed before biopsy
 Chest X-ray- for pleural effusions
7. Renal biopsy
 Microscopy
 Immunochemical test
MANAGEMENT
 General measures:
 Control proteinuria
o Dietary protein restriction: the potential value of dietary protein
restriction for reducing proteinuria must be balanced against risk of
contributing to malnutrition
o ACE inhibitors/Angiotensin II receptors antagonists: to decrease
proteinuria by decreasing glomerular filtration pressure. (monitor blood
pressure and renal function)
o Controlling hypertension: keeping BP below 130/80 reduces proteinuria
 Treatment of complications:
o Edema: should be managed cautiously
 Moderate salt restriction: usually 1 to 2 g/day
 Loop diuretics: can be given in higher doses. It is unwise to
remove >1.0 kg of edema per day as more aggressive diuresis
may precipitate intravascular volume depletion and prerenal
azotemia.
 Start with bendroflumethiazide 5mg daily and add furosemide
40-120mg daily
 Unresponsive patients require furosemide 40-120 mg daily
with addition of amiloride (5mg daily) with serum potassium
concentration being monitored regularly.
 Nephrotic patients may malabsorb diuretics (as well as other
drugs) owing to gut mucosal edema and parenteral
administration is then required initially.
 Albumin infusion can be given to patients who are diuretic-
resistant as well as oliguric and uremic in absence of severe
glomerular damage.

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o Sepsis (e.g. Pneumococcal infection): pneumococcal vaccine should be
given. There should be early detection and aggressive treatment of
infections, rather than long-term antibiotic prophylaxis.
o Thromboembolism: anticoagulation is indicated for patients with deep
venous thrombosis, arterial thrombosis and pulmonary embolism.
Heparin may not be effective because of urinary loss of anti-thrombin III.
o Hyperlipidemia: may need lipid lowering agents (statins-HMG CoA
reductase inhibitors)
o Vitamin D deficiency- Vitamin D supplementation

 Specific treatment of underlying morphologic entity

 Minimal change disease- steroids
 Focal segmental glomerulosclerosis: steroids, cyclosporin A;
cyclophosphamide.
 Membranous nephropathy: Observation if slow progression. Steroids
alternating with either cyclophosphamide or chlorambucil.
 Membranoproliferative glomerulonephritis:
o Non-nephrotic: observe
o Nephrotic or worsening renal function: steroids

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NEPHRITIC SYNDROME
 These are a group of diseases were damage to
the glomeruli is mediated by immune complex
deposition and inflammatory processes.
 They are characterized by:
 Sub-nephrotic range proteinuria
(<3.5g/day): mild to moderate proteinuria
 Sudden onset (days to weeks) of acute
renal failure
 Oliguria (<400ml of urine per day) and
Azotemia
 Hypertension, periorbital edema and salt
retention.
 Macroscopic Hematuria (with recurrent
red blood cell cast)
 Pyuria (white blood cells in urine)
 Presence of urinary sediment.
ETIOLOGY Figure 50: Red cell casts
 Postinfectious glomerulonephritis (including
post-streptococcal)
 Subacute bacterial endocarditis
 Lupus nephritis
 Anti-glomerular basement membrane disease
 IgA nephropathy
 ANCA small vessels vasculitis (Wegener’s granulomatosis, microscopic
polyangitis, Churg-strauss Syndrome)
 Membranoproliferative glomerulonephritis
 Mesangioproliferative glomerulonephritis
DIAGNOSIS AND INVESTIGATIONS
 Definitive diagnosis is by renal biopsy
 If biopsy is not available, use clinical signs/symptoms
 Urinalysis
 Urine microscopy, culture and sensitivity
 U+Es, creatinine

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TRATMENT
 Use ACEi if there is component of proteinuria and the creatinine is stable
 Consider corticosteroids therapy or other immunosuppressive agents (although
benefit depends on histologic type)
 Specific treatments:
 Post-streptococcal glomerulonephritis and subacute bacterial endocarditis
o Supportive care
o Treat infectious etiologies
 Others
o Treat with some combination of steroids, cytotoxic agents and
plasmapheresis.

ACUTE GLOMERULONEPHRITIS (ACUTE NEPHRITIC

SYNDROME)
 This is a clinical correlate of acute glomerular inflammation.
 The hallmark of nephritic syndrome is glomerular inflammation and bleeding
from the glomeruli.
 In its most dramatic form it is characterized by:
 Sub-nephrotic range proteinuria (<3.5g/day)
 Sudden onset (days to weeks) of acute renal failure
 Oliguria (<400ml of urine per day) and Azotemia
 Hypertension, periorbital edema and salt retention.
 Macroscopic Hematuria
 Presence of urinary sediment.
ETIOLOGY
 Acute nephritic syndrome can result from renal-limited primary glomerulopathy
or from secondary glomerulopathy complicating systemic disease.
 Immune-complex glomerulonephritis may be:
 Idiopathic
 Represent a response to known antigen stimulus (e.g. post infectious
glomerulonephritis)
 Part of a multisystem immune complex disorder (e.g. lupus nephritis,
Henoch-Schonlein purpura/Allergic pupura, cryoglobulinemia, bacterial
endocarditis).

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CLINICAL FEATURES
 Subnephrotic range proteinuria (<3.5g/day)
 Periorbital edema
 Hypertension (due to impaired GFR and salt retention)
 Macroscopic Hematuria: with RBC casts and dysmorphic RBCs in urine.
 Oliguria (<400ml of urine per day)
 Azotemia
LABORATORY TESTS
 Urinalysis: as a result of injury to the glomerular capillary wall, urinalysis
typically reveals red blood cell casts, dysmorphic red blood cells, leukocytes and
subnephrotic proteinuria of <3.5g/day (nephritic urinary sediment)
 Hematuria is often macroscopic
 Renal function test: elevated serum creatinine
 Serology: immunologic assays suggesting the underlying disease.
 Renal biopsy:
 Reveals hypercellular inflamed glomeruli
 Immune-complex deposition activate complement
 C5a attracts neutrophils which mediate damage
POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
 This is the prototypical post-infectious glomerulonephritis and leading cause of
acute nephritic syndrome.
 Most cases are sporadic but can also occur as an epidemic.
 Glomerulonephritis develops on average 10 days after pharyngitis or 2 weeks
after a skin infection (impetigo) with a nephritogenic strain of group A beta-
hemolytic streptococcus (Carrying M protein virulence factor).
 Immunity to these strains is type-specific and long-lasting with repeated infection
and nephritis are rare owing to the widespread use of antibiotics.
 Epidemic poststreptococcal glomerulonephritis is most commonly encountered
in children of 2 to 6 years of age with pharyngitis during the winter months.
 Poststreptococcal glomerulonephritis in association with cutaneous infection
usually occurs in a setting of poor personal hygiene or streptococcal
superinfection of another skin disease.
 Nephritic syndrome may occur also after infection with non-strep organisms as
well.

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CLINICAL PICTURE
 Classical presentation (2-3 weeks after infection):
 Full-blown nephritic syndrome with oliguric acute renal failure
 Gross hematuria (red or ‘smoky’ urine)- cola colored urine.
 Headache and generalized symptoms such as anorexia, nausea, vomiting and
malaise.
 Swelling of the renal capsule can cause flank or back pain.
 Physical examination:
 Hypertension
 Periorbital Edema
 Hypovolemia
 Usually seen in children but may occur in adults.
LABORATORY FINDINGS
 Urinalysis: as a result of injury to the glomerular capillary wall, urinalysis
typically reveals red blood cell casts, dysmorphic red blood cells, leukocytes and
subnephrotic proteinuria of <3.5g/day (nephritic urinary sediment).
 Renal function test: the serum creatinine is often mildly elevated at presentation.
 Serology: most patients have circulating antibodies against streptococcal
exoenzymes such as ASO, and DNAase.
 Renal biopsy:
 Hypercellular inflamed glomeruli on H & E.
 Mediated by immune complex deposition (granular IF)
 Subepithelial ‘humps’ on EM
DIAGNOSIS
 Acute poststreptococcal glomerulonephritis is usually diagnosed on clinical and
serologic grounds.
 The characteristic lesion is diffuse proliferative glomerulonephritis.
MANAGEMENT
 Eliminating the streptococcal infection with antibiotics.
 Supportive therapy until spontaneous resolution of glomerular inflammation
occurs:
 Bed rest
 Salt restriction
 Diuretics to control ECF volume

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 Antihypertensive drugs to control high blood pressure
 Dialysis: some patients may need dialysis.
 Some adults develop rapidly progressive glomelomerulonephritis
 This is a nephritic syndrome that progresses to renal failure in weeks to
months.
 Renal biopsy is characterized by crescents in Bowman space (H&E)
comprised of fibrin and macrophages.
COMPLICATIONS
 Congestive heart failure
 Pulmonary edema
 Acute renal failure
 Severe hypertension with hypertensive encephalopathy
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
 This is a nephritic syndrome that progresses to renal failure in weeks to months.
 Renal biopsy is characterized by crescents in Bowman space (H&E) comprised
of fibrin and macrophages.
 Clinical picture and immunofluorescence help resolve etiology
IMMUNOFLUORESCENCE DISEASE COMMENTS
PATTERN
Linear (anti-basement Goodpasture syndrome Antibody against collagen in
membrane antibody) glomerular and alveolar basement
membrane
Presents as hematuria (Renal
involvement) and hemoptysis
(pulmonary involved) classically in
young adult male.
Granular (due to immune Post-streptococcal Diffuse proliferative
complex deposition) glomerulonephritis (most glomerulonephritis is due to diffuse
common) or diffuse antigen-antibody complex
proliferative deposition usually subendothelial,
glomerulonephritis most common type of renal disease
in SLE (lupus nephritis)
Negative IF (pauci-immune) Wegener granulomatosis, Wegner granulomatosis is
microscopic polyangiitis associated with c-ANCA- presents
and Churg-Strauss with hemoptysis (with history of
syndrome sinus pathology) and hematuria.

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Miscroscopic polyangiitis
associated with p-ANCA.
Granulomatous inflammation,
eosinophilia, and asthma distinguish
Churg-strauss from microscopic
polyangiitis

IgA NEPHROPATHY
 IgA immune complex deposition in mesangium of glomeruli.
 Most common nephropathy worldwide.
 Presents during childhood with:
 Episodic gross or microscopic hematuria with RBC casts usually following
mucosal infections.
 IgA immune complex deposition in mesangium on IF (granular)
 May slowly progress to renal failure.
ALPORT SYNDROME
 Inherited defect in type IV collagen, most commonly X-linked
 Results in thinning and splitting of glomerular basement membrane.
 Presents as isolated hematuria, sensory hearing loss and ocular disturbances.

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CHRONIC RENAL FAILURE

 This is progressive and irreversible reduction of the renal function, over a period
of more than 3 months.
 It is defined as GFR <60ml/min per 1.73 m2 for 3months or
 Urinary albumin to creatinine ratio >65mg/mmol or
 Protein creatinine ratio of 100mg/mol
 End-stage renal disease (ESRD) refers to a clinical state or condition in which
there has been an irreversible loss of endogenous renal function, of a degree
sufficient to render the patient permanently dependent upon renal replacement
therapy (dialysis or transplantation) in order to avoid life-threatening uremia.
 Recall the difference between uremia (with symptoms) and azotemia (without
symptoms)
ETIOLOGIES
 Congenital and inherited disease:
 Polycystic kidney disease (infantile and adult forms)
 Medullary cystic disease
 Tuberous sclerosis
 Oxalosis
 Cystinosis
 Congenital obstructive uropathy
 Glomerular disease
 Primary glomerulonephritides including focal glomerulosclerosis
 Secondary glomerular disease:
o SLE
o Polyangiitis
o Wegener’s granulomatosis
o Amyloidosis
o Diabetic glomerulosclerosis
o Accelerated hypertension
o Hemolytic uremic syndrome
o Thrombotic thrombocytopenic purpura
o Systemic sclerosis
o Sickle cells disease
 Vascular disease

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 Hypertensive nephrosclerosis (common cause)
 Diabetic nephropathy (common cause)
 Renovascular
 Small and medium-sized vessel vasculitis
 Tubulointerstitial disease
 Tubulointerstitial nephritis- idiopathic due to drugs (especially nephrotoxic
analgesics), immunologically mediated
 Tuberculosis
 Schistosomiasis
 Reflux nephropathy
 Nephrocalcinosis
 Multiple myeloma (myeloma kidney)
 Renal papillary necrosis (diabetes, sickle cell disease and trait, analgesic
nephropathy)
 Chinese herb nephropathy
 Urinary tract obstruction
 Calculus disease
 Prostatic disease
 Pelvic tumors
 Retroperitoneal fibrosis
 Schistosomiasis
CLASSIFICATION OF CHRONIC KIDNEY DISEASE
Stage GFR (ml/min/1.73 m2) Description
1 ≥90  No impairment
 Normal or increased GFR with other evidence of kidney
damage
2 60-89  Mild impairment
 Slight decrease in GFR with other evidence of kidney
damage
3 3A 45-59  Moderate impairment
3B 30-44  Moderate decrease in GFR with or without other
evidence of kidney damage
4 15-29  Severe impairment
 Severe decrease in GFR with or without other evidence
of kidney damage
5 <15 or on dialysis  Established kidney failure (End-stage kidney disease)

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 Note:
 Stage 1 and 2 also require the presence of kidney damage (persistent
proteinuria or unexplained hematuria, structural disease or
glomerulonephritis)
 The suffix ‘P’ can be applied on the stage of CKD if the patient has significant
proteinuria defined as urinary albumin:creatinine ratio >65mg/mol or
protein:creatinine ratio >100mg/mmol
PATHOPHYSIOLOGY
 Uremic manifestations occur mainly due to accumulation of nitrogenous wastes
and the reason for accumulation of these wastes is decreased renal excretion and
reduced catabolizing capacity of the kidney.
 Most toxins in uremia are by products of proteins and amino acid metabolism,
because unlike carbohydrates and fats which are metabolized to carbon dioxide
and water which can be excreted through the lungs and skin, byproducts of
protein are non-volatile organic acids.
CLINICAL FEATURES
SYMPTOMS
 Early stages of CKD are often completely asymptomatic.
 A rough correlation exists between urea and creatinine concentrations and
symptoms.
 Symptoms are common when the serum urea concentration exceeds 40mmol/L
but many patients develop uremic symptoms at lower levels of serum urea
including:
 Insomnia
 Symptoms due to salt and water retention- peripheral or pulmonary edema
 Symptoms due to anemia
 Loss of appetite
 Malaise, loss of energy
 Nausea, vomiting and diarrhea
 Nocturia and polyuria due to impaired concentrating ability
 Amenorrhea in women, erectile dysfunction in men
 Itching
 Paresthesia due to polyneuropathy
 ‘Restless legs’ syndrome (overwhelming need to frequently alter position of
lower limbs)

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 Bone pain due to metabolic bone disease
 In more advanced uremia CKD stage 5 these symptoms become more severe and
include:
 Mental slowing, clouding of consciousness and seizures
 Myoclonic twitching
 Severe depression of glomerular filtration can result in oliguria. This can occur
with either AKI or in terminal stages of CKD. However, even if the GFR is
profoundly depressed failure of tubular reabsorption may lead to very high urine
volumes, the urine output is therefore not a useful guide to renal function.
SIGNS
 There are few physical signs of uremia per se.
 Findings include:
 Short status (in patients who have had CKD in childhood)
 Pallor (due to anemia)
 Increased photosensitive pigmentation
(which may make the patient look
misleadingly healthy)
 Brown discoloration of nails
 Scratch marks due to uremic pruritus
 Signs of fluid overload
 Pericardial friction rub
 Flow murmurs (mitral regurgitation
due to mitral annular calcification,
aortic and pulmonary regurgitant
murmurs due to volume overload)
 Glove and stocking peripheral sensory
loss (rare)
 The kidneys are usually impalpable
unless grossly enlarged as a result of
polycystic disease, obstruction or
tumor.
 In addition to these findings, there may be
signs of any underlying disease that may
have caused the CKD.
 Cutaneous vasculitic lesions in
systemic vasculitides

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 Retinopathy in diabetes and hypertension
 Evidence of peripheral vascular disease and associated renal artery stenosis
 Evidence of spina bifida or other causes of neurogenic bladder.

COMPLICATIONS
CNS ABNORMALITIES
 Confusion, coma, fits (severe uremia)
CARDIOVASCULAR COMPLICATIONS
 Pericarditis: metabolic toxins are responsible for pericarditis
 The finding of a multicomponent friction rub strongly supports the diagnosis
 The pericardial effusion is often hemorrhagic
 Hypertension
 Is the most common complication of end stage renal disease
 It results from fluid overload
 Sometimes severe form of hypertension may occur
 Congestive heart failure and/or pulmonary edema due to:
 Volume over load
 Increased pulmonary capillary permeability
 Peripheral vascular disease
HEMATOLOGIC ABNORMALITIES
 Normocytic normochromic anemia: which may be severe (Hb 4-6g/dl) and
caused by
 Decreased synthesis of erythropoietin (the most important factor)
 Toxins suppressing bone marrow function
 Bone marrow fibrosis secondary to hyperparathyroidism
 Hematinic deficiency- iron, vitamin B12, folate
 Blood loss (mainly GI blood loss)-occult gastrointestinal bleeding, blood
sampling, blood loss during hemodialysis or because platelet dysfunction.
 Decreased life span of RBC (increased red-cell destruction)
 Abnormal red-cell membranes causing increased osmotic fragility
 ACE inhibitors (may cause anemia in CKD, probably by interfering with the
control of endogenous erythropoietin release).

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 Red-cell survival is reduced in CKD. Increased red-cell destruction may
occur during hemodialysis owing to mechanical, oxidant and thermal
damage.
 Bleeding tendency: attributed to platelet dysfunction
 Patients may manifest with bleeding and easily bruiseability.
 GI bleeding
 Intracranial hemorrhage
 Susceptibility to infection
 Change in leukocyte formation and function
 Lymphocytopenia and atrophy of lymphoid tissue

GASTROINTESTINAL ABNORMALITIES
 Decreased gastric emptying
 Increased risk for reflux esophatitis, peptic ulceration, acute pancreatitis, GI
bleeding and constipation.

FLUID, ELECTROLYTE AND ACID BASE DISTURBANCES

 Volume expansion and contractions (Edema, dehydration)
 ECF expansion is isotonic and patient is normonatremic. Hyponatremia will
be the consequence of excessive water ingestion.
 Patients with chronic renal failure also have impaired renal mechanisms for
conserving sodium and water. When an extra renal cause for fluid loss is
present (e.g. vomiting, diarrhea, sweating, fever) these patients are prone to
volume depletion and dehydration
 In the face of sodium intake patients may retain sodium and water which may
lead to congestive heart failure, peripheral edema and ascites.
 Potassium homeostasis:
 Hyperkalemia occurs when GFR falls below 10ml/min
 Endogenous factors (e.g. hemolysis, trauma, infection) or exogenous factors
(administration of stored blood, potassium containing medications,
potassium containing dietary salt substitute) contribute to hyperkalemia.
 Acidosis: facilitate efflux of potassium from ICF to ECF
 Drugs: potassium sparing diuretic, ACE inhibitors.
 Metabolic acidosis: common in the advancing stages. Total urinary net daily acid
excretion is usually markedly reduced.

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RENAL OSTEODYSTROPHY AND METABOLIC BONE

DISEASE
 This is due to disturbance in bone phosphate and calcium metabolism.
 Hyperphosphatemia is a feature of advanced renal failure. The serum phosphate
concentration rises in patients with a GFR< 20ml/min.
 Total serum calcium in chronic renal
failure is often significantly lower than
normal. These patients tolerate
hypocalcemia quite well, rarely is a patient
symptomatic from the decreased calcium
concentration. Note that the low serum
calcium is attributed to secondary
hyperparathyroidism.
 Reduced synthesis of vitamin D during
chronic renal disease plays a role in the
pathogenesis of hyperparathyroidisim
(active vitamin D metabolite is normally
produced in the proximal tubule), both
directly and through hypocalcemia.
 Bone abnormalities:
 Renal rickets (osteomalacia)
 Osteosclerosis: enhanced bone density
in the upper and lower margins of
vertebrae.
 Osteitis fibrosa cystica: due to
osteoclastic bone resorption (due to
hypocalcemia and PTH) of especially
terminal phalanges, long bones and
distal end of clavicle.

MALIGNANCY
 The incidence of malignancy is raised in patients with CKD and with dialysis.
Malignant change can occur in multicystic kidney disease. Lymphomas, primary
liver cancer and thyroid cancers can occur.

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ENDOCRINE
 Hypogonadism is common
 In men: decreased plasma testosterone level (erectile dysfuction), impotence
and oligospermia
 In women: Olifomenorrhea/amenorrhea, inability to carry pregnancy to term,
hyperprolactinemia (galactorrhea in females as well as males), increased LH
levels
 In children: impaired growth hormone secretion
 Abnormal thyroid hormone levels, partly because of altered protein binding.
Measurement of TSH is the best way to assess thyroid function. True
hypothyroidism occurs with increased frequency in CKD.
 Posterior pituitary gland function is normal in CKD.
METABOLIC ABNORMALITIES
 Gout: due to urate retention. Treatment is complicated by nephrotoxic potential
of NSAIDs. Colchicine is useful for the acute attack and allopurinol should be
introduced under colchicine cover to prevent further attacks. The dose of
allopurinol should be reduced in CKD e.g. 100mg on alternate days.
 Insulin: insulin is catabolized by and to some extent excreted via the kidneys. For
this reason, insulin requirements in diabetic patients decreases as CKD
progresses. By contrast end-organ resistance to insulin is a feature of advanced
CKD resulting in modestly impaired glucose tolerance. Insulin resistance may
contribute to hypertension and lipid abnormalities.
 Lipid metabolism abnormalities: correction of lipid abnormalities by e.g. HMG-
CoA reductase inhibitor therapy (statins) is used in patients with CKD although
without formal proof of survival benefit.
 Impaired clearance of triglyceride-rich particles
 Hypercholesterolemia (particularly in advanced CKD)
DERMATOLOGIC ABNORMALITIES
 Pallor due to anemia
 Echymosis, hematoma
 Pruritus and excoriations (due to retention of nitrogenous waste products of
protein catabolism or hypercalcemia, hyperphophatemia, and secondary
hyperparathyroidism which leads to calcium deposits)
 Yellowish discoloration of skin: urochronmes

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 Uremic frost: is seen in advance uremia, it is due to high concentration of urea in
the sweat and after evaporat9on of the sweat, a fine white powder can be found
on the skin surface.
 Nephrogenic systemic fibrosis: due to Gadolinium-containing contrast agents
which are excreted exclusively by the kidney.
DIAGNOSTIC APPROACH
 History:
 Duration of symptoms
 Drug ingestion, including NSAIDs, analgesics and other medications and
unorthodox treatment such as herbal remedies.
 Past medical and surgical history:
o previous chemotherapy, multisystem disease such as SLE, malaria
o Hypertension
o Diabetes mellitus
o Systemic infectious or inflammatory diseases
o Metabolic diseases
 Previous occasions on which urinalysis or measurement of urea and
creatinine might have been performed e.g. pre-employment or insurance
medical examinations, new patient checks.
 Family history of renal disease.
 Examination
 Blood pressure
 Fundoscopy
 Precordial examination
 Examination of the abdomen for bruits and palpable renal masses
 Extremity examination for edema
 Neurologic examination for the presence of asterixis, muscle weakness and
neuropathy.
 In addition, the evaluation of prostate size in men and potential pelvic masses
in women should be undertaken by appropriate physical examination
 Differentiate acute from chronic renal failure
 Reduced kidney size on ultrasound
 Longstanding nocturia and pruritus
 Finding of broad tubular casts on urine analysis
 Anemia (not always)
 Renal osteodystrophy

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 Identify aggravating factors (acute or chronic)
 Hypovolemia or hypotension
 Hypertension
 Congestive heart failure
 Sepsis
 Nephrotoxins
 Evaluation of reversible underlying etiology
 Malignant hypertension
 Obstructive uropathy
 Systemic lupus erythematosis
INVESTIGATIONS
 Diagnostic investigations
 Urinalysis:
o Hematuria: may indicate glomerulonephritis, but other sources must be
excluded. Hematuria should not be assumed to be due to presence of an
indwelling catheter.
o Proteinuria: if heavy, is strongly suggestive of glomerular disease.
Urinary infection may also cause proteinuria.
o Glycosuria with normal blood glucose is common in CKD
 Urine culture: including early-morning urine samples for TB
 Urine microscopy:
o White cells: indicate active bacterial urinary infection but this is an
uncommon cause of CKD, sterile pyuria suggests papillary necrosis or
renal TB
o Eosinophilia: allergic tubulointerstitial nephritis or cholesterol
embolization
o Casts: granular casts are formed from abnormal cells within the tubular
lumen and indicate active renal disease. Red cell casts are highly
suggestive of glomerulonephritis
o Red cells in the urine may be from anywhere between the glomerulus and
the urethral meatus.
 Urine biochemistry
o Urinary electrolytes measurement not helpful in CKD.
o Urine osmolality: this is a measure of concentrating ability. A low urine
osmolality is normal in the presence of a high fluid intake but indicates

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renal disease when the kidney should be concentrating urine such as in
hypovolemia or hypotension.
 Blood:
o Urea and creatinine (serial measurements help in determining the
severity and chronicity)
o Calculation of eGFR
o Full blood count: Eosinophilia suggests vasculitis, allergic
tubulointerstitial nephritis or cholesterol embolism.
o Fragmented red cells and/or thrombocytopenia suggest intravascular
hemolysis due to accelerated hypertension, hemolytic uremic syndrome
or thrombotic thrombocytopenic purpura.
o ESR: markedly raised viscosity or ESR suggests myeloma or vasculitis.
o Test for:
 Sickle cell disease,
 Hepatitis B (polyarteritis and membranous nephropathy) and C
(cryoglobulinemic renal disease)
 HIV (HIV-associated renal disease)
 Antibodies to streptococcal antigens (ASOT): post-streptococcal
glomerulonephritis
 Antibody screening for SLE, scleroderma, wegener’s granulomatosis
and microscopic polyangitis and Goodpastre’s syndrome
 Imaging: Ultrasound of kidney
o Verifies the presence of 2 symmetric kidneys, provides an estimate of
kidney size and rules out renal masses and obstructive uropathy.
o Symmetric small kidneys support the diagnosis of progressive chronic
renal failure with an irreversible component of scarring. The occurrence
of normal kidney size suggests the possibility of an acute rather than
chronic process. However, in some diseases, chronic renal failure may be
present with normal sized or even enlarged e.g. amyloidosis, polycystic
kidney diseases, diabetic nephropathy.
 CT and MRI may also be useful in diagnosis.
 Renal biopsy: should be performed in every person with unexplained CKD
and normal-sized kidneys, unless there are strong contraindications. If
rapidly progressive glomerulonepheitis is possible this investigation must be
performed within 24 hours of presentation if at all possible

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MANAGEMENT OF CHRONIC RENAL FAILURE
1. Treat reversible causes
 Hypotension or dehydration
 Administration of nephrotoxic drugs
 Urinary tract obstruction
 Severe hypertension (Goal BP <120/80mmHg)
 Infection
2. Prevent or slow the progression of renal disease (Renoprotection)
 ACE inhibitors or angiotensin II receptor blockers slow the progression of
chronic renal failure
o Patients with CKD and proteinuria >1g/24 h
 ACE inhibitor increasing to maximum dose
 Add angiotensin receptor antagonist if goals are not achieved (in type
2 diabetes start with angiotensin receptor antagonist)
 Add diuretic to prevent hyperkalemia and help to control BP
 Add calcium channel (verapamil or diltiazem) if goals not achieved
 Blood pressure control: decreases progression of chronic renal failure
 Target BP:
o With proteinuria= 125/75mmHg
o Without proteinuria= 130/85mmHg
 Additional measures:
o Statins to lower cholesterol to <4.5mmol/L
o Stop smoking (three-fold higher rate of deterioration in CKD)
o Treat diabetes (HBA1c <7%, 53mmol/mol)
o Normal protein diet (0.8-1g/kg bodyweight): The possible efficacy of
dietary protein restriction, in slowing progression of renal diseases, is less
clear.
o Avoid the following drugs:
 Tetracycline (with the possible exception of doxycycline): due to anti-
anabolic effect and tendency to worsen uremia
 Drugs excreted by kidneys e.g. gentamicin (should only be prescribed
when there is no alternative)
 NSAIDs
 Potassium sparing agents e.g. spironolactone and amiloride
 Bardoxolone an antioxidant inflammatory modulator has shown a
reduction in GFR in diabetic CKD.

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3. Treatment of complications of renal dysfunction
 Hyperkalemia:
o Potassium restriction in diet. Stop drugs that cause potassium
o Protect the heart: 10mls 10% Calcium Gluconate over 10 mins. Effect is
temporary but can be repeated after 15 minutes.
o Push Potassium into cells
 50mls 50% Dextrose with 10IU soluble insulin over 15-20 mins. May
be given 2-4 hourly as required. Monitor serum glucose and
potassium 2-4 hourly
 10-20mg Nebulized Salbutamol (or 0.5mg in 100ml of 5% glucose
over 15 min-rarely used)
o Push Potassium out of the body
 Furosemide 1mg/kg IV (hydrate patient first if dehydrated)
 Kayexalate (polystyrene sulphonate)/sodium Resonium 15-30g in 50-
100ml 20% Sorbitol or with lactulose PO/PR
 Consider hemodialysis if refractory
 Hypertension:
o Salt restriction
o Diuretics: loop diuretic are recommended for the treatment of
hypertension and edema in patients with chronic renal failure. Thiazide
diuretics have additive effect when administered with a loop diuretic for
refractory edema
o Antihypertensive drug
 Volume overload- dietary sodium restriction, diuretic therapy (usually with
a loop diuretic given daily)
 Metabolic acidosis: maintain plasma bicarbonate concentration above
22mEq/L. Give sodium bicarbonate (daily dose of 0.5 to 1 mEq/kg per day)
 Hyperphosphatemia: dietary phosphate restriction may limit secondary
hyperparathyroidism in patients with chronic renal failure. An intake of
above 800mg/day may be desirable but can be accomplished only by limiting
protein intake.
 Anemia: blood transfusion (selected patients), recombinant erythropoietin
may be given. Target hemoglobin 11-12 g/dl. Failure to respond may be due
to iron deficiency (due to hepcidin from the liver produced in response to IL-
6), bleeding, malignancy, infection, inflammation or formation of anti-EPO
neutralizing antibodies. Intravenous (rather than oral) iron supplements
optimize response to EPO treatment by repletion of iron stores.

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 Malnutrition:
o Low protein diet, restrict intake to 0.8 to 1g/kg or high biologic value
protein (plant source)
o Since this level of restriction avoids protein malnutrition and may slow
progressive disease. Overall, the diet of most patients with chronic renal
failure should provide approximately 30 to 35kcal/kg per day.
 Male Erectile dysfunction: testosterone deficiency should be corrected. The
oral phosphodiesterase inhibitors e.g. sildenafil, tadalafill and verdenafil are
effective in ESKD and are first line therapy. The use of nitrates is
contraindicated to this treatment.
4. Identification and adequate preparation of the patient in whom renal
replacement therapy will be required
 Educate patient
 Informed choice of renal replacement therapy:
o Chronic hemodialysis
o Kidney transplantation

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URINARY TRACT INFECTIONS

 UTI is an acute infection of the urinary tract. It is
 Bacteriuria: bacteria in urine.
subdivided into 2 general anatomic categories:
May or may not be
 Lower urinary tract infection: urethritis and
symptomatic
cystitis
 Significant bacteriuria: more
 Upper urinary tract infection: acute
than 105 colony forming
pyelonephritis, prostatitis, and intrarenal and
units/ml in midstream urine
perinephric abscess
 UTI: Significant bacteriuria +
 A UTI can be defined when pathogenic
symptoms
microorganisms are detected in urine, urethra,
bladder, kidney or prostate.  Complicated UTI: UTI +
presence of certain risk factor
 In most instances, growth of more than 105 organisms
(renal or urinary tract
per ml from a properly collected midstream “clean-
abnormality, voiding
catch” urine sample indicates infection.
difficulty, decreased kidney
 In symptomatic patients, a smaller number of
function, indwelling catheter,
bacterial 102 to 104/ml may signify infection.
immunosuppression, or
 In urine specimens obtained by suprapubic aspiration
virulent organism e.g. S.
or “in and out” catheterization and in samples from a
aureus)
patient with an indwelling catheter, colony counts of
 Recurrent UTI: reinfection
102 to 104/ml generally indicate infection.
(new organism) or relapse by
 Infections that recur after antibiotic therapy can be
same organism (usually within
due to:
2 weeks). It has no strict
 Persistence of the originally infecting strain (as
definition but 2-3 per year is a
judged by species, antibiogram, serotype and
common one.
molecular type) that become evident within 2
 Abacterial cystitis: symptoms
weeks of cessation of therapy (Relapse).
without bacteria. Sometimes
 Reinfection with a new strain that become
occurs in women.
evident after 2 weeks of cessation of therapy.
 Acute pyelonephritis refers to chronic interstitial
nephritis believed to result from bacterial infection of the kidney. It is manifested
by calyceal dilation and cortical scarring.

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ACUTE URINARY TRACT INFECTION
 The vast majority of acute symptomatic infections involve young women. Acute
symptomatic UTIs are unusual in men under the age of 50.
 The development of asymptomatic bacteriuria is also rare among men under 50
but common among women between 20-50.
 Asymptomatic bacteriuria is more common among elderly men and women with
rates as high as 40 to 50%.
 Epidemiologically can be divided into:
 Community-acquire infections (Non-catheter associated)
 Nosocomial infections (Catheter-associated)
ETIOLOGY
 Routes of inoculation include:
 Urethral inoculation: Ascent of bacteria from the bladder may follow and is
probably the pathway for most renal parenchymal infections. Whether
bladder infection ensues depends on interacting effects of the pathogenicity
of the strain, the inoculum size, and the local and systemic host defence
mechanisms.
 Hematogenous spread: pyelonephritis occurs most often in debilitated patient
who are either chronically ill or receiving immunosuppressive therapy.
Metastatic staphylococcal or candida infections of the kidney may follow
bacteremia or fungemia spreading from distant foci of infection in the bone,
skin, vasculature or elsewhere.
 Pathogens:
 E. coli (90%)
 Staph. saprophyticus: occurs in sexually active women
 Proteus mirabilis: suggest kidney stones
 Enterococcus faecalis: causes prostatitis
 Klebsiella: usually in catheterized patients
 Staph. aureus: from hematogenous spread
 STIs: Chlamydia and gonorrhea

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Community acquired Hospital acquired/ catheter associated
 Commonest:  E. coli (30%)
 E coli (80%)  Enterococci (15%)
 S. saprophyticus (10%)  Pseudomonas (10%)
 Klebsiella pneumoniae (5%)  S. aureus, yeasts and other
 Other (5%) Enterobacteriacea
 In acute urethral syndrome (STI: N.
gonorrhea, Chlamydia trachomatis,
Trichomonas, Candida and Herpes
simplex virus may cause lower UTI)

RISK FACTORS
 Gender and sexual activity:
 Females are prone to colonization with colonic gram-negative bacilli because
of the urethra’s proximity to the anus, its short length (about 4cm) and its
termination beneath the labia.
 Sexual intercourse causes the introduction of bacteria into the bladder and is
temporally associated with onset of cystitis, especially in younger women.
 In men <50 years old and who have no history of heterosexual or homosexual
rectal intercourse UTI is exceedingly uncommon and this diagnosis should
be questioned in the absence of clear documentation.
 Lack circumcision has been identified as a risk factor for UTI in both
neonates and young men.
 Pregnancy: due to altered urethral smooth muscle function. Bladder
catheterization during or after delivery causes additional infections.
 Vesicoureteral reflux:
 This is defined as reflux of urine from the bladder cavity up into the ureters
and sometimes into the renal pelvis.
 It occurs during voiding or with elevation of pressure in the bladder.
 It is common among children with anatomic abnormalities of the urinary tract
as well as among children with anatomically normal but infected urinary tract
(though this disappears with advancing age)
 Vesicoureteral reflux may promote ascending infection in several ways
including increased delivery of bacteria, increased size of inoculum,
incomplete bladder emptying.

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 Obstruction: tumors, strictures, stones or prostatic hypertrophy result in
hydronephrosis. Urinary stasis and impaired host defense greatly increase
frequency of UTI.
 Neurogenic bladder dysfunction: spinal cord injury, tabes dorsalis, multiple
sclerosis, diabetes, and other diseases.
 Diabetes mellitus: neurogenic bladder disturbance and also do to other immune
disorder in diabetes.
 Immunodeficiency: a CD4 count less than 200/L are at increased risk of both
bacteriuria and symptomatic UTI
 Bacterial virulence factors: not all strains of E. coli are equally capable of
infecting the intact urinary tract. Bacterial virulence factors markedly influence
the likelihood that a give strain once introduced will cause UTI.
 Genetic factors
CLINICAL PRESENTATION
URETHRITIS
 In 30% of women presents with acute dysuria, frequency and pyuria. They have
mid-stream urine cultures that show either no growth or insignificant bacterial
growth.
 Chlamydial or gonococcal infection should be suspected in women with a gradual
onset or illness, no hematuria, no suprapubic pain and more than 7 days of
symptoms. The additional history of a recent sex-partner change, especially if the
patient’s partner has recently had chlamydial or gonococcal urethritis should
heighten the suspicions of STI as should the finding of mucopurulent cervicitis.
 Gross hematuria, suprapubic pain, an abrupt onset of illness, a duration of illness
of <3 days and a history of UTIs favor the diagnosis of E. coli UTI.
CYSTITIS
 Patients with cystitis usually report dysuria, frequency, urgency and suprapubic
pain.
 The urine often becomes grossly cloudy and malodorous and it is bloody in about
30% of cases.
 If a genital lesion or a vaginal discharge is evident, then pathogens that may cause
urethritis, vaginitis, or cervicitis such as C. trachomatis, N gonorrhoeae,
Trichomonas, Candida and herpes simplex virus should be considered.

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ACUTE PYELONEPHRITIS
 Symptoms of acute pyelonephritis generally develop rapidly over a few hours or
a day and include fever, shaking chills, nausea, vomiting and diarrhea.
 Symptoms of cystitis may or may not be present.
 Physical examination:
 Fever
 Tachycardia
 Generalized muscle tenderness
 Marked tenderness on deep pressure in one or both costovertebral angles or
on deep abdominal palpation (Costvertebral/Renal angle tenderness)
 In some patients signs and symptoms of gram-negative sepsis predominate.
CATHETER ASSOCIATED UTI
 Affects at least 10-15% of catheterized hospital patients.
 The risk of infection is about 3 to 5% per day of catheterization.
 Most catheter associated infections cause minimal symptoms and no fever and
often resolve after withdrawal of the catheter.
 Gram-negative bacteremia which follows catheter-associated bacteriuria in 1 to
2% of cases, is the most significant recognized complication of catheter-induced
UTIs.
 Gram-negative bacteremia which follows catheter-associated bacteriuria in 1-2%
of cases is the most significant recognized complications of catheter induced
UTIs.

INVESTIGATIONS
 Urinalysis
 Urinary sediments
 Nitrites or leukocyte esterase positive
 Leukocytes are found in urine: >5WBCs/high power field in centrifuged
urine or >10WBCs/high power field in unspun urine suggests UTI
 Microscopic bacteruria: single micro-organism per oil immersion of unspun
urine is indicative of a colony growth on culture of more than 10 5
colonies/ml.
 Gram stain of uretheral discharge may be helpful in patients suspected of
having infection that need treatment

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 Microscopy, Culture and sensitivity of Urine
 Definitive means of diagnosis
 A clean catch, early morning mid-stream urine specimen should be collected
 The growth of more than 105 colonies/ml in the presence of symptoms
signifies infection that needs treatment
 If <105 CFU/ml but pyuria (>20 WBC/mm3) it is known as ‘sterile pyuria’.
Causes include: previously treated UTI, prostatitis, STI, TB, appendicitis,
bladder tumor, stones, polycystic kidney disease or drug-induced cystitis.
 If many different organisms, suspect contaminated sample (i.e. not mid-
stream) and repeat midstream urine
 Blood
 FBC: increased WBC
 U+ Es, CRP and blood cultures for pyelonephritis
 Blood glucose to rule out diabetes.
 Radiologic urologic evaluation: to identify some predisposing conditions e.g.
urolithiasis, BPH, vesicoureteral reflux.
 Kidney ultrasound (Obstruction/hydronephrosis)
 Post-void bladder ultrasound
 KUB X-ray (kidney ureter bladder X-ray)
 Intravenous nephrogram
TREATMENT
 Principles:
 Except in acute uncomplicated cystitis in women, a quantitative urine culture,
rapid diagnostic test should be performed to confirm infection before
treatment is begun.
 Factors predisposing to infection e.g. obstruction and calculi should be
identified and corrected if possible
 Relieve of clinical symptoms does not always indicate bacteriologic cure.
 In general, uncomplicated infections confined to the lower urinary tract
respond to short course of therapy while upper tract infections require longer
treatment.
 Admission criteria (in acute pyelonephritis):
 Inability to maintain oral hydration or take medications
 Concerns about patient compliance
 Uncertainty about the diagnosis
 Severe illness with high fevers, pain and marked debility

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 Paracetamol +/- NSAIDs for symptom relief.
 Remove catheter if present
 Empiric antibiotic choices:
 Fluoroquinolones and aminoglycosides achieve higher tissue levels. So these
drugs are preferred for empiric treatment.
 Ampicillin and sulfonamides should NOT be used for empiric therapy
because of high rates of resistance among causative uropathogens.
 All pregnant women should be screened for bacteriuria in the first trimester
and should be treated if bacteriuria is demonstrated.
 Acute uncomplicated Lower UTI in women:
o Nitrofurantoin (if eGFR>45)
o Trimethoprim-Sulfamethoxazole (TMP-SMX): 480mg 2 tabs PO BD for
3-5 days
o Norfloxacin 400mg PO BD or Ciprofloxacin 500mg PO BD for 5-7 days
 Acute uncomplicated pyelonephritis in women: E.coli, P. mirabilis, S.
saprophyticus
o Norfloxacin 400mg PO BD or Ciprofloxacin 500mg PO BD for 7-14
days or
o Single dose of ceftriaxone 1g or Gentamicin 80mg IV followed by TMP-
SMX: 480mg 2 tabs PO BD for 14 days.
 Complicated UTI in men and women: E. coli, proteus, Klebsiella,
Pseudomonas, Serratia, enterococci, Staphylococci are common etiologies.
o Mild to moderate illness, no nausea or vomiting treat as outpatient
o Norfloxacin 400mg PO BD or Ciprofloxacin 500mg PO BD for 7-14
days
 Severe illness or possible urosepsis: hospitalization is required
o Ceftriaxone 1g IV BD or
o Gentamicin 80mg IV TDS
o Ampicillin 1g IV QID and then 500mg IV QID
o IV quinolones such as Ciprofloxacin 200-400mg IV BD can also be used
if available.
o If enterococcus is suspected based upon the Gram stain, Ampicilin (1 to
2g IV 6 hourly) plus gentamicin (1mg/kg 8 hourly or adjusted for renal
function)
 Note: IV medication should be changed to PO as soon as the patient becomes
afebrile and then given PO TMP-SMX or Ciprofloxacin or Norfloxacin for
10-21 days

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 Parenteral therapy- for hospitalized patients, aminoglycosides (3 to 5mg/kg)
OD are cost effective, associated with low toxicity when used for short
durations and may provide a therapeutic advantage compared with beta
lactams, because of their marked and sustained concentration in renal tissue.
COMPLICATIONS AND PROGNOSIS
 Infectious spread:
 Pyelonephritis
 Perinephric or intrarenal abscess
 Prostatitis
 Sepsis
 Kidney
 AKI
 Hydronephrosis
 Recurrence: 1 in 3 women, usually reinfection (new pathogen)
 Prognosis: symptoms resolve in 3-4 days with an effective antibiotic vs 5-7 days
without treatment (or with a resistant organism)

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ENDOCRINE CONDITIONS

THYROID

HYPERTHYROIDISM

HYPOTHYROIDISM

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ADRENAL GLAND

ADRENAL GLAND  Resulting from Inadequate

production:
 The adrenal gland/Supra-renal
o Addison’s disease:
gland consists of 2 part:
inadequate production of
 Adrenal cortex: which consists
cortisol and aldosterone
of 3 histological layers. All the
hormones produced in this  Disease of the adrenal medulla
layer are derived from  Pheochromocytoma: Excess
cholesterol. production of catecholamine
o Zona Glomerulosa- CUSHING SYNDROME
produces  This is a clinical syndrome
mineralocorticoids such as characterized by excessive
aldosterone concentration of cortisol or other
o Zone Fasciculata- glucocorticoid hormones in the
produces glucocorticoids circulation.
e.g. cortisol  There is a large spectrum of
o Zona reticularis- produces clinical manifestation from
androgens subclinical to overt syndrome
 Adrenal medulla consisting of depending on the duration and the
chromaffin cells (which are intensity of excess steroid
derived from the embryonic exposure.
ectordermal neural crest) and  It occurs most often following the
produce catecholamines e.g. therapeutic administration of
epinephrine and synthetic steroids or ACTH.
norepinephrine
 Spontaneous Cushing’s syndrome
 Common diseases of the adrenal is rare.
cortex
 Resulting from excess ETIOLOGY
production of hormones:  Causes of Cushing’s syndrome are
o Cushing’s syndrome: usually subdivided into:
excess cortisol production  Iatrogenic Cushing’s
o Primary syndrome/ Exogenous
hyperaldosteronism: corticosteroids
excess production of
aldosterone

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o This is the most common benign and malignant
cause but is seldom tumors combined.
reported. o Both adrenal are enlarged.
o Seen in patients receiving  Adrenal tumors, hyperplasia
long term glucocorticoid or carcinoma
treatment for asthma, o Adrenal masses are
arthritis and other discovered incidentally at
conditions. autopsy or by radiographic
o Both adrenal glands studies in 1.3 to 8.7 % of
become atrophic adults, more than 99% of
(decreased production of whom do not present with
ACTH from suppression symptomatic adrenal
by exogenous cortisol) disease.
 Ectopic ACTH syndrome o The affected adrenal gland
(Paraneoplastic ACTH is larger while the normal
secretion) is atrophic, this is due to
o This is the second most suppression of ACTH
common cause of production from excess
Cushing’s syndrome, but production from the
is often not diagnosed. affected adrenal.
o About 1% of patients with
Causes of Cushing’s syndrome
small-cell lung cancer
ACTH dependent Non-ACTH
have ectopic ACTH Cushing’s dependent Cushing’s
syndrome.  Pituitary-  Adrenal
o Small-cell lung carcinoma dependent adenomas and
causes half of all cases of (Cushing’s carcinomas
the syndrome. disease)  Glucocorticoid
o Both adrenals are  Ectopic ACTH- administration
enlarged. producing tumors  Alcohol induced
 Cushing’s disease  ACTH pseudo-Cushing’s
o Cushing’s disease is administration syndrome
pituitary ACTH-dependent
Cushing’s syndrome.
CLINICAL FEATURES
o It is five to six times more
common than Cushing’s  The clinical features of Cushing’s
syndrome caused by syndrome are those of
glucocorticoid excess

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 Progressive obesity: central  Poor wound healing (impaired
obesity with wasting of immune function) and growth
extremities (muscle is broken retardation.
down for gluconeogenesis).  Psychiatric disturbance:
 Pigmentation occurs only with especially depression, are
ACTH-dependent causes, frequently seen.
Purple striae with skin atrophy
and easy bruising.
PROGRESSIVE OBESITY
 Cushignoid appearance- Moon  The most common feature of
face, buffalo hump (cervical patients with Cushing’s syndrome
fat pad) and supraclavicular fat is progressive central/truncal
pads. obesity, usually involving the face
 Impaired glucose tolerance or (moon faces), neck, trunk and
frank diabetes is common, abdomen.
especially in the ectopic  The “moon face”, “buffalo
ACTH syndrome. hump” (cervical fat pad) and
 Hypokalaemia due to the supraclavicular fat pads
mineralocorticoid activity of contribute to the cushingiod
cortisol is common with appearance (excess insulin
ectopic ACTH secretion. produced because of high
 Hypertension: common in all glucose levels, excess insulin
causes of Cushing’s (Results resulting in storage of fat).
from the vascular effects of  The extremities are usually spared
cortisol by upper regulation of and may be wasted.
alpha 1 receptors on arterioles DERMATOLOGICAL
and sodium retention)
FEATURES
 Oligomenorrhea, hirsutism and
 Skin atrophy: the skin usually
acne: due to androgen excess
atrophies, the stratum corneum is
due to stimulation by ACTH.
thinned and there is loss of
 Decreased glucose tolerance:
subcutaneous fat to a sufficient
results from hepatic
degree that subcutaneous blood
gluconeogenesis and decreased
vessels may be seen.
peripheral glucose utilization.
 Easy bruisability: Loss of
 Osteoporosis: due to
subcutaneous connective tissue
catabolism of bone.
due to the catabolic effects of
glucocorticoid results in easy

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bruising after minimal, often excess glucocorticoid on skeletal
unremembered injury. muscle.
 Striae: purple striae occur as the  Many patients cannot rise from a
fragile skin stretches due to the squatting position without
enlarging trunk, breasts and assistance and patients with more
abdomen. The striae appear as severe disease may be unable to
wide, reddish-purple streaks and climb stairs or get up from a deep
are most common on the abdomen chair.
and lower flanks.  The catabolic effects of cortisol are
 Cortisol impairs synthesis of amplified by physical inactivity.
collagen so blood vessels are  Hypokalemia, due to increased
weak and easily rupture mineralocorticoid activity, can
forming striae (ruptured blood accentuate the weakness in
vessel) patients with severe
 Fungal infections: cutaneous hypercortisolism.
fungal infections, especially tinea
versicolor while some patients BONE LOSS
have fungal infections of the nails.  Osteoporosis is common in
 Hyperpigmentation: this is induced patients with Cushing’ syndrome.
by increased ACTH, not cortisol  It is caused by decreased intestinal
secretion. ACTH has a similar calcium absorption, decreased
structure to melanocyte- bone formation, increased bone
stimulating hormone. resorption, and decreased renal
 Hirsutism. calcium reabsorption.
 It can be demonstrated by
MENSTRUAL densitometry of the lumbar
IRREGULARITIES vertebrae even in young patients.
 Menstrual irregularities are  Pathologic fractures may occur,
common in women and they range often resulting in severe skeletal
from oligomenorrhea, amenorrhea pain.
to excess or variable menses.
NEUROPYSCHOLOGICAL
PROXIMAL MUSCLE WASTING CHANGES AND COGNITION
AND WEAKNESS  Symptoms of psychiatric disease
 Weakness and proximal muscle occur in over one-half of patients
wasting are common and are with Cushing’s syndrome of any
induced by the catabolic effects of etiology.

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 The most common psychologic  The mechanism by which
symptoms are: glucocorticoid excess predisposes
 Emotional lability to infection is poorly understood.
 Agitated depression  One mechanisms may be a fall in
 Irritability circulating CD4 cells and decline
 Anxiety in natural killer-cell activity.
 Panic attacks  Another mechanism is cortisol
 Mild paranoia inhibits phospholipase A2 essential
to produce chemical mediators of
INFECTION AND IMMUNE
inflammation.
FUNCTION
 Perhaps the major effect is that
 Glucocorticoids inhibit immune glucocorticoids inhibit the
function, thereby contributing to synthesis of almost all cytokines.
an increased frequency of
infections.

Figure 51: Signs and symptoms of Cushing's syndrome

350
 cortisol levels (although levels
may fall substantially in a few
cases). This test is highly
sensitive (>97%). The
overnight dexamethasone test
is slightly simpler but has a
higher false-positive rate.
 24-hour urinary free cortisol
measurements: this is simple
but non-reliable- repeatedly
normal values render the
diagnosis most unlikely but
some people with Cushing’s
syndrome have normal values
on some collections
(approximately 10%)
 Circadian rhythm: After 48
hours in hospital, cortisol
samples are taken at 09:00
hours and 24:00 hours
(without warning the patient).
Normal subjects show a
pronounced circadian variation
DIAGNOSIS those with Cushing’s
 There are 2 phases: syndrome have high midnight
 Confirmation cortisol levels (>100 nmol/L)
 Differential diagnosis of the though the 09:00 hours value
cause may be normal. Midnight
salivary cortisol collected at
CONFIRMATION home gives the same
 Investigations include: information more simply
 48-hour low-dose where the assay is available.
dexamethasone test: normal
individuals suppress plasma
cortisol to less than 50 nmol/L.
In Cushing’s syndrome there is
inability to suppress plasma

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DIFFERENTIAL DIAGNOSIS  CRH test: an exaggerated
OF THE CAUSE ACTH or cortisol response to
 This can be extremely difficult exogenous CRH suggest
since all cause can result in clinical pituitary dependent disease
identical Cushing’s syndrome. (Cushing’s disease).
 High-dose dexamethasone test:
 The classical ectopic ACTH
syndrome is distinguished by a Failure of significant plasma
cortisol suppression suggests
short history, pigmentation and
weight loss and diabetes and an ectopic ACTH or adrenal
plasma ACTH above 200ng/L. tumor.
 Severe hirsutism/virilization TREATMENT
suggest an adrenal tumor.  Untreated Cushing’s syndrome has
 Radiological tests: a bad prognosis with death from
 Adrenal CT or MRI: adrenal hypertension, myocardial
adenomas and carcinomas infarction, infection and heart
causing Cushing’s syndrome failure.
are large and can be detectable  Whatever the underlying cause
by CT scan. cortisol secretion should be
 Pituitary MRI: a pituitary controlled prior surgery or
adenoma may be seen but is radiotherapy.
usually small and not visible in  Treatment of Cushing’s disease
most cases.  Transphenoidal removal of the
 CXR: to look for a carcinoma tumor (treatment of choice)
of the bronchus.  External pituitary radiation
 Biochemical tests:  Medical therapy to reduced
 Potassium levels: hypokalemia ACTH using Bromocriptine
is common with ectopic  Bilateral adrenalectomy
ACTH secretion. (all diuretics  Treatment of other causes
must be stopped)  Adrenal adenoma- resection
 Plasma ACTH level: Low or  Tumors secreting ACTH
undetectable levels of ACTH ectopically should be removed
(<10 ng/L) on 2 or more surgically, otherwise
occasions is a reliable chemotherapy/ radiotherapy
indicator of a non-ACTH should be used.
dependent disease.  Nelson’s syndrome: this is
increased pigmentation (because of

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high levels of ACTH) associated EXAMINATION
with an enlarging pituitary tumor,  Moon-like facies, acne, hirsutism
which occurs in about 20% of and plethora (From telangiectasia)
cases after bilateral adrenalectomy  Examine the following:
for Cushing’s disease. The  The mouth for superimposed
syndrome is rare now that thrush.
adrenalectomy is an uncommon  The interscapular area for
primary treatment and its ‘buffalo hump’.
incidence may be reduced by  Increased fat pads and bulge
pituitary radiotherapy soon after above supraclavicular fossae
adrenalectomy. (more specific for Cushing
 In chronic alcoholics and patients syndrome).
with depression, there may be  The abdomen for thinning of
increased urinary excretion of skin and purple striae (also
steroids, absent diurnal variation of seen over the shoulders and
plasma steroids and a positive thighs): said to be present on
overnight dexamethasone test. almost all patients.
This is pseudo-cushing  The limbs for bruising,
syndrome. wasting of the limbs, weakness
SALIENT FEATURES OF of the muscles of the shoulders
and hips: get the patient to
CUSHING SYNDROME
squat (proximal myopathy).
HISTORY  Ask the patient whether he or she
 Ask for has back pain and then examine
 History of steroid therapy the spine, looking for evidence of
 Central weight gain osteoporosis and collapse of
 Hirsutism vertebra, kyphoscoliosis.
 Easy bruising  Measure the blood pressure.
 Acne  Tell the examiner you would like
 Weakness of muscle to:
 Menstrual disturbances  Test the urine for glucose
 Loss of libido  Check visual fields (for
 Depression, sleep disturbances pituitary tumor)
 Back pain as a result of spinal  Examine the fundus for optic
osteoporosis atrophy, papilloedema, signs

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of hypertensive or diabetic
retinopathy.
 Comment on signs of asthma,
rheumatoid arthritis, SLE,
fibrosing alveolitis (as these are
conditions that are treated with
long-term steroids).
 Note: Hirsutism is not common in
Cushing syndrome cause by
exogenous steroids because they
suppress adrenal androgen
secretion.

HYPERALDOSTERONISM
 Recall the distal convoluted tube has two types of cells that respond differently
to aldosterone.
 The principle cell: increase the re-absorption of sodium and secretion of
potassium
 The alpha-intercalated cells: increase the excretion of hydrogen ions.
 Presentation:
 Hypernatremia
 Hypokalemia (Due to excretion of potassium)
 Metabolic alkalosis (Due to excretion of hydrogen ion)
 Hypertension (re-absorption of sodium and water)

PRIMARY HYPERALDOSTERONISM
 Most commonly due to adrenal adenoma
 Sporadic hyperplasia and carcinoma are less common causes.
 Characterized by high aldosterone and low renin (increased blood volume)

SECONDARY HYPERALDOSTERONISM
 Activation of renin-angiotensin system (e.g. renovascular hypertension in
fibromuscular dysplasia of renal artery or atherosclerosis of the renal artery)

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 Characterized by high aldosterone and high renin

ADDISONS DISEASE (ADRENAL INSUFFICIENCY)

 In Addison’s disease there is destruction of the entire adrenal cortex leading to
hypofunctioning of the adrenal cortex.
 Endocrine disorder is also known as Adrenal insufficiency.
 Glucocorticoid, mineralocorticoid and sex steroid production are all reduced.
 Addison’s disease occurs when 90% of the adrenal cortex is destroyed.
HORMONE FUNCTION
MINERALOCORTICOIDS  Electrolyte and fluid balance
(Zona Glomerulosa)  Increases sodium and water
retention
 Regulated by renin and angiotensin
GLUCOCORTICOIDS  Carbohydrate, lipid & fat
(Zona fasciculata) metabolism
 Increases blood glucose levels &
gluconeogenesis.
 Increases protein breakdown
 Inhibits protein synthesis
SEX STEROIDS  Low synthesis in adrenals compared
(Zona reticularis) to gonads
 Virilising hormones may be
secreted

 Adrenal insufficiency can be divided into 2 types:

o Acute adrenal insufficiency
o Chronic adrenal insufficiency
ACUTE ADRENAL INSUFFICIENCY
 Waterhouse-Friderichsen syndrome
 Infection with Neisseria meningitidis (classically seen especially in
children) other infections include Pseudomonas, pneumococci, H. influenza
 The pathogenesis is unclear but believed to be endotoxin induced vascular
injury (massive hemorrhage) with associated disseminated intravascular
coagulation (DIC), this results in bilateral necrosis of the adrenal glands.

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 Sudden withdrawal of long term corticosteroid treatment
 xInability of atrophic adrenals to produce glucocorticoids
 Stress with underlying chronic adrenal insufficiency
 Acute adrenal crises on limited physiological reserves
CHRONIC ADRENAL INSUFFICIENCY
 Is divided into
 Primary adrenal insufficiency: Addison’s disease
 Secondary adrenal insufficiency: progressive destruction of adrenals
o Tuberculosis: caseous necrosis of adrenal cortex
o Autoimmune adrenalitis: associated with pernicious anemia, thyroiditis,
IDDM
o AIDS
o Metastatic disease: especially lung carcinomas
o Systemic amyloidosis
o Fungal infection
o Hemochromatosis
o Sarcoidosis
CLINICAL FEATURES
 Insidious onset
 Progressive weakness and fatigability
 Non-specific complaints (anorexia, nausea/vomiting, weight loss)
 Primary adrenal disease: hyperpigmentation (due to increased ACTH).
 Hyperkalemia and hyponatremia.
 Hypotension (volume depletion-hypovolemia) and dehydration
 Hypoglycemia
 Sexual dysfunction
 Adrenal crisis:
 Infections: trauma, surgery-> intractable vomiting, abdominal pain,
hypotension, vascular collapse, death.
 In Addison’s deficiency the heart is small.

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INVESTIGATIONS
SINGLE CORTISOL MEASUREMENTS
 Of little value although a random cortisol below 100nmol/L is highly suggestive
and levels above 550nmol/L makes the diagnosis unlikely.
SHORT ACTH STIMULAION TEST (SHORT SYNACTHEN TEST)
 Absent or impaired response is seen.
ELECTROLYTES AND UREA
 Classically show hyponatraemia, hyperkalemia and high urea.
BLOOD GLUCOSE
 Blood glucose may be low with symptomatic hypoglycemia

 Adrenal antibodies may be present in many cases of autoimmune adrenalitis.

TREATMENT
 Hormone replacement.
 Address the cause (secondary adrenal insufficiency).
 For primary adrenal insufficiency (Addisons disease)- long term treatment with
replacement glucocorticoid and mineralocorticoid is required.
SALIENT FEATURES
HISTORY
 Ask for:
 Dizziness, syncope
 Skin pigmentation (ask if the patient has been sitting in the sun)
 Ask questions regarding fatigue, weakness, apathy, anorexia, nausea,
vomiting, weight loss and abdominal pain
 Depression
EXAMINATION
 The striking abnormality is hyperpigmentation
 Examine for hyperpigmentation, typically localized to palmar creases and
knuckles:
 Hand: compare the creases with your own
 Mouth and lips for pigmentation

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 Areas not usually covered by clothing: nipples, areas irritated by belts,
straps, collars or rings.
 Look for vitiligo
 Tell the examiner that you would like to investigate as follows:
o BP, in particular for postural hypotension
o Looking for sparse axillary and pubic hair
o The abdomen for adrenal scar (if the scar is pigmented, think of Nelson
syndrome and examine field defects)
 If you suspect Addison’s disease, tell the examiner that you would like do a
short ACTH stimulation test.
PHEOCHROMOCYTOMA
 Tumor of chromaffin cells of adrenal medulla.
 Presents with Episodic hypertension, headaches, palpitations, tachycardia and
sweating
 Diagnosed by increased metanephrines and increased 24-hour urine
metanephrines and vanillin mandelic acid (VMA).
 Treatment is surgical excision.
 Before surgery give the patient phenoxynenzamine (irreversible blocker of
alpha receptor) to prevent hypertension from surge of epinephrine and
norepinephrine
 Rules of 10s
 10% bilateral
 10% familial
 10% malignant (90% benign)
 10% located outside of adrenal medulla (e.g. bladder wall)

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PANCREAS AND DIABETES MELLITUS

 Diabetes is a metabolic disorder of carbohydrate metabolism characterized by
persistent hyperglycemia due to either insulin deficiency or resistance.
 Blood glucose levels are closely regulated in health and rarely stray outside
the range of 3.5-8.0 mmol/L (63-144mg/dl) despite the varying demands of
food, fasting and exercise.
 Normal Fasting blood sugar= 3.5-5.5 mmol/l (63-100mg/dl)
 Normal Random Blood sugar= 4.4-7.8 mmol/l (70-144mg/dl)
o Note: a random blood sugar between 7.8-11.1 mmol/l is considered pre-
diabetic.
 Diabetes is a syndrome of chronic hyperglycemia due to absolute insulin
deficiency (Type 1), relative insulin deficiency (Type 2), resistance or both.
 For diagnosis of diabetes mellitus To change mg/dl to mmol/l
 Fasting blood sugar ≥7 mmol/l (126 mg/dl) divide by the factor 18
 RBS ≥ 11.1 mmol/L (200mg/dl)
 2-hour postprandial plasma glucose ≥ 11.1 mmol/L (200mg/dl) after a
glucose load of 75g (during oral glucose tolerance test)
 HBA1c >6.5% (48mmol/mol)
 Diabetes is usually irreversible and although patients can lead a reasonable
lifestyle, its late complications result in reduced life expectancy and major health
costs.
 These include macrovascular disease leading to an increased prevalence of
coronary artery disease, peripheral vascular disease, stroke and microvascular
damage causing diabetic retinopathy and nephropathy. Neuropathy is another
major complication.
 Recall:
 Insulin is coded for on chromosome 11 and is synthesized in the beta cells of
the pancreatic islets.
 The synthesis, intracellular processing and secretion of insulin by the beta
cells is typical of the way that the body produces and manipulates many
peptide hormones.
 Synthesis: Preproinsulin is modified into proinsulin which has its C peptide
chain cleaved to become insulin (A and B chains) which is packed into
granules along with free peptides.

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 Mechanism of secretion: glucose from the GI tract activates GLUT2

receptors of beta cells this increases ATP in the cells which closes the ATP-
gated potassium channel to prevent efflux of potassium leading to
depolarization, increased calcium entry and insulin granule exocytosis.
 After secretion, insulin enters the portal circulation and is carried to the liver,
its prime target organ. About 50% of secreted insulin is extracted and
degraded in the liver, the residue is broken down by the kidneys.
 C-peptide is only partially extracted by the liver hence provides a useful
index of the rate of insulin secretion however, it is degraded by the kidneys.
 Cell membranes are not inherently permeable to glucose. A family of
specialized glucose transporter (GLUT) proteins carry glucose through the
membrane into cells
 GLUT-1: enable basal non-insulin stimulated glucose uptake into
many cells.
 GLUT-2: transports glucose into beta cells, a prerequisite for glucose
sensing. Also found in renal tubules and hepatocytes. Works in both
directions.
 GLUT-3: enables non-insulin mediated glucose uptake into brain
neurons and placenta
 GLUT-4: enables much of the peripheral action of insulin. It is the
channel through which glucose is take into muscle and adipose tissue
cells following stimulation of the insulin receptor.
 Some cells such as neurons, placenta cells and cells of the cornea do not
require insulin for the uptake of glucose.
 Insulin receptor has 4 subunits (two alpha on the periphery and two beta
transmembrane).

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 Recall also that insulin works on predominantly the liver, skeletal muscle and
adipose tissue.
 Inhibits gluconeogenesis
 Increases the uptake and utilization of glucose by muscles
 Inhibits lipolysis and by doing so prevents ketogenesis

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 Enhances uptake of amino acids into muscles for protein synthesis and
inhibition of proteolysis

 Diabetes is classified as:

 Primary (idiopathic) diabetes
o Type 1 DM: has an immune pathogenesis and is characterized by
severe/absolute insulin deficiency.
o Type 2 DM: results from a combination of insulin resistance and a
relative insulin deficiency.
 Secondary diabetes
o Diseases of the exocrine pancreas: Pancreatitis, trauma/pancreatectomy,
neoplasia, cystic fibrosis, hemochromatosis.
o Endocrinopathies: acromegaly, Cushing’s syndrome,
Phaechromocytoma, Somatostatinoma, Aldosteronoma
o Drugs: Nicotinic acid (niacin), beta blockers, thyroid hormone,
diazoxide, beta-adrenergic agonists, thiazides, phenytoin, protease
inhibitors, immunosuppressive (glucocorticoids, ciclosporin,
Tacrolimus), Antipsychotic (clozapine, olanzapine)
o Infectious: congenital rubella, Cytomegalovirus
o Genetic disorders: Down’s syndrome, Huntington’s chorea, Myotonic
dystrophy, Turner’s syndrome

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 Other specific types include: maturity onset diabetes of the young (MODY),
type A insulin resistance, Drug induced diabetes mellitus e.g. with beta
blocker, oral contraceptive, glucocorticoids etc.
 Gestation diabetes mellitus (GDM): occurs when diabetes onsets during
pregnancy and resolves with delivery. These patients are at higher risk of
developing DM at a later date.
TYPE 1 DIABETES MELLITUS
 This was formerly known as insulin-dependent DM. It accounts for 10% of the
cases.
 It usually occurs in childhood or early adulthood (age less than 30).
 This is due to beta-cell destruction, with absolute deficiency of insulin, which is
of multifactorial causes such as:
 Genetic predisposition
 Viral infection: injury is due to molecular mimicry between trigger antigen
(virus) and beta cell antigen e.g. coxsackie virus antigen and that of glutamic
acid decarboxylase (GAD) found within the beta-cell have a similar chemical
structure, so that the antibodies produced to fight the foreign antigen of the
virus also cross react with antigens of self-tissue bearing GAD hence
destroying it.
 Autoimmune attacks (type IV hypersensitivity)
 It may be immune mediated or idiopathic.
 They require insulin for survival and develop ketoacidosis when patients are not
on adequate insulin therapy. Oral hypoglycemic agents will not be effective to
lower the blood glucose level.
PATHOGENESIS
 The disease is progressive going through phases of antibody production, then
phase of impaired glucose tolerance followed by an abnormal fasting blood sugar
and finally culminating in an abnormal fasting blood sugar with ketonemia.
HONEYMOON PERIOD
 In young people who are diagnosed for the first time to have overt DM, the DM
may have been precipitated by acute metabolic stressful condition (such as
infection or pregnancy).

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 In such circumstances, the increased metabolic demand for insulin, may lead to
a relative insulin deficiency and patients become symptomatic and may need
exogenous insulin to control their symptoms.
 With they return to baseline metabolic demands, when the stressful event abates,
the pancreatic reserve may be adequate to maintain normal or near-normal blood
glucose. Such patients may undergo a period of transient “cure” during which
time they may not require exogenous insulin to control their blood glucose level.
Because of this, such patients are said to be in a “HONEYMOON” period.
 This unfortunately is transient and the patients will be needing insulin again when
the progressive destruction of beta-cells leads to absolute insulin deficiency.
CLINICAL FEATURES
 It usually occurs in childhood or early adulthood (age less than 30).
 Patients are usually thin.
 Onset tends to be more sudden.
 Signs and symptoms include:
 Polyuria (due to osmotic diuresis induced by hyperglycemia)
 Polydypsia (increased feeling of thirst and drinking excess water/fluid due to
increased blood osmolality)
 Polyphagia (feeling hunger, a need to eat several times a day)
 Calorie loss, generalized weakness and weight loss
 Visual blurring from lens swelling due to increased osmolality
 Oral and genital thrush
 Muscle cramps
 Lethargy
 Lipoatrophy from insulin use
 They require insulin for survival and develop ketoacidosis when patients are not
on adequate insulin therapy.
 This accounts for 10% of cases of DM.
 Oral hypoglycemic agents will not be effect to lower the blood glucose level.
 Mainstay treatment is insulin.

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TYPE 2 DIABETES MELLITUS
 This was formerly known as non-insulin dependent diabetes mellitus.
 It usually occurs in people older than 40 years of age.
 Most (about 60%) of the patients are obese.
 Type 2 DM occurs with intact beta islet cell function but there is peripheral tissue
resistance to insulin.
 There may be some decrease in insulin production or a hyperinsulin state.
 These patients are not prone to develop ketoacidosis but may develop it under
conditions of stress.
 Patients do not require insulin for survival at least in the earlier phase of diagnosis
but may need it later on as the disease progresses.
 The blood sugar level can be corrected by oral hypoglycemic agents.
PATHOGENESIS
 In type 2 DM insulin resistance plays a central role in the pathogenesis.
 In obesity, increased production of non-esterified fatty acids, leads to resistant of
peripheral organs to insulin which leads to increased gluconeogenesis in the liver
and decreased peripheral uptake and utilization of glucose by muscles.
 Initially there is hypersecretion of insulin by the beta cells to overcome the insulin
resistance but later on the beta cells fail to respond to the level resistance. The
beta cell number is then decreased and amyloid is deposited in islets.
 Genetic association has been seen in the developments of type 2 DM:
 Concordance among identical twins is up to 100%.
 Concordance among fraternal twins is 20%
 Familial aggregation history is common and up to 50% of siblings and 33%
of children of diabetics develop diabetes
 Environment factors:
 Obesity
 Physical inactivity
 Diet
 Natural history includes:
 Stage 1: insulin resistance: increased glucose and non-esterified fatty acids
 Stage 2: increased insulin secretion: compensatory hyperinsulinemia
 Stage 3: impaired glucose tolerance
 Stage 4: overt type 2 diabetes

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CLINICAL FEATURES
 Clinical features:
 Insidious and subtle onset
 Polydipsia and polyuria
 Polyphagia
 Visual blurring from lens swelling due to increased osmolality
 Oral and genital thrush
 Muscle cramps
 Lethargy. This may be the only symptom initially
 Neuro: peripheral neuropathy (found in 50% of type 2 at diagnosis), postural
hypotension due to autonomic dysregulation, Romberg’s positive (loss of
balance when eyes are closed while standing with feet together due to loss of
proprioception) from dorsal column disease
 Eyes: xanthelasma, retinopathy, ophthalmoplegia from mononeuritis
multiplex
 Legs: ulcers, necrobiosis lipoidica
 Lipoatrophy from insulin use
 Some patients may be asymptomatic mainly type 2 patients and GDM.
 Diagnosis is made incidentally during routine medical checkup. ANC follow up
etc. therefore it is advisable to screen patient for DM if the following risk factors
are present:
 Obesity (BMI>25kg/m2)
 First degree relative with DM
 History of Gestational DM (GDM) or delivered a baby weighing more than
4kg
 Hypertensive
 Hyperlipidemia
 History of impaired fasting glucose or impaired glucose tolerance on prior
testing
DIAGNOSIS
 Symptoms of diabetes plus one of the following:
 Fasting plasma glucose > 7 mmol/L (126mg/dl)
 Random blood glucose concentration ≥11.1 mmol/L (200mg/dl)
 2-hour postprandial plasma glucose >11.1 mmol/L (200mg/dl) after a
glucose load of 75g in 300ml water (during oral glucose tolerance test)
 HBA1c >6.5% (48mmol/mol)

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 Note: these criteria should be confirmed by repeat tests on a different day.
 Keep in mind:
 Random is defined as without regard to time since the last meal.
 Fasting is defined as no caloric intake for the last 8 hours.
 Oral glucose tolerance test: blood glucose is measured after ingestion of 75g
anhydrous of glucose dissolved in water.
 The patient is said to have impaired glucose tolerance (IGT) if the fasting
plasma glucose is between 7-11mmol/L.
 During an oral glucose tolerance test, the patient is asked to fast the night
before (for at least 8 hours). The next morning the blood glucose is monitored
and glucose is administered as the blood glucose level is checked and
recorded after 30 minutes and after 2 hours.
INVESTIGATIONS
 Diagnostic
 Plasma glucose: Random blood sugar and Fasting blood sugar
 Oral glucose tolerance test
 Supportive:
 Urinalysis: for proteins, glucose and ketones (recall ketones can also be
seen during starvation, dehydration and not just DKA)
 Full blood count: to rule out infections and anemia
 Urea and electrolytes: to check renal function
 Liver biochemistry: to check liver function
 Lipid profile (Triglycerides, cholesterol, HDL, LDL): diabetes is associated
with dyslipidemia and arteriosclerosis
 Hemoglobin A1C (HbA1c) this is a measure of an individual’s prevailing
blood glucose concentration over several weeks (3 months). An HBA1c
>6.5% (48mmol/mol) would be considered diagnostic of diabetes, whereas
a level of 5.7-6.4% (39-46mmol/mol) would denote increased risk of
diabetes.

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SOMOGYI PHENOMENON/ REBOUND EFFECT
 A low blood glucose in the late evening causes a rebound effect in the body
leading to hyperglycemia in the early morning.
 This occur when the evening dose of insulin is too high, causing hypoglycemia
in the early morning hours, resulting in the release of counter-regulatory
hormones (epinephrine and glucagon) to counteract this insulin-induced
hypoglycemia.
 The patient then has high blood glucose and ketones in the morning.
 The treatment is to actually lower the bedtime insulin dose and not to raise it.
DAWN PHENOMENON
 It is similar to the somogyi effect in that people experience hyperglycemia in the
morning (3am to 8am) but for reasons that differ.
 It results from a rise in early morning blood sugar levels which are triggered by
declining levels of insulin and an increase in growth hormone.
 Testing blood sugar levels at 3am and again in the morning can help distinguish
between the somogyi and dawn phenomenon.
 Blood sugar that is low at 3am indicates somogyi effect while high or normal
blood sugar at that time suggests the dawn phenomenon.
MANAGEMENT
 Goal:
 Acceptable RBS <11.1mmol/L (200mg/dl)
 Ideal RBS <8.9mmol/L (160mg/dl)

 Acceptable FBS < 7.2 mmol/L (130mg/dl)

 Ideal FBS <5.6mmol/L (100mg/dl)
 Management includes:
 Non-pharmacological therapy
 Pharmacological therapy
NON-PHARMACOLOGICAL THERAPY
 Diet therapy
 Stop alcohol
 The diet should be low in sugar (though not sugar free), high in starchy
carbohydrates (especially foods with a low glycemic index i.e. slower
absorption), high in fiber and low in fat (especially saturated fat).

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 Diet should include 60-65% carbohydrates, 25- 35% fat and 10-20% protein
 Decrease cholesterol intake
 Avoid simple sugars e.g. sugar, soft drinks, honey and other sweets
 High fiber diet such as vegetables slow the absorption of digested food in the
form of simple sugars
 Fresh fruit e.g. watermelon and lemon can be taken freely as opposed to
oranges and bananas that must be taken with caution.
 Dividing meal into 4 to 6 equal parts may help in achieving stability in some
cases
 Exercise:
 Regular 20-30 minutes, aerobic exercise such as jogging, walking, swimming
etc. 3-4 days is recommended.
 Note patients on insulin treatment should be cautious to avoid hypoglycemia.
(counsel on signs of hypoglycemia and advise patients to move around with
sweets)
 Weight:
 Maintain BMI of 20 and 25.
 Educate patient on diabetes, treatment plan, alcohol intake, smoking, exercise,
proper foot care, complications of diabetes, insulin injection technique, self-
glucose monitoring and signs & symptoms of hypoglycemia + first aid
management.
PHARMACOLOGICAL THERAPY
 Treat infections if any.
INSULIN
 Insulins derived from beef (bovine) or pig (porcine) pancreas have been replaced
in most countries by biosynthetic human insulin (through genetic engineering).
 The duration of action of short-acting, unmodified insulin (‘soluble’ or ‘regular’
insulin) which is a clear solution, can be extended by addition of protamine and
zinc at neutral pH (isophane or NPH insulin) or excess zinc ions (lente insulins).
These modified ‘depot’ insulins are cloudy preparations.
 Types include: rapid acting, short-acting, intermediate-acting, long-acting and
very long-acting.
o Rapid acting (insulin analogues: lispro, aspart, glulisine): onset= less than
30 mins, peak= 30 mins-2hrs 30 mins, duration= 3hrs-4hrs 30 mins.

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 These enter the circulation more rapidly than human soluble insulin
and also disappear more rapidly.
o Short acting (neutral, soluble, regular): onset is 30min to 1 hour, peak is
1-4 hours and duration is 4-8 hours
 Short acting insulins are used for pre-meal injection in multiple dose
regimens, for continuous intravenous infusion in labor or during
medical emergencies e.g. diabetic ketoacidosis and in patients using
insulin pumps. It can be administered IV, IM or SC
 Human insulin is absorbed slowly, reaching a peak of 60-90 minutes
after subcutaneous injection and its action tends to persist after meals
predisposing to hypoglycemia.
o Intermediate acting: used for ambulatory long term control of sugar level.
Given not more than twice a day. Route of administration is limited to SC.
 Isophane (peak 6-8h and duration 16-24h)
 Biphasic (peak 4-6h and duration 12-20h)
 Semilente (peak 5-7h and duration 12-18h)
o Long acting (lente, ultralente and PZI): onset:1-2 hours, peak 6-12h & 12-
30hrs duration.
 These have their structure modified to delay absorption or to prolong
their duration of action.
 Inhaled insulin was withdrawn from the market in 2007 on grounds of limited
clinical demand, although lung cancer was also observed.
 Insulin pumps are now being used to achieve better glucose control and to
improve lifestyles
 Type 1 DM patients must be started on insulin at the time of diagnosis.
 Daily insulin requirements 0.3-0.5 unit/kg/day (25 units/day).
 Current regimen uses soluble insulin and lente. A multiple injection regimen
with short-acting and longer acting insulin at night is appropriate for most
younger patients.
 2 subcutaneous injections are given before breakfast and at dinner.
 2/3 of total insulin requirement is given in the morning (alternatively 70% can
be used)
 2/3 of this being lente
 1/3 of this being soluble insulin
 1/3 of total insulin requirement is given at dinner (alternatively 30% can be
used)
 2/3 of this being lente and 1/3 of this being soluble insulin or

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 50% lente and 50% soluble insulin
 Example if daily requirements is 30IU/day
 Morning= 2/3 x 30IU= 20IU (2/3 is lente-13IU and 1/3 is soluble
insulin-7U)
 Evening= 1/3 x 30IU= 10IU (2/3 is lente-6IU and 1/3 is soluble insulin
4IU)
 Monitoring
 Daily blood glucose: before all meals and at bedtime. Ask patient to record
reading.
 Glycosylated hemoglobin level reflecting diabetic control for the past 2-3
months, should be check every 3 months.
 Watch for hypoglycemia: all patients should have parenteral glucagon
available in case of seizure or coma secondary to low blood sugar.
 Watch for “honeymoon” period.

 Adjust dose to keep blood sugar levels between 6-8 mmol/L. Changes to insulin
should be done by 0.5IU
 Principles of insulin treatment:
 Injections:
o The needles used are very fine and sharp Even though most injections are
virtually painless, patients are understandably apprehensive and treatment
begins with a lesson in injection technique.
o Insulin is usually administered by a pen injection device but can be drawn
up from a vial into special plastic insulin syringes marked in units (100U
in 1ml).
o Injections are given into the fat below the skin on the abdomen, thighs or
upper arm and the needle is usually inserted to its full length.
o Slim adults and children usually use a 31 gauge 6mm needle and fatter
adults a 30gauge 8 mm needle.

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o Both reusable and disposable pen devices are available together with a
range of devices to aid injection.
o The injection site used should be changed regularly to prevent areas of
lipohypertrophy (fatty lumps)
o The rate of insulin absorption depends on local subcutaneous blood flow
and is accelerated by exercise, local massage or a warm environment.
o Absorption is more rapid from the abdomen than from the arm and slowest
from the thigh. All these factors can influence the shape of the insulin
profile.
 Complications of insulin therapy
o At injection site:
 Shallow injections result in intradermal insulin delivery and painful,
reddened lesions or even scarring.
 Injection site abscesses occur but are extremely rare
 Local allergic responses sometimes occur early in therapy but usually
resolve spontaneously
 Generalized allergic responses are exceptionally rare
 Fatty lumps known as lipohypertrophy may occur as the result of
overuse of a single injection site with any type of insulin (atrophy or
hypertrophy)
o Insulin resistance especially with obese patients. Insulin resistance may
also be associated with antibodies directed against the insulin receptor
especially in patients reported with acanthosis nigricans (dark velvety skin
especially in skin folds e.g. armpits).
o Weight gain: Many patients show weight gain on insulin therapy,
especially if the insulin dose is increased inappropriately, but this can to
some extent be overcome by emphasis on the need for diet and exercise,
plus addition of metformin. Patients who are in poor control when insulin
is started tend to gain (or regain) most weight.
o Hypoglycemia

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ORAL HYPOGLYCEMICS
 Used for type 2 diabetics:
Drug Comment Dosage
Sulfonylureas MOA: Stimulate pancreatic beta Glyburide (Glibenclamide/Daonil)
cells to secrete insulin. 2.5 to 20mg PO
Effectiveness of Glipizide 5 to 20mg PO
sulfonylureas declines
up to 10% annually as Glyburide is more likely to result in
the failure of beta cell glycemic control when used once a
function progresses day than glipizide.

Glyburide should be used twice a

day if dosing 20mg/day total is
required.
Metformin Reduces blood glucose levels by Initial dosage: 500mg PO daily
improving hepatic and until initial nausea and anorexia are
Side effects: lactic peripheral tissue sensitivity to tolerated and then increase to 500
acidosis (rare). Risk is insulin without affecting mg BD
minimized if metformin secretion of insulin.
is avoided in patients Dosage can be increased by 500mg
with renal disease, CHF Used as monotherapy or in weekly to maximum dose of 250mg
or pulmonary disease. combination with above. if reasonable control is not
achieved.
Hypoglycemia not a problem
with metformin Use with or after food may lessen
the GI side effects
Alpha glycosidase Reduce absorption of Acarbose 25mg with evening meal,
inhibitors carbohydrates thus reduce may increase to a maximum dose of
postprandial hyperglycemia. 50-100 in weeks.
In general this group of
drugs is less effective Can be used as monotherapy or
than other classes in combination with insulin or
sulfonylureas.
Thiazolidinediones Reduce insulin resistance and Pioglitazone 15-45mg/day in a
increase peripheral glucose single daily dose
Side effects: utilization Rosiglitazone 2-8 mg total dose
idiosyncratic given once or in 2 divided doses
hepatocellular injury

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 The 2 main classes of drugs used in Zambia are Sulfonylureas and biguanides.
 Sulfonylureas
o Glibenclamide initially can be given orally OD or in two divided doses.
Usual dose is 5mg orally daily taken before breakfast up to a maximum
of 20mg in divided doses before food, depending on the patient’s
response. Doses above 20mg will not result in any improvement in
glucose control.
o Chlopropamide 250mg PO OD taken with breakfast. Dosage may be
adjusted to a maximum of 500mg depending on the patients response
o Sulfonylureas can be given together with biguanides.
 Biguanides
o This is preferred drug in obese patients in addition to dietary control and
exercise. It may also be added in patients who have reached the
maximum dose of a sulfonylurea without achieving control of blood
sugar levels.
o Metformin 500mg PO BD or TDS daily or 850mg PO BD or TDS with
or after food. Maximum dose is 2.55g daily in doses.
 NOTE: dosage increments in oral antidiabetic drugs should be gradual i.e. at
1 to 2 week intervals.
 Withdrawal of oral (sulfonylureas and biguanides) drugs should be
commenced only after the insulin therapy has been initiated. In some patients,
metformin and insulin combination can be given.
 Use of insulin in type 2 DM:
 Insulin is usually added to an oral agent when glycemic control is suboptimal
at maximal doses of oral medications.
 An intermediate-acting agent is used starting with a low dose and increasing
as needed for glycemic control (such as 5 to 10 U of NPH increasing as
needed)
 Adding NPH at bedtime is generally more efficacious than using it during the
day.
 If using only insulin, start with an AM (morning) injection. The dose can be
increased by 5U every 3 to 7 days until adequate control is achieved.
 If early morning hyperglycemia is a problem, intermediate acting insulin can
be given twice daily as a split dose.

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PATIENT FOLLOW UP
 Points of emphasis:
 Symptoms of hyper or hypoglycemia
 Weight
 Blood pressure
 Visual acuity (+ fundoscopy), examine the eyes for cataracts and other
opacities
 Examine oral cavity
 Examine feet
 Examine injection site
 Lab tests: blood or urine sugar and urine albumin or protein
COMPLICATIONS
 These can be classified as:
 Acute:
o Hypoglycemia
o Diabetic ketoacidosis
o Hyperglycemic hyperosmolar state (Non-ketotic hyperosmolar coma)
 Chronic: due mainly to non-enzymatic glycosylation as well as osmotic
damage
 High levels of glucose are taken in by cells which do not require
insulin for glucose uptake e.g. neurons. These cells have the enzyme
aldose reductase which converts excess glucose to sorbitol which
causes damage to these cells.
 Retinopathy
 Neuropathy
 Nephropathy
 Diabetic foot ulcer

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ACUTE COMPLICATIONS
HYPOGLYCEMIA
 This is caused by overdose of insulin or hypoglycemic agents, missing of meal,
strenuous exercise.
 Clinical manifestation:
 Early: one may feel the effects of sympathetic stimulation such as cold sweat,
tremor, hunger or palpitations
 Late: if early symptoms are neglected then symptoms of the effect of
hypoglycemia on the brain such as dizziness, blurring, headache, nightmares
and coma may occur
 Management:
 Any patient with diabetes losing consciousness should always be considered
hypoglycemic until proven otherwise by blood sugar determination and
should be managed by rapid IV administration of glucose or PO/ NG tube
administration of any concentrated sugar solution.
 Prolonged unconsciousness requires continuous 10% IV glucose
administration.
DIABETIC KETOACIDOSIS
 Diabetic ketoacidosis (DKA) is a medical emergency principally associated with
diabetes type 1 (due to insulin deficiency) although it has also been recently
reported to be associated with diabetes type 2 (due to a relative insulin
deficiency).
 It is an acute severe manifestation of insulin deficiency.
 DKA is an acute metabolic crisis in patients with diabetes characterized by:
 Hyperglycemia (Blood glucose >11 mmol/L (200mg/dl))
 Metabolic ketoacidosis (venous bicarbonate <15mmol/L and/or venous pH
<7.3)
 Hypotension and features of dehydration
 Hyperketonemia (>3mmol/L) and ketonuria (more than 2+ on standard urine
sticks)
 Precipitating factors include:
 Infection (30%)
 Poor compliance with insulin or discontinuation of insulin (poor diabetic
control)- 15%

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 Dehydration
 Stressful conditions such as trauma, surgery, MI or of emotional crisis
 Excessive alcohol ingestion
 It can occur in a patient who is not known to be diabetic i.e. the presenting
complaint (10%)
 There is no obvious cause in about 40% of episodes.
 The majority of cases reaching the hospital could have been prevented by earlier
diagnosis, better communication between patient and doctor and better patient
education.
 The most common error of management is for patients to reduce or omit insulin
because they feel unable to eat, owing to nausea or vomiting.
 DKA presents at any age although there is a well-defined peak at puberty.
PATHOPHYSIOLOGY
 Any event that decreases insulin availability or causes stress that increases insulin
demand leads to severe insulin deficiency and the effect of counter regulatory
hormones such as glucagon, cortisol, epinephrine and growth hormone to become
overwhelming.
 Insulin deficiency is a necessary precondition since only a modest elevation
in insulin levels is sufficient to inhibit hepatic ketogenesis and stable patients
do not readily develop ketoacidosis when insulin is withdrawn.
 Other factors include counter-regulatory hormone excess and fluid depletion.
 The combination of insulin deficiency with excess of its hormonal antagonist
leads to the parallel processes seen in DKA.
 The biochemical changes include:
 Increased production of glucose by the liver (gluconeogenesis) and increased
glycogen degradation to glucose (glycogenolysis)
 Decreased glucose uptake and utilization by muscles (because of lack of
insulin)
 Rising glucose levels lead to an osmotic diuresis, loss of fluid and electrolytes
and dehydration. Plasma osmolality rises and renal perfusion falls.
 Lipolysis: enhanced breakdown of free fatty acids (beta-oxidation) and
subsequent ketogenesis in mitochondria. This increases blood levels of
ketone bodies such as acetoacetic acid, beta-hydroxybutyric acid, and
acetone resulting in metabolic acidosis (decrease in pH and bicarbonates).
Accumulation of ketone bodies causes metabolic acidosis.

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 The above biochemical processes result in significant hyperglycemia and
ketoacidosis which are responsible for the clinical manifestations of DKA.
 The excess ketones are excreted in urine but also appear in the breath, producing
a distinctive smell similar to that of acetone.
 Respiratory compensation for the acidosis leads to hyperventilation, graphically
described as ‘air hunger’ (Kussmaul’s respiration).
 As the pH falls below 7.0, pH dependent enzyme systems in many cells function
less effectively. Untreated severe ketoacidosis is invariably fatal.
SEVERITY
 According to pH:
 <7.3: Mild
 <7.2: Moderate
 <7.1: Severe
 One of more of the following suggests severe DKA.
 Clinical
o Pulse >100b/min or <60b/min
o Systolic BP <90mmHg
o Glasgow coma Score <12
o Oxygen saturation <92% on air (if normal respiratory function)
 Blood
o Blood ketones >6 mmol/L
o Bicarbonate <12 mmol/L
o Venous/Arterial pH <7.1
o Hypokalemia on admission <3.5mmol/L
CLINICAL FEATURES
 Mental status changes: some patients are mentally alert at presentation but
drowsiness, lethargy and confusion may evolve into coma (5%) with severe
DKA.
 Dehydration: dry tongue and buccal mucosa, poor skin turgor, hypotension but
with an increase in heart rate. (due to osmotic diuresis)
 Polydipsia, polyuria and nocturia
 Kussmaul respiration: deep and fast breathing resulting from metabolic acidosis.
Hyperventilation becomes less marked in very severe acidosis owing to
respiratory depression.
 Acetone (“fruity”) odour of breath due to acetone

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 Nausea and vomiting (due to gastroparesis and attempt to remove H+) with
frequent abdominal pain (this may even be confused with surgical acute
abdomen)
 Leg cramps
 Weight loss
 Weakness (which may be extreme –prostration)
 Hypothermia
 Sign of infection which may precipitate DKA (pyrexia in late stages)
 A history of diabetes (unless first presentation)
 Cerebral edema: an extremely serious complication of DKA especially in
children.

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DIAGNOSIS
 Diagnosis (requires all 3) Anion gap: This is the
 Random blood sugar (capillary glucose): hyperglycemia measurement of the
(>11mmol/l) or a known diabetic interval between the sum
 Urine dipstick for ketones: hyperketonuria (2+ ketones) or of “routinely measured”
serum Ketone (≥3+ or >6mmol/L) cations minus the sum of
 Arterial blood gas analysis: can diagnose metabolic the “routinely measured
acidosis which is indicated by low serum bicarbonate anions in the blood.
(<15mmol/L) or low blood pH (<7.35)
 Other investigations The anion gap= (Na+ +
o Urea and creatinine: raised K+) – (Cl- + HCO3-)
o Serum potassium: The anion gap can be
 Hyperkalemia (>5.5 mmol/L) (In early stages due normal (16 ± 4mEq/l if
to H-K exchanger on RBCs to offset the acidosis) the calculation employs
 Hypokalemia (<3.5mmol/L) (due to osmotic potassium and 12 ±
diuresis as well as hyperaldosteronism) 4mEq/L if the calculation
o Serum sodium: tends to be low because of dilution as does not employ
the osmotic effect of hyperglycemia increases ECF potassium), high or low
volume
The test is commonly
o Serum osmolality is high
performed in patients who
o Increased anion gap
present with altered
o Increased WBC
mental status, unknown
o CXR, urine culture and sensitivity, blood cultures
exposures, acute renal
should also be done to identify an infectious process.
failure and acute illnesses.
MANAGEMENT
A high anion gap
 Management should be carried out in a high dependency area indicates metabolic
(preferably the ICU). acidosis.
 Principles:
 Assess, send blood to the lab, set up IV infusion A low anion gap is
 Fluid, electrolyte and acid-base balance relatively rare but may
 Insulin replacement and glucose stabilization occur from the presence
 Potassium of abnormal positively
 Antibiotics (or treatment of underlying cause) charged proteins, as in
multiple myeloma.
Management mnemonic: “SIPA”
S-solutions, I-insulin, P-potassium, A-antibiotics

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 Fluid replacement: normal saline and 5% Dextrose are used
 Given through large bore cannula.
 Average loss of water is 5-7 liters with a sodium loss
Investigations:
of 500mmol. Normally 6-8L should be given in the
first 24 hours.  Blood glucose:
 If systolic blood press (SBP) <90mmHg give 500ml of  Measure baseline
normal saline over 15mins and repeat if required (Give and hourly for 8
1L in 30 minutes) hours initially
 If/when SBP> 90 give 1L in 1 hour then 1 liter in 2  Aim for fall 3-6
hours, then 1L in 4 hours then 1 liter in 8 hours. mmol/L (55-
 When the serum glucose level falls to <14mmol/L 110mg/dl) per hour
(13.9mmol/L) change the IV fluid to 5% Dextrose-  Urea and electrolytes
saline to prevent hypoglycemia  Do at baseline and
 If sodium level more than 150mmol/L give half hourly until 6 hours,
strength (hypotonic) saline. then 12 hours and 24
 Carefully monitor the urine output hours
 Insulin  Full blood count
 Soluble insulin IV 0.1 U/Kg/h (5-10 units/hour) by  Creatinine- at 0, 6, 12,
infusion. 24 hours
o 50 short/rapid acting insulin in bag with normal  Blood gases- at 0, 2 and
saline made up to 50ml. If glucose remains high 6 hours
(>7) after 2 hours, increase dose.  Bicarbonate- at 0, 1, 2,
o Alternatively, 6IU SC every hour (8IU) for obese- 3, 6, 12, 24 hours.
this is what is used
 Note: soluble insulin given as an IV bolus is rapidly destroyed within a few
minutes. IV insulin must always be given as a continuous infusion.
 When blood sugar levels reach 10-14 mmol/L (13.9) reduce to 0.05
units/kg/h (2-4 units/hour) or titrate against blood glucose level.
 When patient is able to take oral feeds give soluble insulin 2-3 times before
meals
 Alternative:
o 20 units IM stat followed by 5-10 units IM hourly until blood sugar is
14mmol/l.
o When blood glucose is 10-14mmol/L give 8 units 4 hourly
subcutaneously until the patient is able to take oral feeds.
o When patient is taking food orally, change to soluble subcutaneously
twice or three times before meals.

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 For blood glucose measure baseline and hourly initially. Aim for fall of 3-
6mmol/L (55-110mg/dl) per hour.
 Potassium (KCL)
 Add dosage below to each 1L of infused fluid
o If plasma K <5.5mmol/L do not include potassium chloride in the first
bag of fluids. Dehydration may cause AKI so that should be treated first.
o If plasma K <3.5mmol/L, add 40mmol KCL
o If plasma K 3.5-5.5mmol/L, add 20mmol KCL
 Insulin therapy leads to uptake of potassium by the cells with a consequent
fall in plasma potassium levels. Potassium is therefore given as soon as
insulin is started.
 Antibiotics: broad spectrum antibiotics e.g. Ceftriaxone 1g IV BD
 Sodium bicarbonate: 600ml of 1.4% or 100ml of 8.4% in large cannulated vein
if pH<7.0
 Once stable and able to eat and drink normally, transfer the patient to 4 times
daily subcutaneous insulin regimen.
 Sliding-scale regimens are unnecessary and may even delay the establishment of
stable blood glucose.
 Other management measures:
 Bladder catheter if no urine passed in 2 hours or 3 hours of hydration.
 Nasogastric tube if drowsy.
 Give subcutaneous prophylactic LMW heparin
 Other investigations:
o Blood and urine culture
o Cardiac enzyme
o CXR
o ECG (monitor if electrolyte problems or severe DKA)

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PROBLEMS OF MANAGEMENT
 Hypotension: this may lead to renal shutdown. Plasma expanders (or whole
blood) are therefore given if the systolic blood pressure is below 80mmHg. A
central venous pressure line is useful in this situation. A bladder catheter is
inserted if no urine is produced within 2 hours, but routine catheterization is not
necessary.
 Coma: The usual principles apply. It is essential to pass a nasogastric tube to
prevent aspiration, since gastric stasis is common and carries the risk of aspiration
pneumonia if a drowsy patient vomits.
 Cerebral edema: this is a rare, but serious complication and has mostly been
reported in children or young adults such as 8.4% bicarbonate may sometimes be
responsible. The mortality is high.
 Hypothermia: severe hypothermia with a core temperature below 33oC may occur
and can be overlooked unless a rectal temperature is taken with a low-reading
thermometer.
 Late complications: these include pneumonia and deep-vein thrombosis (DVT
prophylaxis is essential) and occur especially in the comatose or elderly patient.
 Complications of therapy: these include hypoglycemia and hypokalemia, due to
loss of potassium in the urine from osmotic diuresis. Overenthusiatic fluid
replacement may precipitate pulmonary edema in the very young or the very old.
Hyperchloraemic acidosis may develop in the course of treatment since patients
have lost a large variety of negatively charged electrolytes, which are replaced
with chloride. The kidneys usually correct this spontaneously within a few days.

HYPERGLYCEMIC HYPEROSMOLAR STATE

 Previously called non-ketotic hyperosmolar coma.
 This is a condition, in which severe hyperglycemia develops without significant
ketosis, it is a metabolic emergency characteristic of uncontrolled type 2 diabetes.
 Patients present in middle or later life, often with previously undiagnosed
diabetes.
 Common precipitating factors:
 Consumption of glucose-rich fluids
 Concurrent medication such as thiazide diuretics or steroids
 Intercurrent illness such as myocardial infarction, stroke, pneumonia, sepsis
etc.

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 The hyperosmolar hyperglycemic state and ketoacidosis represent 2 ends of a
spectrum rather than 2 distinct disorder.
 The biochemical differences may partly be explained as follows:
 Age: the extreme dehydration characteristic of hyperosmolar hyperglycemic
state may be related to age. Old people experience thirst less acutely and more
readily become dehydrated. In addition, the mild renal impairment associated
with age result in increased urinary losses of fluid and electrolytes.
 The degree of insulin deficiency: this is less severe in the hyperosmolar
hyperglycemic state. Endogenous insulin levels are sufficient to inhibit
hepatic ketogenesis, but insufficient to inhibit hepatic glucose production.
PATHOPHYSIOLOGY
 Increase in glucose leads to osmotic shift out of the cells resulting in intracellular
dehydration.
 No ketoacidosis due to basal insulin which is sufficient to stop ketogenesis, but
not to reduce glucose.
 Usually it is seen in old patients and is the first presentation of diabetes.
 It can be precipitated by illness and dehydration.
 In rare cases mixed HHS and DKA states can occur reflecting some degree of
insulin deficiency.
CLINICAL FEATURES
 Symptoms:
 Such patients present with several weeks history of polyuria, weight loss and
diminished oral fluid intake that is followed by mental confusion, lethargy,
stupor or coma (10%).
o Onset over several days: generalized weakness, leg cramps, visual
impairment.
 Impairment of consciousness is directly related to the degree of
hyperosmolality.
 Physical examination:
 Patients have extreme dehydration, hypotension, tachycardia and altered
state of consciousness or coma. The dehydration is caused by a
hyperglycemia induced osmotic diuresis, when it is not matched by adequate
fluid intake.
 Signs of underlying infection.

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DIAGNOSIS
 Diagnostic criteria:
 Glucose >30 mmol/L
 Serum Osmolality >320 mOsm/kg
 No significant ketosis: less than 3+ on urine or <3 mmol/L
 Other tests:
o Bloods: FBC, CRP, U&Es
o Septic screen if infection is suspected
o ECG
o Arterial blood gases: should be normal
MANAGEMENT
 Treatment involves:
 Fluid replacement: administration of IV fluids. Rehydrate with normal saline,
slower than DKA (older population). The standard fluid for replacement is
normal saline. Avoid 0.45% saline, rapid dilution of the blood may cause
more cerebral damage than a few hours of exposure to hypernatremia.
o Frequently required 6-10 liters.
o 1L in 30 minutes
o 1L in 1 hour
o 1L in 2 hours
o 1L in 4 hours
o 1L in 8 hours
 Bringing down the sugar rapidly by using rapidly acting insulin preparations
o Give insulin after 1 hour at half the rate of DKA as HHS is highly insulin
sensitive.
o Insulin is not needed if glucose dropping with fluids along. Glucose
should drop by 3 mmol/hr.
o It is sometimes useful to infuse insulin at a rate of 3 U/hour for the first
2-3 hours, increasing to 6U/hour if glucose is falling too slowly.
o When glucose is less than 14mmol/L check for random blood sugar every
2 hours and use 5% dextrose saline.
 Identifying and treating the precipitating factor:
 Monitor fluid balance, glucose and U&Es. Correct electrolytes if needed
 DVT prophylaxis
o Low molecular weight heparin should be given to counter the increased
risk of thromboembolic complications associated with this condition.

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COMPLICATIOSN
 Cerebral edema
 Pulmonary embolism
 Ischemia: MI, stroke
 Much higher mortality (>10%) than DKA, in part reflecting patients’
underlying poor health.
CHRONIC COMPLICATIONS OF DIABETES MELLITUS
 These are due mainly to non-enzymatic glycosylation as well as osmotic damage.
 They are a result of poor glycemic control.
 Multiple organs are affected due to macro-microangiopathy include:
 Diabetic retinopathy
 Diabetic neuropathy
 Diabetic nephropathy
 Diabetic foot
DIABETIC RETINOPATHY
 This is one of the commonest chronic complications (30%) and one of the leading
causes of blindness in developed countries.
 It is a retinal disease due to diabetic microvascular damage.
 Diabetes also causes increased risk of cataracts and glaucoma.
 Symptoms include:
 Difficulty of reading
 Blurring of vision
 Floaters
 Shadowing which may later on progress to total blindness (in advanced
stages).
 Signs: seen on fundoscopy or ideally, retinal photograph
 Microaneurysns: earliest sign. Small red dots.
 Dot and blot hemorrhages from aneurysm rupture.
 Hard exudates: lipid and protein leak from vessels.
 Cotton wool spots: retinal nerve fiber ischemia
 Venous beading (dilation) and loops: retinal ischemia
 Intraretinal microvascular abnormalities (IRMA): redomelled capillary beds.

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 Classification:
 Non-proliferative retinopathy (NPDR): formerly divided into ‘background
retinopathy’-microaneurysms and hard exudates only- and pre-proliferative
retinopathy-everything else.
o “Mild” if there are only microaneurysms,
o “Severe” if there is 4-quadrant hemorrhage/aneurysms, ≥2 quadrant
venous bleeding or ≥1 quadrant IRMA
o “Intermediate” for anything in-between
 Proliferative retinopathy:
o Defined by presence of neovascularization
o Vitreous hemorrhage. May cause symptoms such as floaters, flashes and
sudden painless loss of vision.
o Tractional retinal detachment: appears as ‘tented’ retina.
 Macular edema:
o Appears as blurring of retinal layers
o Present with gradual blurring of vision
o Can occur in NPDR and PDR
o Commonest cause of vision loss in diabetes.
 Management:
 Glucose and BP control
 Laser therapy
 Vitrectomy if there is vitreous hemorrhage persisting >6 months or tractional
retinal detachment.
 Aspirin 100mg/day prevents further occlusion of small capillaries
 Surgery: viterotomy removes blood clots and fibrosis that obstruct vision
DIABETIC NEUROPATHY
 Symptoms include:
 Burning sensation
 Numbness
 ‘Pins and needles’
 Constipation or nocturnal diarrhea
 Impotence
 Foot ulcer

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 Classification:
 Polyneuropathy: is the commonest neuropathy, characterized by distal
symmetrical predominant sensory impairment which manifests with tingling
sensations, numbness, burning sensation etc.
 Radiculopathy: characterized by neurogenic pain, it is often self-limiting.
 Amyotropy: atrophy of proximal muscles mainly around the hip girdle
 Autonomic neuropathy (dysregulation): Postural hypotension, GI
manifestations (gustatory sweating, gastroparesis, nocturnal diarrhea),
Genitourinary manifestations (neuropathic bladder, erectile dysfunction-
impotence)
 Mononeuropathy: paralysis of a specific nerve or nerves e.g. diplopia due to
third and sixth nerve palsies.
 Management:
 Symptomatic treatment: pain control
 Diarrhea control
 Treatment of impotence.
 Painful neuropathy: TCAs are 1st line. Gabapentin or Carbamazeppine are 2nd
line
DIABETIC NEPHROPATHY
 This is a common complication in diabetes.
 Clinical features:
 Periorbital edema (eye or facial puffiness), pedal edema, anasarca
 Anemia, uremia and osteodystrophy in patients with end stage renal disease
 Lab findings:
 Progression from micro albuminuria to macroalbuminuria
 Management:
 Tight blood pressure control
 ACE inhibitors: decreases the progression of renal disease
 Renal transplantation or dialysis in End stage renal disease
DIABETIC FOOT
 Symptoms include: numbness and burning, aching pain, swelling, darkening,
abscess and cold extremity.
 Mechanisms involved include:
 Neuropathy: loss of pain sensation exposes to injury and loss of sweating
results in dry skin that is susceptible to injury.

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 Vascular: poor blood supply to the foot causes decreased healing of wound
poor recovery from secondary infection.
 Abnormal pressure loading: due to neuropathy (Charcot’s joints) or
anatomical deformity of the feet. Since the foot is not in a normal anatomic
position it is exposed to abnormal load and pressure sores develop.
 Foot care should be an essential part of diabetes care:
 Put on comfortable shoe
 Check for pebbles in shoe and do not walk barefoot (wear comfortable and
spacious shoes)
 Examine the foot daily to detect problems earlier
 Wash and dry and oil the feet
 Take caution during nail cutting
 Treat athletes’ foot or any other foot infection as early as possible
 Remove corn
 Do not use hot water to wash the feet
 Stop smoking

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NEUROLOGY
NERVOUS SYSTEM EXAMINATION
 The examination is best done in the sitting position except meningeal signs which
require the lying position and coordination/ Gate/ Balance which require the
patient to stand.
 In severely ill patients, the nervous system exam can be completed in the lying
position.
 Always perform the neurological exam systematically so that you do not omit
anything.
 Note any deficits and the anatomic site of the neurologic lesion.
 It is traditional to start rostrally and proximally and to work caudally and distally.
 Always report all of the nervous system examination
 General examination
 Mental status/Higher centers
 Cranial nerves
 Meningeal signs
 Upper limb examination and Lower limb examination
 Inspection and posture
 Tone
 Reflexes
 Power
 Sensation
 Coordination/ gate/ balance

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SUMMARY OF THE NEUROLOGICAL EXAMINATION
Conscious level and cognitive function (determined during history taking)

 Is the patient's conscious level clouded?

 Is the history given accurately, concisely and with insight? Or is the patient concrete, circumlocutory or vague?
 Is the patient neatly dressed and well cared for?
 Is the patient's behaviour normal?
 Is the patient aphasic or dysarthric?

Vision

 Acuity: For each eye, using normal refractive correction, test ability to read small and large print, or use Snellen chart if available. If
this fails, test counting of fingers, perception of light.
 Visual fields: Test all four quadrants for each eye individually.
 Fundi: Check for papilloedema, optic atrophy, retinopathy.
 Pupils: Check equality and consensual and direct reactions to light and accommodation (Moving object towards eye).

Eye movements

 Test both eyes together in 'H' pattern for range of movement and diplopia.
 Test both eyes together in '+' pattern for smooth pursuit and nystagmus.

Remainder of cranial nerves

 Nerve V: Pinprick on left and right in ophthalmic, maxillary and mandibular distributions; clenching of teeth; jaw jerk.
 Nerve VII: Appearance and symmetry; screwing up eyes against pressure, forcing lips closed against pressure, blink reflexes.
 Nerve VIII: Hear whispered numbers in each ear/rubbing fingers.
 Nerves IX and X: Ask patient to say 'ah' and observe palate.
 Nerve XI: Ask patient to shrug shoulders and move head to either side and flex against resistance while you observe sternomastoids.
 Nerve XII: Inspect tongue. Ask patient to protrude tongue and press against inside of cheek on either side.

Limbs and trunk

 Inspection for wasting, fasciculation, skin lesions.

 Posture of outstretched arms with wrists pronated and supinated, looking for drift, tremor, abnormal movements.
 Tone at wrist, elbows, knees and ankles, ankle clonus.
 Power of proximal, axial and distal muscles on both sides.
 Reflexes: Deep tendon reflexes of biceps, supinator, triceps, fingers, quadriceps, gastrocnemius; plantar responses.
 Sensation: Test pinprick distally to proximally up arms and legs medially and laterally; and up trunk bilaterally, anteriorly and
posteriorly. Vibration sense or joint position sense at little finger, great toe (moving proximally if failed).
 Co-ordination: Finger-nose test; rapid alternating movements; heel-shin test.

Gait and stance

 Observe walking pattern.

 Standing still with feet together and eyes closed.
 Walking heel to toe.
 Jumping and hopping.

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 Before starting the examination
 Introduce yourself to the patient.
 Explain the examination and ask for their consent to carry it out.
 Ensure that they are comfortable.
GENERAL EXAMINTION
 Begin the examination from the foot-end of the bed.
 Examine the patient and look for:
 Build
 Nourishment
 Orientation to time place and person
 Handedness- right or left
 Jaundice- Hepatic encephalopathy and Wilson disease
 Pallor- Vitamin B12 deficiency
 Examine the facial appearance and note:
 Mask-like facies in Parkinsonnism.
 Drooping eyes and sleepy appearance in myasthenia gravis.
 Risus sardonicus in tetanus.
 Facial asymmetry in 7th nerve palsy.
 Examine the spine to rule out disc prolapse and spina bifida.
 Examine the extremities to look for presence of thickened nerves (leprosy)
 Look out for neurocutanoeus markers:
 Café au lait spots (neurofibromatosis)
 Painful rashes in herpes zoster
 Hypopigmented patches in leprosy
 Adenoma sebaceum and ash leaf macules in tuberous scelorosis.
 Facial naevus in Sturge Weber syndrome
HIGHER CENTERS
 Observe the patient for:
 Physical appearance
 Posture
 Grooming
 Eye contact with examiner
 For the internal doctor, you should at very least observe the level of
consciousness and orientation.

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 Level of consciousness: this is the state of awareness of one’s self and his
surroundings.
 In extremely ill patients consciousness can be quantified with the Glasgow
Coma Scale (GCS). This is the sum of Eye, Verbal and motor responses as
below:
Value Eye (Out of 4) Verbal response Motor response
(out of 5) (out of 6)
6 Obeys commands
5 Oriented & Localizes to pain
converses (gives (brings hand
name, place and above clavicle to
date) stimulus on
head/neck)
4 Opens eyes Disoriented but Withdraws from
spontaneously Converses pain (bends arm at
(communicates elbow rapidly but
coherently) features not
predominantly
abnormal)
3 Opens to verbal Inappropriate Decorticate/
command (sound) response Abnormal flexion
(intelligible single (Bends arms at
words) elbow rapidly but
features clearly
predominantly
abnormal)
2 Opens to pain Inappropriate Decerebrate/
sounds (only Extension
moans/groans) (Extends arms at
elbow)
1 No response No response No response

 Interpretation
 Normal state- score 15
 Mild head injury- Score 13 to 15
 Moderate head injury- Score 9 to 12
 Severe head injury= less than 8

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 Orientation: check to see if the patient is oriented to person, place and time. Do
they know who they are (their name, age, date of birth), where they are (city,
hospital, floor) and when it is (year, month, day, time).
 Alert: patient is awake, aware and responsive to stimuli
 Clouding of consciousness: mild form of altered status where patient has
inattention and reduced wakefulness.
 Confusion: there is disorientation and difficult in following commands
 Lethargy (drowsy): patient can be aroused by moderate stimuli and then
patient drifts back to sleep.
 Obtundation: lowered interest in surrounding, slower responses to stimuli
and more than normal sleep with drowsiness in between sleep state.
 Stupor: vigorous and repeated stimuli is required to awake the patient and
returns to unresponsive state after removal of stimuli
 Coma: it is a state of deep stupor where the patient is unarousable and
unresponsive
 Delirium: acute state of confusion and agitation.
 Affect and mood:
 Affect is the patient’s immediate expression of emotion. The affect may be
broad, restricted, labile or flat. Affect is inappropriate when there is
dissonance between his experience and immediate reaction.
 Mood is the sustained emotional makeup of the patient’s personality.
 Speech: do they have dyarthria, expressive aphasia (Broca aphasia), or receptive
aphasia (Wernicke’s aphasia)?
 Sensory (Wernicke’s aphasia): failure to comprehend verbal or written
messages but speech output is normal
 Motor (Broca’s aphasia): comprehension is normal but speech is non-fluent
 Conduction Aphasia: intact auditory comprehension but repetition of words
is lost.
 Global aphasia: there is complete derangement of speech. Patients can neither
read nor write.
 Dysarthria: it is a motor speech disorder due to impaired movements of
muscles of speech.
 Language:
 Comprehension: it is the ability to understand, it is assessed by asking simple
yes or no questions, or by asking patient to point out at things that you
instruct.

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 Repetition: it is tested by making the patient repeat the sentence: No If’s
and’s or but’s
 Naming: ask the patient to name common and unusual objects.
 Word fluency: ask the patient to say as many words possible in a given
category in a fixed period.
 Reading: ask the patient to read out loud and listen for error. Make the patient
do things written in command.
 Memory: This is the mental capacity or faculty to retaining and reviving facts,
events and impression or of recalling or recognizing previous experiences. It can
be immediate recall, short term memory or long term memory.
 Immediate recall: it can be tested by asking to read newspaper or random
sentences and then repeat it without looking.
 Short term: it can be tested by asking the patient to learn the names of 4
unrelated objects, a short sentence and an address and then recall the
information 3-5 minutes later.
 Long term memory: it can be tested by asking the patient to recall personal
or social events e.g. the past presidents of the country, birthdays, distant
public events etc.
 Apraxia and constitutional inability
 Apraxia is the inability to perform previously learnt motor skills. It is tested
by asking the patient to use an imaginary scissor, cigarette, pen etc.
 Constitutional inability is the loss of ability to generate drawing or to
manipulate block designs from verbal command or visual reproduction.
 Intelligence: it is the ability to quickly and successfully apply previous
knowledge to a new situation and to use reason in solving practical problems. It
can be tested by making the patient do:
 Simple arithmetic problems
 Simple puzzles
 Test vocabulary
 Mini-Mental state examination: it is a 30-point questionnaire to measure
cognitive impairment. The components include
 Orientation
 Registration (Immediate- registering 3 words and recent-recalling 3 words 5
minutes later)
 Attention and calculation (serial 7s, spell “world” backwards)
 Language (naming, repetition, comprehension)
 Complex commands

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 Visuospatial ability (Copy of design)
Parameter Detail and Score
Orientation  What is the date (day of week, day of month, month, season and year)- 1
point for each correct answer-Maximum of 5 points
 Where are we? (State, Country, City/Town, Hospital, floor?)- 1 point for
each correct answer)- Maximum of 5 points
Registration  Name 3 objects and repeat them- 3 points (Maximum=3)
Attention  Serial 7s (Subtract 7 from 100 and continue subtracting 7 from each
and answer) or spell “World” backward- Maximum 5 points
calculation
Recall  Name the 3 objects above 5 minutes later (Maximum= 3 points)
Language  Naming: name a pen and a clock (2 points)
 Repetition: Say “No If’s ands or buts” (1 point)
 Verbal comprehension (3 step command): Take a pencil in your hand, put
in your left hand and put it on the floor (3 points)
 Written comprehension: Read the statement written on a piece of paper and
do what it says: “close your eyes” (1 point)
 Writing: Write a sentence (1 point)
 Visuospatial skills: Draw two intersecting pentagons (1 point)
 Results:
 Maximum score= 30
 Score >24 is normal
 Score <24 suggests dementia
CRANIAL NERVES
 The examination of the cranial nerves can be summarized as follows:
 CN I: smell
 CN II: Visual acuity, visual field and ocular fundi
 CN II, III: pupillary reactions
 CN III, IV, VI: extraocular movements
 CN V: corneal reflexes, facial sensation and jaw movements.
 CN VII: Facial movements
 CN VIII: hearing
 CN IX, X: swallowing and rise of the palate, gag reflex
 CN V, VII, X, XII voice and speech
 CN XI: shoulder and neck movements
 CN XII: tongue symmetry and position

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 CN I (Olfactory): smell is tested with non-irritant and familiar odors. First make
sure that each nasal passage is open by compressing one side of the nose and
asking the patient to sniff through the other. It is important to ask the patient to
close the eyes during the test to prevent visual identification of the substance.
 Substances with pungent odor must not be used as noxious stimuli is detected
by sensory fibers of the trigeminal cranial nerve.
 To examine olfactory nerve each nostril must be tested separately. Ask the
patient to close one nostril, as well as both eyes while they smell and identify
the substance with the other nostril, repeat the same on the opposite side.
 Bottle containing essence of familiar smell (vanilla, coffee, pepper mint)
must be tested separately.
 Ask if the patient smells anything and if so what.
 Anosmia entails loss of smell of taste and is seen in: nasal disease, tumors,
head trauma, aging, use of cocaine, congenital anomalies, meningitis and
smoking.
 This test is often omitted during a brief bedside exam.

 CN II (optic)
 The optic nerve is tested through: Pupillary reflexes, Visual acuity, Visual
fields, Color vision, and fundoscopy.
 Ask the patient to look straight and inspect the pupil for size, shape and
alignment as you compare one side with the other
 Pupillary light reflex
 Ask the patient to look straight during examination. Shine the light at a
lateral angle and not directing in front of the eye.
 Direct light reflex: shine torch into one eye and look for immediate
constriction of pupil in the same eye.
 Consensual light reflex: shine torch into one eye and look for immediate
constriction of pupil in the opposite eye. (perform a swinging motion of
the tourch)
 Swinging light test: may reveal a relative afferent pupillary defect (Marcus-
Gunn pupil).
 Swing the light back and forth between the eyes. Normally the pupil
will constrict with one eye, dilate a little as the light passes over the
nose and constrict again with the other eye. Thus you get constrict-
constrict-constrict-constrict.

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 When one eye doesn’t see as well, the pupils don’t constrict quite as
well. In fact, the pupils appear to dilate a little when you hop over
to the bad eye with the flashlight. Thus you get constrict-dilate-
constrict- dilate.
 Check for the accommodation reflex (constriction and convergence)
 Ask patient to look at an object then bring it closer to their face.
 Avoid standing in front of the patient stand on the side and ask the
patient to look forward.
 Test visual acuity with Snellen chart (far vision) at 6m (20 feet)
 Ask the patient to remove the glasses or contact lenses while testing
visual acuity.
 Each eye must be tested separately.
 Make the patient stand at a distance of 6m from the chart and ask the
patient to close one eye and read the chart from the other eye, the
lowest possible line on the chart must be read.
 For illiterate patients tumbling E chart is used, where the patient is
supposed to identify the direction the letter E is facing.
 Visual acuity is expressed as a fraction. Normal visual acuity is 6/6.
Numerator indicates distance from the chart, denominator indicates the
distance at which a person with normal eye sight read the same line the
patient correctly read.
 If the patient is unable to read at 6m:
o Move closer (3m)
o If still unable- move closer again (1m)
o If still unable- assess ability to count fingers
o If still unable- assess ability to detect moving hand
o If still unable- assess light perception
 For near vision the Jaeger’s chart is used. The card is held at a
distance of 36 cm from the patient’s eye. The card must be adequates
illuminated. Ask the patient to read the smallest possible line on the
chart and record the J value of the line J1 corresponds to 6/6 vision.
 Visual fields (Each quadrant one eye at a time) with fingers moving test.
 Visual field is the total portion of space in which objects are visible
in the peripheral vision as you focus your eyes on a central point.
 Normal visual field is 100 degrees temporal, 60 degrees nasal, 60
degrees superior and 75 degrees inferior.
 The examiner must have normal visual field to conduct the test.

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 Examiner and patient must be seated facing each other at a distance
of 1 meter.
 To test patient’s left eye, ask the patient to close his right eye with
his right hand and to gaze into the examiner’s right eye.
 The examiner must close his left eye with his left hand.
 To test vision, the examiner stretches his hands and brings the index
finger from periphery of each quadrant (superior, inferior, temporal
and nasal) towards the center.
 Patient is asked to say ‘yes’ when he visualizes the finger.
 In normal acuity both the examiner and the patient visualizes the
finger at the same time.
 Assess color vision using ishihara chart
 Perform fundoscopy to rule out papilledema, optic nerve atrophy, macular
haemorrhage, pappilitis etc.

 CN III, IV, VI (Oculomotor, Trochlear, Abducens): have patient keep their head
still and follow with their eyes as you trace an ‘H’ 1m away. Test smooth pursuit
and nystagmus by tracing an “H” and a ‘+’.
 Note any ptosis (oculomotor lesion)
 Note any restriction of eye movement
 Note any nystagumus (stroke, head injury, antiepileptic drugs- phenytoin,
high refractive errors, bilateral cataract)
 Check for the corneal reflex: Ask the patient to look into distance, touch the
cornea and conjunctival margin with a wisp of cotton. Normally there will be
bilateral blinking. Reflex is lost in lesion of reflex arc and parietal lobe.

 CN V (Trigeminal): Check sensation to light touch and pin prick in all 3 branches
of the trigeminal nerve on both sides of the face. If the patient is sedated or
comatose, touch cotton to the corneal surface to illicit bilateral blink corneal
reflex. Palpate masseter and temporalis muscles as patient clenches teeth to assess
motor function.
 Test for light touch sensation using a wisp of cotton. Ask the patient to close
their eyes and say yes each time the examiner touches any part of their face.
(ensure first you show them how it feels with their eyes open first before you
begin the test).

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 Test the motor aspect of the trigeminal nerve. Inspect for wasting of the
temporal and masseter on both sides of the face as the patient clenches their
teeth
 To test for the temporalis and masseter muscles ask the patient to
clench the teeth and then palpate for muscles above the angle of the
mandible. They must stand out equally on both sides. Test the strength
of the muscle by making the patient move his/her jaw sidewards as the
examiner resists the movements with the palm.
 To test for the pterygoids ask the patient to hold the mouth open and
then attempt to close if forcefully. Normally the examiner will not be
able to close the mouth. Unilateral weakness of pterygoids causes jaw
to deviate to towards the paralysed side on attempting to open the
mouth.
 Jaw jerk: Ask the patient to open the mouth slightly. Place your finger
on the chin of the patient (below lower lip) and then tap it lightly with
a tendon hammer. Normally there is slight closure of the mouth. It is
exaggerated in pseudobulbar palsy.

 CN VII (Facial):
 Inspect for facial asymmetry (unilateral weakness) while conversing with the
patient, symmetry is maintained in bilateral facial nerve palsy.
 Observe the blinking and closure of eye, the eyelid on affected side may close
just a trace later than the opposite
 Observe the nasolabial folds, it is lost on the affected side. There will be
drooping of eyes on affected side and movements of mouth may be restricted
while speaking.
 Check for movement of upper face:
 Ask patient to raise the eyebrows, look up and wrinkle the forehead.
Inspect for asymmetry or loss of wrinkling.
 Ask patient to close the eyes tightly. Look for incomplete closure of
eyelids on the affected side. Try to force open each eye, eye on the
affect side can be opened forcefully.
 Check for movement of lower face:
 Ask the patient to smile or show teeth. In case of unilateral palsy the
angle of mouth is drawn to the healthy side.
 Ask the patient to inflate mouth and blow out against closed moth.

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 Palpate each cheek by tapping it. Air easily escapes when tapped on
affected side.
 You can also check taste with various solutions: ‘Sweet’ with sugar, ‘salt’
with salt, ‘sour’ with citric acid and ‘bitter’ with quinine.Check movement of
the lower face by having the patient smile, bare teeth and hold air in the
cheeks while you tap on them.

 CN VIII (Vestibulocochlear):
 Inspect for presence of any hearing aid, examine the pinna and look for scars
and sinuses. Examine the external auditory meatus and the tympanic
membrane for any abnormalities.
 Test hearing with Ticking clock or Whispering testing:
 Occlude one ear of the patient by rubbing fingers near the ear and
whisper as softly as possible in the other ear letters and numeral.
 Whispering should be done at a distance of 60cm from the ear.
 Ask the patient to repeat the letters, if there is abnormal result perform
Rinne’s and Weber’s test.
 Rinne’s Test: This is done to compare air conduction with bone conduction
in same ear. Strike a tuning fork and place the foot piece/base of the tuning
fork on the mastoid process and ask the patient to say “now” when he/she
stops hearing. When the patient says “now” take the tuning fork and keep its
vibrating blades near the external auditory meatus on the same side.
 Normal: the patient continues to hear the sound when the tuning fork
is removed from mastoid process and kept near external auditory
meatus. This is because air conduction is better than bone conduction.
 Rinne’s positive: Air conduction is better than bone condition. It is
seen in normal hearing and sensorineural hearing loss.
 Rinne’s negative: Bone conduction is better than air conduction. It is
seen in conductive deafness and mixed hearing loss.
 Rinne’s false negative: it is seen in severe unilateral sensorineural
hearing loss. Here bone conduction is heard longer due to transmission
through the skull to the other ear.
 Weber’s Test: Keep vibrating tuning fork on the center of the forehead or
vertex of the patient. Ask the patient if the sound can be heard equally in both
ears or better in one ear
 Normal: sound is heard equally in both ear.

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 Abnormal: sound is lateralized to affected ear in conductive deafness
and lateralized to better ear in sensorineural deafness.
 Schwabach’s test: the test, the patient’s bone conduction is compared to that
of the examiner presuming the examiner has normal hearing. Keep the
footplate of the vibrating tuning fork over the mastoid bone of the patient and
when the patient stops hearing the tuning fork it is placed on the examiner’s
mastoid process. In absolute bone conduction (ABC) test, the same procedure
is done with occluded external auditory meatus of both the patient and
examiner
 Normal: patient and examiner hears for same duration.
 Conduction deafness: patient hears for longer duration than examiner
 Neurosensory deafness: examiner hears for longer duration than
patient
 Check the vestibular function at the end of the neuro exam during the
coordination, gait and balance assessment with the Romberg test, and heel to
toe walking. You can perform horizontal head impulse test.
 Make the patient get seated and relaxed, approach the patient from
front. Instruct the patient to keep the head loose and gaze at examiner’s
eyes, hold the head from both the sides and rotate it to the sides (20
degrees rotation from center).
 Normally the patient’s eye deviate to the left as the head is moved to
the right and vice versa. In CNS involvement when the head is rotated
towards a vestibular lesion there will be corrective gaze shift.

 CN XI (glossopharyngeal): Test for motor function by having patient stick their

tongue out. Test for taste on the posterior part of the tongue and gag reflex.

 CN X (Vagus): as the patient says ‘ah’, confirm soft palate elevates and the uvula
stays midline.

 CN XI (Spinal Accessory):
 From behind, look for atrophy or fasciculations in the trapezius muscles, and
compare one side with the other.
 Ask the patient to shrug both shoulders upward against your hands.
 Note the strength and contraction of the trapezii.
 Injury to spinal accessory nerve will manifest as dropping shoulders.

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 Ask the patient to turn his or her head to each side against your hand. Observe
the contraction of the opposite sternocleidomastoid and note the force of the
movement against your hand.
 A supine patient with bilateral weakness of the sternocleidomastoids has
difficulty raising the head off the pillow.

 CN XII (hypoglossal)
 Listen to the articulation of the patient’s words.
 Inspect the patient’s tongue as it lies on the floor of the mouth. Look for any
atrophy or fasciculations (fine, flickering, irregular movements in small
groups of muscle fibers)
 Then, with the patient’s tongue protruded, look for asymmetry, atrophy or
deviation from the midline.
 Ask the patient to move the tongue from side to side and note the symmetry
of movement.
 In ambiguous cases, ask the patient to push the tongue against the inside of
each cheek in turn as you palpate externally for strength.
 In a unilateral cortical lesion, the protruded tongue deviates transiently in a
direction away from the side of the cortical lesion.

SIGNS OF MENINGEAL IRRITATION

 Neck stiffness: passively but gently flex the patient’s neck to see if they can touch
the chest without pain.
 Kernig’s sign: with the patient supine on the bed passively extend the patient’s
knee on either side when the hip is fully flexed and look for patient spasm.
 Brudzinski’s sign: when forced flexion of the neck elicits a reflex flexion of the
hips.

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UPPER LIMB EXAMINATION
INSPECTION
 Inspect the upper limbs and comment on:
 Symmetry of muscles
 Wasting of muscles
 Hypertrophy of muscles
 Contractures
 Fasciculations: these are fine, intermittent and involuntary contractions of
muscles that occur spontaneously
 Abnormal movements
 Note the distribution of wasting or hypertrophy, whether unilateral or bilateral,
predominantly proximal or distal or both.
PALPATION
INITIAL PALPATION
 Palpate the muscles and feel for
consistency.
 Check for muscle bulk and
tenderness.
 If the muscles are atrophied, it
may feel flabby.
 If the muscles are hypertrophied,
may feel firm and resilient.
 In pseudohypertrophy there will
be woody consistency.

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TONE
 Tone is the resistance offered by muscles when moved
passively through its range of movements. It refers to the
tension present in relaxed muscle.
 Before beginning with the examination make sure that
the patient is relaxed, comfortable and not in any pain
(enquire if they are in pain- if so, always examine that
limb last).
 Tone can be tested by moving a part through its range of
movements.
 To examine the tone of muscles of the upper limb, the
examiner must support the patient’s elbow in one hand,
and hold the patient’s hand with the other hand.
 Move it passively by flexing and extending at the elbow,
supinating and pronating at the wrist.
 Feel the tension in the muscles as you move them.
 Raise the patient’s hand and elbow and allow it to fall on
the bed.
 In a normotonic patient there will be checking
movement to prevent the limb from falling.
 In hypotonia the limb falls to the bed without any
resistance.
 Rigidity is a state of hypertonia where the tone is
uniformly increased in both agonist and antagonist group
of muscles.
 Spasticity is a state of hypertonia affecting both agonist
and antagonist group of muscles, but tone is higher in one
of the group of muscles.
 In clasp knife spasticity: on passively flexing a joint
there will be initial increase in resistance and on
further pressure there is rapid decrease in resistance
giving a movement like a clasp knife.
 In lead pipe rigidity: there is uniform resistance to
passive movement through the whole range of
movement

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 In cog wheel rigidity: there is a combination of lead pipe rigidity and tremors
where the resistance offered is interrupted by tremors which present as jerky
resistance
REFLEXES
BICEPS REFLEX (C5-C6)
 Make the patient sit with the forearms resting on
their thigh or support it by resting it on your forearm.
 Keep the patient’s elbow midway between flexion
and extension.
 Place you thumb over biceps tendon (located at the
medial aspect of elbow joint) and tap it with a tendon
hammer.
 Normally there will be slight flexion at the elbow
(look at the bicep muscle for contraction).
BRACHIORADIALIS/SUPINATOR RELFEX
(C5-C6)
 Support the patient’s hand or make it rest on the
patient
 Slightly flex the elbow and wrist must be halfway
between pronation and supination.
 Identify the brachioradialis tendon which inserts at
the base of the styloid process of the radius.
 Strike the tendon directly with the hammer.
 Normal reflex-
 Supination at wrist
 Slight flexion of forearm
 Slight flexion of fingers
 While eliciting supinator reflex if there is absence of
contraction of brachioradialis and if the only
response present is finger flexion and elbow
extension, it is called an inverted supinator reflex.
TRICEPS REFLEX (C7)
 Support the patient’s forearm with one hand.
 Identify the triceps tendon at its insertion.
 Normally, there is extension at elbow joint.

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POWER
 Power of a muscle is tested by instructing the patient to
resist the examiner’s forceful movements or to move a body
part against examiner’s resistance.
 While examining an individual muscle careful positioning
must be done to prevent use of accessory muscles.
 Grading of power:
 Grade 0- No contraction
 Grade 1- Flickering movements
 Grade 2- Active movement with gravity eliminated
 Grade 3- Active movement against gravity
 Grade 4- Active movement against gravity and
resistance
 Grade 5- Normal power
 Muscles tested:
 Deltoid (C5)- abduction of shoulder
o Ask the patient to raise the arm by the side.
Examiner must provide resistance at the elbow.
 Biceps (C5-C6)- flexion at the elbow
o Patient should flex the elbow with forearm
supinated.
Examiner must provide resistance at the wrist.
 Triceps (C7)-extension of elbow
o Patient should extend the elbow with forearm
supinated.
o Examiner must provide resistance at the wrist.
 Serratus Anterior (C5, 6, 7)- Scapula protraction
o Make the patient bring both the hands anteriorly and
push them against a wall. In case of paralysis there
will be winging of the scapula.
 External carpi radialis longus (C6)- wrist extension
o Provide support at the forearm.
o Make the patient extend their wrist while the
examiner resists the movements a the dorsum of
hand.

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 Supinator (C6, 7)
o Hold the patient’s hand in a
handshake and ask the patient to
supinate as you resist the action.
 Muscles of the hand
o Finger flexion (C8): make the patient
hold the examiner’s fingers by
making a fist. Ask them to not let go
while the examiner tries to pull the
finger out. Normally the examiner
cannot remove the fingers.
o Finger abduction (T1): make the
patient abduct the fingers. Examiner
must compress them back while the
patient tries to resist it
o Thumb opposition (C8-T1)- make the
patient touch the little finger with the
thumb (opposition). Examiner mist
provide resistance at the thumb.

SENSATION
 Temperature (small fibers/ spinothalamic
pathway): use cold metal (usually not done)
 Light touch (moderately myelinated fibers/ combined pathways) use finger or
cotton and ask patient to tell you when the feeling the touch. The patient should
close their eyes when this is done however the examiner should first show the
patient should feel with their eyes open. Follow the dermatomes.
 Pinprick (small fibers/spinothalamic pathway): use a pin, start distal and move
proximally. The patient should close their eyes when this is done however the
examiner should first show the patient should feel with their eyes open. Follow
the dermatomes.
 Joint position sense (large myelinated fibers/ dorsal column pathway) test a finger
and toe on each limb. Move it up or down and asking the patient to tell you which
direction you moved it. (first show the patient the movement with their eyes
open). Hold the sides of the finger or toe to avoid giving the patient a clue about
the direction of movement.

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 Vibration sense (large myelinated fibers/ dorsal column pathway) use a vibrating
tuning fork placed over bony prominences. With the patient’s eyes closed ask
them to tell you when they cannot feel the vibrations as you stop the tuning fork
from vibrating.
 Two-point discrimination: normally 2mm separation can be recognized as
separate stimuli on the finger tips, but only 1cm separation on the bottoms of the
toes.
COORDINATION (CEREEBELLAR INJURY)
 Finger to nose test: ask the patient to touch his nose
and then the tip of your finger, held at arm’s length in
front of the patient’s face using their index finger.
(move your finger sideways as the patient is doing
this)
 Ask the patient to do rapid alternating movements of
supination and pronation of hands. (Patients with
cerebellar lesions will be unable to perform the test-
this is known as Dysdiadochokinesia)

LOWER LIMB EXAMINATION

INSPECTION
 Inspect the lower limbs and comment on:
 Symmetry of muscles
 Wasting of muscles
 Hypertrophy of muscles
 Contractures
 Fasciculations: these are fine, intermittent and involuntary contractions of
muscles that occur spontaneously
 Abnormal movements
 Note the distribution of wasting or hypertrophy, whether unilateral or bilateral,
predominantly proximal or distal or both.

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PALPATION
INITIAL PALPATION
 Palpate the muscles and feel for consistency.
 Check for muscle bulk and tenderness.
 If the muscles are atrophied, it may feel flabby.
 If the muscles are hypertrophied, may feel firm and resilient.
 In pseudohypertrophy there will be woody consistency.
TONE
 Tone is the resistance offered by muscles when moved passively through its range
of movements. It refers to the tension present in relaxed muscle.
 Before beginning with the examination make sure that the patient is relaxed,
comfortable and not in pain (enquire if
they are in any pain- if so always examine
that limb last).
 Inspect and palpate the muscle to get a
general idea of tone.
 Tone can be tested by moving a part
through its range of movements.
 To examine the tone of the lower limb
make the patient lie in a supine position
and ask the patient to relax the lower
limbs.
 Keep your hand under the patient’s knee
and quickly lift it off the table.
 In a normotonic patient- heel slides up
the table
 In hypotonia- limb is hyperextensible
and feels flabby
 In hypertonia- heel rises off the table

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REFLEXES
 Grading:
 Absent
 1- present (As a normal ankle jerk)
 2- brisk (as a normal knee jerk)
 3- very brisk
 4- clonus
KNEE JERK (L3 & L5)
 Make the patient lie in a supine position
or in the sitting position with the knees
swinging by the side of the bed.
 If the patient is in the supine position,
slightly flex the knee by lifting it with
your forearm.
 Strike the patellar tendon located at the
lower aspect of the patella directly with
the tendon hammer.
 Normally there will be extension of the
knee with contraction of quadriceps
muscle (look at the quadriceps muscles and watch out for contraction).

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ANKLE JERK (S1, 2)
 There are 2 methods to do this
 Method 1:
 Make the patient lie in the supine position
with the knees slightly flexed.
 Gently dorsiflex the foot and strike on the
Achilles tendon.
 Method 2:
 Make the patient kneel on a chair with
knees resting against the back of the chair
and the feet must be out of the chair.
 Dorsiflex the foot slightly and tap on the
Achilles tendon.
 Normally there will be plantar flexion at the
ankle joint due to contraction of
gastrocnemius muscle.

ANKLE CLONUS
 Clonus is rhythmic
sustained involuntary
muscular contraction and
relaxation caused by sudden
passive stretch of muscles
and tendon. It can be elicited
at the ankle and patella.
 Support the patient’s lower
limb at the knee.
 Dorsifelex and partially
evert the foot with sustained
pressure (do not leave the
pressure after dorsiflexion).
 Ankle clonus is felt as
repeated dorsiflexion and plantar flexion at the ankle joint.

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 NOTE: If the knee jerk and ankle
reflex cannot be elicited, make the
patient do the Jendrassik manoeuver
(Reinforcement) and repeat the
examination.
 Ask the patient to make a fist in
both the hands and interlock the
fingers in a hook like form.
 Instruct the patient to clench their
teeth and pull the hands apart
while keeping the fingers locked.
Immediately elicit the reflex.

PLANTAR/BABINSKI
REFLEX (L5, S1,2)
 Make the patient lie in supine
position.
 Fix the foot by holding at the ankle
joint.
 Strike the lateral part of the sole
with a blunt object.
 The strike must begin just above
the heel moving upwards and then
curve inwards (medially) from
little toe to the great toe.
 Normal response (Babinski negative): plantar flexion of great toe, flexion and
adduction of other toes, inversion of foot.
 Babinski positive: dorsiflexion of great toe, abduction (fanning) of other toes,
dorsiflexion of ankle. It is seen in pyramidal tract lesions, meningitis, multiple
sclerosis, poliomyelitis, stroke.

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POWER
 Power of a muscle is tested by instructing the patient to resist
the examiner’s forceful movements or to move a body part
against examiner’s resistance.
 While examining an individual muscle careful positioning
must be done to prevent use of accessory muscles.
 Grading of power:
 Grade 0- No contraction
 Grade 1- Flickering movements
 Grade 2- Active movement with gravity eliminated
 Grade 3- Active movement against gravity
 Grade 4- Active movement against gravity and resistance
 Grade 5- Normal power
 Muscles tested:
 Illiopsoas (L2, L3): hip flexion
o Ask the patient to lie down and raise the legs straight
while the examiner provides resistance at the anterior
aspect of the thigh.
 Biceps femoris (L5, S2): Hip extension
o Make the patient lie down. The examiner must place
a hand under the leg and provide resistance as the
patient pushes the leg down.
 Adduction of hip (L2, L3, L4)
o Adductor (brevis, longus, magnus): examiner must
place hands on inner aspects of thigh and provide
resistance as the patient tires to bring both thighs
together.
 Abduction of hip (Gluteus maximus and minimus L4, 5,
S1)
o Examiner must place hands on outer aspect of thigh
and provide resistance as the patient tries to move the
thighs apart.
 Flexion at knee (Hamstrings S1, S2)
o Provide support at the thighs with one hand and
resistance at the ankle with another hand as patient
tries to flex the knee.

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 Extension at knee (Quadriceps L3, L4)
o Provide support at the thigh with one hand and resistance at the shin as
the patient tries to extend the knee.
 Dorsiflexion at ankle (Tibialis anterior L4, 5)
o Provide resistance at the dorsum of the ankle as the patient tries to pull
the foot upwards.
 Plantar flexion (Grastrocnemius S1, S2)
o Provide resistance at the bottom of the foot as the patient tries to push
down.
SENSATION
 Temperature (small fibers/ spinothalamic pathway): use cold metal (usually not
done)
 Light touch (moderately myelinated fibers/ combined pathways) use finger or
cotton and ask patient to tell you when the feeling the touch. The patient should
close their eyes when this is done however the examiner should first show the
patient should feel with their eyes open. Follow the dermatomes.
 Pinprick (small fibers/spinothalamic pathway): use a pin, start distal and move
proximally. The patient should close their eyes when this is done however the
examiner should first show the patient should feel with their eyes open. Follow
the dermatomes.
 Joint position sense (large myelinated fibers/ dorsal column pathway) test a finger
and toe on each limb. Move it up or down and asking the patient to tell you which
direction you moved it. (first show the patient the movement with their eyes
open). Hold the sides of the finger or toe to avoid giving the patient a clue about
the direction of movement.
 Vibration sense (large myelinated fibers/ dorsal column pathway) use a vibrating
tuning fork placed over bony prominences. With the patient’s eyes closed ask
them to tell you when they cannot feel the vibrations as you stop the tuning fork
from vibrating.
 Two-point discrimination: normally 2mm separation can be recognized as
separate stimuli on the finger tips, but only 1cm separation on the bottoms of
the toes.

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COORDINATION
HEEL TO SHIN
 Ask the patient to run heel of one leg from the
knee, down the shin to the ankle of the other leg.
Repeat it many times.
GAIT AND STANCE
 Balance/ Stance: Test with the Romberg’s test
 Standing with feet firmly together, have the
patient close his or her eyes and see if balance
worsens (do they sway or fall).
 Ask the patient to walk a short distance away from
you and towards you.
 Ask the patient to walk back on heels and then on
their toes
 Abnormal gait patterns include:
 Hemiplegic gait (Circumduction gait): it is seen in patients with unilateral
weakness (hemiparesis). The affected arm is flexed, adducted and internal
rotated, leg is extended with plantar flexion of foot and toes. While walking,
the patient drags the affected leg in a semicircle (circumduction)
 Ataxic gait (cerebellar gait): it is seen in patients with cerebellar lesion. The
gait is similar to that of a person under influence of alcohol. Patient walks
with a broad base and staggering movements. Heel to toe (tandem) walking
will not be possible. When made to stand, the patient sways back and forth
and from side to side.
 Festinant gait (Parkinsonian/shuffling gait): It is seen in patients with
Parkinson’s disease. The patient assumes stooped posture (head and neck bent
forward with flexed knees and upper extremities). Patient walks with typical
rapid, short little steps as if trying to catch gravity (festination).
 Sensory ataxic gait (stomping gait): it occurs in patients with loss of
proprioception (dorsal column lesion). Due to loss of position sense the
patient cannot assess where the feet are and hence will lift the leg very high
and hit the ground forcefully. There is exacerbation of this gait in dark as the
patient cannot see.

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 Steppage gait (neuropathic/equine gait): It is seen in patients with foot drop.
The patient tries to lift the leg high while walking to prevent the foot from
dragging on the floor.
 Waddling gait (Myopathic/Trendelenburg gait): It is caused due to weakness
of proximal muscles of pelvic girdle. When the patient walks the pelvis on
contralateral side drops downwards. To overcome the weakness, the patient
moves upper body and lower leg forwards. Patient walks like a drunk broad
base. It is seen in patients with muscular dystrophy.
 Choreiform gait (hyperkinetic gait): it is seen in patient with Syndeham’s
chorea and Huntington’s chorea. The patient walks with irregular, involuntary
and jerky movements of extremities.

 Ending the examination:

 Thank the patient
 Cover the patient
 Summarize findings, offer an impression and some relevant investigations.

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SEIZURES AND EPILEPSY

 The word “Seizure” comes from the Latin word “sacire” meaning “to take
possession of”.
 A seizure can be defined as abnormal paroxysmal firing of the cerebral neurons.
 A Convulsion is the outward manifestation of a seizure.
 A seizure may be subtle or dramatic and are often sudden in onset with or without
an aura.
 Depending on the distribution of discharge manifestation seizures can be
classified as (newer classification):
 Motor (e.g. automatisms, clonic, tonic movements)
 Non-motor:
o Sensory,
o Autonomic or
o Psychiatric.
 It may be difficult at times to differentiate a seizure from syncope and it is
important to obtain a complete history from any individual who witnessed the
event.
 Generally, patients with syncope will not complain of significant postictal
symptoms (symptoms after the seizure including disorientation, sleepiness,
and muscle aches)
 Epilepsy- is a syndrome characterized by recurrent (2 or more) unprovoked
seizure attacks due to a chronic, underlying process in the brain.
 Epilepsy is age-dependent being highest at the extremes of life, most cases
starting before the age of 20 and after the age of 60.
 A person with a single seizure or recurrent seizures due to correctable or
avoidable circumstances does not necessarily have epilepsy.
 A seizure often has 3 distinct phases:
 Aura: involves alterations in taste, smell, visual perception (flashing lights),
hearing and emotional state (strange gut feeling), Deja vu. This is a partial
seizure that is followed by a larger event. It is common in temporal seizures
and uncommon in generalized seizures.
 Ictus: this is the seizure.
 Postictal: these are events after the seizure, the person experiences
drowsiness and confusion. This is the period in which the brain recovers from
the insult it has experienced.

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ETIOLOGY
 Causes of seizures can be remembered by the mnemonic “VITAMINS”:
 V-vascular (Stroke, bleed, arteriovenous malformations)
 I- infection (meningitis, abscess, encephalitis): encephalitis, toxoplasmosis,
cerebral malaria, neurological cysticercosis.
 T- trauma (especially penetrating): depressed skull fracture, intracranial
hemorrhage and prolonged post traumatic coma are associated with risk of
having seizure disorder. Seizure within 30 days of traumatic brain injury
aren’t classified as epilepsy and conversely seizures occurring many years
later are often not related to injury.
 A- autoimmune (CNS vasculitis)
 M- metabolic (hyponatremia, hypocalcemia, hypomagnesemia,
hypoglycemia, hypoxia, drug overdose/withdrawal, uremia)
 I-idiopathic (account for the majority)
 N-neoplasms: metastatic or primary brain tumors.
 pSyschiatric
 Other causes include:
 Genetic factor: family history
 Perinatal cause: perinatal asphyxia, birth trauma, perinatal infection
 Inflammatory causes: systemic lupus erythematous
 Degenerative disease: alzheimer’s disease
 Drugs: Theophylline, cocaine, Lidocaine
 Developmental: Cerebral palsy, Down syndrome
CLASSIFICATION OF SEIZURES
 Seizures can either be classified as:
 Partial/focal seizures:
o Simple partial seizures (with motor, sensory, autonomic or psychic signs)
o Complex (dyscognitive) partial seizures
o Partial seizures with secondary generalization
 Generalized seizures:
o Tonic-clonic (grand mal)
o Absence (petit mal)
o Tonic
o Myoclonic
o Atonic
 Unclassified: neonatal seizures and infantile spasms

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PARTIAL (FOCAL) SEIZURES
 This is caused by electrical discharge restricted to a limited part of the cortex of
one cerebral hemisphere.
 These type of seizures often suggest an underlying structural disease.
 These arise from localized regions of the brain (involve one hemisphere of the
brain).
 They can either be:
 Simple partial seizures: when consciousness is not impaired e.g. one limb
jerking (a Jacksonian seizure)
 Complex: when consciousness is lost e.g. a temporal lobe seizure.
 Partial with secondary generalization.
 The patient will often complain of involuntary jerking of a finger or hand.
SIMPLE PARTIAL SEIZURES
 These are partial seizures in which consciousness is not impaired.
 Manifestation can be motor, sensory, autonomic or psychiatric.
 Motor manifestation is usually focal clonic or tonic movement of angle of
mouth, finger or thumbs.
 This seizure activity may spread over one side of the body (Jacksonian
march) to involve larger body part (e.g. the convulsive activity can start in
the face, move to ipsilateral arm and then to the leg).
 The visible spread of activity of the seizure is called the march of a seizure.
Local temporal paralysis of the limbs affected sometimes follows-Todd’s
paralysis.
 With some frontal seizures, conjugate gaze deviates away from the epileptic
focus and the head turns (adversive seizure)
 The rest of manifestations include transient sensory abnormalities, flushing
and sweating, pallor or odd feelings.

COMPLEX (DYSCOGNITIVE)PARTIAL SEIZURES (TEMPORAL

LOBE SEIZURES)
 These are focal seizures accompanied by impairment of consciousness.
 They usually arise in the temporal lobe (60%).
 The person is unable to respond appropriately to visual or verbal commands
during the seizure and has impaired recollection or awareness of ictal phase.

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 The seizure frequently begins with an aura, which may manifest with rising
epigastric sensation and nausea, fear, hallucination (e.g. olfactory, visual-
micropsia or macropsia, auditory or gustatory) and complex illusions (e.g.
having experienced a new event, Déjà vu or jamais vu).
 Start of ictal phase is often a sudden behavioral arrest or motionless stare. There
may be complete or partial loss of awareness of surroundings lasting for 1-2
minutes on average (as opposed to 10 seconds in absence seizures)
 This is often accompanied by automatism, which is involuntary automatic
behavior (repeated complex activities like chewing, lip smacking, “picking
movement” of the hands, and display of emotions).
 Post-ictal confusion and transition to full recovery may take minutes to hours.
PARTIAL SEIZURE WITH SECONDARY GENERALIZATION
 These are focal seizures which evolve into generalized seizures. These are usually
tonic-clonic type and difficult to differentiate from primary generalized tonic-
clonic seizure.
 Note: this is the only time a generalized seizure can have an aura.

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TABLE 11.1: PARTIAL SEIZURES
SEIZURE TYPE FEATURES
TEMPORAL  Autonomic symptoms: rising sensation or pain in the abdomen,
LOBE vomiting, flushing, pallor, altered heart rate
 Altered ‘higher’ functions: déjà or jamais vu, amnesia, altered
emotions, delusions, hallucinations (including smell or taste),
dysphasia (also post-ictal)
 Motor symptoms: complex movements e.g. singing, driving,
undressing- and automatisms e.g. lip smacking, fumbling
FRONTAL  Often affects motor complex, causing abnormal movements-e.g.
LOBE eye and head movements, peddling movements-or motor arrest.
 Onset and timing: usually short, quick onset with rapid recovery.
Can be night and come in clusters.
 Jacksonian march: tingling spreading from one area to another e.g.
from the hand up to the face
 Speech symptoms: vocalisations, dysphasia, speech arrest
 Behavioral changes
 Recovery usually rapid but post-ictal phase can feature weakness
(Todd’s palsy)
BENIGN  Commonest epilepsy syndrome in children especially aged 5-10
ROLANDIC years.
EPILEPSY  Starts around the central sulcus (Rolandic Fisssure) which divides
the frontal and parietal lobes.
 Nocturnal seizures: facial twitches including eye flickering and lip
smacking, aphasia, salivation
 No true post-ictal phase but may feel a little weak or have altered
sensation
 Occasionally can progress to Generalized tonic-clonic seizure.
PARIETAL  Often affects somatosensory cortex causing abnormal sensations
LOBE such as tingling or numbness
 Motor symptoms if it spreads to pre-central gyrus
OCCIPITAL  Affects the visual cortex causing visual symptoms such as shapes
LOBE and /or flashes
 Shapes are often more colorful and circular than migraine.

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GENERALIZED SEIZURES
 These occur because of abnormal electrical discharge from both cerebral
hemispheres simultaneously, without any detectable focal onset.
 They are always associated with loss of consciousness or awareness.
GENERALIZED TONIC-CLONIC SEIZURE (GRAND MAL/ MOTOR)
 This is the most common type of seizure.
 Typically seen in genetic epilepsy syndrome and in seizures arising from
metabolic abnormalities (e.g. hyponatremia, alcohol withdrawal, medications,
CNS infections).
 Seizure usually begins abruptly without warning (no aura or focal
manifestations).
 Ictal phase:
 Begins with tonic contraction (stiffening) of muscles throughout the body
which is responsible for loud moan or cry (due to tonic contraction of the
muscles of respiration and the larynx)
 Tonic posturing, respiration is impaired and the patient falls to the ground
and there may be tongue biting due to tonic contraction of the jaw muscles.
 After 10-20 seconds the tonic phase evolves to a clonic phase characterized
by bilateral jerking clonic movement involving the whole body. This lasts for
another 1 minute as they reduce in frequency.
 Post-ictal phase:
 Unresponsiveness, muscle flaccidity, excessive salivation and Tonic- a contracted
frothing of saliva which may cause stridorous breathing and muscle
partial airway obstruction.
 Bladder or bowel incontinence may occur at this point. Clonic: referring to
 Patients gradually regain consciousness over minutes to hours clonus, having
and during this transition there is typically a period of postictal spasmodic
confusion, headache, muscle ache and fatigue that can last for contractions
many hours.
ABSENCE SEIZURES (PETIT MAL/NONMOTOR)
 It is characterized by sudden and brief lapses (<10s) of consciousness without
loss of postural control.
 The seizure typically lasts for only few seconds; consciousness returns as sudden
as it was lost.

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 It usually manifests with blank staring and they may have also subtle motor
manifestations like blinking of the eyes, chewing movements.
 There is no post-ictal confusion.
 The seizure may occur as many as hundreds of times per day.
 It is usually detected by unexplained daydreaming and decline in school
performance.
 Typical absence attacks are never due to acquired lesions such as tumors- they
are a manifestation of primary generalized epilepsy.
 It usually begins in childhood (4-8 years) and it often has a good prognosis with
60-70% of such patients having spontaneous remission during adolescence.
 Children with absence seizures may go on to develop generalized convulsive
seizures.
 It is often characterized by 3Hz spike and slow-wave complexes on EEG.
 Absence seizures are often confused with the complex partial seizures of
temporal lobe epilepsy.
TONIC SEIZURES
 Tonic seizures consist of stiffening of the body, not followed by jerking.
MYOCLONIC SEIZURES
 These are characterized by sudden and brief muscle contraction that may involve
one part of the body or the entire body.
 There is sudden jerk of bilateral limbs (usually arms), face, or trunk. It may lead
to a fall. They can be single or multiple and may occur on waking.
 A normal common physiologic form of myoclonus is sudden jerking movement
observed while falling asleep (Hypnic jerk).
 Pathologic myoclonus is most commonly seen with metabolic disorders
(especially uremia), degenerative diseases of CNS or anoxic brain injury.
 They are usually not epileptic.
ATONIC (AKINETIC) SEIZURES
 Characterized by sudden loss of postural muscle tone, lasting 1 to 2 seconds.
 Consciousness is briefly impaired.
 It usually manifests as a head drop or nodding movement, while a longer seizure
may cause the patient to collapse.
 Primarily seen with inherited forms of childhood epilepsy.

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TRIGEERS
 Decreased sleep
 Alcohol
 Fever
 Flickering or flashing lights
 Drugs or drug withdrawal
DIAGNOSTIC APPROACH/EVALUATION
 The patient’s history and physical examination can aid in the determination of
whether or not a seizure or some other transient event was responsible for the
patient’s symptoms.
 History should include:
 History of the event (Before, during and after)
 Presence of any prodromal symptoms (differentital aura from
presyncopal prodrome)
 Description of seizure by reliable observer (convulsion, automatism
vs brief syncopal blackout and pallor)
 Post ictal symptoms (Post-ictal confusion and headache vs rapid
recovery in syncope)
 Urinary incontinence, myalgia and tongue bite or oral lacerations are
clues to the proper diagnosis
 History of suggesting cause and risk factors (triggers):
 Febrile convulsion (history of high grade fever)
 CNS infection (current/ previous)
 Head injury
 Stroke
 Developmental abnormality
 HIV status
 Family history
 Social history (like alcohol abuse, recent travel, not sleeping under a
mosquito net (malaria), sleep deprivation, prolonged standing)
 Diet (pork intake and generally electrolyte intake)
 Past medical history: Previous seizures
 Medications

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 Physical examination: features that should be looked for include:
 Skin for evidence of neurofibromatosis
 Organomegaly: metabolic storage disease
 CVS/ Carotid artery: stroke
 Complete neurological exam
INVESTIGATIONS
ELECTROENCEPHALOGRAPHY (EEG)
 This is the most useful test in diagnosis of seizure disorder.
 It should be performed while the patient is asleep and awake.
 Abnormal EEG supports the diagnosis of seizure and may give information about
the type of seizure.
 Abnormal EEG is not adequate for diagnosis of seizure and normal EEG can be
found in epileptics.
NEUROIMAGING
 Preferably MRI: may help to see any space occupying lesion in the brain.
 A CT scan of the head can also be used.
 MRI and CT scans are indicated to rule out a structural lesion as the cause of the
seizure
OTHER ROUTING LABORATORY ASSESSMENT
 Full blood count: to rule out infections
 Urinalysis
 Serum glucose: rule out hypoglycemia
 Liver function test
 Renal function test
 Electrolytes: hyponatremia, hypocalcemia and hypomagnesemia
 Blood arterial gases: to rule out hypoxia
 Lumbar puncture: when infection or inflammatory disease is a concern
 Toxicological screening
DIFFERENTIAL DIAGNOSIS FOR SEIZURE
 Syncope
 Psychogenic seizure (hysteric conversion)
 Transient ischemic attack
 Migraine

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COMPLICATIONS
 Status epilepticus
 Accidents
 Hypoxic brain damage
 Mental retardation and impairment of intellectual function
 Sudden death
 Psychosocial (social stigma)
MANAGEMENT
EMERGENCY MEASURES
 The first step in the treatment of any acutely seizing patient is to secure the
airway, breathing and circulation.
 Airway- ensure the airway is patent, suction any secretions, During the
seizure place the patient on the side with a mouth gag to prevent them from
biting their tongue.
 Breathing- ensure the patient is breathing
 C-gain venous access
 Monitor vitals.
 During the ictal phase immobilize the main large joints
 Most seizures last only minutes and end spontaneously. A prolonged seizure (>5
min) or repeated seizures may be treated with rectal diazepam, IV lorazepam or
buccal midazolam.
 5-10mg IV diazepam
 Once this is achieved the next step is to simultaneously evaluate and treat any
precipitating cause of seizure. If a reversible cause is identified, it should be
treated aggressively.
 The goal is:
 Complete control of seizure
 Prevent development of complications and socioeconomic consequences
 Management includes:
 Treatment of underlying condition: metabolic causes (hypoglycemia,
hyponatremia or drug intoxication) should be corrected. Structural CNS
lesions like tumors may be removed surgically.
 Avoidance of precipitating factor: maintain normal sleep schedule, avoid
taking excess alcohol, reduce stresses using physical exercise, meditation or
counseling.

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 Suppression or control of recurrent seizure: Antiepileptic drug therapy
 If the patient continues to seize manage as status epilepticus.
 In patients with first-time seizure, anticonvulsant therapy should be started only
if the patient has an abnormal neurologic exam, presented with status epilepticus,
has a strong family history of seizure or has an abnormal EEG. Otherwise first-
time seizures are generally not treated with long term anticonvulsant therapy.
 Anti-epileptic drugs can be started if:
 There are recurrent seizures of unknown cause
 Single seizure due to:
o Identified CNS lesion (tumor, infection, trauma)
o With abnormal neurologic exam
o Presenting as status epilepticus
o With post-ictal Todd’s paralysis
o With strong family history of seizure disorder
o With abnormal EEG
 Anticonvulsant therapy is not often initiated in patients with a single, unprovoked
convulsion, a normal neurologic examination and a normal neuroimaging study
and EEG unless they experience a second seizure.

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ANTIEPILEPTIC DRUGS
 Principles in the introduction of antiepileptic drugs:
 Introduce antiepileptic drugs at low dose and slowly titrate upwards until the
seizures are controlled or side effects become unacceptable.
 Aim for monotherapy- 70% of patients will have seizure control with a single
drug.
 If seizures are not controlled with first antiepileptic drugs, gradually
introduce second agent and then slowly withdraw the first drug. If still not
seizure free then combination therapy is required.
 Epilepsy is one of the few disorder where non-generic (‘brand name’)
prescribing is justified to ensure consistent drug levels.
 Routine monitoring of drug levels is not needed and should be reserved for
assessing compliance and toxicity. Measuring sodium valproate levels is
rarely useful as levels fluctuate widely.
 There are interactions between antiepileptic drugs (and with other
medications) e.g. between sodium valproate and lamotrigine. New generation
drugs have fewer interactions.
 Phenytoin is no longer considered as a first line antiepileptic drug. It is used
principally in emergency control of seizures (status epilepticus)
Seizure type Drug of choice
Partial seizure First line: Carbamazepine and phenytoin
 Simple
 Complex Alternative: Valproic acid and Lamotrigine
 With secondary generalization  Therapy may be stopped if the patient has
been free of seizures for 2-3 years.
Generalized tonic-clonic seizure First line: Valproic acid and lamotrigine
Alternative: carbamazepine, phenobarbitone or
phenytoin
Absence seizures First line: Valproic acid, Ethosuximide

Second line: lamotrigine, clonazepam

Atypical absence, myoclonic, atonic First line: valproic acid

Second line: Lamotrigin, clonazepam,
Topiramate

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 Carbamazepine
 Dose: 100-200mg PO BD and gradually increase the dosage by 200mg
Every week until the best response is achieved or maximum dose of
1600mg daily.
 Side effects:
o Aplastic anemia
o Dizziness, drowsiness
o Skin rash
o Transient diplopia
 Valproic acid: can be used for all types of epilepsy
 Dose: 600mg PO OD/BD then increased in steps of 150-300g every 3 days,
maintenance 1-2g daily.
 Side effects:
o Menstrual disturbance
o Extrapyramidal disorders
o Aggression
o Anemia
o Confusion, confusion, nystagmus
o Transient hair loss (regrowth may be curly)
o Weight again
 Lamotrigin
 Dose 25mg PO OD daily for 14 days, then increase to 50mg OD daily for
further 14 days then increased in steps of up to 100mg every 7-14 days.
Maintenance 100-200mg daily in 1-2 divided doses, increased necessary up
to 500mg daily, dose titration should be repeated if restarting after internal
of more than 5 days
 Side effects:
o Blurred vision, nystagmus, diplopia
o Anemia
o Exacerbation of Parkinson’s disease
o Rash
o Tremor
 Phenytoin
 Dose 100mg BD or TDS which may be gradually increased to a maximum
of 200mg PO TDS (i.e. 600mg daily)
 Side effects:
o CNS: nystagmus

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o Gingival hyperplasia
o Coarsening of facial features
o Toxic hepatitis and liver damage
STATUS EPILEPTICUS
 This is a seizure lasting more than 5 minutes (used to be 30-35 minutes) or 2 or
more seizures without recovery of consciousness between them over a similar
period. It is a medical emergency.
 Any seizure lasting more than 5 minutes is unlikely to remit spontaneously and
carries the risk of permanent neuronal injury.
 It usually occurs in known epileptics but can be a presenting complaint.
 The longer the duration of status, the greater the risk of permanent cerebral
damage.
 Rhabdomyolysis may lead to acute kidney injury in convulsive status epilepticus.
 Not all status is convulsive. In absence status, for example status is non-
convulsive- the patient is in a continuous, distant, stuporose state. Focal status
also occurs.
 Epilepsia partialis continua is continuous seizure activity in one part of the body
such as finger or a limb without loss of consciousness. This is often due to cortical
neoplasm or in the elderly a cortical infarct.
 Status epilepticus can be precipitated or caused by:
 Non-compliance with antiepileptic drugs
 CNS infections: encephalitis
 Metabolic derangement: electrolyte imbalance, altered glucose
 Alcohol
 Withdrawal
 Tumors
 Trauma
 Stroke
 Refractory epilepsy
CLINICAL FEATURES
 Generalized status epilepticus is obvious when the patient is having convulsions,
however after 30-35 minutes of uninterrupted seizure, the signs may become
increasingly subtle.
 Seizures are often tonic-clonic with fever and sweats.

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 Patients may have mild clonic movement of only fingers or fine, rapid
movements of the eyes.
 Can also be non-convulsive, characterized by confusion, altered mental status,
odd behavior and derealization.
COMPLICATIONS OF STATUS EPILEPTICUS
 Aspiration
 Hypoxia (death may result from cerebral hypoxia)
 Metabolic acidosis
 Hypotension
 Hyperthermia
 Rhabdomyolysis and associated myoglobinuria (acute kidney injury)
 Multiple physical injuries including vertebral bone fracture
 Irreversible neuronal injury
TREATMENT
 ABCs
 Keep airway patent and maintain breathing
 Administer oxygen, monitor ECG, BP
 Secure IV line and take blood for Labs: Draw labs for metabolic
abnormalities e.g. glucose, electrolytes (sodium, potassium, chloride,
bicarbonate, calcium), drug screen, anticonvulsant levels
 Pharmacologic:
 Administer thiamine (vitamin B1) and glucose
 Thiamine: 25-100mg PO OD for mild deficiency or 200-300mg PO
daily in divided doses. (Intravenous administration should be by
infusion over 30 minutes)
 Glucose: 10-25g (20-50ml 50% solution or 40-100ml of 25% IV)
 Benzodiazepines are first line anticonvulsants for status epilepticus (Early
status- up to 30 mins).
 Give lorazepam IV 4mg slow bolus (3 seconds). Repeat once after 10
min if necessary (beware of respiratory arrest) or
 Give Diazepam IV 5-10mg IV. Repeat once after 10 min if necessary
 If seizure continues (Established Status 30-90mins):
 Give phenytoin: 15-20 mg/kg IV diluted to 10mg/ml in saline into a
large vein at 50mg/min (ECG monitoring required) or

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 Fosphenytoin: this is a pro-drug of phenytoin and can be given faster
than phenytoin. Doses are expressed in phenytoin equivalents (PE):
Fosphenytoin 1.5mg=1mg phenytoin. Give 15mg/kg (PE)
fosphenytoin (15mg x 1.5=21.5 mg) diluted to 10mg/ml in saline at
50-100mg (PE)/min
 If seizure persists, the next step is to give a second loading dose of phenytoin
or fosphenytoin using an additional 5-10mg/kg IV load or move directly to
the next step.
 If seizure continues, the next step is to administer phenobarbital, or valproate
o Phenobarbital 10mg/kg IV diluted 1 in 10 in water for injection at <100
mg/min or
o Valproate IV 25mg/kg
 If patient is still seizing, then general anesthesia is needed (Refractory status-
over 90mins)
o Only in intensive care setting, intubation and ventilation usually required
o Profofol bolus 2mg/kg, repeat followed by continuous infusion of 5-
10mg/kg/hr
o Thiopentone and midazolam infusions may also be used
o Continuous EEG monitoring used to assess efficacy of treatment- aim for
EEG burst suppression pattern
o Reinstate previous anti-epileptic medication via NG tube
o Establish diagnosis: CT or MRI may reveal an underlying cause
o Remember: 25% of apparent status turns out to be pseudostatus.

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INFECTIONS OF THE CNS

MENINGITIS
 This is inflammation of the leptomeninges (the pia and arachnoid matter).
CLASSIFICATION
 Based on etiology:
 Infectious
 Bacterial meningitis: Neisseria meningitidis, Streptococcus
pneumoniae (accounts for 70% of acute bacterial meningitis outside
the neonatal period), Staphylococcus aureus, Group B Streptococcus,
Listeria monocytogenes, Gram-negative bacilli e.g. E. coli,
Mycobacterium tuberculosis, Treponema pallidum, Hemopilus
influenza B (Hib)-although cases are now rare due to immunization,
and Pseudomonas aeruginosa.
 Viral meningitis (Aseptic meningitis): Enteroviruses (ECHO,
Coxsackie), Arboviruses, Polio virus (mainly eradicated worldwide),
Mumps virus, herpes simplex, Human immunodeficiency virus
(HIV), Epstein-Barr virus, Cytomegalovirus (CMV), measles,
varicella zoster virus (VZV), Adenovirus, Influenza A, parainfluenza,
rabies and rubella virus.
 Fungal meningitis: Cryptococcus neoformans, Candida albican,
Coccidiodes immitis, Histoplasma capsulatum, Blastomyces
dermatitidis.
 Parasitic: Plasmodium (malaria)
 Non-infectious: malignant meningitis, intrathecal drugs and blood following
subarachnoid hemorrhage.
 Based on onset:
 Acute meningitis: usually caused by typical bacterial causes of meningitis. It
has a sudden onset.
 Chronic meningitis: it is usually caused atypical bacterial causes of
meningitis e.g. TB, Secondary syphilis and fungi e.g. Cryptococcus,
Coccidiodes, Histoplasma, Blastomyces. It may also be caused by non-
infectious causes such as CNS or metastatic neoplasms, leukemia,
lymphoma, vasculitis, sarcoid and subarachnoid/subdural bleeds. Symptoms
last from weeks to months with persistent CSF pleocytosis- WBCs in CSF
(usually lymphocytic).

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BACTERIA MENINGITIS
 Bacterial meningitis is the most common form of suppurative CNS infection.
 Bacterial meningitis is fatal unless treated.
 Micro-organisms reach the meninges either by:
 Droplet infection through the upper airways: e.g. Neisseria meningitidis
 Direct extension from ears (otitis media), nasopharynx (sinusitis), cranial
injury or congenital meningeal defect.
 By bloodstream spread (hematogenous spread).
 Immunocompromised patients are at risk of infection by unusual organisms.
 In acute bacterial meningitis the pia-arachnoid is congested with polymorphs. A
layer of pus forms. This may organize to form adhesions causing cranial nerve
palsies and hydrocephalus.
 In chronic infection (e.g. TB) the brain is covered in a viscous grey-green exudate
with numerous meningeal tubercles. Adhesions are invariable.
 Cerebral edema occurs in any bacterial meningitis.
ETIOLOGICAL AGENTS
 The causes of bacterial meningitis vary with age:
 Infants (<1 year): E. coli, Group B streptococcus, Listeria monocytogenes
are the commonest causative agents.
 Young children/toddler (age 1-6 years): Haemophilus influenza,
Meningococcus account for more than 50% of cases.
 Adolescents and Adults: Meningococcus, Pneumococcus are the commonest
etiologies
 Immunocompromised and cancer patients: Listeria, Staphylococcus,
Pseudomonas aeruginosa etc.
CLINICAL FEATURES
 Incubation period for meningococcal meningitis may range from 1-10 days
however most clinical manifestation occurs within 2-4 days.
 It may manifest as an acute fulminant illness that progresses rapidly in few hours
or as a subacute infection that progressively worsens over several days.

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 Meningitis triad: Seen in over 90% of patients.
 Neck stiffness (pathognomonic sign of meningeal irritation and is present
when the neck resists passive flexion)
 Headache
 Fever
 Alteration in mental state occurs in over 75% of patients and can vary from
drowsiness, lethargy to coma (loss of consciousness).
 Photophobia (avoiding light), Nausea and vomiting (projectile) are common
symptoms.
 Seizures can occur as part of the initial presentation of bacterial meningitis or
during the course of the illness in 20-40% of patients.
 In acute bacterial infection there is usually intense malaise, fever, rigors, severe
headache, photophobia and vomiting developing within hours or minutes.
 In meningococcal meningitis of sudden onset with severe course, patients
develop diffuse erythematous maculopapular rash which rapidly becomes
petechial, purpural or bullous lesions.
 The petechiae are found on the trunk, lower extremities, in the mucous
membrane and the conjunctiva and occasionally on the palms and soles.
 Meningococcemia may be associated with vascular collapse (Waterhouse-
Friderichsen syndrome)
 Meningeal signs:
 Neck stiffness: when head is flexed passively
 Kerning’s sign: elicited with the patient in the supine position. The thigh is
flexed on the abdomen, with the knee flexed, attempts to passively extend the
knee elicit pain when meningeal irritation is present. (with hip and knee
flexed, pain limits passive extension of the knee).
 Brudzinski’s sign: upon passively flexing the head, one notices flexion of
both legs at the knees.
 Cranial nerve abnormalities may occur (facial nerve palsy, oculomotor nerve
palsy and occasional deafness).
 Note: the classic meningeal signs may not be seen in infants, older people
and patients in coma. The sensitivity of the Kernig’s and Brudzinski’s sign are
uncertain. Both may be absent or reduced in very young or elderly patients,
immunocompromised individuals or patients with a severely depressed mental
status. The high prevalence of cervical spine disease in older individuals may
result in false-positive tests for nuchal rigidity.

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 Clinical clues:
 Petechial rash- Meningococcal infection
 Skull fracture, ear disease, congenital CNS lesion- pneumococcal infection
 Immunocompromised patients- HIV opportunistic infection
 Rash or pleuritic pain- Enterovirus infection
 Recent travel- malaria
 Occupational (work in drains, canals, polluted water, recreational
swimming): leptospirosis. Features: myalgia, conjunctivitis, jaundice
DIAGNOSIS AND INVESTIGATIONS
 Principle of diagnosis:
 History and Physical examination
 Investigate possible source of infection (pneumonia, otitis media, sinusitis,
head injury)
 CSF analysis and identification of the organism from CSF and blood
(culture, PCR etc.)
 Investigations:
 Lumbar puncture and CSF analysis is done if there are no clinical suspicion
of a mass lesion. If the is a suspected mass lesion an immediate CT scan must
be performed because coning of the cerebellar tonsils may follow LP.
o CSF Microscopy, Culture and Sensitivity: Stains used include Gram
Stain (For Gram-positive intracellular diploccoci- pneumococcus, Gram-
negative cocci-meningococcus), Ziehl-Neelsen stain (AFB stain for TB),
India ink (for fungi)
o CSF biochemistry
o CSF PCR
 Full blood count (with differential count), Serum glucose and Blood cultures
 RPR for Syphilis and RDT for malaria
 Chest and skull X-ray when appropriate.
 CT scan/MRI (rule of space occupying lesion)

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Feature Normal Bacterial meningitis Viral meningitis Tuberculous
meningitis
Pressure 50-250mm Normal/increased Normal Normal/increased
of water
Appearance Crystal Turbid Clear Cob-web appearance
clear
Cell count/ <10 RBCs Several thousands Several hundreds Several hundreds
microliter <5 WBCs (1000-5000 (10-2000 (50-5000
polymorphs) lymphocytes) lymphocytes)
Cell type None Granulocytes Lymphocytes Lymphocytes and
(Polymorphs) monocytes
Glucose 2/3 to ½ Decreased (<30mg/dl) Normal Decreased
blood < ½ blood glucose > ½ blood (<30mg/dl)
glucose glucose < ½ blood glucose
Protein 0.2-0.4 g/l Increased (>120mg/dl) Normal (0.4- Increased (>120
0.5-2.0g/l 0.8g/L) mg/dl)
0.5-3.0g/l
Lactate >3.5mmol/L <3.5 mmol/L >3.5mmol/L
dehydrogenase

DIFFERENTIAL DIAGNOSIS
 It may be difficult to distinguish between the sudden headache of subarachnoid
hemorrhage, migraine and acute meningitis.
 Meningitis should be considered seriously in anyone with headache and fever and
in any sudden headache.
 Neck stiffness should be looked for- it may not be obvious.
 Chronic meningitis sometimes resembles an intracranial mass lesion with
headache, epilepsy and focal signs.
 Cerebral malaria can mimic bacterial meningitis.

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MANAGEMENT
EMPIRICAL ANTIBIOTIC THERAPY
 Antibiotics should be initiated immediately before the result of the CSF gram
stain and culture are known as bacterial meningitis is a medical emergency.
 Antibiotics should be given intravenously at higher doses:
 In adults without underlying disease: Ceftriaxone 2 g IV BID plus Ampicillin
2g IV QID for 2 weeks.
 Crystalline Penicillin 3-4 million IU, IV every 4 hours plus
Chloramphenicol 1g IV QID (50-100mg/kg 6 hourly) are alternative
antibiotics.
 Ampicilin 100-200mg/kg IV QID (6 hourly)
 Patient with ENT infection or head injury: Ceftriaxone 2g IV BID and
Vancomycin 1g IV BID + treatment of the underlying cause.
 Hospital acquired infection: Ceftriaxone 2g IV BID plus Vancomycin 1g IV
BID plus Gentamycin (80mg TDS)
 Immunodeficient patients: Ceftriaxone 2g IV BID plus Vancomycin 1g IV
BID plus Ampicillin (2g IV QID)
 Intravenous antibiotics should be put in place for the first 72 hours or for as long
as the patient is unconscious and then changed to the oral form. Treatment should
generally be continued for at least 1 week after the fever subsides and the CSF
returns towards normal.
SPECIFIC ANTIBIOTIC THERAPY
 N. meningitidis: Even though Ceftriaxone or Cefotaxim provide adequate
empirical coverage, Penicillin G remains the drug of choice (Crystalline
Penicillin 3-4 million IU, IV every 4 hours for 7-10 days)
 Pneumococcal meningitis: antibiotic therapy initiated with cephalosporins plus
vancomycin (Ceftriaxone 2g IV BID and Vancomycin 1g IV BID for 2 weeks)
 H. Influenza: Ceftriaxone 2g IV BID for 1-14 days may be enough.
Chloramphenicol 1gm IV QID may be an alternative antibiotic for patients who
may not afford ceftriaxone.
 TB: antituberculous drugs- Rifampicin, Isoniazid and pyrazinamide- for at least
9 months. Ethambutol should be avoided because of its eye complications.
Adjuvant corticosteroids e.g. prednisolone 60mg for 3 weeks are now
recommended (often tapered off)

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GENERAL MEASURES AND ADJUNCT THERAPY

 Resuscitate and give O2.
 Regulate water and electrolyte balance.
 Treat increased intracranial pressure:
 Elevation of the patients’ head to 30-45o
 Intubation and hyperventilation (till PaCO2 is lowered to 25-30mmHg)
 Mannitol IV infusion: 20% mannitol IV 5ml/kg over 300 minutes and a
corticosteroid 4 hourly (e.g. prednisolone 1mg/kg, dexamethasone
0.15mg/kg or hydrocortisone 4mg/kg).
 Steroids:
 Dexamethasone: when imitated before antibiotic therapy reduces the number
of unfavorable outcomes e.g. death and neurologic complications. It is

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advantageous in children predominantly with meningitis due to H. influenza
and Pneumoniae.
 Dose: 10mg IV 15-20 minutes before the first dose of antibiotics and 4 mg
IV QID for 4 days.
 Patients with meningococcal meningitis should be isolated.
 Thromboembolism prophylaxis.
COMPLICATIONS
 Brain edema
 Hydrocephalus
 Brain abscess
 Septic vein thrombosis
 Hearing impairment
 Fulminant meningococcal sepsis: Waterhouse-Friedrichsen syndrome, a clinical
condition resulting from hemorrhagic necrosis of the adrenal gland, with multi-
organ failure. Patients are hypotensive or in shock. DIC with skin and mucosal
purpura and bleedings are commonly associated features.
CHEMOPROPHYLAXIS
 In case of N. meningitides, all close contacts to the patient should be given
chemoprophylaxis with:
 Rifampicin 600mg PO BID for 2 days in adults and 10mg/kg PO BID for
children >1 year
 Ciprofloxacin 750mg PO stat can be given as an alternative for adults.
 MenC, a meningococcal C conjungated vaccine is part of many countries’
immunization programme and often given to case contacts.
 A combined A and C meningococcal vaccine can be given to people in endemic
regions e.g. Africa and Asia. A quadrivalent ACWY vaccine for specific events
e.g. the Hajj and Umrah in mecca can be given.
 Note: there is no vaccine for Group B.
 A polyvalent pneumococcal vaccine as well as HiB (Haemophilus influenzae)
vaccine is given routinely in childhood.

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VIRAL MENINGITIS
 Viral meningitis is almost always benign, self-limiting condition lasting 4-10
days.
 Headache may follow for some months. There are no serious sequelae unless an
encephalitis is present.
 In viral meningitis there is a predominantly lymphocytic inflammatory CSF
reaction without pus formation, Polymorphs or adhesions. There is little or no
cerebral edema unless encephalitis develops.
ETIOLOGY
 It is commonly caused by:
 Enteroviruses: Coxsackie, echovirus
 Herpes simplex, HSV (type 2 more commonly causes meningitis than HSV
1)
 Mumps
 Measles
 Poliomyelitis
 HIV
 Epstein-Barr virus (EBV)
CLINICAL FEATURES
 Meningitis triad: headache, neck stiffness and fever. Photophobia and vomiting
are often present.
 In viral meningitis there are less prominent meningitic signs.
 It is benign, self-limiting lasting 4-10 days.
 Headache may follow for some months.

DIAGNOSIS AND INVESTIGATIONS

 Principle of diagnosis:
 History and Physical examination
 Investigate possible source of infection (pneumonia, otitis media, sinusitis,
head injury)
 CSF analysis and identification of the organism from CSF and blood
(culture, PCR etc.)

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 Investigations:
 Lumbar puncture and CSF analysis is done if there are no clinical suspicion
of a mass lesion. If the is a suspected mass lesion an immediate CT scan must
be performed because coning of the cerebellar tonsils may follow LP.
o CSF Microscopy, Culture and Sensitivity: Stains used include Gram
Stain (For Gram-positive intracellular diploccoci- pneumococcus, Gram-
negative cocci-meningococcus), Ziehl-Neelsen stain (AFB stain for TB),
India ink (for fungi)
o CSF biochemistry
o CSF PCR
 Full blood count (with differential count), Serum glucose and Blood cultures
 RPR for Syphilis and RDT for malaria
 Chest and skull X-ray when appropriate
 CT scan and MRI to rule of space occupying lesion
Feature Normal Bacterial meningitis Viral meningitis Tuberculous
meningitis
Pressure 50-250mm Normal/increased Normal Normal/increased
of water
Appearance Crystal Turbid Clear Cob-web appearance
clear
Cell count/ <10 RBCs Several thousands Several Several hundreds
microliter <5 WBCs (1000-5000 hundreds (10- (50-5000
polymorphs) 2000 lymphocytes)
lymphocytes)
Cell type None Granulocytes Lymphocytes Lymphocytes and
(Polymorphs) monocytes
Glucose 2/3 to ½ Decreased (<30mg/dl) Normal Decreased
blood < ½ blood glucose > ½ blood (<30mg/dl)
glucose glucose < ½ blood glucose
Protein 0.2-0.4 g/l Increased (>120mg/dl) Normal (0.4- Increased (>120
0.5-2.0g/l 0.8g/L) mg/dl)
0.5-3.0g/l
Lactate >3.5mmol/L <3.5 mmol/L >3.5mmol/L
dehydrogenase

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MANAGEMENT
 Self-limiting.
 Supportive therapy:
 Check viral signs, restrict fluid and give antipyretics
 Treat seizures and/or give prophylactic therapy
 Antiviral therapy can be given:
 IV acyclovir (10mg/kg TDS for 14-21 days)
 Gancyclovir (5 mg/kg BID) or Foscarnet (60mg/kg TDS) are especially
recommended for CMV infections.
CHRONIC MENINGITIS
 Tuberculous meningitis (TBM) and cryptococcal meningitis commence typically
with vague headache, lassitude, anorexia and vomiting.
 Out of 39 known Cryptococcal species only 2 cause disease C. neoformans
neoformans and C. neoformans gatti
 Cryptococcus can also cause pulmonary, cutaneous and disseminated forms
of illness.
 The neoformans variant dominates in AIDS patients. It can be isolated from
the environment although it is most often found in pigeon excreta. Growth
from soil appears to be enhanced by certain nitrogenous compounds like
creatinine in pigeon droppings
 Birds are not infected although their crop is heavily infested
 Acute meningitis can occur but is unusual.
 Meningitic signs often take some weeks
to develop.
 Drowsiness, focal signs (e.g. diploplia,
papilloedema, hemiparesis) and seizures
are common.
 Syphilis, sarcoidosis and Behçet’s (a
rare disorder causing inflammation of
blood vessels) also cause chronic
meningitis.
 In some cases, the organism is never
identified.

Figure 52: Cryptococcus neoformans (India Ink)

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 Investigations are the same as those of Bacterial meningitis.
 Prompt Lumbar puncture with measurement of CSF opening pressure (which
is usually high in Cryptococcal meningitis) and rapid CSF cryptococcal
antigen (CSF CrAg) assay or rapid serum Cryptococcal antigen is the
preferred diagnostic approach for C. meningitis.
o Note: Serum CAT (Cryptococcal antigen test) remains positive for
months after therapy even when CSF smears are negative.
 Fungal culture remains the gold standard for confirmation of the diagnosis of
initial Cryptococcal disease, confirmation of relapses or cases refractory to
treatment and adequate response to treatment.
 Brain imaging, usually with MRI, may show meningeal enhancement,
hydrocephalus and tuberculomas although it may remain normal.
 Treatment:
 TB: Rifampicin, Isoniazide and Pyrazinamide for 12 months.

MANAGEMENT OF CRYPTOCOCCAL MENINGITIS

 Management is divided into 3 phases:
 Induction: this is for 14 days (at least 10 days)
o The drug of choice is amphotericin B combined with fluconazole or
flucytosine.
o Flucytosine has been associated with increased risk of bone marrow
toxicity and clinical research showed no increased benefit when
compared to amphotericin B and fluconazole.
o In settings where amphotericin B is not available, regimens containing
fluconazole combined with flucytosine or high dose fluconazole
monotherapy are alternatives.
o Amphotericin B 0.7mg/kg slow infusion over 4 hours + Fluconazole
800mg PO daily, to be given over 10-14 days or
o Amphotericin B 0.7mg/kg slow infusion over 4 hours + Flucytosine
100mg/kg/day every 6 hours
o Amphotericin B daily dosage should not exceed 1mg/kg for adults or
children.

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o Note: fluconazole is also effective for Cryptococcus infection, but should
not be used as monotherapy particularly in the initial
period of treatment. Types of Amphotericin B
 Consolidation: This is for 8-10 weeks 1. Amphotericin B Lipid
o Oral fluconazole is the recommended option. complex (ABLC)
o Oral fluconazole 400-800mg/day for at least 8-10 2. Liposomal
weeks. Amphotericin B (L-
 Maintenance (Secondary prophylaxis): variable AB)
o Oral fluconazole is the recommended option 3. Amphotericin B
o Long-term maintenance for HIV positive individuals: colloidal dispersion
Oral fluconazole 200mg/day until CD4 count >200 (ABCD)
for at least 6 months. It may be reasonable to stop
prophylaxis if the CD4 count increase to more than
100-200 for more than 6 months in response to antiretroviral.
o Repeat LP until symptoms resolve in patients with coma or other signs
of elevated ICP.

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Drugs Pre-hydration +
Induction phase Consolidation Maintenance/secondary
available electrolyte replacement (2 weeks) phase (8 prophylaxis
+ toxicity
Options weeks)
monitoring/management Options
Amphotericin Available a. Amphotericin Fluconazole Fluconazole 200mg
B ± 0.7-1 400- daily
flucytosine mg/kg/day + 800mg/day
Flucytosine
100mg/kg/day
b. Amphotericin
0.7 mg/kg/day
+ fluconazole
800mg/day
Amphotericin Not available for full 2 Amphotericin Fluconazole
B weeks induction period 0.7-1mg/kg/day 800mg/day
short course (5-7
days) +
fluconazole
800mg/day (2
weeks)
Amphotericin Not available a. Amphotericin Fluconazole
B not 1200 mg/day 800mg/day
available ± Flucytosine
100mg/kg/day
b. Fluconazole
1200mg/day
alone

Side effects of
 In HIV patients initiation of ART should be delayed due to high Amphotericin B:
risk of IRIS. It should be delayed until there is evidence of a
sustained clinical response to anti-fungal therapy and  Arrhythmias
 After 2-4 weeks of induction and consolidation treatment  Renal dysfunction
with amphotericin B containing regimens combined with  Hypokalemia
flucytosine or fluconazole or  Hypomagnesemia
 After 4-6 weeks of induction and consolidation treatment  Abnormal liver
with high dose oral fluconazole regimen. disorder
 Thrombocytopenia
and anemia

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 Pre-requisites to treatment
 Always check LFTs, U&Es, Creatinine and FBC before starting patient on
antifungals.
o Serum potassium and creatinine should be checked twice weekly,
especially in the second week of amphotericin B administration
o Hemoglobin should be checked weekly
 Careful attention to fluid monitoring of intake and output and daily weight
 Pre-emptive hydration and electrolyte supplementation
o 1 liter of normal saline solution with 1 ampoule (20 mmol) of KCL over
2-4 hours before each controlled infusion of amphotericin B (with 1 L of
5% dextrose) and one to two 8mEq KCL tablets orally twice daily.
o An additional one 8 mEq KCL tablet twice daily may be added during
the second week.
o If available magnesium supplementation should be provided (two 250mg
tables of magnesium trisillicate BD)
o Potassium replacement should not be given in patients with pre-existing
renal impairment or hyperkalemia.
o If saline is unavailable then other intravenous rehydration solutions that
contain potassium can be used e.g. Darrow’s or Ringer’s lactate
solutions.
o A test dose of amphotericin B is not recommended.
 Also given an antiemetic (Promethazine) and steroid (hydrocortisone) as
premedication
 Management
o If significant hypokalemia (Potassium <3.3 mmol/L) increase potassium
supplementation to 2 KCL ampoules (40mmol) or one or two 8mEq KCL
tables TDS. Monitor potassium daily.
o If hypokalemia remains uncorrected, double magnesium oral
supplementation.
o If creatinine increased by more than 2 fold from baseline value either
temporary omission of an amphotericin B dose or increase pre-hyrdration
to 1 L 8 hourly. Once improved, restart at 0.7mg/kg/day and consider
alternate day amphotericin B.
o If creatinine remains elevated discontinue amphotericin B and continue
with fluconazole at 1200mg/day. Monitor creatinine daily.

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MALIGNANT MENINGITIS
 Malignant cells can cause subacute or chronic non-infective meningitis process.
 A meningitic syndrome, cranial nerve lesions, paraparesis and root lesions are
seen often in confusing and fluctuating patterns.
 The CSF cell count is raised, with high protein and low glucose.
 Treatment with intrathecal cytotoxic agents is rarely helpful.
ENCEPHALITIS
 This is acute inflammation of brain parenchyma; it is usually viral.
 In viral encephalitis fever (90%) and meningism are usual but in contrast to
meningitis the clinical picture is dominated by brain parenchyma inflammation.
 Personality and behavioral change is a common early manifestation which
progresses to a reduced level of consciousness and even coma.
 Seizure (focal and generalized) are very common and focal neurological deficits
e.g. speech disturbance often occurs (especially in herpes simplex encephalitis).
VIRAL ENCEPHALITIS
 This is inflammation of the brain parenchyma, with or without involvement of
the meninges, caused by virus.
 The spinal cord and/or nerve roots may also be rarely involved.
ETIOLOGY
 Common: Arboviruses, Enteroviruses, HSV-1, Mumps
 Less common: CMV, EBV, HIV, Measles, VZV, Human Herpes viruses 6 and 7
 Rare: Adenoviruses, Influenza A, Parainfluenza, Rabies, Rubella, Flaviviruses
(Japanese encephalitis, West Nile virus, Tick-borne encephalitis)
CLINICAL FEATURES
 Acute febrile illness with evidence of meningeal involvement (meningeal signs)
 Altered level of consciousness (ranging from lethargy to coma)
 Abnormal mental state (hallucinations, agitation, personality change, behavioral
disorder, psychosis)
 Evidence of either focal or diffuse neurologic signs or symptoms.
 Focal or generalized seizures occur in more than 50% of cases.
 Most common focal findings are aphasia, ataxia, hemiparesis (with hyperactive
tendon reflexes), involuntary movements and cranial nerve deficits.

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INVESTIGATIONS
 CSF examination:
 Check for increased intracranial pressure first
 Characteristic profile is undistinguishable from viral meningitis and consists
of lymphocytic pleocytosis (95%), elevated protein, normal glucose level.
 CSF culture, usually negative (especially in HSV 1 infections)
 Viral detection by CSF PCR (if available) is highly sensitive for several viruses
such as HSV and VZV. However, a false negative result may occur within the
first 48hours after symptom onset.
 Serology (blood and CSF) is also helpful.
 MRI shows areas of inflammation and swelling generally in the temporal lobes
in HSV encephalitis. Raised intracranial pressure and midline shift may occur
leading to coning.
 MRI, CT and EEG are done to exclude alternative diagnoses and assist in
differentiation between focal and diffuse encephalitic processes.
 EEG shows periodic sharp and slow wave complexes.
 Brain biopsy is rarely required since the advent of MRI and PCR.
TREATMENT
 Supportive therapy (usually in ICU)
 Check vital signs, restrict fluid, and give antipyretics.
 Treat seizures and/or give prophylactic therapy (high risk for seizures).
 Medication:
 Suspected HSV and VZV encephalitis is treated immediately with IV
acyclovir (10mg/kg TDS for 14-21 days) even before investigation results.
 Gangicyclovir (5mg/kg BID) or Foscarnet (60mg/kg TDS) are especially
recommended for CMV infections.
 Early treatment significantly reduces both mortality and long term neurological
damage in survivors.
 Seizures are treated with anticonvulsants.
 Occasionally decompressive craniectomy is required to prevent coning but coma
confers a poor prognosis.
 Long term complications:
 Memory impairment
 Personality change
 Epilepsy

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POST-INFECTIOUS ENCEPHALOMYELITIS
 Acute disseminated encephalomyelitis (ADEM) follows many infections (e.g.
measles, mycoplasma, mumps and rubella) and rarely follows immunization after
1-2 weeks.
 There is a monophasic illness with multifocal brain, brainstem and often spinal
cord inflammatory lesions in white matter with demyelination.
 ADEM is caused by an immune mediated host response to infection and occurs
principally in children and young adults.
 Mild cases recover completely. Survivors often have permanent brain damage.
 Treatment is supportive with steroids and anticonvulsants.
AUTOIMMUNE ENCEPHALITIS
 Autoantibodies directed against neuronal epitopes cause a subacute encephalitis
illness- limbic encephalitis or panecephalitis.
 Limbic encephalitis presents over weeks or months with memory
impairment, confusion, psychiatric disturbance and seizures (usually
temporal lobe seizures reflecting involvement of the hippocampus and mesial
temporal lobes)
 Paraneoplastic limbic encephalitis (PLE):
 Seen particularly with small cell lung cancer and testicular tumors
associated with a variety of antibodies including anti-Hu and anti-Ma2.
 Antibodies can be detected in 60% of cases.
 MRI usually shows a hippocampal high signal.
 PLE precedes the diagnosis of cancer in most cases and should prompt
investigation to identify the tumor.
 Voltage gated potassium channel (VGKC) limbic encephalitis:
 VGKC antibodies (which can be tested for) produce a variety of disorders
including limbic encephalitis, characteristic faciobrachial dystonic seizures,
neuromyotonia and peripheral nerve hyperexcitability syndromes.
 This usually occurs in patients older than 50 but is rarely associated with
cancer (thymoma)
 AntiNMDA receptor antibody panecephalitis:
 Presents as limbic encephalitis followed by coma and often status
epilepticus.
 Orofacial dyskinesias are characteristic.
 Usually younger patients, some have ovarian teratomas.

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 Patients may respond to immunotherapy-IV immunoglobulin or plasma
exchange initially followed by steroids, rituximab or cyclophosphamide.
PLE responds less well to treatment.

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CEREBROVASCULAR DISEASE
 This is defined as a syndrome of an abrupt onset of non-convulsive, focal
neurologic deficit resulting from sudden interruption of the blood supply to parts
of the brain lasting 24 hours or longer.
 Avoid using the vague term ‘cerebrovascular accident’ as it is vague can mean
one of many presentations.
CLASSIFICATION
 Can be classified according to:
 Duration
 Etiology
CLASSIFICATION BASED ON DURATION
 This includes:
 Transient ischemic attack (TIA): focal neurologic deficit lasting less than 24
hours confined to an area of the brain perfused by specific artery. Neurologic
deficit resolves in less than 24 hours. In a majority of cases they resolve
within an hour.
 Reversible ischemic neurologic deficit (RIND): sudden onset focal
neurologic deficit which lasts for more than 24 hours but the neurologic
deficit recovers/resolves.
 Stroke in evolution: a focal neurologic deficit, the degree of which is
progressing over a couple of hours or days.
 Complete stroke: sudden onset of focal neurologic deficit, in which the deficit
neither improves nor gets worse over time. It is often associated with
infarction of part of the brain. It can either be ischemic or hemorrhagic.
C LASSIFICATION ACCORDING TO ETIOLOGY
 There are 2 main types:
 Ischemic stroke (80-90% in developed countries): due to
o Embolic
o Thrombotic
 Hemorrhagic stroke (10-20% in developed countries but is higher in
developing countries): associated with unrecognized or poorly controlled
hypertension. Includes:
o Primary intracranial hemorrhage (PICH): intraparenchymal or
intraventricular

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o Subarachnoid hemorrhage (SAH)
 The nature of the focal neurologic deficit caused by strokes depends on the
vascular territory involved and the region of the brain supplied.
EPIDEMIOLOGY AND RISK FACTORS
 In developed countries stroke is the third most common cause of death (behind
coronary heart disease and cancer) and the leading cause of adult disability
worldwide.
 Stroke rates are higher in Asian and Black African populations than in
Caucasians.
 Stroke risk increases with age but ¼ of all strokes occur before the age of 65.
 The death rate following stroke is 20-25%.
 Risk factors:
 Non-modifiable:
o Increasing age
o Male gender
o Race: Blacks and Asians
 Modifiable:
o Cardiovascular: Hypertension, Congestive heart failure, Myocardial
infarction, Atrial fibrillation, Hyperlipidemia, rheumatic heart disease,
sick cell anemia
o Coagulation abnormalities:
 Thrombophilia-Ischemic,
 Coagulopathy (warfarin, liver disease)-Hemorrhagic
o Endocrine: Diabetes
o HIV
o Lifestyle: Smoking, Acute alcohol abuse
o Combined contraceptive pill
o Inflammatory and congenital: vasculitis (SLE, Takayasu Arteritis),
Homocystinuria, amyloid angiopathy, mitochondrial disease, syphilis
 Stroke should be considered as a medical emergency, as it affects vital functions
of an individual.

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DIFFERENTIAL DIAGNOSIS
 Space occupying lesion (neoplasm or infectious-sepsis, encephalitis)
 Trauma (subdural or epidural hematoma)
 Toxins (including medications)
 Hypo/hyperglycemia
 Electrolyte abnormalities (e.g. hypo/hypernatremia)
 Migraine
 Seizures especially Todd’s palsy
 Syncope
 Old strokes with intercurrent illnesses
ISCHEMIC STROKE
 This is the more common type of stroke (80-90%). It is caused by occlusion of
arterial blood flow to the brain.
 It usually occurs in elderly patients except in cases of sickle cell anemia or
rheumatic heart disease.
 Mortality rate is low in the first week (10-20%) however, many patients die of
complications in the first 1-2 months.
 Complications include: aspiration pneumonia, septic decubitus ulcers and DVT.

ETIOLOGIES
 Embolic:
 Occurs when an extracranial thrombus dislodges and embolizes to and
occludes one of the large intracranial arteries.
 Emboli most common arise from atherosclerotic plaques, atrial fibrillation,
rheumatic heart disease or endocarditis.
 Paradoxical emboli can arise from right to left shunting of venous thrombi
and emboli across an atrial septal defect.
 Embolism usually occurs suddenly when the patient is awake, most often
early in the morning, giving maximum deficit at onset.
 Thrombotic: usually related to atherosclerosis.
 Thrombosis often occurs during sleep hour or present upon arising from bed
progressing in a stepwise fashion.
 Thrombotic strokes are associated with previous transient ischemic attacks.

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CLINICAL FEATURES
 The most common clinical features are hemiparalysis, aphasia and coma.
 Clinical features of ischemic stroke are variable depending on the artery and part
of the brain affected:
 Anterior cerebral artery: hemiplegia (legs affected more than arms),
confusion, urinary incontinence, primitive reflexes
 Ophthalmic artery: ipsilateral monocular vision loss (amaurosis fugax)
 Middle cerebral artery (most common)- hemiplegia (face/arm affected more
than arms), hemianesthesia, aphasia (if dominant hemisphere)
 Posterior cerebral artery- thalamic syndromes with contralateral hemisensory
disturbances.
 Cerebellum- vertigo, nystagmus, nausea, vomiting, ipsilateral incoordination
 Brain stem- double vision, vertigo, nausea, vomiting and cranial nerve
deficits
 Lacunar (involving internal capsule)- pure hemiplegia
 Physical examination should include:
 Cardiovascular system looking out for rhythm, murmurs, carotid and
subclavian bruits as well as signs of peripheral emboli such as Janeway
lesions or splinter hemorrhage.
 A complete and thorough neurological examination.
INVESTIGATIONS
 Diagnostic:
 Imaging:
o Urgent non-contrast head CT scan (if available- will help distinguish
ischemic from hemorrhagic stroke). MRI is best for characterizing the
location and size of ischemic strokes.
o ECG: for arrhythmias (atrial fibrillation and flutter), myocardial
infarction
o Also consider a transesophageal echocardiograph for cardiac sources of
emboli
o Also consider Doppler ultrasound, CTA or MRA of the extracranial
carotid arteries to evaluate for significant stenosis (>70%)
 Blood work should include
o HIV test
o Creatinine
o Lipid profile

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o Serum glucose and electrolytes (to rule out electrolyte imbalance or
hypoglycemia)
o PT/PTT if you are considering a hemorrhagic stroke as you want to
reverse coagulopathies

MANAGEMENT
 General management:
 Airway maintenance: Keep the head of the bed elevated to prevent aspiration.
 Fluid management (Normal saline). AVOID GLUCOSE AS IT IS
NEUROTOXIC
 Close monitoring of blood pressure and correction of both hyper- and
hypotension.
 Control of body temperature: fever occurs in 44% of patient with acute stroke
due to stroke or infections.
 4-6 hourly bed turning to prevent decubitus ulcers.
 After 48 hours start physical therapy. It is very important in stroke
management. It should be started early and continued for at least 2-3 months.
 Lifestyle modification: improving diet, increased exercise, cessation of
smoking and drinking. No driving for 1 month.
 Specific management (drugs)
 Consider thrombolysis with tPA (tissue plasminogen activator)/alteplase (if
available) if onset of symptoms is within 3 hours, there is a large deficit and
there is no evidence of hemorrhage or other contraindications to lysis (INR
>1.7, thrombocytopenia, uncontrolled hypertension SBP>185 and prior
intracranial hemorrhage). We usually do not perform lysis in our setting
 Start ASA 150mg daily for 30 days (only if hemorrhage stroke is ruled out
by CT).
 BP should not be lowered in the first 48 hours unless it is very severe (systolic
blood pressure> 200 or diastolic pressure> 120) after 48 hours, lower blood
pressure slowly. Short acting antihypertensive drugs are preferred.
 Start statin (simvastatin 20mg)
 Start ranitidine or proton pump inhibitor to prevent stress ulcers (Cushing’s
ulcer).
 Start subcutaneous heparin to prevent DVT (if hemorrhagic bleed has been
ruled out).

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 Watch out for signs of cerebral edema/elevated ICP (usually peaks at 3-4
days post stroke), if evidence of elevated ICP (like declining GCS or
papilledema) start mannitol.
o 20% mannitol, intravenously 5ml/kg over 20 minutes and corticosteroid
intravenously or intramuscularly 4 hourly (e.g. prednisolone 1mg/kg or
hydrocortisone 4mg/kg)
HEMORRHAGIC STROKE
 This is less common (10-20%) but more severe.
 It usually occurs in elderly patients or middle aged patients with severe
hypertension.
 Patients often present with coma, headache and/or vomiting. Otherwise
symptoms are similar to ischemic stroke.
 Almost 50% mortality in first week.
 Hemorrhagic strokes occur suddenly while the patient is awake, patients may be
physically active or staining, it progresses within minutes to hours.

ETIOLOGY
 Primary intracerebral hemorrhage (PICH): usually associated with hypertension
and sometimes coagulopathy.
 Subarachnoid hemorrhage (SAH): ruptured aneurysm, arteriovenous
malformation, vasculitis, trauma.

CLINICAL FEATURES
 Primary intracerebral hemorrhage: sudden impairment in level of consciousness,
vomiting +/- headache, may see progressive focal neurologic deficit depending
on site of bleeding.
 Subarachnoid hemorrhage: severe headache, nausea and vomiting. Often
described as ‘thunderclap’. Can see nuchal rigidity (blood is a meningeal irritant),
impairment in level of consciousness.

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INVESTIGATIONS
 Diagnostic:
 Imaging:
o Urgent non-contrast head CT scan (if available- will help distinguish
ischemic from hemorrhagic stroke)
o ECG: for arrhythmias, myocardial infarction
o Also consider a transesophageal echocardiograph
 Blood work should include
o PT/PTT for coagulopathies
o HIV test
o Creatinine
o Lipid profile
o Serum glucose, urea and electrolytes (to rule out electrolyte imbalance or
hypoglycemia)

MANAGEMENT
 General management:
 Airway maintenance: Keep the head of the bed elevated to prevent aspiration.
 Fluid management (Normal saline). AVOID GLUCOSE AS IT IS
NEUROTOXIC
 Close monitoring of blood pressure and correction of both hyper- and
hypotension.
 Control of body temperature: fever occurs in 44% of patient with acute stroke
due to stroke or infections.
 4-6 hourly bed turning to prevent decubitus ulcers.
 After 48 hours start physical therapy. It is very important in stroke
management. It should be started early and continued for at least 2-3 months.
 Specific management:
 Blood pressure control with goal of systolic blood pressure 140-160mmHg
(diastolic <110mmHg) to prevent further bleeding.
o Drugs used include hydralazine (if diastolic >110mmHg) and nifedipine
(if diastolic <110mmHg)
 Ranitidine to prevent stress ulcer.
 Consider nimodipine (a calcium channel blocker) and phenytoin if you
suspect SAH as they decrease the risk of vasospasm and seizure in these
patients.

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FEATURE ISCHEMIC STROKE HEMORRHAGIC STROKE

Frequency 80-90% 10-20%
Etiology  Embolic: atherosclerotic  Primary intracerebral hemorrhage:
plaque, atrial fibrillation, Hypertension and coagulopathy
rheumatic heart disease and  Subarachnoid hemorrhage: Ruptured
endocarditis aneurysm, trauma
 Thrombotic: atherosclerosis
Onset of  Embolic: sudden, occurs when  Occur suddenly while patient is awake.
symptoms patient is awake early in the  Patients may be physically active or
morning. Maximum deficit at straining.
onset. Not associated with  It progresses within minutes to hours.
TIA (warning sign)
 Thrombotic: occurs in a
stepwise fashion, occurs
during sleep hour and presents
upon waking up. Associated
with TIAs
Common Hemiparalysis, apahasia and Coma, headache and/or vomiting.
Clinical coma. Others depend on blood Otherwise symptoms similar to ischemic
features vessel involved. stroke.
 Primary intracerebral hemorrhage:
sudden impairment in level of
consciousness, vomiting, headache and
progressive focal neurologic deficit
depending on blood vessel involved.
 Subarachnoid hemorrhage: severe
headache (thunderclap), nausea and
vomiting, impaired level of
consciousness and nuchal rigidity
CT SCAN  Embolic: Decreased density  Primary intracerebral hemorrhage:
 Thrombotic: Decreased increased density
density  Subarachnoid hemorrhage: usually
abnormal
LP  Embolic: usually clear  Primary intracerebral hemorrhage:
 Thrombotic: usually clear usually bloody
 Subarachnoid hemorrhage: invariably
blood

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SYNCOPE
 Syncope (a faint) is a sudden transient loss of consciousness and postural tone
mostly due to global cerebral hypoperfusion.
 A faint is characterized by a rapid onset, short duration and spontaneous recovery.
 Syncope may occur suddenly, without warning, or may be preceded by symptoms
of faintness (“pre-syncope”).
 These include lightheadedness, “dizziness” without true vertigo, a feeling of
warmth, diaphoresis (sweating), nausea and visual blurring occasionally
proceeding to blindness.
 Pre-syncopal symptoms vary in duration and may increase in severity until loss
of consciousness occurs or may resolve prior to loss of consciousness if the
cerebral ischemia is corrected.
 Syncope may occur as a single event or may be recurrent.
 Recurrent, unexplained syncope, particularly in an individual with structural
heart disease is associated with a high risk of death.
 The differentials of syncope include:
 Seizure: a sudden, uncontrolled electrical disturbance in the brain.
 Transient ischemic attack
 Hysterical fainting: the attack is usually unattended by an outward display of
anxiety. Lack of change in pulse and blood pressure or color of skin and
mucous membranes distinguishes it from the vasodepressor.
 The distinction between a fit (seizure), a faint (syncope) or another type of attack
is primarily clinical and dependent on history and an eyewitness account.
 Mistaking a syncopal loss of consciousness for a seizure is the most frequent error
made in differential diagnosis.
 The simple faint that over half the population experiences at some time
(particularly in childhood, in youth or in pregnancy) is due to sudden reflex
bradycardia with vasodilation of both peripheral and splanchnic vasculature
(neurocardiogenic or vasovagal syncope)
PRECIPITANTS
 Prolonged standing
 Fear
 Venesection
 Pain
 Syncope almost never occurs in the recumbent posture.

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PATHOPHYSIOLOGY
 Syncope results from a sudden impairment of brain metabolism usually brought
about by hypotension with reduction of cerebral blood flow.
 Several mechanisms sub-serve circulatory adjustments to the upright posture.
 Approximately ¾ of the systemic blood volume is contained in the venous bed
and any interference in venous return may lead to a reduction in cardiac output.
 Cerebral blood flow may still be maintained as long as systemic arterial
vasoconstriction occurs, but when this adjustment fails, serious hypotension, with
resultant cerebral under-perfusion to less than half of normal, results in syncope.
 Normally, the pooling of blood in the lower parts of the body is prevented by:
 Pressor reflexes that induce constriction of peripheral arterioles and venules.
 Reflex acceleration of the heart by means of aortic and carotid reflexes.
 Improvement of venous return to the heart by activity of the muscle of the
limbs.
STAGES OF SYNCOPE
 They include:
 Prodromal/Presyncope: usually brief. Dizziness and light-headed feeling
often with nausea, sweating, feeling of heat and visual grey-out.
 Blackout: usually lie still but jerking and twitching movements can occur and
are sometimes mistaken for a convulsion. Appearance is pale. Incontinence
of urine or faeces can occur and is not a good discriminator between seizure
and syncope.
 Recovery: is rapid, usually seconds but may be followed by a feeling of
general fatigue (as opposed to post-ictal drowsiness and confusion following
a seizure).

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CAUSES OF SYNCOPE Loss of consciousness without
 Transient cerebral hypoperfusion is usually due to global cerebral hypoperfusion
one of three mechanisms: (Nonsyncopal causes):
1. Cardiogenic syncope
 Epilepsy: complex partial or
2. Neurogenic syncope (Reflex syncope)
generalized seizures
3. Orthostatic hypotension
 Metabolic disorders:
CARDIOGENIC SYNCOPE hypoglycemia, hypoxia and
 Cardiac syncope results from a sudden reduction in hypercapnia
cardiac output caused most commonly by a cardiac  Drugs: medical or
arrhythmia. recreational
 Cardiogenic syncope has no warning signs and can occur in any position
(including lying flat). The patient may have had palpitations and chest pain at the
time or recently.
 Cardiogenic syncope usually lasts seconds to minutes, with no incontinence. The
patient may look pale during and after. They may also have a few clonic jerks.
Recovery is quick.
 Heart rate between 30 and 180 beats/min do not reduce cerebral blood flow,
especially if the person is in the supine position.
 As the heart rate decreases, ventricular filling time and stroke volume increase to
maintain normal cardiac output.
 At rates greater than 180 beats/min, ventricular filling time is inadequate to
maintain adequate stroke volume.
 Upright posture, cerebrovascular disease, anemia, loss of atrioventricular
synchrony and coronary, myocardial or valvular disease all reduce the tolerance
to alterations in rate.
 Causes of cardiogenic syncope include
 Cardiac arrhythmias
o Bradyarrhythmias
 Sinus bradycardia, sinoatrial block, sinus arrest, sick-sinus
syndrome (especially in sepsis), Atrioventricular block (especially
2o type 2 or 3o resulting in syncope and presyncope may be called
Stokes-Adams attacks).
 May cause syncope if the escape pacemaker rate is insufficient to
maintain cardiac output.
 Syncope may occur abruptly without presyncopal symptoms and
recur several times daily.

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 Patients with sick sinus syndrome may have sinus pauses (> 3s)
and those with syncope due to high degree AV block (Stokes-
Adams-Morgagni syndrome) may have evidence of conduction
system disease (e.g. prolonged PR interval bundle branch block).
 Drugs such as Digoxin, beta adrenergic receptor antagonists,
calcium channel blockers and many antiarrhythmic drugs may
suppress SA node impulse generation or slow AV nodal
conduction.

o Tachyarrhythmias
 This is usually preceded by palpitation or lightheadedness but may
occur abruptly with no warning symptoms.
 Supraventricular tachycardia is unlikely to cause syncope unless
with structural cardiac disease such as Wolf-parkinson-white
syndrome, cerebrovascular disease, disorder of vascular tone or
blood volume or a rapid ventricular rate.
 Atrial fibrillation associated with the Wolff-Parkinson-White
syndrome.
 Atrial flutter with 1:1 atrioventricular conduction.
 Ventricular tachycardia. Patients with aortic valvular stenosis and
hypertrophic obstructive cardiomyopathy are also at risk for
ventricular tachycardia.
 Drugs (such as certain antiarrhythmics and erythromycin) and
electrolyte disorders (i.e. hypokalemia, hypocalcemia,
hypomagnesemia) can prolong QT interval and predispose to
torsades de pointes.
 Structural causes
 Valve disease, especially severe aortic stenosis
 Cardiomyopathy especially hypertrophic cardiomyopathy
 Other cardiac disease: MI, Pericardial disease (Pericardial constriction or
tamponade), atrial myxoma (tumor), congenital heart disease
 Extracardiac: Pulmonary embolism, Pulmonary hypertension, Aortic
dissection.

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NEUROGENIC SYNCOPE (REFLEX SYNCOPE)
 Mainly due to reflex increase in vasovagal stimulation. It results from reflex drop
in heart rate and peripheral vascular resistance.
 During onset, patients can be standing or sitting (but not lying flat), they may
have presyncope (nausea, pallor, sweating, visual field narrow). During the event
patients may have myoclonic jerks and even urinary incontinence. Duration is
brief with quick recovery.
 This type of syncope is usually recurrent and commonly precipitated by a hot or
crowded environment, alcohol, extreme fatigue, severe pain, hunger, prolonged
standing, emotional and stressful situations.
 These are the common faints that many normal persons may experience,
accounting for approximately half of all episodes of syncope.
 Causes include:
 Vasovagal syncope (neurocardiogenic/simple/uncomplicated syncope or
common faint):
 Commonest cause of transient loss of consciousness
 Often due to orthostatic stress: long-standing, hot weather, and/or reduced
fluid intake
 May also be caused by emotional stress: pain, emotion, blood, needles.
 3 Ps suggestive of vasovagal syncope: Postural, Provocation, Prodrome.
 Carotid sinus hypersensitivity (Carotid sinus syncope): Altered heart rate and
blood pressure due to hypersensitive baroreceptors. Syncope on minimal
stimulus of the neck e.g. shaving, tight shirt collar.
 Situational syncope: vasovagal syncope due to a specific physical trigger.
o Cough
o Postprandial
o Micturition
o Defecation
o Valsalva
o Deglutition
o Exercise (though syncope during exercise most often indicates cardiac
pathology)
 Glossopharyngeal neuralgia

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ORTHOSTATIC (POSTURAL) HYPOTENSION
 This is seen in patient that have just stood up. There is a fall in blood pressure
greater than 20 mmHg systolic or 10 mmHg diastolic.
 It is typically tested by checking BP while lying or sitting then 1 minute after
standing.
 Syncope or presyncopal symptoms occur on standing. It is worse in the morning.
 This type of syncope may cause ‘coat hanger pain’ across neck and shoulders due
to neck muscle hypoperfusion.
 Causes include:
 Drug (especially antihypertensive or vasodilator drugs, antianginals,
antiarrhythmics, sedatives, antidepressants-TCAs)
 Peripheral neuropathy (diabetic, alcoholic, nutritional, amyloid)
 Idiopathic postural hypotension
 Multisystem atrophies
 Physical deconditioning
 Decreased blood volume (hypovolemia): Diarrhea, burns, hemorrhage,
diuresis, adrenal insufficiency, Ruptured ectopic pregnancy, Abdominal
aortic aneurysm.
 Decrease in peripheral resistance: autonomic dysfunction (diabetes mellitus,
Parkinson’s, multiple system atrophy, amyloidosis), Addison disease,
pheochromocytoma

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TYPES OF SYNCOPE
 They include:
 Neurocardiogenic/Vasovagal syncope: This is due to sudden reflexive
bradycardia with vasodilation of peripheral and splanchnic vasculature. It is
seen in childhood, youth and pregnancy.
 Cardiac syncope (Stokes-Adams attacks): these are potentially serious and
often treatable. There is little to no warning. Cardiac arrhythmias e.g. due to
heart block or left ventricular outflow tract obstruction may be the cause,
syncope during exercise is often cardiac in origin.
 Micturition syncope: Occurs during micturition in men, particularly at night.
 Cough syncope: occurs when venous return to the heart is obstructed by bouts
of severe coughing. Also occasionally seen with laughter.
 Postural hypotension: can cause syncope and occurs in elderly in autonomic
neuropathy with some drugs e.g. antihypertensive.
 Carotid sinus syncope: due to a vagal response caused by pressure over the
carotid sinus baroreceptors in the neck e.g. due to a tight collar.
 Convulsive syncope: collapsing in a propped up position following a syncope
results in a delayed restoration of cerebral blood and may result in a
secondary anoxic seizure following syncope.
INVESTIGATIONS
 Blood tests:
 Full blood count (anemia)
 Serum glucose
 U&Es + Creatinine
 HIV
 RPR (for syphilis)
 Liver function tests
 Lipid profile
 Clotting profile
 Imaging:
 Chest X-ray
 12-lead ECG: to identify heart block, pre-excitation or long QT syndrome.
 Echocardiography
 CT and MRI of the head are rarely indicated unless there was concomitant
head trauma.
 EEG is useful only when seizures are suspected.

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 Tilt table testing is sometimes diagnostic, but has low sensitivity.
 Patients with suspected neurocardiogenic (vasovagal) syncope should be
investigated by tilt testing.
 The patient is secured to a table which is tilted to +60o to the vertical for ≥45
minutes. The ECG and blood pressure are monitored throughout. If neither
symptoms nor signs develop, isoprenaline may be slowly infused or glyceryl
trinitrate inhaled and the tilt repeated.
 A positive test results in hypotension, sometimes bradycardia and
presyncope/syncope and supports the diagnosis of neurocardiogenic
syncope.
 If symptoms and signs appear, placing the patient flat can quickly reverse
them.
 The effect of treatment can be evaluated by repeating the tilt test, but it is not
always reproducible. The overall sensitivity, specificity and reproducibility
is low.

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APPROACH TO THE PATIENT

Figure 53: Approach to a syncope patient

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MANAGEMENT
 Management is dependent on the underlying cause.
 Provide first aid and general advice to patients who have fainted:
 Lay the fainted individual on a flat surface
 Remove any ties, necklaces, shoes or anything strangulating the patient.
 Check blood sugar, vitals and pupillary response to light
 Elevate the legs above the head level
 When patient recovers take a history, full physical examination and order
investigations to determine underlying cause.
o History focuses on: (use the mnemonic BAD BALANCE)
 What happened Before, After and During the episode
 B-Banged their head? Any associated head injury?
 A-Arrhythmic symptoms: palpitations, chest pain?
 L-Loss of consciousness or do they remember the fall?
 A- Alcohol: have they been drinking?
 N-New medication?
 C-Collateral history (from an observer)
 E- Ever happened before?
 In cases of benign causes, reassure the patient and advise them to avoid
triggers.
 Give general advice to patient on maneuver to prevent fainting:
o Educate the patient on the warning signs that precede a syncopal attack.
o Avoid tight clothing around the neck
o Avoid standing fixed in one place for too long, if individual is standing
in one place for too long they should repeated squeeze their toes and
hands. As well as move their legs about.
o If they feel dizzy they should lay down flat with legs in the air (on chair
or against the wall), or sit down and tuck their head in-between their
knees.
o Avoid hypoglycemia for extending periods and always keep hydrated
 Hospitalize if risk factors for cardiac syncope are present or if syncope is
suspected to be 2o to arrhythmic or obstructive/low cardiac output, as patients
with cardiogenic syncope are at increased risk of sudden death.

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HEADACHE
 Headache is defined as pain located in the head, neck or jaw.
 This is the commonest complaint in medical practice.
 It results from distention, stretching, inflammation or destruction of pain
sensitive cranial structures. These pain sensitive structures are the scalp, dura,
sinuses, paranasal sinuses, falx cerebri, middle meningeal arteries, proximal
segments of large pial arteries, eyes, teeth and cranial nerves V, IX and X. The
brain parenchyma is not pain sensitive.
 A pain (sensory stimuli) from these structures is conveyed to the brain either via
trigeminal nerve (CN V), Glossopharyngeal (CN IX) or first three cervical
sensory roots.
 All patients presenting with headache merit a detailed history and neurologic
evaluation (including fundoscopy exam for papilledema).
CLASSIFICATION
 Headache can be pathophysiologically classified into:
 Primary Headache syndromes
 Migraine headache
 Cluster headache
 Tension headache
 Miscellaneous (orgasmic, hangover)
 Secondary headache disorders (usually due to life-threatening and/or
treatable causes)
 Traction-inflammation headache
o Cranial arteritis e.g. temporal arteritis
o Meningitis
o Brain tumor
o Increased/decreased ICP: intracranial hemorrhage
 Cranial neuralgia
 Extracranial lesions
o Paranasal sinusitis
o Dental problems
o Ear problems
o Ocular problems e.g. glaucoma
o Cervical problems

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PRIMARY HEADACHE SYNDROMES
 These can be classified as
 Migraine headache
 Cluster headache
 Tension headache
 Miscellaneous (orgasmic, hangover)
MIGRAINE HEADACHE
 This is the commonest cause of episodic headache (90%).
 Its onset is before 40 years (in childhood or young adult life) and affects women
(15-20%) more than males (5-10%).
 90% of patients have a strong family history (genetic link).
 Some environmental triggers have also been liked such as emotional
stress/depression, altered sleep pattern/sleep deprivation, Menses/Oral
contraceptives, Alcohol intake (especially red wine), caffeine withdrawal,
various foods (e.g. chocolates, nuts, aged cheese, monosodium glutamate, meals
containing nitrates), hunger, perfumes and even after minor head injury.
 Episodes of headache are associated with sensory sensitivity such as light, sound
or movement and sometimes with nausea and vomiting.
 Severity varies greatly among individuals.
 Migraine is usually high impact with inability to function normally during
episodes.
 Headache frequency in migraine varies from an occasional inconvenience to
frequent headaches severely impacting quality of life and may transform into
chronic daily headache.
MECHANISMS
 Genetic factors play a part in causing the neuronal hyperexcitability that is
probably the biological basis of migraine.
 The pathophysiology of migraine is now thought to have a primarily neurogenic
rather than vascular basis.
 Spreading cortical depression- a wave of neuronal depolarization followed by
depressed activity spreading slowly anteriorly across the cerebral cortex from the
occipital region- is thought to be the basis of the migraine aura.
 Activation of trigeminal pain neurons is the basis of the headache.
 The innervation of the large intracranial vessels and dura by first division of the
trigeminal nerve is known as the trigeminovascular system.

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 Release of calcitonin gene-related peptide (CGRP), substance P and other
vasoactive peptides including 5-HT by activated trigeminovascular neurons
causes painful meningeal inflammation and vasodilation.
 Peripheral and central sensitization of trigeminal neurons and brainstem pain
pathways makes otherwise innocuous sensory stimuli (such as CSF pulsation and
head movement) painful and light and sound perceived as uncomfortable.
CLINICAL FEATURES
 Benign, recurrent headaches that classically produce unilateral (in a few cases
can be bilateral), retro-orbital, throbbing or pulsating pain lasting 4-72 hours
often accompanied by nausea, vomiting, and photophobia.
 They may sometimes be associated with anorexia and
phonophobia/sonophobia (dislike and avoidance of loud sounds or noises)
 Severity may range from moderate to severe.
 Migraines are exacerbated by physical activity.
 Patients often report improvement with resting in a dark, quiet room or by sleep
and exhilaration, sumatriptan and pregnancy.
 They can be associated with or without a visual aura.
 Subtypes include:
 Common migraine (Migraine without aura)
 This is the commonest variation of migraine headache.
 No focal neurological disturbance precedes the recurrent headache.
 It starts around puberty with increasing prevalence into the 4 th decade.
 Classic migraine (Migraine with aura-20%):
 It is associated with aura consisting of sensory, motor or visual
symptoms. Most common symptoms reported are visual which
include scotomas (a small area in the field of vision where someone
cannot see i.e. blind spots) and/or hallucinations.
 The pathognomic aura for classic migraine is the scintillating
scotoma.
 Fortification spectra/teichopsia are also seen. (these are complicated
images e.g. zig-zag lines that can float in the vision during a
migraine)
 Visual auras are also described as stars, sparks and flashes of light.
 They may evolve into hemianopia or tunnel vision.

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 Positive sensory symptoms (mainly tingling), dysphasia and rarely
loss of motor function may also occur and may occur successively
within the same episode of aura following the visual symptoms.
 The aura usually evolves over 5-20 minutes with symptoms
changing as the wave of spreading neuronal depression moves
across the surface of the cortex. It rarely lasts longer than 60 minutes
and followed immediately by the headache phase.
 Focal neurologic symptoms usually occur during the headache rather
than as a prodrome.
 Classic migraine has 5 phases
 Prodromal phase: characterized by lassitude (a state where a
person does not want to do anything), irritability, difficulty in
concentrating.
 Aura phase: patients with aura often report visual complaints,
vertigo, aphasia or other neurological deficit before the onset of
the headache.
 Headache phase: characteristic migraine headache
 Headache termination: usually occurs within 24 hours
 Post-headache phase: feeling fatigued, sleepiness and irritability.
 Complicated migraine
 Migraine associated with dramatic transient neurological deficit or a
migraine attack that leaves a persisting residual neurological deficit.
 Other types of migraines include:
 Migraine equivalent: focal neurologic symptoms without the classic
complaints of headache, nausea and vomiting.
 Basilar migraines: migraine headaches associated with symptoms
consistent with brain-stem involvement (vertigo, diplopia, ataxia or
dysarthria).
 Hemiplegic migraines: rare autosomal dominant disorders which
causes hemiparesis, and/or coma and headache with recovery within
24 hours. Some patients have permanent cerebellar signs as it is allelic
with episodic ataxia.
 Ophthalmologic migraines: unilateral CN III palsy and pupillary
abnormality

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DIAGNOSIS
 Based on the history, with a focus on the exact character of the headache as well
as the presence of a strong family history.
 Headache lasting 4 hours to 3 days (untreated) with:
At least 2 of: At least 1 of:
 Unilateral pain (may become  Nausea/vomiting
holocranial later in attack)  Photophobia/phonophobia
 Throbbing type pain  Normal examination and no other
 Moderate to severe in intensity cause of headache
 Motion sensitivity (headache made
worse with head movement or
physical activity)

TREATMENT
 Remove inciting agent when possible.
 Explanation
 Avoidance of trigger factors and lifestyle modification where possible
 Treatment of a migraine attack should be guided by response to previous
treatment and the severity of the attacks. A simple analgesic such as aspirin,
paracetamol (preferably in a soluble or dispersible form) or a NSAID is often
effective, concomitant antiemetic treatment may be required.
 If treatment with an analgesic is inadequate an attack may be treated with a
specific antimigraine compound such as 5HT 1- receptor agonists (‘triptans’).
 Acute/abortive treatment of migraine:
 NSAIDs: for mild to moderate attacks and are most effect when take early.
o ASA-900mg
o Paracetamol- 1g
o Ibuprofen-250-500mg
o Side effects: dyspepsia and GI irritation
 5-hydroxytryptophan-1 Agonists: these are serotonin agonists that decrease
substance P release at trigeminovascular junction. They are used to relief
acute attack
o Non selective- Ergot preparations (ergotamine and dihydro-ergotamine)
 Dose: initial dose 1-2mg oral/sublingual/rectal and repeat and repeat
every hour if there is no relief of headache to a maximum of 6-8mg
over 24 hours.

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 Route of administration: oral, sublingual, rectal, nasal and parental.
Parenteral forms are used for rapid relief.
 Side effects: nausea, vomiting, chest discomfort, peripheral ischemia
and even angina. Excess use may lead to rebound headache and
dependency.
 Contraindications: patients with vascular diseases like coronary heart
disease
o Selective- Triptans (Naratriptan, Ritatriptan, Sumatriptan and
Zolmitriptan)
 Sumatriptan- Single 6mg Subcutaneous dose is effective in 70-80%
of patients
 Dopamine agonist: used as adjunct therapy, can act as antiemetic.
 Prophylactic treatment:
 Medical therapy:
o This is indicated if patient has 3 or more attacks per month.
o Drugs: Beta-blockers (slow release propranolol 80-160mg daily),
Tricyclic antidepressants (amitriptyline-10mg increasing weekly in
10mg steps to 50-60mg) and calcium channel blockers (verapamil),
valproic acid (800mg).
o Start with low dose and gradually increase if there is no adequate
response.
 Biofeedback therapy: it is simple and cost effective. It lessens migraine
attacks by helping patients deal more effectively with stress.
SECONDARY HEADACHE DISORDERS
 Traction-inflammation headache
o Cranial arteritis
o Meningitis
o Brain tumor
o Increasaed/decreased ICP
 Cranial neuralgia
 Extracranial lesions
o Paranasal sinusitis
o Dental problems
o Ear problems
o Occular problems
o Cervical problems

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IMPAIRMENT OF CONSCIOUSNESS AND COMA

 Structural, metabolic or toxic insult of diffuse nature to cerebral hemispheres,
reticular activating system found in brain stem and corticothalamic connections
results in alteration of conscious level of different degree
 Drowsiness: a state of reduced consciousness characterized by easy arousal
that can be maintained only for brief period of time.
 Stupor: is a sleep like unarousability from which the patient can be awakened
by vigorous stimuli.
 Coma: is severe degree of reduce consciousness (alertness and
responsiveness) from which the patient cannot be aroused.
 Vegetative state: is characterized by the patient’s unawareness of self or
external stimuli. Autonomic functions are relatively well maintained and a
sleep-wake cycle exists. The patient cannot interact with others in a
meaningful fashion. The patient can survive with medical and nursing
support.
 Brain death: this is a state in which there has been cessation of cerebral blood
flow, as a result there is global loss of brain function while respiration is
maintained by artificial means and the heart continues to pump.

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ETIOLOGY
Diseases that cause no focal  Metabolic disturbances: hepatic encephalopathy,
neurologic deficit or lateralizing hypoglycemia, diabetic ketoacidosis, electrolyte
neurologic signs (patient have imbalances (hyponatremia, hypernatremia,
diffuse bilateral hemispheric hyperkalemia, hypocalcemia), hypoxia,
impairment with normal brain stem hypercapnia etc.
function)  Intoxication: alcohol, sedative drugs, opiates
 Severe systemic or CNS infection: meningitis,
encephalitis, cerebral malaria, cerebral abscess
 Post-seizure state: status epilepticus
 Hypertensive encephalopathy, eclampsia
 Severe hyper or hypothermia
 Head trauma: brain concussion
Diseases that cause Supratentorial  Epidural or subdural hematoma
focal neurologic (hemispheric  Intraparenchymal hemorrhage (hemispherical
deficit (Disorders lesions) hemorrhage)
affect the reticular  Large ischemic infarction
activating system)  Tumor, abscess, trauma
Infratentorial  Pontine or cerebellar hematoma
 Basilar artery thrombosis
 Ischemic cerebellar infarction
 Tumor, abscess

APPROACH TO A PATIENT IN COMA

 Complete and rapid assessment of the patient is critical for optimal care
ASSESSMENT AND MAINTENANCE OF VITAL FUNCTION
 This is the initial step
 Maintain the airways and ensure adequate breathing (ABC of life)
 Maintain circulation
ESTABLISHMENT OF CAUSE OF COMA
 This is done by taking a careful history, doing rapid but thorough physical
examination and investigations.

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HISTORY
 Look for diseases like diabetes, hypertension, cirrhosis, chronic renal diseases,
malignancies, and other disease e.g. CNS infections.
 History of medications: legal or illicit drugs (sedative, hypnotics, narcotics) and
history of drug and alcohol abuse.
 Circumstances and rapidity with which changes in mental status developed:
 Sudden onset indicating vascular causes
 Gradual onset indicating metabolic and infectious causes
 Fluctuations suggest subdural hematoma
 Recent patient complaints preceding loss of consciousness: Medical and
neurological symptoms (fever suggesting infection, polyuria and polydipsia
indicating DKA)
 Details regarding the site where the patient was found e.g. the presence of empty
drug vials or evidence of fall or trauma.
PHYSICAL EXAMINATION
 Vital signs: Extremes of BP, pulse or temperature and abnormal patterns of
breathing.
 Fever: systemic or CNS infection or neurogenic fever
 Tachypnea- pulmonary infections or acidosis
 Hypertension- hypertensive encephalopathy
 Head and neck: evidence of trauma and presence of meningism.
 Skin: look for signs of trauma or injection.
 General examination: looking for evidences of systemic illnesses like cirrhosis,
chronic renal failure, meningococcemia etc.
NEUROLOGICAL EXAMIANTION
 Level of consciousness: Glasgow coma scale
Score Eye opening Verbal (best response) Motor (best motor response)
6 Obeys commands
5 Oriented Localizes pain
4 Spontaneous Confused Flexion & Withdrawal from pain
3 To verbal Inappropriate words Abnormal arm flexion to pain
stimulus (Decorticate)
2 To pain Unintelligible words Abnormal arm extension to pain
(Decerebrate)
1 None None None

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 Brain stem reflexes:

 Pupillary light response: Should be examined with a bright, diffuse light.
Note size, shape, symmetry and reaction to light in both eyes.
o Normally reactive and round pupils of midsize (2.5 to 5mm) essentially
exclude midbrain damage
o Enlarged (>6mm) and unreactive pupil on one side signifies a
compression or stretching of the 3rd cranial nerve from the effects of a
mass above
o Bilateral dilated and unreactive pupils indicate severe midbrain damage,
usually from compression by a mass.
o Bilaterally small (1 to 2.5mm) and reactive pupils (not pinpoint) are seen
in metabolic encephalopathies or deep bilateral hemispheral lesions such
as hydrocephalus or thalamic hemorrhage
o Very small but reactive pupils (<1 mm)/pinpoint pupils characterize
narcotic or barbiturate overdoses but also occur with extensive pontine
hemorrhage
 Ocular movements: before maneuvers of the eye, elevate the lids and note
the resting position and spontaneous movements of the eyeballs.
o Lid tone is tested by lifting the eyelids and noting their resistance to
opening and speed of closure. Resistance to opening the eyelid suggest
hysteric conversion. Easy eyelid opening with slow closure indicates
severe coma.
o Midline deviation suggests frontal/pontine damage
o Dysconjugate gaze (abduction or adduction) suggest cranial nerve
abnormalities.
o Spontaneous eye movements roving, dipping, bobbing suggest damages
being at different sites
o The eyes look towards a hemispheric lesions and away from a brainstem
lesion.
o Occulocephalic reflex: this is elicited by moving head from side to side
or vertically with eyes held open. In comatose patient with intact
brainstem:
 If the eyeballs move to the opposite direction of the head movement
brainstem function is intact (“doll’s eyes” movement is positive)

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 If the eyeballs move to the same direction of the head movement there
is brainstem dysfunction.
o Caloric (occulovestibular) reflex: this test is performed by irrigating the
ear with ice (cold) to stimulate the vestibular apparatus. In patients with
intact brain stem the eyes move to the irrigated ear
 Corneal reflex: This test assesses the integrity of dorsal midbrain and pontine.
It is lost if the reflex connections between the fifth (afferent) and the seventh
(efferent) cranial nerves within the pons are damaged.
 Respiration: Abnormalities of respiratory pattern can help in coma diagnosis
but are of less localizing value in comparison to other brainstem signs
o Shallow, slow but regular breathing: suggests metabolic or drug
depression
o Cheyne Stokes respiration (irregular breathing with short breaths
gradually increasing to deep breaths then reducing again until breathing
appears to stop): signifies bihemispherical damage or metabolic
suppression and commonly accompanies light coma.
o Rapid deep (Kussmaul) breathing: usually implies metabolic acidosis but
may also occur with pontomesencephalic lesions and severe pneumonia
o Agonal gasps: reflects bilateral lower brainstem damage and are
indicators of severe brain damage and a near death situation
 Motor function/response: Assess posture of the patient, tone, response to painful
stimuli and presence of asterixis. Asymmetric motor responses have localizing
value.
 Quadriparesis and flaccidity: suggest pontine or medullary damage
 Decorticate posturing: flexion of the elbows and the wrists with supination
of the arms and extension of the legs, suggests severe bilateral or unilateral
hemispheric or diencephalic lesion (damage above the midbrain)
 Decerebrate posturing: extension of elbows and the wrist with pronation of
the forearm and extension of the legs, indicates damage to the brainstem
(midbrain or pontine compromise)
 Spontaneous activities: if the patient is yawning, swallowing, coughing or
moaning the coma is not deep
 Abnormal body movement: Seizures, myoclonus may suggest the cause of
the coma is status epilepticus, uremia etc.

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INVESTIGATIONS  Psychogenic coma (hysteric coma): patient
 Blood: often has history of psychiatric illness and
 Full blood count non-physiologic response on physical
 Serum glucose examination.
 Renal function tests  Resistance to having the eyelids open (the
 Liver function tests patient resists eyelid opening when the
 Electrolytes examiner tries to open it)
 Blood Culture  Failure of the patient’s arm, when held by
 Arterial blood gasses the examiner over the patient’s face to fall
 Urine analysis up on the face when released by the
 Lumbar puncture and CSF examiner
examination: should be done unless  Nystagmus when the ear is irrigated with
if there is increased intracranial colder water.
pressure. Exclude infections and  Aversive head and eye movement
subarachnoid hemorrhage
 EEG, CT/MRI of head if available to rule out SOL and other causes
MANAGEMENT
 This is ideally started with the initial assessment to identify the etiology.
 Initial therapy (ABCs): maintaining an adequate airway, optimal ventilation and
maintaining adequate perfusion (blood pressure)
 Immobilization of the neck if there is a possibility of a cervical fracture
 Endotracheal intubation is often indicated to protect the airway
 Blood samples for: FBC, electrolytes, glucose, Renal function tests, Liver
function tests etc. should be obtained
 Intravenous thiamine: 100mg IV with 50% glucose solution is given. This
treatment is given if hypoglycemia is even remote possibility, and thiamine
is given with glucose in order to avoid eliciting Wernicke disease in
malnourished.
 Naloxone (0.4mg) should be administered in case of opiate intoxication
 Flumazenil can be given if benzodiazepine or haptic coma is suspected
 Care given:
 Monitor vital signs
 Nurse while propped up (appropriate position) with 4 hourly turning
 Provide adequate ventilation, oxygenation and warmth
 Catheterized and insert an NT tube (NG tube feeds)
 Manage the primary cause of the coma

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PARKINSON DISEASE

BULBAR AND PSEUDOBULBAR PALSY

 The ‘bulb’ refers to the medulla and bulbar palsy is dysfunction of the cranial
nerves 9 to 12 (hypoglossal, Vagus, accessory and glossopharyngeal)- whose
nuclei lie within it.
 It presents with dysphonia, dysarthria and/or dysphagia.
Bulbar palsy Pseusdobulbar palsy
 Lower motor neuron lesion of the  Upper motor neuron lesions of the
medulla (nuclei) or cranial nerve corticobulbar tract. Commoner than
fibers. bulbar palsy
 Causes:  Causes:
 Brain stem stroke or tumor  Stoke e.g. of the bilateral
 MND especially progressive internal capsule
bulbar palsy  Multiple sclerosis
 Guillain Barre  Progressive supranuclear palsy
 Myasthenia gravis  MND
 Central pontine myelinolysis  Tumors higher in the brainstem
 Iatrogenic: surgery,  Syphilis
radiotherapy  Distinguishing features:
 Distinguishing features:  Bilateral defects
 Fasciculating tongue which may  Paralyzed tongue with Donald
sit in one side of the mouth duck speech
 Also non-bulbar symptoms- as
corticobulbar tract supplies all

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motor cranial nerves- including
hyper-reflexia (jaw jerk, gag)
and facial paralysis
 Emotional lability

INFECTIOUS DISEASES
PARASITIC  P. falciparum can be associated
with severe morbidity and
INFECTIONS: MALARIA symptoms can progress to coma or
MALARIA death very rapidly.
 Malaria is a protozoal infection of  The risk of severe disease is highest
the genus plasmodium. among non-immune individuals,
 Human malaria is usually caused asplenic individuals, children less
by one of four species of the genus than 5 and pregnant women.
Plasmodium: P. falciparum, P.  Malaria is transmitted by the bite of
vivax, P. ovale, P. malariae. an infected female anopheles
 P. knowlesi is also another simian mosquitoes.
plasmodium specie.  Autochthonous malaria can
 The majority of malaria infection in result if a mosquito feeds on a
Africa (and Zambia) is caused by P. malaria-infected individual and
falciparum while P. vivax infection transmits the infection by biting
is more commonly seen in Central someone else.
America, the Middle East and  It also be transmitted in
India. contaminated blood transfusions. It
has occasionally been seen in

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injecting drug users sharing needles this is pre-erythrocytic (or hepatic)
and as a hospital-acquired infection sporogeny.
related to contaminated equipment.  After a few days (6-16 days), the
 Malaria is characterized by infected hepatocytes rupture,
paroxysms of chills, fever and releasing merozoites into the blood
sweating and may lead to anemia from where they are rapidly taken
and splenomegaly. up by erythrocytes (48-72 hours).
 In the case of P. vivax and P.
LIFE CYCLE ovale, a few parasites remain
 The female mosquito becomes dormant in the liver as
infected after taking a blood meal hypnozoites. These may
containing gametocytes, the sexual reactivate at any time
form of the malarial parasite. subsequently causing relapsing
 The developmental cycle in the infection.
mid-gut of the mosquito usually  In species which lack
takes 7-20 days (Depending on hypnozoites i.e. P. knowlesi, P.
temperature), culminating in falciparum and P. malariae
infective sporozoites migrating to recurrence of infection occurs
the insect’s salivary glands. from persistent blood stages of
 In the mid-gut the gametocytes malaria parasite this is term
fuse to form a zygote which recrudescence.
matures to a ookinete and  Inside the red cells, some parasites
eventually an oocyst which again multiply changing from
ruptures and gives off merozoite to trophozoite to
sporozoites. erythrocytic schizont and finally
appearing as 8-24 new merozoites.
 The erythrocyte ruptures releasing
the merozoites to infect further
 The sporozoites are inoculated into cells.
a new human host and those which  Each cycle takes about 48hours
are not destroyed by the immune in P. falciparum, P. vivax and
response are rapidly taken up by the P. ovale and about 72 hours in
liver within 30 minutes. P. malariae.
 In the liver they multiply inside  P. vivax and P. ovale mainly
hepatocytes forming pre- attack reticulocytes and young
erythrocytic schizonts which erythrocytes, while P. malariae
contain thousands of merozoites; tends to attack older cells.

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 P. falciparum will parasitize
any stage of erythrocyte.
 A few merozoites do not develop
into trophozoites but into
gametocytes (microgametes and
macrogametes). These are not
released from the red cells until
taken up by a feeding mosquito to
complete the life cycle.

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Figure 54: Life cycle of Malaria (Adapted from Kumar and Clark)

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Figure 55: Life cycle of Malaria

PATHOGENESIS Splenomegaly & sequestration

 Red cells infected with malaria are and folate depletion.
prone to hemolysis.  Death of non-infected cells,
 P. falciparum invades red cells bone marrow suppression and
at all ages hypoglycemia due to high
 P. vivax and P. ovale invade parasite burden cause severe
reticulocytes anemia leading to hypoxia and
 P. malariae invades older red metabolic acidosis
blood cells  In P. falciparum malaria, red cells
 The anemia seen in malaria is containing schizonts adhere to the
multifactorial. lining of capillaries in the brain,
 Causes include: hemolysis of kidneys, gut, liver and other organs
infected red cells, Hemolysis of e.g. placenta by formation of
non-infected red cells ‘Knob’ protein. They also form
(blackwater fever), ‘rosettes’ and rouleaux with
Dyserythropoiesis, uninfected red cells.

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 There is accumulation of mature  The spleen appears to play a role in
parasites in capillary and post controlling infection and
capillary venules including brain, splenectomized people are at risk of
muscle, kidneys and kidneys. This overwhelming malaria. Some
leads to tissue hypoxia and individuals appear to have a genetic
contributes to the metabolic predisposition for developing
acidosis. cerebral malaria following
 There is a significant increase in a infection with P. falciparum.
number of pro-inflammatory  Pregnant women are especially
cytokine factors in particular TNF. susceptible to severe disease.
There is a clear relationship
between their concentration and the
severity of illness seen. The
CLINICAL FEATURES
mechanisms of damage are likely to  Normal incubation period is 10-21
include direct effects on cellular days but can be longer.
metabolism and stimulation of the  This is because symptoms of
release of other toxins. It is also malarial infection develop only
thought the cytokine factors release with the erythrocytic stage thus
act to up regulate cytoadherence of patients may remain
cells contributing to the asymptomatic after being bitten
sequestration process and its by an infected mosquito.
consequences.  The most common symptom is
 Certain genetic traits also confer fever, although malaria may
some immunity to malaria. present initially with general
 People who lack the Duffy antigen malaise, myalgias, headache,
on the red cell membrane (a nausea, vomiting, abdominal pain
common finding in West Africa) or diarrhea.
are not susceptible to infection with  At first the fever may be continual
P. vivax. or erratic: the classical tertian (P.
 Iron deficiency may also have some falciparum, P. ovale & P. vivax) or
protective effect. quartan fever (P. malariae) only
appears after some days. The
 P. falciparum does not grow well in
temperature often reaches 41
red cells that contain hemoglobin F,
degrees and is accompanied by
C or especially S. Hemoglobin S
rigors (chills) and drenching
heterozygotes (AS) are protected
sweats.
against the lethal complications of
malaria.

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 Classically malaria manifests in minutes, the hot or flush phase
regular paroxysms of high grade begins and lasts several hours
fever, chills and rigor occurring giving way to profuse perspiration
every 2 days in P. vivax and P. and a gradual fall in temperature.
ovale and every 3 days in P.  The cycle is repeated 48 hours
malariae but irregularly in P. later.
falciparum.  Gradually the spleen and liver
 Malarial febrile paroxysms (which enlarge and may become tender.
are due to rupture of schizonts and  Anemia develops slowly.
release of pyrogens) typically have  Spontaneous recovery usually
3 stages: occurs within 2-6 weeks, but
 The “cold stage” the patient hypnozoites in the liver can cause
feels intensely cold and has relapses for many years after
shivering. This lasts 30 minutes infection.
to 1 hour. IT is characterized by  Repeated infections often cause
vasoconstriction of vessels and chronic ill health due to anemia
the temperature rises rapidly. and hyperactive splenomegaly.
 The “hot stage” the patient
feels hot and uncomfortable P. MALARIAE INFECTION
and becomes delirious. This  This also causes a relatively mild
stages lasts for 2-6 hours. illness but tends to run a more
 The “sweating stage” patient chronic course.
will have profuse sweating and  Bouts of fever appear every third
become very much exhausted. day.
 Parasitaemia may persist for years,
P. VIVAX AND P. OVALE with or without symptoms.
INFECTION  In children it is associated with
 The illness is usually relatively glomerulonephritis and nephrotic
mild (although P. vivax can syndrome.
occasionally cause severe disease).
 The illness starts with several days
of continued fever before the
development of classical bouts of
fever on alternate days. Fever
starts with a rigor. The patient feels
cold and the temperature rises to
about 40 degrees Celsius, after 30

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P. FALCIPARUM INFECTION o Disconjugate gaze due to
 This is the most dangerous of the cranial nerve palsy
malarias and patients are either o Malaria retinopathy with
‘killed or cured’. Roth’s spot
 The onset is often insidious with  Respiratory
malaise, headache and vomiting. o Tachypnea
Cough and mild diarrhea are also o Acute respiratory distress
common. syndrome due to
 Jaundice is common due to pulmonary edema
hemolysis and hepatic dysfunction. o Secondary bacterial
The liver and spleen enlarge and pneumonia
may become tender. Anemia  Cardiovascular
develops rapidly as does o Shock (‘algid malaria’)
thrombocytopenia. o Cardiac failure
 It may also cause serious o Dysrhythmias with quinine
complications and the vast majority  Gastrointestinal/Liver
of malaria deaths are due to P. o Diarrhea
falciparum. o Jaundice (bilirubin >50
micromol/L), tender liver
 Mature P. falciparum parasites
edge with hepatitis
(schizonts) bind to vascular
o Splenic rupture
endothelium leading to capillary
 Renal
obstruction and ischemia. If left
o Hemoglobinuria
untreated this can lead to
(blackwater fever)
hypoglycemia, cerebral malaria,
o Oliguria and acute renal
nephritis, renal failure and
failure
pulmonary edema.
o Uremia (Serum creatinine>
 Features of severe malaria:
250 micromol/L) (Acute
 CNS:
tubular necrosis)
o Cerebral malaria (coma-
 Blood
unarousable for more than
o Severe anemia (<6g/dl)
30 minutes, convulsion= 3
(hemolysis and
seizures in 24 hours only
dyserythropoiesis)
attributed to malaria)
o Thrombocytopenia
o Cranial nerve palsies
o Disseminated intravascular
o Opisthotonus (trunk is in
coagulation (DIC)
position like in tetanus)

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o Bleeding e.g. retinal
hemorrhages
 Metabolic
o Hypoglycemia
(<2mmol/L- particularly in
children)
o Metabolic acidosis (blood
pH< 7.25)
 Others: Gram-negative
septicemia, hyperpyrexia

Figure 56: Severe Malaria (Image adapted from Kumar and Clark Clinical Medicine)

 Patients can deteriorate rapidly and children in particular progress from

reasonable heath to coma and death within hours.
 A high parasitaemia (>1% of red cells infected) is an indicator of severe disease,
although patients with apparently low parasite levels may also develop
complications.

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UNCOMPLICATED stages, only by symptoms like poor

MALARA appetite, fever, restlessness, cough,
 Prodromal symptoms are usually diarrhea, malaise and loss of
non-specific and are often interest in the surroundings.
characterized by intermittent SEVERE MANIFESTATIONS
febrile illness. AND COMPLICATIONS OF
 Fever is the most common
MALARIA
symptom. Headache, aching joints,
(1) Cerebral malaria (more than 2
back pain, nausea and vomiting and
convulsions- generalized tonic
general discomfort usually
clonic in 24 hours or unarousable
accompany the fever.
coma/altered level of
 The patient may not present with
consciousness for more than 30
fever but may have had a recent
minutes attributed only to malaria)
history of fever. This is due to the
(2) Acute pulmonary edema &
natural malaria cycle.
respiratory distress
 A history of fever during the (3) Shock (‘Algid malaria’): cold
previous 2 days along with other moist skin, low blood pressure
symptoms of malaria is a critical (SBP<80mmHg), Increased
basis for suspecting malaria. capillary refill time, collapse
 It is equally important to note that (4) Acute renal failure (oliguria of
fever is a common symptom for <400ml/24 hours), blackwater
other infections besides malaria fever
such as ear infections, measles and (5) Severe anemia (Hb<6 g/dl or Hct
pneumonia. Malaria has been <15%)- normocytic normochromic
nicknamed “the great imitator” (6) Spontaneous bleeding and
because of this. coagulopathy
 The possibility of other infection, (7) Hyperpyrexia (Temperature
either co-existing with malaria or as o
>39 C)
the sore cause of fever, should (8) Hypoglycemia (blood glucose <2.2
always be borne in mind in arriving mmol/L): due to parasites
at the diagnosis. It is therefore consuming glucose, catabolic state
important to carry out a differential increases glucose demand of the
diagnosis. host, anorexia associated with the
 In children the onset of malaria may illness, drugs e.g. qunine
be characterized, in the early

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(9) Metabolic acidosis (pH <7.25 or  The parasite may not be
Bicarbonate <15mmol/L) detected in peripheral blood
(10) Hyperparasitemia (>5% of film.
erythrocytes affect by plasmodium  Treatment:
or >100 000 plasmodium/L)  Antimalarial prophylaxis for a
long time, usually for the
TROPICAL duration of malaria exposure
SPLENOMEGALY  Drugs commonly used are
SYNDROME chloroquine (in areas not
(HYPERACTIVE MALARIAL resistant) or mefloquine.
SPLENOMEGALY) o Mefloquine 250mg PO per
 This is a syndrome resulting from week
an abnormal immunologic response o Doxycycline 100mg PO
to repeated infection. It is seen in daily (not to be used in
some residents of malaria endemic children <8 years and
areas. during pregnancy)
 It is characterized by:  The enlarged spleen and liver
 Huge spleen (>10cm below the usually regress over a period of
lower costal margin) with or months with effective
without hepatomegaly antimalarial prophylaxis
 Hypersplenism (anemia,  Splenectomy is only indicated
pancytopenia) for those with failure of
 Marked elevation of serum IgM antimalarial prophylaxis at
and anti-malarial antibody least given 6 months.
 Hepatic sinusoidal DIAGNOSIS
lymphocytes  Malaria should be considered in the
 Peripheral B-cell differential diagnosis of anyone
lymphocytosis who presents with a febrile illness
 Clinical features: in or having recently left, a
 Abdominal mass or dragging malarious area.
sensation in the left upper  Diagnosis is usually made by
quadrant and sometimes identifying parasites on a Giemsa-
abdominal pain stained thick or thin blood film
 Anemia and sometimes (Malaria parasite slide- MPS)
pancytopenia (susceptibility to  Thick slide (not methanol
infection) fixed, RBC are lysed during

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staining, parasites are seen free  Peripheral morphology-
from RBC): used to confirms normocytic normochromic
the diagnosis. anemia (low or normal WBC)
 Thin slide (methanol fixed, you  Serum LDH
can see intact RBC with  Clotting panel (DIC)
parasites inside it) it confirms  Further investigations include a
the diagnosis, identifies the lumbar puncture, may be needed to
species and even quantifies the exclude bacterial infection.
parasite load.  DNA detection (PCR) is used
 At least 3 films should be mainly in research and is useful for
examined before malaria is determining whether a patient has a
declared unlikely. recrudescence of the same malaria
 First smear is positive in 95% parasite or a re-infection with a new
of the cases. parasite.
 Because of the cyclical nature
of the parasitemia, smear
should be taken every 6-12
hours for 48 hours.
 Rapid antigen detection tests are
available for near-patient use.
 They detect the P. falciparum
histidine-rich protein 2
(HRP2), these tests do not
detect other species of
plasmodium and so should be
used in parallel with blood film
examination.
 Serological tests are of no
diagnostic value.
 Other labs:
 Full blood count (Anemia,
thrombocytopenia)
 AST & ALT (may be raised)
 U & Es, Creatinine
 Serum bilirubin
 Serum glucose

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MANAGEMENT
Uncomplicated  Artemisin based combination therapy (ACT) is the recommended oral
malaria treatment for uncomplicated falciparum malaria worldwide.
 Co-artemether (CoArtem) contains artemether (20mg) and lumefantrine
(120mg) and is given as 4 tablets at 0, 8, 24, 36, 48 and 60 hours (first and
second tablet taken 8 hours in between then 16 hours after then 12 hourly).
 Side effects of Coartem: dizziness, fatigue, anorexia, nausea, vomiting,
abdominal pain, palpitations, myalgia, sleep disorders, arthralgia, headache
and rash.
 Alternatives are quinine by mouth (600mg of quinine salt PO TDS for 5-7
days), together with or followed by either doxycycline (100mg PO OD for 7
days) or clindamycin (450mg 3 times daily for 7 days).
 Side effects of quinine: Cinchonism (tinnitus, hearing loss, dizziness, tremor,
nausea, restlessness, blurring) and hypoglycemia (most common side effect)
 Doxycycline should not be used in pregnancy and artemether should be
avoided in early pregnancy. In first trimester use quinine whilst in the second
and third trimester Artemisin based combination therapy can be used (though
guidelines advocate for quinine).
 P. malariae, P. vivax and P. ovale respond to chloroquine. It is given as
600mg PO initial dose followed by 300mg after 6, 24 and 48 hours.

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 Following successful treatment of P. vivax or P. ovale malaria, it is necessary
to give a 2 to 3 week course of primaquine (15mg daily) to eradicate the
hepatic hypnozoites and prevent relapse. This drug can precipitate hemolysis
in patients with G6PD deficiency.

Complicated  Severe malaria indicated by the presence of any of the complications

malaria discussed above, or a parasite count above 1% in a non-immune patient
 Intravenous artesunate is more effective than intravenous quinine and should
be used where available. Absorption from intramuscular injection is less
reliable than from intravenous injection.
 If intravenous administration is not possible, Artesunate may be given
intramuscularly into the anterior thigh.
 Give 2.4mg/kg IV at 0, 12 and 24 hours. If patient does not improve then
once daily. However, as soon as the patient has recovered sufficiently to
swallow tablets, commence full course of recommended ACT such as
Artemether plus Lumefantrine.
 Intensive care facilities may be needed, including mechanical ventilation and
dialysis
 Severe anemia may require transfusion
 Careful monitoring of fluid balance: both pulmonary edema and pre-renal
failure are common.
 Quinine can also be used and is started with a loading dose infusion of
20mg/kg diluted in 10ml of 5% or 10% dextrose over 4 hours up to a
maximum of 1.4g followed by a maintenance dose of 10mg/kg quinine given
as 4-infusions 2-3 times daily up to a maximum of 700mg per dose until the
patient can take drugs orally, then oral quinine 10mg/kg 8 hourly to complete
7-day course of treatment.
 By intramuscular injection, quinine 10mg/kg diluted in saline or water for
injection (to a concentration of 60-100mg salt/ml), repeated after 4 hours and
then 8 hourly. A loading dose is not recommended by this route.
 Hypoglycemia can be induced both by the infection itself and by quinine
treatment. It is also associated with arrhythmias.
 Superadded bacterial infection is common
 Quinine is sometimes used in combination with tetracycline or clindamycin,
doxycycline in places where there is reduced sensitivity to Quinine. In
Zambia, quinine sensitivity is still very high and there is no justification for
using the combination.
 In very heavy infections (parasitemia> 10%) there may be a role for exchange
transfusion, if the facilities are available.

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SUMMARY OF MANAGEMENT
 Take and record a confirmatory history
 Do a confirmatory clinical assessment including body temperature.
 Make a differential diagnosis on clinical basis.
 Do a lumbar puncture if there is need to exclude meningitis
 Prepare a thick and thin blood smear (collect blood in a purple bottle)
 Do a full blood count
 Decide on treatment and method of administration
 Keep treatment, follow-up and referral records. Record treatment failures and
adverse events
 Give oral, subcutaneous, intravenous or intramuscular medications
 Decided on need for referral
 Supportive therapy:
 Bring down fever (cold sponges, paracetamol)
 Monitoring and correction of fluid and electrolyte balance
o Check input and output
o Ensure adequate fluid intake
 Correct management of anemia
o Transfusion
 Management of hypoglycemia
o Administer glucose IV or PO and encourage early PO intake of food.
 Management of any other complications
MANAGEMENT OF COMPLICATIONS
 Cerebral malaria (coma):
 Maintain airway, intubate if necessary
 Position the patient on his/her sides or nurse while propped up.
 2 hourly turning to avoid bed sores
 Exclude other treatable causes of coma e.g. hypoglycemia, bacterial
meningitis
 Catheterize the patient and monitor input- output
 Monitor blood glucose regularly
 Ensure adequate nutrition, insert an NG tube
 Avoid fluid overload

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 Avoid harmful ancillary treatments such as corticosteroids, heparin and
adrenaline
 Convulsions:
 Maintain airway
 Treat promptly with diazepam injection
 Exclude other treatable causes of coma e.g. hypoglycemia, bacterial
meningitis
 Monitor blood glucose regularly
 Aspiration pneumonia should be suspected in any unconscious patient with
convulsions, particularly with persistent hyperventilation.
 Intravenous antimicrobial agents and oxygen should be administered and
pulmonary toilet should be undertaken.
 Acute pulmonary edema:
 Nurse at 45o
 Give oxygen (high flow-3-5L of 100% oxygen)
 Venesect 250ml of blood
 Give diuretics (loop diuretics 60-80mg Furosemide)
 Intubate if necessary and Positive-pressure ventilation should be started early
if immediate measures fail
 Aspiration pneumonia:
 Give parenteral antimicrobials
 Change position
 Physiotherapy
 Give oxygen
 Hypoglycemia:
 An initial slow injection of 50% dextrose (0.5g/kg i.e. 20-50ml of 50%
Dextrose or 40-100ml of 25% dextrose) should be followed by an infusion
of 10% dextrose (0.10 g/kg per hour)
 Regular checking blood glucose (1, 2 or 4 hourly)
 Severe anemia:
 Transfuse whole blood or packed cells.
 Acute renal failure:
 Exclude pre-renal causes
 Rehydrate the patient however if the level of BUN or creatinine rises despite
adequate rehydration, fluid administration should be restricted to prevent
volume overload.
 Dialysis can be performed.

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 For blackwater fever: give antimalarials, intravenous fluids and dialysis if
indicated
 Spontaneous bleeding and coagulopathy:
 Transfuse screened fresh whole blood or cryoprecipitate/fresh frozen plasma
and platelets.
 Give Vitamin K injection
 Shock (“algid malaria)
 Suspect Gram-negative septicemia
 Take blood culture
 Give parenteral antimicrobials
 Correct hemodynamic disturbances
 Hyperpyrexia:
 Tepid sponging, fanning, cooling blanket
 Antipyretic drug (paracetamol)
 Hyperparasetemia: consider exchange or partial exchange transfusion, manual or
hemophoresis (e.g. >10% of circulating erythrocytes parasite in non-immune
patient with severe disease)
 Metabolic acidosis:
 Exclude or treat hypoglycemia, hypovolemia and gram-negative septicemia
 Fluid resuscitation
 Give oxygen

 Note: hypoglycemia or gram negative septicemia should be suspected when the

condition of any patient suddenly deteriorates for no obvious reason during
antimalarial treatment. Systemic Salmonella infections are common
complications among African children with falciparum malaria.

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PREVENTION AND CONTROL

 Treatment, vector eradication and personal protection from vector bites e.g.
insecticide (permethrin) treated nets, spraying of the house (indoor residual
spraying), mosquito repellants, health education.
 Vitamin A supplementation and immunization in children.
 Prophylaxis in sickle cell anemia and post splenectomy used Pyrimethamine
25mg once weekly.
 Non-immune travelers to malarious areas should take antimalarial prophylaxis,
although this is never 100% effective.
 Zambia has no prophylaxis policy for visitors. Recommendations are provided
from their country of origin. Some countries e.g. UK are using Mefloquine.
Sulphadoxine/ Pyrimethamine (Fansidar) is not recommended for this purpose.
 The use of other drugs like amodiaquine, dapsone-pyramethamine (maloprim)
and mefloquine for prophylaxis needs further evaluation and is not therefore
recommended.

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SCHISTOSOMIASIS
 These are a group of diseases caused by the trematode (blood fluke) of genus
Schistosoma affecting mainly the gastrointestinal and genitourinary organs.
 Schistosomiasis in man is caused by 5 species
 S. mansoni- found in Africa even in Zambia (affects the gastrointestinal
system i.e. Intestinal schistosomiasis)
 S. haematobium- also found in African including Zambia (affects the
genitourinary system i.e. urinary schistosomiasis/Bilharziasis)
 S. japonicum- found in South-east Asia
 S. makongi- found in South East Asia (Makongi valley, Laos, Cambodia)
 S. intercalatum- endemic in Congo basin
 S. mansoni, S. haematobium and S. japonicum are common causes of
schistosomiasis.

Figure 57: Schistosoma Eggs: note S. haematobium has a Terminal spine (Mnemonic: remember the "T"
for haematobium helps you remember that it has a terminal spine), S. mansoni has a lateral spine while S.
japonicum is round

 Recall in contrast to other trematodes which are hermaphrodites (which have both
sexes), adult schistosomes exist as separate sexes but live attached to each other.
The female resides in a groove in the male, the gynecophoric canal (“Schist”)
where he continuously fertilizes her eggs.

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 Man is the definitive host where sexual reproduction takes place after cercarial
entry by skin penetration and snail are intermediate hosts in which asexual
regeneration continues.
 The life cycle is as follows:
 Fork-tailed free-swimming Cercariae released by snail into water from snail
infects humans and penetrates the skin (this causes itching and dermatitis-
swimmer’s itch)
 Cercariae lose their tails during penetration and become shistosomulae
(larvae) as they enter the blood and are carried via the veins into the arterial
circulation. They also migrate through the pulmonary vessels.
 Those that enter the superior mesenteric artery pass into the portal circulation
and reach the liver where they mature into adult flukes.
 S. mansoni and S. japonicum adults migrate against the portal flow to reside
in the mesenteric venules.
 S. haematobium adults reach the bladder veins through the venous plexus
between the rectum and the bladder.
 In their definitive venous sites the female lays fertilized eggs which penetrate
the vascular endothelium and enter the gut or bladder lumen respectively.
 The eggs are excreted in the stools or urine and must enter fresh water to
hatch.
 Once hatched, the ciliated larvae (miracidia) penetrate snails and undergo
further development and multiplication to produce many cercariae.
 Each species of Schistosoma has a specific snail host i.e.
o S. mansoni- Biomphalaria species
o S. haematobium- Bulinus species
o S. japonicum- Onchomelania species
 Cercariae leave the snails enter fresh water and complete the cycle by
penetrating human skin.

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Figure 58: Life-cycle of Schistosomiasis

CLINICAL MANISFESTATIONS
 S. haematobium is responsible for urinary schistosomiasis while the other species
cause intestinal schistosomiasis.
 Intestinal schistosomiasis affects the large bowel, liver, distal colon and rectum.
 Manifestations are dependent on the stages of infection.
 Urinary schistosomiasis affects the bladder and urinary tract.
 The first 2 stages are the same for all species of Shistosoma.

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STAGE 1: SWIMMER’S ITCH (STAGE OF INVASION
 This is the first clinical sign of acute infection appearance 24-48hours after
exposure.
 It is characterized by itching at sites of cercarial entry (commonly known as
Swimmer’s itch)
 It is seen in new comers and not common in indigenous people.
STAGE 2: ACUTE STAGE (TOXEMIA STAGE/KATAYAMA
SYNDROME)
 This is an early allergic manifestation to egg deposition (3-10 weeks) in response
to massive antigenic stimulus of eggs and include:
 Fever
 Headache
 Chills
 Myalgias, Malaise
 Profuse diarrhea
 Nausea and vomiting
 Patients may have generalized lymphadenopathy, hepatosplenomegaly,
urticarial and leukocytosis with marked eosinophilia.
 Severity depends on intensity of infection and tends to be mild in indigenous
population. It is most common with S. Japonicum.
STAGE 3 & 4 (CHRONIC STAGE)
 Occurs 3 months to several years later, coincides with deposition of eggs in the
tissues.
 Clinical picture represents the effect of the pathologic lesions caused by the eggs
on the urinary and gastrointestinal systems.
 Urinary schistosomiasis:
 Deposition of eggs in the wall of the urinary bladder induces the formation
of pseudo tubercles and epithelial hyperplasia with subsequent fibrosis and
calcification causing dribbling, incontinence, frequency, dysuria and
hematuria.
 Chronic infection leads to obstructive uropathy, hydronephrosis, Chronic
pyelonephritis, renal failure and contraction of the bladder as well as bladder
squamous cell carcinoma.
 In rare instances gonads, CNS (brain, spinal cord), lungs and endocrine
organs can be involved.

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 Intestinal schistosomiasis:
 The disease is very light and symptom-less for months and then presenting
with recurrent diarrhea with blood and lethargy.
 They may have intestinal polyps and progressive fibrosis of the intestinal
wall leading to formation of strictures but intestinal obstruction is very rare.
 Granulomatous hepatitis followed by progressive peri-portal fibrosis (also
called pipe-stem fibrosis) may develop resulting in portal hypertension with
associated splenomegaly, ascites and esophageal varices that occasionally
may bleed.
DIAGNOSIS AND INVESTIGATIONS
 Clinical diagnosis:
 Urinary schistosomiasis
o Urinalysis: blood
o Cystoscopy- demonstrate fibrosis and calcification of the bladder
o Bladder biopsy and histology demonstrates ova in biopsy sample
o Radiological
 Plain abdominal X-ray may detect calcification of bladder
 Ultrasound of kidneys and ureter
 Intravenous pyelogram to see the presence of obstructive uropathy
 Intestinal Schistosomiasis
o Sigmoidoscopy and rectal snip identifies lesions and ova of the parasite
o Ultrasound of the liver and spleen to demonstrate peri-portal fibrosis and
spleen enlargement
o Liver biopsy
 Laboratory diagnosis
 Full blood count: marked eosinophilia
 Identification of characteristic ova in stool or urine by
o Direct smear method: it is easy but light infection can be missed.
o Sedimentation/concentration method
o In rectal snip/bladder biopsy sample: if it cannot be detected in the stool
or urine
 Seroimmunological diagnosis lacks specificity (Serology is positive after 3
months)

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TREATMENT
 Praziquantel single oral dose
 S. mansoni and S. haematobium= 40mg/kg Orally once
 S. japonicum= 60mg/kg orally once
PREVENTION
 Environmental sanitation: avoidance of pollution of surface water
 Provision of latrine and sanitary waste disposal
 Prevention of human contact with infected water
 Provision of safe and adequate water
 Protective clothing when contact is unavoidable
 Health education to reduce contact with infected water bodies
 Elimination of the disease in the reservoir by chemotherapy
 Case finding and treatment and mass (community) drug administration in
selected populations.
 Snail control
 Physical control- alteration of habitat e.g. removal of vegetation, drainage of
swamps etc.
 Chemical control (moluscicide) Yurimin, Frescon, “Enodd” (phytholacca
dedocandra)
 Biological control- Fish or other snails that feed on vector snails

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VIRAL INFECTIONS
HUMAN IMMUNE DEFICIENCY VIRUS AND AIDS
(RETROVIRUS)
 HIV belongs to the lentivirus group of the retrovirus family.
 There are two types:
 HIV-1: most frequently occurring strain globally. It is more aggressive than
HIV-2. It has several groups and subtypes
o M group: comprises of 9 subtypes i.e. A, B, C, D, F, G, H, J, K as well
as growing numbers of major circulating recombinant forms (CRFs) e.g.
AE, AG etc.
o O group (Outliers): relatively rare seen in Cameron and Gambia
o N group (reported only in Cameroon)
o In Africa more than 75% of strains recovered to date have been subtypes
A, C and D with C being the most common
o Europe and America: Subtype B is the predominant strain
o Asia: recombinant forms such as AE account for the infections in South
East Asia while subtypes C is prevalent in India. Subtype B is also seen
in Asia
 HIV-2: almost entirely confined to West Africa. It has only 40% structural
homology with HIV-1 and although it is associated with immunosuppression
and AIDS, appears to take a more indolent course than HIV-1.
 Many drugs that are used in HIV-1 are ineffective in HIV-2.
 Retroviruses are characterized by the possession of the enzyme reverse
transcriptase which allows viral RNA to be transcribed into DNA and thence
incorporated into the host cell genome.
 Reverse transcription is an error-prone process with a significant rate of mis-
incorporation of bases. This combined with a high rate of viral turnover, leads to
considerable genetic variation and a diversity of viral subtypes.
TRANSMISSION
 Despite the fact that HIV can be isolated from a wide range of body fluids and
tissues, the majority of infections are transmitted via semen, cervical secretions
and blood.
 Sexual intercourse-90% (vaginal and anal): passage of HIV appears to more
efficient from men to women and to the receptive partner in anal intercourse,
than vice versa.

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 Anal sex appears to be the sexual practice that carries the highest risk
of transmitting HIV. The reason being rectal mucosa is thin and
fragile and there are susceptible cells (Langerhans’ cells) in rectal
mucosa.
 Vaginal sex is also an effective form of transmission.
 Presence of other STIs like syphilis, Gonorrhea increases the risk of
infection by several folds as the quantity of virus in seminal or vaginal
fluid significantly increases and the number of infected monocytes is
high around the genital area in patients with STIs.
 Oral sex may have some risk however there are no reports so far
attributable to oral sex.
 Mother to child 30-45% (transplacental, perinatal, breast-feeding): vertical
transmission is associated with advanced disease in the mother, maternal
viral load, prolonged and premature rupture of membranes and
chorioamnionitis. Transmission can occur in utero, although the majority of
infections take place perinatally. Breast-feeding (mixed feeding practices)
has been shown to double the risk of vertical transmission.
o Pregnancy -10% before the 3rd trimester
o Labor and delivery- 70% late pregnancy and during labor
o Breast feeding- 10-15%
 Contaminated blood, blood products and organ denotation (risk has reduced
due to screening using antibody and p24 antigen testing to identify donors in
the window period)
 Contaminated needles (intravenous drug misuse, infections, needle-stick
injuries)
 There is no evidence that HIV is spread by social or house-hold contact or by
blood-sucking insects such as mosquitoes and bed bugs.
MORPHOLOGY
 HIV is a spherical shaped virus.
 It is a positive-sense RNA virus. In the nucleocapsid there are 2 identical strands
of positive sense RNA (retroviruses are diploid).
 The genome organization is similar for all retroviruses. They have the following
genes: gag, pol and env which encode structural proteins:
 Gag gene (group specific antigen): determines the core and shell of the virus
(capsid proteins)

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o It encodes for p25 (capsid protein), p7p9 (core nucleocapsid protein) and
P17 (matrix protein)
 Pol gene endcodes: Reverse transcriptase, integrase, protease and
endonuclease
 Env gene: determines the synthesis of envelope glycoprotein GP 160 which
is cleaved into GP120 and GP 41
 It is an enveloped virus and has many small spikes which consist of 2 important
glycoproteins gp41 and gp120 which play an important role when the virus
attaches to its host cells.
 gp120 binds CD4 receptors on CD4+ T-lymphocytes, microglial cells,
monocytes, macrophages, follicular dendritic cells (in spleen and lymph
nodes) or Langerhans’ cells.
 gp41 helps in the ultimate
fusion of the viral membrane to
the host cells. (this is the target
of certain drugs such as fusion
inhibitors)
 Matrix protein (p17) stabilizes the
envelope proteins.
 The viral capsid (core) is composed
of p24 proteins.
 p24 is a relatively stable protein
that is not associated with entry
and fusion.
 Antibodies against p24 (anti-
p24 antibodies) are not
protective.
 Antibodies and p24 protein in
blood are diagnostic.
 Also found in the capsid are the
enzymes
 Reverse transcriptase (which is
a characteristic of retroviruses)
 Integrase
 Protease

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 HIV attaches via gp120 to the CD4 surface receptors and undergoes a
conformational change and expresses 2 more active sites.
 Depending upon the target cell, different receptors are expressed:
 On macrophages, monocytes, microglial, dendritic cells and Langerhan’s
cells chemokine co-receptor 5 (CCR5) is expressed.
 T-helper cells express CXCR-4.
 Once primary glycoproteins (gp120) and co-receptors bind, gp 41 causes fusion
of the HIV with the host cells. (gp41 is a fusion molecule).

 Complete Lack of CCR5 receptors (due to a homozygous mutation) is associated

with immunity to HIV.
 In heterozygous mutation the progression of HIV is slow.

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LIFE CYCLE
 Attachment/binding and fusion of the virus to the host cells: the receptor and co-
receptors of CD4 cells interact with HIV’s gp 120 and gp 41 proteins during entry
into a cell.
 Uncoating: of the viral capsid and release of viral RNA into the cytoplasm of the
host cell.
 Reverse transcription: viral RNA is converted into double stranded DNA by
reverse transcriptase enzyme
 Translocation: viral DNA is imported to cell nucleus
 Integration: of proviral DNA to host-cell DNA
 Cellular activation causes transcription (copying): of HIV back to RNA
 Some RNA translated to HIV proteins
 Other RNA moved to cell membrane
 Viral assembly: HIV assembled under cell membrane and buds from cell
 Maturation: viral proteases enzymes cleave longer proteins into important viral
proteins and help to convert immature viral particle into infectious HIV.

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PATHOGENESIS
 CD4 positive T-lymphocytes play central role in the defense mechanism of the
body against infection.
 They mainly coordinate the cell mediated immune system and also assist the
antibody mediated immune system.
 HIV virus has special affinity to CD4 T-cells and infects them leading to a
progressive decline of T-helper cells (profound immunodeficiency).
 The pathogenetic mechanism of HIV disease is multi-factorial and multiphasic
and it differs in different stage of disease. Depletion of CD4 cells is due to
 HIV- mediated direct cytopathicity (single cell killing)- infected CD4 cells
die
 HIV- mediated syncytia formation
 Defect in CD4 T-cell regeneration in relation to the rate of destruction.
 Maintenance of homeostasis of total T-lymphocytes (decreased CD4,
increased CD8)
 HIV specific immune response (killing of virally infected and innocent cells)
 Autoimmune mechanism
 Programmed cell death (apoptosis)
 HIV is a unique infection in that, though the body reacts by producing antibodies
to destroy the virus, the virus is not cleared, except partially in the early period
of infection.
 A chronic infection is established and it persists with varying degrees of viral
replication.
 Viral replication is continuous in all stages (Early infection, during the long
period of clinical latency and in advanced stage). There is no virological latency.
 HIV evades the immune system because:
 High level of viral mutation- HIV has an extraordinary ability to mutate.
 Large pool of latently infected cells that cannot be eliminated by viral-
specific Cytotoxic T-lymphocytes.
 Virus homes in lymphoid organs while antibody is in circulation. HIV seeds
itself in areas of the body where sufficient antibodies might not reach e.g. the
central nervous system.
 Exhaustion of CD8 T-cells by excessive antigen stimulation
 HIV attacks CD-4 T-cell which are central to both humeral and cell-mediated
immunity

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HIV PROGRESSION
 Include:
 Rapid progressors (15%): develop OIs very quickly and die within 2-3 years.
 Normal progressors (80%): remain health for 6-8 years before they start
having overt clinical manifestations.
 Long term survivors: patients who remain alive for 10-15 years after initial
infection. In most the disease might have progressed and there may be
evidences of immunodeficiency.
 Long term-non progressors: these have been infection with HIV for more
than 10 years. Their CD4 count may be in the normal range and they may
remain clinically stable for several years.
 Factors affecting progression include:
 Immune response
o High CD8 slow progression
o Low CD8 rapid decline
 Viral type: HIV 2 slow course
 Concomitant conditions: malnutrition hastens the progression of HIV,
chronic infectious conditions e.g. TB also hasten the progression.
CLINICAL MANIFESTATIONS OF HIV INFECTION
SEROCONVERSION ILLNESS
 Seroconversion (the time it takes the body to make antibodies against the HIV
virus, it varies in individuals and generally takes 3-12 weeks)
 Lymphadenopathy
 Pharyngitis
 Systemic: fever, malaise
 Pain: myalgia, headache
 GI symptoms: anorexia, nausea, vomiting, diarrhea
 Maculopapular rash
 Lasts 1-2 weeks
PRESENTATIONS BY SYSTEM
NEUROLOGICAL
 Toxoplasma encephalitis: protozoal infection. Focal neurological signs
 Cryptococcal meningitis: fungal infection. Causes insidious, chronic meningitis
usually without stiff neck
 Primary cerebral lymphoma

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 Progressive multifocal leukoencephalopathy (PML): JC virus infection
 HIV dementia: neurological decline in multiple domains, in the absence of other
infection
 HIV peripheral neuropathy
EYE
 CMV retinitis (Mozzarella pizza sign on fundoscopy)
RESPIRATORY
 Pneumocystis jiroveci pneumonia (PJP or PCP), fungal infection causes dry
cough, sweats, SOB and desaturation on exertion but no chest signs
 Other fungal infections: Aspergillus, Cryptococcus, Histoplasma
 TB: pulmonary TB or atypical and disseminated forms such as miliary TB and
TB meningitis
 Strep and Staph pneumonia
 CMV
MOUTH
 Oral and esophageal candidiasis
 Oral hairy leukoplakia: non-malignant white growths on lateral tongue due to
EBV
 HSV and aphthous mouth ulcers
GIT
 Cryptosporidiosis: Protozoa. Chronic diarrhea
 CMV colitis
 HIV wasting syndrome: Unexplained weight loss >10%
 Mycobacterium avium complex (MAC): GI, Lung, or disseminated
 Fungal: Cryptococcus, Histoplasma
 Other bacteria: Salmonella, Shigella
 Hepatitis B and C
SKIN
 Kaposi’s sarcoma: due to human herpes virus 8. Purple papules on the face,
mouth, back, lower limbs or genitalia. Can also affect GI and respiratory tract
 Multi-dermatomal zoster (Shingles)
 Recalcitrant psoriasis

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CANCER
 B-cell lymphoma, EBV related
 Cervical and anal cancers. HPV-related
 Lung cancer
 Head and neck cancers
INFECTIONS BY CD4 LEVEL
 200-500: TB, Candida, VZV, Kaposi’s, other pneumonias
 100-200: PCP, histoplasmosis, PML
 50-100: atypical TB, CMV retinitis/colitis, toxoplasmosis, cryptosporidiosis,
Cryptococcal meningitis
 <50: MAC
DIAGNOSIS
 Serologic tests:
 HIV antibody tests: detect antibodies formed by the immune system against
HIV
o ELISA: used to be standard screening test for HIV
 Tests for a number of antibody proteins
 A very sensitive (99.5%) but not very specific
 A positive result needs to be confirmed by Western blot for
confirmation.
 The test needs skilled personnel, takes several hours
o Western blot: is an excellent confirmatory test
 It has high specificity but relatively poor sensitivity
 It should not be used for screening purpose
o Rapid HIV antibody tests:
 Rapid tests have reasonable good sensitivity and specificity (>99%)
 Easy logistically, do not need continuous water or electric supply
 Can be done by less skilled personnel and the interpretation of results
is easy.
 Test result can be available in <30 minutes.

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Note: When the first test is non-reactive then the client can receive the
negative HIV result. When both tests are reactive the final HIV result is
positive. If one test is reactive and the other is non-reactive, then a third test
known as a tiebreaker is performed. The tie-breaker determines the final
result- if the tiebreaker is reactive then the final HIV result is positive, if the
tiebreaker is non-reactive then the final HIV result is negative.

Screening test- determin test

Conformation test- unigold test
Tie breaker test- bioline test

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 HIV antigen assays (Tests)
o P24 antigen capture assay: this test detects p24 viral protein in the blood
of HIV infected individuals. This viral protein can be detected during
early infection, before seroconversion. Thus this test is used to detect
blood donors during the window period.
 DNA PCR: Viral replication
 Extremely sensitive test can detect 1-10 copies of HIV proviral DNA per ml
of blood.
 Uses PCR technology to amplify proviral DNA
 This test is costly and needs sophisticated instruments and highly skilled
professional
 It is highly sensitive and the chance of false positive is high hence it should
not be used for making initial diagnosis of HIV infection
 It is used for
o Making early diagnosis of HIV in HIV exposed infants as serology tests
are unable to diagnose HIV till the infant is 18 months old.
o To diagnose or confirm virologic failure in patients who are not
responding to ART
o When there is indeterminate serology
 CD4 T cell count
 This is an indicator of the level of immune suppression that a patient with
HIV has.
 The average CD4 count of a normal person is in the range of 1000-1200/mm3.
 In patients with HIV CD4 count drops by an average of 50-100 cells per year
 It should not be used to make a diagnosis of HIV.
 CD4 count no longer used in deciding on initiation of ART as all HIV
positive patients are started on ART immediately
 CD4 may be used to follow the progress of a patient on ART however, viral
load is a more important measure.
 It should be done 3 to 6 monthly.
 CD4 count may be variable depending on circumstances:
o Diurnal variation: high evening, low at midnight
o Intercurrent infection, use of steroids and stress could affect CD4 count.
 Additional tests:
 Viral load
 Hepatitis Panel (especially B and C)
 Full blood count and ESR

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 AST and ALT
 Serum creatinine
 Syphilis serology: RPR
 AFB chest X-ray where possible
 Stool examination for parasites
 Malaria blood slide
 Pregnancy test for women in child bearing age
 Serum HIV combined antibody + P24 antigen test to screen, to confirm with
Western blot. 50% detectable within 1 month of infection and nearly all by 6
months.
 If positive screen for TB, PCP (CXR shows bilateral interstitial infiltrates),
hepatitis A-C, syphilis, toxoplasma (Contrast-enhancing lesions on CT/MRI
brain), CMV, Cryptococcal (Cryptococcal antigen test on CSF and serum)
 Genotype testing to guide drug treatment
 Pregnancy test for women
 Baseline bloods: FBC, U&Es, LFT, Lipids, Glucose
STAGING OF HIV
 WHO stages HIV as:
 Stage 1: Asymptomatic
 Stage 2: Minor symptoms
 Stage 3: Moderate symptoms
 Stage 4: AIDS defining illness
 CDC staging is by CD4 count
 Stage 1: CD4 >500
 Stage 2: CD4 200-500
 Stage 3: CD4<200 (or stage 3-defining opportunistic infection)
WHO STAGING
STAGE 1
 Asymptomatic
 Persistent generalized lymphadenopathy (presence of lymph node> 1cm in 2
extra inguinal sites and persisting for more than 3 months)

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STAGE 2
 Unexplained moderate weight loss (<10% of body weight)
 Recurrent upper respiratory tract infections (sinusitis, tonsillitis, otitis media and
pharyngitis)
 Minor mucocutaneous manifestations/pruritic pupular eruption (seborrheic
dermatitis, fungal nail infections, recurrent oral ulcerations, angular chelitis)
 Herpes zoster within the past 5 years (single dermatome)
STAGE 3
 Unexplained severe weight loss (>10% of body weight)
 Unexplained chronic diarrhea longer than 1 month
 Unexplained prolonged fever >1 month
 Oral hairy leukoplakia
 Persistent oral candidiasis
 Pulmonary TB
 Severe bacterial infection (pneumonia, pyomyositis, empyema, meningitis,
bacteremia)
 Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis
 Unexplained anemia (<8g/dl), neutropenia <500/mm3 and or chronic
thrombocytopenia (<50 000/mm3)
 AIDS-related complex is an associated term describing weight loss, fever
diarrhea, minor infections, occurring before AIDS criteria are met
STAGE 4
 HIV wasting syndrome
 AIDS defining conditions: note the term Acquired immunodeficiency syndrome
(AIDS) was traditionally used to describe a CD4 count <200 or the presence of
AIDS defining illness.
 The term AIDS is now less used in clinical practice. This partly reflects the
huge decline in AIDS (due to cART) but also the possible stigma surrounding
the term. More practically it is more useful to refer to specific CD4 counts,
viral load and infection history to give a picture of someone’s clinical
condition than the non-specific “AIDS”.
 Advanced or Late-stage HIV may be useful alternative terms to ‘AIDS’
 Pneumocystis jiroverci pneumonia
 CNS toxoplasmosis
 Cryptosporidosis or Isosporiasis related watery diarrhea >1 month

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 Extrapulmonary cryptococcosis
 CMV disease of an organ other than liver, spleen, or lymph nodes e.g. CMV
retinitis
 Chronic HSV- orolabial, genital anorectal lasting for more than 1 month
 Any disseminated endemic mycosis (e.g. Histoplasmosis, coccidiodomycosis)
 Esophageal candidiasis (involving esophagus, trachea, bronchi or lungs)
 Recurrent bacterial pneumonia
 Recurrent septicemia
 Disseminated atypical mycobacterium
 Extrapumonary TB
 Lymphoma (cerebral or B-cell Non-Hodgkin’s lymphoma)
 Invasive cervical carcinoma
 Kaposi’s sarcoma
 HIV encephalopathy
 Symptomatic HIV associated neuropathy
MANAGEMENT OF HIV
 Lifestyle and preventative:
 Counselling to prevent high-risk sexual behavior
 Lifelong condom use traditionally recommended but good evidence that
those with undetectable viral load cannot transmit even during condomless
sex.
 Specific methods are available for reproduction in serodiscordant couples
e.g. IUI with sperm washing, IVF with ICSI
 Assistance with partner notification and contact tracing
 Vaccines: hepatitis A and B, annual flu, pneumococcal vaccine, HPV. Avoid
live vaccine if CD4 <200 (VZV, MMR, BCG and oral and intranasal
vaccines, yellow fever)

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 Combination antiretroviral therapy (cART)/High active  EFV400a is the lower dose of
ART (HAART): EFV-400mg/day and is
 Treatment is now initiated for all patients found preferred ARV agent in
positive regardless of CD4 count, WHO clinical HIV/TB patients on TB
stage, pregnancy status or AIDS-related illness. treatment
 Triple therapy: (2 x NRTI) + (NNRTI or Protease  TAFc is tenofovir
inhibitor or integrase inhibitor) alafenamide. Avoid in
o Currently preferred regimen (2020): TDF (or pregnancy and HIV/TB
TAFc) + XTCd (3TC or FTC) + DTGe patients on Rifampicin
o Alternative regimen: (currently not recommended)
 TDF (or TAFe) + XTCd + EFV400a  XTCd: can either be 3TC or
 ABC + 3TC + DTG* FTC. FTC is not available as
 ABC + 3TC + EFV a single drug and is expected
 ABC + 3TC + NVP to be part of the fixed dose
o Past recommended first line(TLE): TDF + (3TC combination TAF + FTC +
or FTC) + (EFV or NVP) DTG
o Second line:  DTGe: Dolutegravir to be
 AZT + 3TC (or FTC) + LPV-r (or ATV-r) given to ART naïve
 Indications for changing from first line to second adolescents and adults. For
line: HIV/TB patients on
o Clinical failure Rifampicin and cannot
o Immunologic failure tolerate EFV400 increase the
o Virological failure frequency of DTG to 50mg
BD instead of the usual 50mg
OD where single tablet is
available
 DTG*: ABC + 3TC + DTG
can be used as an alternative
for those with renal
insufficiency or where TAF is
not available and EFV is not
tolerated

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 Visit 1 (enrollment/initiate ART based on patient readiness)

o Complete history and examination
o Screen for TB and other OIs
o WHO clinical staging
o Initiate CTX if eligible (CD4 <350 cells/L or stage I, II or IV or
pregnant)
o Initiate TB prophylaxis if TB screening is negative if not initiated
o Adherence counseling
o Urinalysis
o Lab tests: Full blood count, CD4 count, ALT, Creatinine (Calculate Cr
clearance), ALT, HBsAg (if not vaccinated), Pregnancy test (adolescent
or woman or reproductive age), syphilis test (adolescent or adult),
cholesterol and triglycerides (especially if starting PI), HPV test or visual
inspection with acetic acid in sexually active adolescent or woman.

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 Visit 2 (1-2 weeks later initiate ART if not initiated on visit 1)
o Target history and examination
o Screen for TB, cryptococcus and PCP
o Review CTX adherence (if already started)
o Initiate CTX (if eligible and not initiated at enrollment)
o Initiate TB prophylaxis if TB screening is negative if not initiated
o Review lab test result.
o Initiate ART if not imitated
o Lab tests: Urinalysis, sputum AFB smear/geneXpert MTB RIF in
individuals with a positive screening, serum Cryptococcal antigen test for
adolescents and adults with CD4 count< 100cells/L.
 Visit 3 (2-4 weeks from enrollement, initiate ART if not imitated)
o Targeted history and examination
o Screen for TB and other OIs
o Review CTX adherence
o Initiate TB prophylaxis if TB screening is negative if not initiated
o Initiate ART if not started in the last 2 visits
o Adherence counselling
o Lab tests: urinalysis, sputum AFB, serum Cryptococcal antigen test for
adolescents and adults with CD4 count< 100cells/L.
(140−𝑎𝑔𝑒)×𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)×(𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡)
Creatinine clearance=
𝑆𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑖𝑛 𝑚𝑖𝑐𝑟𝑜𝑚𝑜𝑙/𝐿)

Constant= 1.23 for males and 1.04 for women.

 If creatinine clearance >50ml/min you can use TDF

 If creatinine clearance between 30 to 50 ml/min replace TDF
with TAF
 If creatinine clearance <30ml/min replace TDF with ABC and
adjust dose of 3TC
 Note: if evidence of renal disease replace TDF with TAF or
ABC. Avoid TAF in pregnant women or TB patients on
Rifampicin, also increase DTG to 50mg BD.

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 Treat co-infection
 Active TB: 4FDCs. Overlapping toxicities and drug interactions make TB-
HIV co-treatment difficult, but if CD4 <350 (and especially <100), treat TB
then initiate HAART after 2 weeks of treatment.
 Latent TB: 6 months isoniazid and pyridoxine
 Hepatitis C: combination direct-acting antiviral, paying attention to drug
interaction.
 Prophylactic antibiotics:
 Co-trimoxazole for PCP and toxoplasma if CD4 <200.
 Azithromycin for MAC if CD4 <50
TREATMENT FAILURE
 Treatment failure can be:
 Clinical: Treatment failure should be considered when clinical symptoms
appear whilst on therapy that is suggestive of deteriorating status.
 Immunological: treatment failure is indicated by a drop of CD4 values to
below pre-treatment levels or 50% from the peak value on treatment or
perisistant CD4 levels below 50 cells/mm3 after 12 months on therapy.
Note: patients initiating at very low CD4 may not be able to mount an
adequate CD4 recovery in this case viral load is indicated.
 Virologic: plasma HIV viral load >400 copies/ml after 6 months on
therapy.
 Patients who appear to be failing on treatment while viral load is undetectable
should be considered to have undiagnosed opportunistic infection or other
concomitant illness.
 It should not be concluded on the basis of clinical criteria, that an ARV regimen
is failing until there has been a reasonable trial of 1 st line therapy lasting at least
6 months, adherence has been assessed and optimized, intercurrent OIs have been
treated and resolved and IRIS has been excluded.
 Clinical events that occur before the first 6 months of therapy are excluded from
this definition because they often represent immune reconstitution inflammatory
syndroems related to pre-existing conditions.
 Factors leading to treatment failure:
 Poor adherence to treatment
 Prior exposure to antiretroviral treatment with development of resistance
 Primary viral resistance (infected with resistant HIV strain)
 Inadequate drug absorption

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 Suboptimal dosing (e.g. sharing dose because of side effets)
 Inadequate or inconsistent drug therapy
 Drug interactions

PROGNOSTIC FACTORS
 CD4 count: measures the degree of immune compromise and predicts the risk of
opportunistic infections
 HIV viral load: measures HIV replication rate, gauges the efficacy of anti-
retrovirals and predicts CD4 count decline.

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ANTIRETROVIRAL DRUGS
 Selection of the appropriate combination is based on:
 Avoiding the use of 2 agents of the same nucleoside analogue
 Avoiding overlapping toxicities and genotypic and phenotypic characteristics
of the virus
 Patient factors such as disease symptoms and concurrent illnesses
 Impact of drug interactions
 Ease of adherence to the regimen
 The goals of therapy are to maximally and durably suppress HIV RNA
replication, to restore and preserve immunologic function, to reduce HIV-related
morbidity and mortality and to improve quality of life.
 Common side effects of antivirals: GI upset (diarrhea, vomiting, hepatitis
especially with Nevirapine), Skin (mild rash, in rare cases hypersensitivity or
SJS/TEN), Metabolic (lipodystrophy- fat reduction peripherally i.e. head and
limbs but gain central it is seen with NRTIs and PIs; diabetes and dyslipidemia
especially with PIs but possible with all)
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
 These are prodrugs (chain terminators). They use non-specific kinases to be
activated (and so carry a risk of bone marrow suppression).
 They are used with protease inhibitors (PIs) in HAART.
 Drugs:
 Zidovudine (azidothymidine)- (AZT)
 Tenofovir (TDF)
 Abacavir (ABC)
 Lamivudine (3TC)
 Emtricitabine (FTC)
 Stavudine (D4T)
 Didanosine (DDI)
 Mechanism of action: NRTIs are analogs of native ribosides (nucleosides or
nucleotides containing ribose) which all lack a 3’ hydroxyl group. Once they
enter cells, they are phosphorylated by cellular enzymes to the corresponding
triphosphate analog which is preferentially incorporated into the viral DNA by
reverse transcriptase. Because the 3’ hydroxyl group is not present, a 3’5’
phophodiester bond between an incoming nucleoside triphosphate and the
growing DNA chain cannot be formed and DNA chain elongation is terminated.

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 Resistance occurs by mutations (multiple) in the gene (pol gene) that codes for
reverse transcriptase, integrase and aspartate protease.
 Not complete cross-resistance between NRTIs. Mutations confers a high degree
of resistance to lamivudine and emtricitabine but more importabtly restores
sensitivity to zidovudine and tenofovir.
 Because cross-resistance and antagonism occur between agents of the same
analog class (thymidine, cytosine, guanosine and adenosine), concomitant use of
agents with the same analog target is contraindicated (e.g. Zidovudine and
stavudine are both analogs of thymidine and should not be used together)
 Common combinations
 First line combinations
o Lamivudine/tenofovir (3TC/TDF)
o Emtricitabine/tenofovir (FTC/TDF)
o Abacavir/Lamivudine (ABC/3TC)
 Second line combination: Lamivudine/ zidovudine (3TC/ AZT)
 Others: didanosine, stavudine
Drug Comment Side effect
Zidovudine  Prototype drug  Myleosuppression (bone marrow
(AZT)  Pyrimidine analogue (thymidine) suppression)/hematotoxicity- this
 Both stavudine and ribavirin are activated is the major and dose limting side
by the same intracellular pathway and effect, patients may require blood
should not be given with AZT transfusion before initiating
therapy
 Anemia
 Neutropenia
 Headache, asthenia (Extreme
fatigue), myalgia, myopathy,
peripheral neuropathy
Tenofovir  It is an adenosine analog.  Renal failure
(TDF)  The drug should not be used with  GIT compliaints: nausea and
didanosine (DDI) due to drug interactions bloating
 Tenofovir decreases the concentrations of  Osteoporosis
the PI atazanavir such that atazanavir
must be boosted with ritonavir if these
agents are given concurrently
Lamivudine  Inhibits the reverse transcriptase in both  Least toxic of NRTIs and least
(3TC) HIV and HBV. It does not affect potent

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mitochondrial DNA synthesis or bone  Has some GI effects and
marrow precursor cells resulting in less neutropenia
toxicity.
Zalcitabine  Do not combine DDI and DDC because  Peripheral neuropathy (major and
(DDC) of pancreatitis as a side effect dose limiting)
 GI distress, pancreatitis,
neutropenia, rash
Abacavir  It is a guanosine analogue  GI distress, headache, and
(ABC) dizziness. 5% show
hypersensitivity reactions to drug
 Myocardial infarction
Didanosine  This is a precursor for both adenine and  Pancreatitis (major and dose
(DDI) guanine limiting)
 Peripheral neuropathy,
hyperuricemia, liver dysfunction
Emtricitabine  This is a derivative of lamivudine and  Headache, diarrhea, nausea and
(FTC) inhibits both HIV and HBV reverse rash
transcriptase.  It may also cause
 It is more active than lamivudine hyperpigmentation of soles and
palms.
Stavudine  Thymine analogue  Peripheral neuropathy (major and
(D4T)  Should not be used with AZT as it would dose-limiting)
compete for phosphorylation and site of  Myelosuppression <zidovudine
action on the DND provirus

NON-NUCLESIDE REVERSE TRANSCRIPTASE INHIBITORS

 These do not require activation by cellular enzymes to inhibit reverse
transcriptase inhibitor. (they are not prodrugs, no risk of myelosuppresion)
 They are additive or synergistic with NRTIs
 Drugs:
 Efavirenz (EFV)
o Can disrupt sleep cycle (insomnia and “dysphoric dreams”-nightmares)
and cause psychosis
o Avoid in pregnant women
 Nevirapine (NVP)
o A single dose of NVP given at the time of delivery will decrease vertical
transmission of HIV by 50%.

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o Primary side effects: Rash and increased liver function tests
(hepatotoxicity) as well as Stevens-Johnson syndrome and Toxic
epidermal necrolysis
o It is an inducer of cytochrome P450 3A4 and so shows drug interactions
(i.e. with warfarin)
PROTEASE INHIBITORS
 Mechanism of action
 Aspartate protease (pol gene encoded) is a viral enzyme that cleaves
precursor polypeptides in HIV buds to form the proteins of the mature virus
core
 Enzyme contains a dipeptide structure not seen in mammalian proteins. PIs
bind to this dipeptide inhibiting the enzyme
 Resistance occurs via specific point mutations in pol gene such that there is
not complete cross-resistance between different PIs
 These drugs are combined with NNRTIs as second line e.g. AZT, 3TC, LPV/r
 Drugs:
 Lopinavir/ritonavir (LPV/r): due to poor bioavailability it is boosted with
ritonavir
 Saquinavir (SQV): one of the least toxic and has low oral bioavailabity and
so is also boosted with low dose ritonavir
 Ritonavir (RTV): no longer used as a single PI but used as a booster of other
PIs
 Indinavir (IDV): combined with ritonavir nearly always in combination
regiemns with 2 NRTIs

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 Atazanavir (ATV)
 Darunavir (DRV)
 Side effects:
 Crystalluria (indinavir)
 Syndrome of disordered lipid and carbohydrate
metabolism with central adiposity and insulin
resistance (less with atazanavir)
 Gall stones (atazanavir)
 Kidney stones (indanavir)
 Major drug interactions (Ritonavir works on
cytochrome P450)
o Rifampicin
o Digoxin (use lower dose of digoxin dose)
o Oral contraceptives: use higher dose
contraceptives
Figure 59: Accumulation of fat at the base
FUSION INHIBITORS of the neck in a patient receiving a PI
 Drugs:
 Enfuvirtide (fusion inhibitor)
 Maraviroc (Entry inhibitor-CCR5 inhibitor)
INTEGRASE INHIBITORS
 Inhibit intergrase preventing integration of viral genome into host genome
 Drugs:
 Dolutegravir
 Raltegravir
 Cross-resistance between raltegravir and elvitegravir can occur although
dolutegravir has limited cross-resistance to other integrase inhibitors.
 Side effects: nausea, diarrhea are most common as drugs are well tolerated.

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PRE-EXPOSURE PROPHYLAXIS (PrEP)

 PrEP is used as a preventive measure of HIV transmission in people at substantial
risk of HIV acquisition.
 Eligibility criteria:
 No suspicion of acute HIV infection
 Test HIV negative
 Perceives to be at substantial risk of HIV acquisition and willing to be
adherent
 Able to attend regular 3 month reviews and HIV testing
 Able to concomitantly apply other methods such as barriers to prevent the
transmission of other STIs
 Willing to stop taking PrEP when no longer eligible
 People at high risk: engaging in 1 or more of the following in last 6 months
o Vaginal/anal intercourse without condomes with more than 1 partner
o Sexually active with a partner who is known positive or at substantial
risk of being HIV positive
o Sexually active with an HIV positive partner who is not on effective
treatment (ART for <6 months or not virally suppressed)
o History of STI

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o History of PEP use
o Sharing injection material or equipment
 ARVs are used for oral PrEP and PEP
 Oral PrEP containing Tenofovr disoproxil fumarate (TDF) or alternatively
Tenofovir alafenamide (TAF) with with either Emtricitabine (FTC) or
Lamivudine (3TC) should be offered as an additional prevention choice for
people at substantial risk of HIV acquisition as part of combination HIV
prevention approaches.
 Drugs used:
 TDF + XTC (emtricitabine FTC or lamivudine 3TC) is safe in pregnancy and
during breastfeeding. It is also active against hepatitis B infection thus
discontinuation of this combination requires close monitoring in those
infected with hepatitis B due to concern of rebound viremia
 TAF + FTC can be used in patients with a Creatinine clearance between 30
and 50ml/min, though TAG is not currently recommended for use in patients
with TB or pregnancy.
 Persons with osteopenia/Osteomalacia/osteoporosis may be at risk of bone loss
associated with TDF therefore TAF would be recommended in such population
 TDF should not be co-administered with other nephrotoxic drugs e.g.
aminoglycosides.
 Standard TB medication or oral contraceptives do not interact with PrEP drugs
and there is no need for dose adjustments.
 PrEP clients must be routinely test for HIV infection and ART offered
immediately if the PrEP user seroconverts.
 PrEP should be taken a minimum of 7 days in men and 21 days in women to
achieve maximal protection from HIV acquisition before engaging in high risk
sexual exposure and must be continued as long as risky exposure persists or one
remains negative.
 PrEP should be discontinued after 4 weeks of elimination of the risky exposure.
 Note: PrEP alone is not 100% effective at preventing HIV and clients need to be
counselled that they should use other prevention methods as well.

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POST-EXPOSURE PROPHYLAXIS (PEP)

 This is the use of ART to prevent HIV transmission.
 There is no risk of transmission when the skin is intact.
 Factors associated with increased risk:
 Deep injury
 Visible blood on the device that caused the injury
 Injury with a large bore needle from artery or vein
 Unsuppressed HIV viral load in source patient
 Body fluids and materials that pose risk of HIV transmission are amniotic
fluid, cerebrospinal fluid, human breast milk, pericardial fluid, peritoneal
fluid, pleural fluid, saliva in association with dentistry, synovial fluid,
unfixed human tisues and organs, vaginal secretions, semen, any other visibly
blood stained fluid and fluid from burns or skin lesion.
 Management:
 Immediately after exposure
o Clean the site: wash skin wounds with soap and running water. Do not
squeeze, allow wound to freely bleed. If the exposed area is an eye or
mucous membrane, flush with copious amounts of clean water. Do not
use bleach or other caustic agents/disinfectants to clean the skin
 Contact incharge or supervisor
 Consult medical officer to determine the need for PEP based on the risk of
transmission and risks and benefits of taking (or not taking) ART

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SYSTEMIC MANIFESTATIONS OF HIV INFECTION
 These include:
 Neurological manifestations (second most
common)
o Directly related to HIV
o Secondary to immunodeficiency
 Opportunistic infections (AIDS
defining)
 Opportunistic malignancies (AIDS
defining)
o ART related
 Respiratory manifestations (most common)
o Opportunistic infections (AIDS defining)
o Opportunistic malignancies (AIDS
defining)
 Gastrointestinal manifestations
o Oral candidiasis
o Oral hairy leukoplakia
o Diarrhea
 Persistent cryptosporidiosis (AIDS
defining)
 Chronic diarrhea of unknown cause
(HIV enteropathy)
o Weight loss of unknown causes
o Infection with Salmonella, Shigella,
Campylobacter, Hepatitis B infection,
Hepatitis C infection
 Dermatological
o Kaposi’s sarcoma (AIDS defining)
o Severe/recalcitrant seborrheic dermatitis
o Multidermatomal/Recurrent herpes zoster
 Oncology (Opportunistic malignancies)
o Kaposi’s sarcoma
o Lymphomas
o Cervical cancer

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 Opportunistic infections are infections that develop as a result of HIV-inflicted
damage to the immune system. They are the leading cause of morbidity and
mortality in HIV infected persons. Most opportunistic infections and
complications of HIV develop when the CD4 count drops below 200cell/ml.
 Opportunistic malignancies are neoplastic conditions which tend to occur more
frequently in patients with underlying immunodeficiency.
NEUROLOGICAL MANIFESTATIONS
 This is the second commonly affected organ system by HIV next to the
respiratory system.
 Neurological manifestations can occur at any stage of HV.
 All lelves of the neuro-axis are involved.
 Clinical manifestations are variable and include:
 Directly related to HIV
o Aseptic meningitis
o AIDS dementia complex: Acute demyelinating distal polyneuropathy
(AIDP), monouritis multiplex (MNM) and Distal sensory
polyneuropathy (DSPN)
o Myelopathy
o Peripheral neuropathy
o Myopathy
o Vasculitis
 Secondary to immunodeficiency
o Opportunistic infections
 CNS toxoplasmosis
 Cryptococcal meningitis
 Tuberculous meningitis/Tuberculoma
 Progressive multifocal leucoencephalipathy
 CMV polyradiculopathy/Encepalitis
o Opportunistic malignancies: Primary CNS lymphoma
 ART related
o Peripheral neuropathy: didanosine (DDI) and stavudine (D4T)
o Myopathy: zidovudine (AZT)
o Psychiatric manifestations (psychosis): Efavirenz (EFV)

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NEUROLOGIC MANIFESTATIONS DIRECTLY RELATED TO HIV

ASEPTIC MENINGITIS
 This may occur at any time in the course of HIV infection, most commonly at
the time of acute HIV infection.
 It becomes increasingly rare following the development of AIDS.
 Patients experience a syndrome of:
 Headache
 Photophobia
 Sometimes: Frank-encephalitis and cranial nerve involvement (Commonly
VII cranial nerve is affect)
 CSF findings:
 Lymphocyte pleocytosis 10-100 cells/L
 Increased protein level
 Normal glucose level
 Diagnosis of HIV: HIV serology may be negative if it occurs during the primary
HIV infection. To confirm the diagnosis of HIV p24 antigen or DNA PCR may
be done or repeat serology after few weeks.
 The syndrome usually resolves spontaneously within 2-4 weeks.
AIDS DEMENTIA COMPLEX
 This may be the first AIDS defining illness in up to 5-10%. It is a major cause of
dementia in young people.
 A major feature of this entity is the development of dementia which is defined as
a decline in cognitive ability, motor and behavioral dysfunction.
 Triad:
 Cognitive dysfunction
 Motor dysfunction
 Behavioral dysfunction
Cognition Behavior Motor
Early Inability to concentrate Altered
personality
Middle Mental slowing Social withdrawal Poor coordination
Forgetfulness
Late Global dementia Apathy Paraparesis

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 Diagnosis:
 Neuropsychological tests
 Mini-mental test
 It is often a diagnosis of exclusion
 Treatment:
 Antiretroviral therapy especially with those that penetrate the CNS
(zidovudine, Stavudine, abacavir and nevirapine)
 Supportive care
PERIPHERAL NEUROPATHY
 Occurs in 1/3 of patients with AIDS.
 Types:
 Mononeuropathy e.g. Bell’s palsy
 Mononuritis multiplex
 Distal sensory peripheral polyneuropathy (DSPN)
 DSPN: is the most common, it presents with symmetric bilateral painful burning
sensation, paresthesia and tingling of the feet and lower extremities.
 Diagnosis:
 Clinical
 Nerve condution study
 Exclsion of other causes
 Treatment: Symptomatic treatment and discontinuation or changing the drug
causing it when symptoms are severe.
OPPORTUNISTIC INFECTIONS
CNS TOXOPLASMOSIS
 This is caused by the protozoa Toxoplasma gondii.
 It is a zoonotic infection and cats are the definite host and excrete the oocysts in
their feces and can be transmitted from animal to humans.
 T. gondii cysts are also found in under-cooked meat.
 This is the second most common cause of secondary CNS infection in patients
with AIDS.
 It is generally a late complication of HIV infection and usually occurs when the
CD4 cell count is less than 100/mm3.
 It is though to represent a reactivation syndrome of prior infection
 Clincal features:
 Onset- subacute

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 Fever, headache, hemiparesis, seizures and altered mental status
 Focal neurological signs (90%)
 Encephalitis picture (10%)- confusion or common and become more toxic
 Commonly affected areas- basal ganglia, brain stem and cerebellum
 Extracranial manifestations:
o Chorioretinitis
o Myocarditis
o Pneumonitis (lung)
 Diagnosis:
 Clincial: history and physical examination
 Neuroimaging (CT/MRI):
o Multiple ring enchancing lesions are
seen in 90% of patients with mass
effect and edema. (A solitary lesion on
MRI makes the diagnosis unlikely)
o Preferential location: basal ganglia,
grey-white junction, white matter
 Therapeutic trial +/- histology (biopsy)
o Histology: brain biopsy- in patients
with treatment failure (not possible in
Zambia)
 Serologic assays are of limited value, a
negative toxoplasma antibody test makes the
diagnosis less likely.
 Treatment:
 Regimen one: Loading dose of
Figure 60: : CT showing a ring enhancing lesion
pyrimethamine 200mg (loading dose with adjacent edema (Pyogenic cerebral abscess).
200mg, then 50mg daily) combined with
sulfadiazine (2-4g/day) and folinic acid (10-20mg/day)
 Regimen two: Fansidar (Pyrimethamine 25mg + Sulfadoxine 500mg) +
Folinic acid 10-20mg/day
o Dose: 525mg (2 tabs) PO BD for 2 days and then 1 tab PO/day, if
patient is very critical add Doxycycline 100 PO BD.
 Regimen 3: Pyrimethamine (loading dose 200mg, then 50mg daily) and
Folinic acid 10-20mg/day plus Clindamycin 450mg 8 hourly
 Note: Clindamycin and pyrimethamine may be used in patients allergic to
sulphonamide

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 Duration of treatment is 6 weeks or 3 weeks after complete resolution of
lesions on CT.
 Continue suppressive therapy for life: Pyrimethamine 25mg/day +
Sulfadiazine 2g/day + folinic acid 5-10mg/day.
 HAART should be initiated as soon as the patient is clinically stable,
approximately 2 weeks after acute treatment has begun to minimize the risk
of IRIS.
 Side effect:
o Leucopenia (main side effect of treatment). A higher dose of fansidar (2
tab/day) has been found to be associatd with frequent incidence of fatal
hemorrhage
o Check for bleeding tendency such as gum bleeding, epistaxis, hematuria
o Do FBC once per week
o To prevent effects give folinic acid 10mg PO
o If there is bleeding tendency stop fansider and start Doxycycline 100mg
PO BD
o Alternatives:
 Co-trimoxazole or Clindamycin + Pyrimethamine/Primaquine
 Azithromycin, Clarithromycin, Doxycycline
 Indications for steroid use:
o Evidence of marked increased intracranial pressure and altered mentation
o Dose: administer: dexamethasone 8mg IV stat and then 4mg IV DIQ till
the suppressive/maintenance therapy: Fansidar 1 tab per day should be
continued. Suppressive therapy (Secondary prophylaxis) can be stopped
when the CD4 count is more than 200 for 6 months.
 Prevention: for all with CD4 count <100cells/microliter
 Use TMP-SMX 2 tablets per day
 TMP-SMX 2 tablets three times per week
 Alternatively: Dapson plus pyrimethamine plus folinic acid.
 Primary prophylaxis can be stopped if CD count> 200cells/ml for more than
3 months following antiretroviral therapy

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CRYPTOCOCCAL MENINGITIS
 This is caused by Cryptococcus neoformans which is a yeast-like fungus.
 Pigeon dropping common contain serotypes A or D.
 Infection is acquired through inhalation.
 It is the leading cause of meningitis in patients with AIDS.
 It occurs late in the course of HIV/AIDS when the CD4 count drops below 100.
 Clinical features:
 Low grade fever, nausea, vomiting, headache
 Both fever and nuchal rigidity are often mild or lacking
 Papilledema is seen in 1/3 of patients
 Neck stiffness, photophoba- meningeal signs (30%)
 Late manifestations: confusion, altered state of consciousness coma.
 Extracranial manifestations:
o Pulmonary or disseminated disease that includes the skin (10%)
o Cutaneous Cryptococcosis: centrally umbilicated multiple lesions on the
face (look very much like Molluscum contagiosum)
o Pulmonary disease
o Fungemia
o Lymphadenopathy
o The prostate gland may be a reservoir for smoldering infection
 Diagnosis:
 LP-CSF analysis
o Opening pressure is high
o WBC with differential, protein, glucose is normal in 1/3 of patients
o India Ink- positive in 60-80%
o CSF cryotptoccal antigen- Positive in 95-99%
o Cryptococcal culture- Gold standard
 Treatment (See meningitis for details)
 Induction: Amphotericin B 0.7-1 mg/kg for 2 to 3 weeks with fluconazole
800mg
 Consolidation: Fluconazole 400mg PO daily for 8-10weeks or until CSF is
sterile
 Maintenance: Fluconazole 200mg PO daily life long
o Discontinue maintence or secondary prophylaxis when CD4 count >200
for more than 6 months after completion of treatment following patient
who are taking HAART

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 Adjunct treatment:
o Management of raised intracranial pressure: if CSF opening pressure-
CSF drainage until CSF pressure <200mmHg, repeat LP daily until stable
or CSF pressue normalizes.
o There is no place for dexamethasone
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
 This is due to reactivation of JC virus (John Cunningham virus).
 It is seen in 2-4% of AIDS patients.
 PML is characterized by progressive damage (-pathy) or inflammation of the
white matter (leuko-) of the brain (encephalo-) at multiple locations (multiple)
 Clincal presentation:
 Occurs late in the course of HIV when CD count <100
 Subacute onset
 The patient is afebrile, alert without headache
 Multifocal neurologic deficit
 Classic triad:
o Dementia
o Hemiparesis
o Hemianopsia
 Diagnosis:
 CSF is often non-diagnostic.
o CT shows multifocal, non-contrast enhancing hypodense lesions without
mass effect but MRI is more sensitive.
o Common areas of involvement: cortical white matter of frontal and
parietaloccipital lobes. Lesions can occur anywhere
 Serology: 90% adults are seropositive for JC virus so this is not useful in
diagnosis
 JCV PCR or brain biopsy may help to make diagnosis
 There is no effective treatment but initiation of HAART increases survival.
OPPORTUNISTIC MALIGNANCIES
PRIMARY CNS LYMPOMA
 This occurs late in the coruse of HIV (CD<100)
 Clinical features:
 Confusion, lethargy, memory loss (57%)
 Hemiparesis or aphasia (40%)

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 Seizures (14%)
 Cranial nerve palsy (9%)
 Headaches only (3%)
 No fever unless concomitant infection
 Diagnosis
 CT/MRI: Multiple lesions as frequent or as single lesions (irregular and solid
enhancement, subependymal enhacement more specific, variable mass
effect. Localization mainly periventricular)
 CSF: EBV DNA PCR- CSF (85-100% sensitive, 98-100% specific)
 Histology: diffuse infiltrating, multicentric tumor of B cell lineage with the
presence of EBV genome in approximately 100%.
 Treatment:
 Cytotoxic chemotherapy is not effective
 Radiotherapy can help some patients
 Response to steroid variable
SEIZURES
 These are a relatively frequent complication of HIV infection.
 They may be due to opportunistic infections, neoplasms or HIV encephalitis.
 The seizure threshold is often lower than normal in patients with HIV infection
owing to the frequent presence of electrolyte abnormalities.
 CNS infections may cause increased released of ADH (SIADH) with
reabsorption of water and a Euvolemic hyponatremia.
 Common causes:
 CNS toxoplasmosis
 Primary CNS lymphoma
 Cryptococcal meningitis
 HIV encephalopathy
 Treatment:
 Most of the time patient will have 2 or more seizures suggesting that
anticonvulsant therapy is indicated in all patients with HIV infection and
seizures unless a rapidly correctable cause is found.
 While phenytoin (100mg PO TDS) remains the initial treatment of choice.
Phenobarbital (100mg PO every night) or Valproic acid are aslo alternative.

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RESPIRATORY MANIFESTATIONS
 There is a widespread spectrum of pulmonary manifestations.
 Opportunistic infections include:
 Bacterial: Stretococcal, H. influenza, gram negative, Staphylococcal
 Mycobacterial: M. tuberculosis, M. kansasi, M. avium intracellularie
 Fungal: PJP, Cryptococcus neoformans, Histoplasmosis,
Coccidiodeocomycosis, Aspergillosis
 Viral: Cytomegalovirus, Herpes simplex infection
 Parasitic: Toxoplasmosis, Strongliodosis
 Opportunistic malignancies include:
 Pulmonary Kaposi’s sarcoma
 Non-Hodgkin’s lymphoma
 The types of opportunistic infections and malignancies develops depending on
the degree of immunosuppression.
CD4 COUNT /mm3 MANIFESTATIONS
Any CD4 level  Upper respiratory tract infection (URTI): Sinusitis, Pharyngitis
 Acute bronchitis
 Bacterial pneumonia
 Tuberculosis
 Non-Hodgkin’s lymphoma
<500  Bacteria pneumonia
 Pulmonary TB
<200  Pneumocystis jiroverci pneumonia
 Cryptococcus neoformans pneumonia
 Bacterial pneumonia (associated with bacteremia/sepsis)
 Disseminated or extrapulmonary tuberculosis
<100  Pulmonary Kaposi’s sarcoma
 Bacterial pneumonia (Gram-negative bacilli and
Staphylococcus aureus increased)
 Toxoplasma pneumonitis
<50  Disseminated Histoplasma capsulatum
 Disseminated Coccidiodes immitis
 Cytomegalovirus pneumonitis
 Disseminated mycobacterium avium complex
 Disseminated mycobacterium (non-tuberculous)
 Aspergillus species pneumonia

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BACTERIAL PNEUMONIA
 Common etiological agents: S. pneumoniae.
 As the degree of immunosuppression worsens pneumonia may be recurrent and
associated with sepsis
 Clinical presentation:
 Abrupt onset fever
 Cough
 Production of purulent sputum
 Dyspnea
 Pleuritic chest pain
 Recommended investigations:
 Chest Xray:
o Pneumonic consolidation
o Infiltrate
o Pleural effusions
 Blood culture
 FBC: leukocytosis
 Gram stain of the sputum
 Sputum culture and sensitivity
 Treatment:
 Antibiotics: Penicillin (procaine Pen/Crystalline Pen), Amoxicillin,
Fluoroquinolones
 Supplemental oxygen
PNEUMOCYSTIS JIROVECI PNEUMONIA
 This is caused by a fungus Pneumocystis jiroveci.
 It is one of the commonest OIs in industrialized countries however, due to
initiation of antiretroviral therapy and use of CTX prophylaxis its incidence has
declined.
 50% of patients experience at least one bout of PCP during the course of their life
time.
 It is transmitted from human to human or from environmental reservoirs to
human.
 Clinical presentations:

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 Indolent course characterized by weeks of vague symptoms prior to
presentation or diagnosis.
 Median duration of symptom is 28 days.
 Dyspea and fever are cardinal symptoms
 Cough with scanty sputum in more than 2/3 of cases
 Physical examination reveals: (findings may be minimal, usual findings or
pneumonia may not be noted)
o Respiratory distress +/- cyanosis
o Little abnormality on chest examination: rhonchi or wheeze may be heard
especially in patients wiith some other underlying pulmonary disease;
findings of consolidation are usually absent.
o P. jiroveci appears to be capable of hematogenically spread with seeding
of a variety of organ systems as well as causing primary infection of the
ear.
 Diagnostic work up:
 Chest X-ray: could be normal or show diffuse bilateral alveolar/interstitial
infiltrates.
 LD is elevated in more than 90% cases: has a very high negative predictive
value i.e. if LDH level is low in a patient the diagnosis of PCP is less likely.
 Definitive diagnosis- demonstration of the trophozoite or cyst from the
organisms in camples obtained from induced sputum in which the yield is
60% or Broncho-alveolar lavage in which the yield is 95%. Staining: Wright-
Giemsa, Methenamine silver, Direct IF, PCR.
 Other tests: Gallium 67 scan, PFT, ABG
 Treatment
 Antibiotics:
o Gold standard: Co-trimoxazole IV/PO
o Dose: 15mg/kg/day (trimethoprim) in 3-4 divided doses (3-4 tabs 480mg
QID)
o Duration of treatment: 21 days (3 weeks)
o Side effects: rash, fever, leucopenia
o Response to treatment may not occur until the end of the first week and
the patient may get worse during the first few days owing to the
inflammatory response resulting from the death of large number of
organism in the lungs.
o Alternatives:

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 Clindamcin 600mg IV 8 hourly or 300-400mg PO 6 hourly +
Primaquine 15-30mg base/day x 21 days
 Pentamidine 4mg/kg/day IV x 21 days
 Atovaquone 750mg PO BD with meal x 21 days
 Adjunct treatment
o Supplemental oxygen
o Steroids: reduce need for mechanical ventilation and mortality in 50%
 Start within 72 hours of presentations
 Indications: moderate/severe respiratory distress or cyanotic (PaO2
<70mmHg)
 Dose: Prednisolone 40mg PO BD x 5days, 40mg PO daily for 5 days,
20mg PO daily for 11 days
 PCP prophylaxis
o Primary prophylaxis:
 Recommended for HIV infected persons with evidence of significant
immune deficiency
 CD4 <200/microliter
 HIV associated thrush
 Unexplained fever
o Secondary prophylaxis: for patients with prior episode of PCP
o Regimens:
 TMP-SMX 2 tablets/day (single strength)
 TMP-SMX 2 tables three times a week
o Alternatives
 Dapsone 100mg PO daily
 Dapsone 50mg PO daily plus pyrimethamine 50mg PO weekly plus
folinic acid 25mg PO weekly
 Aerosolized pentamidine 300mg monthly via nebulizer
 Atovaquone 1500mg daily
o Prevention of PCP may also be beneficial in reducing the risk of having
other HIV associated infections such as CNS toxoplasmosis and other
bacterial infections.

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TUBERCULOSIS
 This is the leading opportunistic infection in developing countries.
 HIV is the most potent factor known to increase risk of progression form M.
tuberculosis infection to active disease.
 Clinical presentation depends on degree of immunosuppression.
Early stage of HIV Late stage of HIV
infection (CD4 infection (CD4 <200
3
>200cells/mm ) cells/mm3)
Clinical presentation Similar to Non-HIV Atypical presentation:
infected with productive Extrapulmonary TB is
cough more common. TB tends
Pulmonary to be disseminated
manifestations dominate (involving different
organs like meningitis,
pleura, pericardium,
lymph nodes etc)
Laboratory diagnosis  Often positive  Often negative
sputum smear  Often reactive with  Often negative or
PPD >10mm annergic
Chest X-ray  Typical CXR findgins  Atypical CXR
of TB findings
 Upper lobe and/or  CXR may show
bilateral infiltrates interstitial infiltrates
 Cavitations especially in lower
 Pulmonary fibrosis zones with no features
of cavitations and
fibrosis
 Negative CXR can be
associated with
sputum AFB (+ 12%
with pulmonary
disease)

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 Treatment:
 When TB and HIV are co-existing TB is more life threatening and it should
be treated first and patients should be stabilized.
 The same combination anti-TB drugs are given based on the treatment
category
 Close follow up of patinets on DOTS is required
 Complete cure from TB may be achieved in 6 to 8 months.
 ART can usually be deferred for about 14 days and started as soon as the
patient can tolerate anti-TB medication.
 Challenges/Problems in treatment of TB/HIV co-infected patients:
 Increased morbidity, mortality and high case fatality rate
 Increased drug toxicity
 Decreased drug absorption
 High pill burden which decreases adherence to treatment
 Drug interaction between anti-TB drugs and ART e.g. TDF/TAF and
Rifampicin (TDF has to be substituted for ABC)
 INH preventive therapy:
 Advised for HIV infected patients
 Patients should be screened for active TB before they are given preventive
therapy
 INH 300mg/day for 6-9 months
 Alternatively, Rifampicin for 4 months can be used.

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GASTROINTESTINAL MANIFESTATIONS
 These include:
 Candidiasis
 Oral hairy leucoplakia
 Diarrhea
CANDIDIASIS
 This is due to infection with Candida albicans.
 It can manifest as:
 Oral candidiasis
o Appears as white, chessy exudates, often on an
erythematous mucosa (most commonly seen on
the soft palate) which gives an erythematous or
bleeding surface on scrapping
o Erythematous form: there is predominantly
erythema rather than white patches
 Esophageal candidiasis
o Usually coincides with CD4 count of <50/L Figure 61: Oral candidiasis
o Causes substernal pain or a sense of obstruction
on swallowing
o Most lesions occur on the distal third of the
esophagus and appears on endoscopy as
redness, edema and focal white patches or
ulcers.
o If an HIV infected person has oral thrush and
substernal pain on swallowing presumed
diagnosis of esophageal candidiasis can be
made.
o Endoscopy is needed to prove the diagnosis but
is unnecessary if the patient responds to
Figure 62: Esophageal candidiasis
antifungal therapy
o Linear ulcerations of the esophagus may be seen on barium X-ray.
 Treatment:
 Oral candidiasis:
o Nystatin IU/ml suspension 2.5-5ml gargled 5times daily
o 2% Miconazole oral gel applied 2-3 times daily
o Amphotericin B lozenges

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o Fluconazole 100-200mg PO/day for 7-14 days in severe and persistent
cases
o Oral hygiene, discontinue steroids and antibiotics if the patient is taking
any.
 Esophageal candidiasis: Fluconazole 200mg/day PO (up to 400mg/day) for
14-21 days
ORAL HAIRY LEUCOPLAKIA
 This is characterized by white plaques with vertical ridging on the sides of the
tongue.
 Unlike with oral Candida the lesions cannot be peeled off.
 It was first recognized in HIV disease but can rarely occur in other forms of
immunosuppression.
 It is thought to be due to co-infection with Epstein-Barr virus.
 Treatment is with acyclovir, ganciclovir or foscarnet.
DIARRHEA IN HIV POSITIVE PATIENTS
 This is a common clinical condition in over 50% of HIV infected patients
 It may be acute or chronic, watery, mucoid or bloody
 It may or may not be associated with fever.
 Spectrum of condition varies with degree of immunodeficiency state.
 Pathogens may be:
 Bacterial
 Viral
 Protozoal
 Fungal
 Spirochetal
 Mycobaterial
 Metazoa
 Others (malignancies)
 Mechanism of diarrhea:
 Adhesion to mucosal surface
 Enterotoxin
 Entero-invasion
 Atrophy of mucosal
 Chronic diarrheas

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 This is diarrhea lasting for more than 2 weeks with a single watery bowel
motion and/or 3 or more loose stools per day.
 Frequency of diarrhea increases as the CD4 count falls
 With Antiretroviral therapy, incidence of chronic diarrhea decreases
 Protozoa causing chronic diarrhea:
o Cryptosporidium parvum
o Isospora belli
o Microsporidium
 HIV enteropathy (AIDS enteropathy)
 This is a chronic diarrheal syndrome for which no etiologic agent other than
HIV can be identified (Chronic diarrhea of unknown cause).
 Clinical features
o Early stage: intermittent self-limiting diarrhea however in advanced
stage, persistent life threatening diarrhea
o Copious amount of stool several times per/day associated with abdominal
cramp, nausea and vomiting
o Significant weight loss (wasting) may occur due to the associated
malabsorption
o Fluid and electrolyte depletion
DIAGNOSTIC INVESTIGATIONS
 Stool microscopy, culture and sensitivity
 Special stains: Modified AFB stain (Modified ZN stain)
 Intestinal biopsy
TREATMENT
 General treatment of chronic diarrhea
 Hydration: oral, parenteral with electrolyte replacement
 Symptomatic treatment: Anti-diarrheal agents
o Loperamide 2-4mg QID
o Lomotil 5mg QID
o Tincture of opium 0.3ml QID
o Codeine tablets
 Specific treatment
 Cryptosporidium
o Nitazoxanide 0.5-1.0g BD or
o Paromomycin 1g BD + Azithromycin 600mg QID
 Isospora

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o Cotrimoxazole 2 tabs QID for 10 days then BD for 3 weeks or
o Pyrimethamine 75mg + Folinic acid 10
o Chronic suppression (Secondary prevention) Cotrimoxazole 2 tabs/day
or pyrimethamine 25mg + folinic acid 5mg QID
STRONGYLOIDIAS
 This is a parasitic infection caused by Strongyloid stercolaris.
 It is acquired through skin penetration of its larva form.
 Auto-infection is common
 In its life cycle there is transition via the lungs and settles in the GIT, primarily
small intestine free-living or parasitic.
 Usually a mild disease in immunocompetent individuals.
 Disseminated infection common in immune-compromised hosts
 Systemic manifestation may mimic sepsis.
 Clinical manifestations:
 Immunocompetent: asymptomatic to mild symptoms with occasional severe
pruritus. It may manifest with mild diarrhea, epigastric pain.
 Immunocompromised: large amount of filariform larva are released and may
invade
o GIT tract: causing enteritis with severe diarrhea and malabsorption
o Lungs: manifest with cough, shortness of breath (Lofflers’ pneumonia)
o CNS, peritoneium and liver may also be invaded
o Severe systemic symptoms are commonly seen in disseminated infection
o May be complicated by gram negative sepsis
 Treatment:
 Ivermectine 200g 1-2 days
 Thiabendazole 75mg/kg BD for 3 days
 Albendazole 400mg/day for 5 days

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SKIN MANIFESTATIONS
 80-90% of HIV patients have skin manifestations.
 The skin problems could be the first organ system to be affected.
Manifestation/ Feature Diagnosis & Treament
Etiology comments
BACTERIAL INFECTIONS ASSOCIATED WITH HIV
Staphylococcus  Bullous impetigo  Microscopy, Topical antibiotics or
aureus  Folliculitis Culture and systemic antibiotics
 Furuncle sensitivity depending on severity of
 Carbuncle the disease
 Cellulitis
Syphilis  Atypical presentation in HIV  VDRL can be  Benzathine penicillin
(Treponema patients negative due to 2.4 Mega unit IM
pallidum)  Primary chancre usually painless high titer weekly 3 doses
can be tender antibody level  Penicillin IV 2 to 4
 Latent period befor development  Screening mega unit every 4
of meningovascular syphilis is tests- VDRL hours for 10 to 14 days
shorter (Venereal (with CNS
 Rapidly progresses to tertiary disease involvement)
syphilis research  Azithromycine +
 Pleomorphic skin lesions reported laboratory Benzathine penicillin +
test), RPR Amoxicillin
(Rapid plasma  Relapses without re-
reagin) exposure
 Specific test-  Follow up at 1, 2, 3, 6,
FTA-ABS- 9 and 12 months
fluorescent
treponemal
antibody
absorption
VIRAL DISEASE ASSOCIATED WITH HIV
Herpes simplex  Due to reactivation of latent virus  Clinical  Systemic acyclovir
 Usual manifestations are grouped  Biopsy 200mg 5x a day 5-10
vesicle with erythematous base  PCR days
 Atypical presentation in HIV  Acyclovir 50mg/kg
patients every 8 hours were
 Chronic non healing deep ulcer absorption is poor
 Verrucous erosion

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 Widespread local extension  Acyclovir 400mg BD
 High incidenc of dissemination in frequent relapse
 Viremic spread to visceral organs  High frequency of
which is life threatening reactivation

Varicella-  Hemorrhagic necrotic lesion  Clinical  Primary varicella-

Zoster virus  Chronic verrucous lesion  Biopsy acyclovir IV 10mg/kg
 Multiple dermatormal  PCR every 8 hours for 7 to
involvement 10 days
 Tendency to be generalized  Herpes zoster:
 May occur recurrently  Acyclovir 800mg
5x a day for 7-10
days
 Famcyclovir
500mg 5x a day for
7 days
 Valacyclovir 1g
TDS for 7 days
Human  Warts  Clinical  Podophyllin 20% or 5-
papilloma virus  Refractory to treatment  Biopsy fluorouracil
 Complications are neoplastic  PCR  Cyrotherapy or
changes and increased risk of excision of big tumors
cervical carcinoma
Molluscum  Occurs in HIV patients with low  Clinical  Cryosugery or
contagiosum CD4 count  Biopsy curettage or
(Pox virus)  Atypical presentations are  PCR electrosurgery
common  Podophyllin or
 It tends to be generalized cantridine or 5-
 Giant molluscum contagiosum fluorouracil
(Umbilicated papules)
 Secondary infection

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PRURITIC PAPULAR ERUPTION (PPE)
 This is a chronic itchy condition commonly seen in HIV infected patients.
 Symmetrical non-folliclar papules are seen on the trunk and extensors of
extremities.
 It is the most common cutaneous manifestations in HIV.
 Diagnosis: Biopsy
 Treatment:
 Topical: Antipruritic lotion, corticosteroid, oatmeal bath
 Systemic: Antihistamines, Corticosteroids, Phototherapy, UV-B, UV-A +
Psoralen
OPPORTUNISTIC MALIGNANCIES
 These include:
 Kaposi’s sarcoma
 Lymphoma
 Cervical cancer
KAPOSI’S SARCOMA
 This is a tumor of vascular and lymphatic endothelium that presents as purplish
nodules and plaques on skin and mucosa.
 It was first described by Moritz Kaposi in 1872.
 Immunosuppression increases risk of KS 400-500 times higher than general
population.
 The presence of human herpes virus 8 (HHV-8) is found in all types of KS.
 KS has a worldwide distribution. In Africa it occurs largely in the south of the
Sahara.
 Prevalence of AIDS-related KS has decreased due to widespread availability of
HAART.
 KS associated with other forms of immunosuppression include those with
iatrogenic suppression from oral prednisolone or other chronic
immunosuppressive therapies as may be given to transplant patients.
 It affects more men than women (2:1 ratio).
 It is the most common cutaneous malignancy in HIV disease.
 This condition carries a variable clinical course ranging from minimal
mucocutaneous disease to extensive organ involvement.
 Various visceral organs can also be affected.

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 It has several subtypes which have different presentations, epidemiology and
prognoses.
ETIOPATHOGENESIS
 KS is formed by abnormal proliferation of vascular endothelial cells.
 Infection with HHV-8 has been associated with the development of KS.
 HHV-8 (human herpes virus-8) is found in KS lesional tissue irrespective of
clinical type.
 Transmission of HHV-8: mainly through saliva, organ transplantation, blood
transfusion it is even believed to be transmitted sexually.
 HHV-8 titers 2-3 times higher in saliva than in semen, anorectal or prostate
fluid samples.
 HHV-8 is known to encode products that lead to growth dysregulation or evasion
of immune surveillance.
 A virally encoded G protein induces VEGF (vascular derived endothelial
growth factor) production, stimulating endothelial growth
 Cytokines produced by inflammatory cells recruited to the sites of lytic
infection also create a local proliferative milieu
 Other proteins disrupt normal cellular proliferation and prevent apoptosis by
inhibiting p53.
 HIV virus Tat protein potentiates the milieu conducive to KS growth.
CLINICAL FEATURES
 Can affect almost any organ system.
 Cutaneous lesions in Kaposi sarcoma are
characterized as follows:
 Cutaneous lesions may occur at any location
but typically are concentrated on the lower
extremities and the head and neck region.
 Lesions characterized by brown, pink, red or
violaceous macules/patches, papules/plaques,
nodules.
 Nearly all lesions are palpable and non-
pruritic
 Lesions may range in size from several
millimeters to several centimeters in diameter.

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 Lesions may assume a brown, pink, red or
violaceous color and may be difficult to
distinguish in dark-skinned individuals.
 Lesions may be discrete or confluent and
typically appear in a linear, symmetrical
distribution, following Langer lines.
 Mucous membrane involvement is common
(palate, gingiva, conjunctiva)
 Lesions may vary depending on the clinical
variant.
 Mucous membrane, cutaneous and visceral
involvement is common (lymph nodes, GIT and lungs).
 The subtypes of KS include:
 Classic or sporadic
 African cutaneous (Endemic)
 AIDS-associated (Epidemic)
 Immunosuppressant therapy related (iatrogenic)
CLASSIC KAPOSI SARCOMA
 It is an indolent disease.
 It is seen chiefly in middle-aged men of southern and Eastern European origin.
 It is not associated with HIV.
 Early lesions appear most commonly on the toes or soles as reddish, violaceous
or bluish-black macules and patches that spread and coalesce to form nodules or
plaques.
 Brawny edema of the affected limb may be present
 Macules or nodules may appear, usually much later on the arms and hands and
rarely may extend to the face, ears, trunk, genitalia or oral mucosa.
 Classic KS has a slowly progressive course.
AFRICAN CUTANEOUS (ENDEMIC)
 Endemic in tropical Africa.
 Mostly seen in men between the ages of 20 and 50.
 It is seen in HIV-seronegative persons.
 It has a locally aggressive but systemically indolent course.
 Characterized by nodular, infiltrating, vascular masses on the extremities.

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 A particularly severe form, with prominent lymph node and visceral
involvement, occurs in pre-pubertal children, the prognosis is poor, with an
almost 100% mortality rate within 3 years. (African lymphadenopathic Kaposi
sarcoma)
 An aggressive disease of young patients mainly children under age 10.
 Lymph node involvement with or without skin lesions.
 Has an aggressive course, often terminating fatally within 2 years on onset.
AIDS ASSOCIATED KAPOSI SARCOMA (EPIDEMIC)
 KS in patients immunosuppressed by AIDS.
 AIDS-related Kaposi sarcoma, unlike other forms of the disease, tends to have
an aggressive clinical course.
 It is the most common presentation of Kaposi sarcoma.
 Cutaneous lesions begin as one or several red to purple-red macules, rapidly
progressing to papules, nodules, and plaques.
 There is a predilection for the head, neck, trunk and mucous membranes.
 A fulminant, progressive course with nodal and systemic involvement is
expected.
 It may be the presenting manifestation of HIV infection (HIV stage 4).
IMMUNOSUPPRESION-ASSOCIATED KAPOSI SARCOMA
 Occurs in patients on immunosuppressive therapy
 Clinical features may be similar to that of classic KS, however, site of
presentation is more variable.
 Removal of immunosuppression may result in regression of the KS.
INTERNAL ORGAN INVOLVEMENT
 Classic KS: GIT is most frequently involved (intestinal blockage and bleeding).
Lungs, heart, liver, conjunctiva, adrenal glands, abdominal lymph nodes, and
bones may also be affected.
 African cutaneous KS (endemic): frequently accompanied by massive leg edema
and frequent bone involvement.
 African lymphadenopathic KS: reported among Bantu children who develop
massive lymph node involvement, preceding appearance of skin lesions. The
children also develop lesions on the eyelids and conjunctiva.
 Eye involvement is often associated with swelling of the lacrimal, parotid,
and submandibular glands.

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 AIDS-associated KS: Lungs (37%), Gastrointestinal tract (50%), and lymph
nodes (50%).
DIAGNOSIS
 Skin and oral lesions can be diagnosed by visual examination even though skin
biopsy is most accurate to make diagnosis.
 Lung and GI-tract lesions would need endoscopy and biopsy for accuracy.
 Resolution of skin lesions with HAART can give a presumptive diagnosis.
 Testing for HHV-8 is more research than clinically applicable.
DIFFERENTIAL DIAGNOSIS
 Bacillary angiomatosis
 Pyogenic granuloma
 Leukemia cutis
 Cellulitis
 Severe stasis dermatitis
 Small-vessel vasculitis
WORK-UP
 Baseline investigations: Full blood count,
Liver enzymes, Urea & electrolytes,
Creatinine, RPR (syphilis)
 Skin biopsy
 Prominent spindle cells
 Prominent slit-like vascular spaces
 Extravasated red blood cells
 Immunohistochemistry
 HIV test
 HHV-8 PCR
 CXR/CT-scan
 Endoscopy
TREATMENT
 Topical retinoid (Alitretinoin gel 35-50% response)
 Surgical excision
 Local Radiation (20-70% response)
 Cryotherapy (85% response)
 Laser

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 Anti-retroviral therapy for epidemic KS
 Chemotherapy:
 Liposomal doxorubicin, liposomal daunorubicin
 Vincristine, Bleomycin, Doxorubicin: 1st line at UTH/CDH
 Paclitaxel monotherapy: 2nd line agent
COURSE
 Classic KS: Progresses slowly, rare lymph node or visceral involvement. Death
occurs years later from unrelated causes.
 African cutaneous KS: Aggressive, early nodal involvement, death from KS
expected within 1-2 years.
 AIDS-related KS: although widespread, most patients die of intercurrent
infection
 Immunosuppression related KS: removal of immunosuppression may result in
resolution of the KS without therapy.
LYMPHOMA
 Lymphomas occur with increased frequency in immunodeficiency states.
 As HIV disease progresses the risk of lymphoma increases.
 The incidence of lymphoma has not shown dramatic decrease even after HAART
is being widely used by HIV patients worldwide.
 It is a late manifestation which often occurs when the CD4 count falls below
200/mm3
 3 main categories are seen with HIV
 Grade III or IV immunoblastic lymphoma (60%)
 Burkitt’s lymphoma (20%)-associated with EBV
 Primary CNS lymphoma
 Treament:
 In patients with high CD4 count- intensive chemotherapy, low dose
chemotherapy in patients with low CD count.
 Palliative measures to decrease the size of the lesion and associated edema
o Radiotherapy
o Glucocorticoides

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CERVICAL CANCER
 There is a 5 fold increased risk of developing cervical cancer in women with
AIDS.
 It is associated with human papilloma virus infection.
 Invasive carcinoma of the cervix is an AIDS defining illness
 Abnormal PAP smear is seen in 60% of HIV infected women
 Anorectal CA may also be seen in homosexual men

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SEXUALLY TRANSMITTED INFECTIONS

 Sexually transmitted infections are a diverse group of infections, caused by
different types of microbial agents that are frequently transmitted by sexual
contact, and for which sexual transmission is epidemiologically important, are
considered sexually transmitted infection.
 “Sexual” includes the full range of heterosexual or homosexual behavior
including genital, oral-genital, oral-anal and genital-anal contact.
 At present there are more than 20 known causes of STD. No single STI can be
regarded as an isolated problem because multiple infections are common and
because the presence of one STI denotes high-risk sexual behavior that is often
associated with other more serious infections.
 Most STIs are rarely if ever transmitted by formites, food, flies or causal contact.
 At least one sexual partner is always infected, the apparent exceptions usually
can be attributed to prolonged sub-clinical infection in one or both partners.
Therefore, risk assessment (including elicitation of a sexual history) and
management of sexual partners are of paramount importance.
 Treatment of STIs reduces transmission of HIV.
 STIs can be classified and managed in 3 different ways (approaches)
 Clinical approach: where one depends on past experience and own
knowledge
 Etiologic approach: where one collects specimens for laboratory
identification of causative agent prior to treatment
o Advantages: accurate diagnosis, accurate treatment proper use of
antibiotics (decreases over treatment and antibiotic resistance). It is the
better way to diagnose and treat asymptomatic infections.
o Disadvantages: needs lab support and expertise, expensive (cost may be
incurred due to lab tests) and it is time consuming.
 Syndromic approach: where one identifies on the basis of symptoms and
signs and treats to cover the majority of organisms that may cause those
symptoms.
o Advantages: Treatment can be given immediately, mixed infection may
exist and may be addressed, there is no need for laboratory diagnosis and
the treatment can be given by middle level health professionals. Hence
this approach may be a good alternative for in resource limited settings.

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o Disadvantages: over treatment with antibiotics, there is risk of creating
antibiotic resistance and decreased compliance. There is also increased
cost of drugs. Moreover, asymptomatic infection missed.
APPROACH TO MANAGEMENT
 Approach includes:
 Risk assessment of:
o Sexual orientation and practice
o Number of recent and current sexual partners
o History of STI in the patient
o Recent history of STI of the partner
o Sociodemographic and other markers of high risk
 Clinical assessment: elicitation of information on specific current symptoms
and signs of STIs.
 Laboratory tests: if available, confirmatory diagnostic or screening tests may
be then ordered.
 Comprehensive case management: this is vital approach for controlling STIs.
So health care providers should undertake the following measure besides
treating individual patients
o Partner notification and management
o Condom promotion and supply
o Health education and risk education counseling
o Linkage with HIV counseling and testing
o Follow-up visits for patients with STI
STI SYNDROMES
 These include:
 Urethral discharge syndrome
 Vaginal discharge
 Genital ulcer
 Genital growth
 Inguinal bubo
 Scrotal swelling
 Lower abdominal pain
 Neonatal conjunctivitis

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URETHRAL DISCHARGE SYNDROME
 Urethral discharge is the most common presenting compliant of men with STI.
 In urethral discharge, exudate is present in the anterior urethra and the discharge
(which may be copious or mucoid) is often accompanied by dysuria or urethral
discomfort.
ETIOLOGY
 STI-related urethritis is divided into:
 Gonoccocal urethritis:
o This is an acute inflammatory condition of the columnar epithelial lining
of the urethra.
o Caused by Neisseria gonorrhea (Gram negative intracellular
diplococcus)
o Has a short incubation period (2-3 days)
o Vast majority of cases present with abundant (copious) and purulent
yellowish green discharge.
o The lip of the meatus may be red and swollen.
o Tend to produce more severe urinary tract infection symptoms like
dysuria, urgency and frequency.
o The patient may have pharyngitis, proctitis and PID.
o Disseminated gonococcal infection is associated with 2 syndromes:
 Fever, malaise, migratory polyarthralgia or polyarthritis, tenosynovitis
and painful vesiculopustular skin lesions.
 Purulent arthritis without skin lesions.
o Complications:
 Acute epididymo-orchitis: this is an important complication which is
usually unilateral swelling and tenderness of the testis and
epididymis.
 Bilateral epididymo-orchitis may result in sterility.
 Urethral strictures: this is a late complication occurring in cases which
are treated inadequately or not at all. This could occur 10 to 25 years
after an infection or in cases of recurrent infection.

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 Non-gonoccocal urethritis (NGU):
o Usually caused by Chlamydia trachomatis or Ureaplasma urealyticum.
o Other pathogens include Mycoplasma genitalium, HSV, Trichomonas
vaginalis.
o Has a long incubation period (1-3 weeks)
o It has scanty to moderate, white, mucoid or serous discharge.
o Although the discharge may be slight and the symptoms mild, they are
frequently more marked in the morning when the lips of the meatus are
often stuck together with dried secretions.
o Mild urinary tract infection symptoms.
o On examination the meatus may be red, with evidence of dried secretion
on underwear. Occasionally the onset is more acute, with dysuria,
frequency and a copious purulent discharge.
o Other syndromes include proctitis, epididymitis, and PID. NGU has a
known association with postinfectious reactive arthritis.
o Complications:
 Epididymitis
 Urethral stricture
 Perihepatitis
 The quantity and appearance of the discharge can be used to distinguish
accurately gonococcal and non-gonococcal urethritis in about 75-80% of patients
who have not urinated recently. It can’t of course, be used to diagnose dual
infection with N. gonorrhea and C. trachomatis. Milking of the urethra may be
necessary to get a good amount of discharge sample.
INVESTIGATIONS
 Microscopy of urethral discharge stained with methylene blue or Safranin or
Gram stain shows pus cells with characteristic intracellular coffee bean shaped
diplococci (this is indicative of N. gonorrhea)
 Pus cells without intracellular diplococci is indicative of NGU.

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Figure 63: Pus cells with multiple intracellular and extracellular gram negative diplococci of a smear
from a urethral discharge indicative of gonococcal urethritis

 Other tests for include:

 Culture on Thayer-Martin media (Gonococcal urethritis)
 Nucleic acid amplification test (NAAT)
 DNA Probe
TREATMENT
 Gonococcal urethritis:
 Ciprofloxacin 500mg PO stat or
 Ceftriaxone 250mg IM stat or
 Spectinomycin 2mg IM stat
 NGU:
 Doxycycline 100mg PO BID for 7 days or
 Tetracycline 500mg PO QID for 7 days or
 Erythromycin 500mg PO QID for 7 days if the patient has contraindication
for TTC.
 Azithromycin 1g PO Stat
 When there is no etiologic diagnosis: Treatment should cover both gonococcal
and chlamydial infections (combine the above treatments)
 Persistent urethral discharge one week after treatment consider Trichomonas
vaginalis, then treatment Metronidazole 2g PO stat.

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PREVENTION
 Avoiding multiple sexual partners and unprotected casual sexual intercourse.
 Condom use is advised.

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MISCELLANEOUS
POISONING
 This is the exposure by ingestion, inhalation or other means of a substance
capable of causing harm to the body.
 Clinical features:
 The patient may present a variety of
symptoms ranging from mild to serious
ones like loss of consciousness.
 Diagnosis
 Assess for vitals (Airways, Breathing and
Circulation) and:
o Level of consciousness: GCS
o Ventilation: pulse oximetry
o Blood pressure and pulse rate
o Pupil size and reaction to light
o Evidence of intravenous drug use
o A head injury complicating poisoning
o If the patient is unconscious also
check for:
 Cough and gag reflex: present or
absent
 Temperature: measured with a
low-reading rectal thermometer if the ear temperature suggests it is
low
 History
o Ascertain as far as possible, the nature and quantity of the poison and
when it was taken.
o In the unconscious patient a history from friends or relatives is helpful.
o In any patient with an altered level of consciousness, acute poisoning
must always be considered in the differential diagnosis.

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 Management:
 Depends on the type of poison taken and the clinical condition of the patient.
 It is aimed at slowing down, reducing or preventing further absorption of the
poison and to counteract the effects of the poison already absorbed.
 Emergency resuscitation:
o Obstructed airway
 Pull the tongue forward
 Remove denture, foreign bodies (e.g. food) and oral secretion
 Hold the jaw forward and insert an oropharyngeal airway if possible
 Put the patient in a semi-prone position with the head down to
minimize the risk of inhaling vomit.
o Inadequate respiration
 Give continuous oxygen
 Apply assisted ventilation with an ambu bag or mouth to mouth or
intubate and do mouth to tube respiration.
 Do not use respiratory stimulants as they cause harm
o Hypotension
 Keep the patient in a position with his head downwards by elevating
the foot of the bed.
 Gain venous access and send blood for: Urea, electrolytes, creatinine,
full blood count, blood sugar, and liver function
 Administer normal saline intravenously
o Recurrent fits
 Control with diazepam 5-10mg intravenously stat. Repeat as
necessary
o Removal of poison from the stomach
 Gastric emptying carries the risk of the victim inhaling gastric contents. The
benefit of the procedure should therefore be weighed against this risk. The
procedure should not be performed in the following circumstances:
o When corrosive substance (e.g. acids, alkalis and petroleum products)
have been swallowed.
o When there is marked hypothermia (less than 30oC)
o When the amount of poison swallowed is minimal
o If poison was ingested more than 2 hours earlier (except in the case of
poisoning with salicylate, tricyclic anti-depressants and beta blockers).
 To remove poison from the stomach, two methods may be used:

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o Inducing vomiting by giving: Ipecacuanha syrup 30ml followed by a
glass of water. Repeat after 20 minutes if necessary.
o Gastirc lavage: if done in an unconscious patient, a cuffed endotracheal
tubeshould be passed to prevent aspiration of stomach contents into the
lungs.
 After vomiting has occurred:
o Activated charcoal: 50mg mixed with 400ml water in a bottle and shaken
well. Administer the suspension in a dose of 5ml/kg. Repeat every 4
hours. Total dose of 100g. If necessary
o Magnesium sulphate mixture or magnesium hydroxide mixture, 50ml to
avoid constipation.
o Milk, cooking oil or beaten raw egg may also be given in the absence of
activated charcoal to delay absorption of the poison.
DRUG FEATURES TREATMENT
Aspirin and other  Increased rate and depth  Induce emesis with ipecacuanha unless
salicylates of respiration respiration is depressed
 Respiratory alkalosis  Give activated charcoal
 Tachypnea, sweating,  If respiration is depressed, do airway-protected
vomiting, epigastric pain, gastric lavage
tinnitus, and deafness.  Gastric emptying is effective up to 4 hours after
ingestion of poison
Carbon monoxide  Headache  Remove patient from further exposure
 Exertional dyspnea  Give oxygen for several hours
 Coma  Maintain blood pressure and normal body
 Convulsions temperature
 Cardiorespiratory arrest  To reduce cerebral edema give 20% mannitol IV
 Metabolic acidosis 5ml/kg body weight over 20 minutes and an IV
 Myocardial ischemia or IM corticosteroid 4 hourly (prednisolone
 Hypertonia 1mg/kg or dexamethasone 0.15mg/kg or
 Extensor plantar hydrocortisone 4mg/kg)
responses  Control convulsions or hyperactivity with
 Retinal hemorrhages diazepam 0.1mg/kg by slow intravenous or per
 Papilloedema rectum
 Neuropsychiatric
features
Ethanol  Emotional lability  Remove unabsorbed ethanol by gastric lavage or
induce emesis with ipecacuanha syrup

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 Impairment of  Give activated charcoal
coordination  Maintain adequate airway
 Visual impairment  Maintain normal body temperature
 Slow reaction time  If patient is hypoglycemic give dextrose 50%
 Slurred speech followed by 5% IV
 Hypoglycemia  May need vitamin B compound if chronic
 Stupor alcohol abuser
 Hypothermia
 Convulsions
 Depressed reflexes and
respiration
Organochlorides  Convulsions,  Remove patient from source of poisoning and
hyperactivity and tremors remove contaminated clothing
 Respiratory depression  Give ipecacuanha syrup
 After vomiting give activated charcoal followed
by gastric lavage with 2-4 liters water.
 Give a laxative such as magnesium hydroxide
 Do not give milk, fats or oils as they will
increase absorption of poison
 Scrub the skin with soap and cold water to
remove skin contamination
 Give artificial respiration with oxygen if there is
respiratory depression
 Give diazepam 10mg slow IV or phenobarbitone
100mg IM to control convulsions, hyperactivity
or tremors
Organophosphates  Anxiety, restlessness,  Remove patient from source of poisoning and
and carbamate tiredness, headache remove contaminated clothing
 Muscarinic features:  Establish airway and give artificial respiration if
nausea, vomiting, necessary
abdominal colic,  Remove excess bronchial secretion by suction
diarrhea, tenesmus,  Give ipecacuanha syrup or start gastric lavage
sweating, sweating,  Give atropine 2mg IV stat every 3-8 minutes
hypersalivation, until signs of atropinisation appear (hot dry skin,
lacrimation and chest dry mouth, widely dilated pupils and fast pulse)
tightness. Miosis
 Nicotinic signs:
fasciculations and flaccid

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paresis of limb muscles,
respiratory muscles and
occasionally extraocular
muscles.
Paraffin, petrol  Prevent the substance from entering the lungs to
and other avoid damage to tissue
petroleum  Do not induce vomiting
products  Do not do gastric lavage
 Look out for pulmonary edema and chemical
pneumonitis and treat accordingly.
Paracetamol  Anorexia, nausea and  Keep the patient quiet and warm
poisoning vomiting  Induce emesis with ipecacuanha syrup
 Liver damage result in  Where there is depressed respiration use airway-
paracetamol overdose. protected gastric lavage
The damage occurs  N-acetylcysteine 20% solution, orally 140mg/kg
within a few hours of as a loading dose, followed by 70mg/kg every 4
ingestion hours for 3 days it may be necessary to
administer through an NGT.
 Dextrose 5% intravenously for the first 48 hours
 Phytomendione 1-10mg IM if the prothrombin
time ratio exceeds 2.0
 Do not force diuresis
Chloroquine  Blurred vision  Induce emesis
poisoning  Tinnitus, weakness,  Stomach wash (air-war protected gastric lavage
hemoglobinuria, oliguria if respiration is depressed)
 Low blood pressure,  Give activated charcoal
shock  Treat symptomatically
 Convulsions, cardiac
arrest
Mushroom or  Abdominal pain  Symptomatic:
other food  Nausea  Bed rest
poisoning  Vomiting  Keep patient warm
 Diarrhea  Stomach wash using normal saline
 Shock in severe cases  Give ORS or IV fluids to re-hydrate
 If no improvement refer to specialist
Snake bites  Pain  Immobilize limb and keep slightly elevated
 Swelling  Administer tetanus toxoid (0.5ml)
 Tissue necrosis  IV Dextrose 5% in saline

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 Regional lymph node  Treat shock
swelling  Vitamin K 1-10mg intramuscularly
 Hemorrhagic symptoms,  Anti-snake venom if available
bleeding at wound sites  Transfer patient to specialist
and other parts of the
body
 Danger signs:
drowsiness, slurred
speech, excessive oral
secretion, difficulty in
breathing and
neurological signs

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ORGANOPHOSPHATE PATHOPHYSIOLOGY
POISONING  OP insecticides form an irreversible
bond with acetylcholinesterase (the
 Organophosphorus (OP)
enzyme responsible for the
insecticides are used widely
breakdown of acetylcholine).
throughout the world and are a
common cause of poisoning,  When this enzyme is inhibited there
causing thousands of deaths is an accumulation of acetylcholine
annually, in the developing world. at central as well as peripheral
cholinergic nerve endings.
 Intoxication may follow ingestion,
inhalation or dermal absorption.  This results in overstimulation of
both muscarinic and nicotinic
 Because some are very lipophilic
receptors resulting in the signs and
they may be released from fat
symptoms seen.
depots over a period of many days.
 Recall that:
 Organophosphorus insecticides
 Acetylcholine is found in
inhibit acetylcholinesterase causing
autonomic ganglia (both
accumulation of acetylcholine at
sympathetic and
central and peripheral cholinergic
parasympathetic ganglia).
nerve endings, including
 Terminal postganglionic
neuromuscular junction.
parasympathetic nerves fibers
 Many OP insecticides require
at the motor endplates of nerves
biotransformation before becoming
in skeletal muscle as well as
active and so the features of
some cranial nerves
intoxication may be delayed.
innervating visceral contain
 Metabolism occurs by
acetylcholine.
oxidation and hydrolysis by
 Both muscarinic and nicotinic
esterases and by reaction with
receptors are widely distributed
glutathione.
in the central nervous system as
 Elimination of OP is mostly in the
well as all over the body.
urine and lesser amounts in feces
and expired air.

CHOLINOCEPTORS LOCATION MECHANISM ACTIONS

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Muscarinic, M1 CNS neurons, Gq coupled protein Enhances cognitive
sympathetic with formation of processes which may
postganglionic IP3 and DAG, lead to improved
neurons, some increased intra- memory, increases
presynaptic sites, in cellular calcium gastric acid secretion
the stomach (oxyntic
cells)
Muscarinic, M2 Myocardium, and Gi coupled Decreases heart rate,
smooth muscle protein, opening force of contraction
potassium of AV conduction.
channels,
inhibition of
adenylyl cyclase
Muscarinic, M3 Exocrine glands, Gq coupled protein Increased secretions
Vessels (smooth with formation of in GIT and lungs,
muscle and IP3 and DAG, contraction of smooth
endothelium), eye increased intra- muscle in walls of
(iris circular muscle cellular calcium GIT & bladder,
and ciliary muscle) relaxation of
sphincters of GIT &
urinary tract,
constriction of pupil
(miosis) and ciliary
muscle (lens
broadens for near
accommodation)
Muscarinic, M4 CNS neurons, Gi coupled -
possibly vagal nerve protein, opening
endings potassium
channels,
inhibition of
adenylyl cyclase
Muscarinic, M5 Vascular Gq coupled protein Synthesis and release
endothelium, with formation of of endothelium-
especially cerebral IP3 and DAG, derived relaxation
vessels, CNS increased intra- factor (nitric oxide)
neurons cellular calcium leading to
vasodilation of
cerebral vessels

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Nicotinic, NN Postganglionic Opening of sodium Transmission of
neurons, some and potassium action potential
presynaptic channels,
cholinergic terminal depolarization
Nicotinic, NM Skeletal muscle Opening of sodium Increase in muscle
neuromascular end and potassium tone
plates channels,
depolarization

CLINICAL FEATURES  The characteristic features of the

 Poisoning is characterized by: syndrome are weakness of muscles
 Anxiety of respiration (Diaphragm,
 Restlessness intercostal muscle and accessory
 Tiredness muscle including neck muscle) and
 Headache of proximal muscle.
 Muscarinic (cholinergic) features  Accompanying features often
such as nausea, vomiting, include weakness of muscles
abdominal colic, diarrhea, innervated by some cranial nerves.
tenesmus, sweating,  Delayed polyneuropathy is a rare
hypersalivation and chest tightness. complication of acute exposure to
Miosis may be present. some OP insecticides not marketed
 Nicotinic effects include muscle in most countries. It is initiated by
fasciculation and flaccid paresis of phosphorylation and subsequent
limb muscles, respiratory muscles aging of at least 70% of neuropathy
and occasionally of extraocular target esterase (NTE) in peripheral
muscles. nerves.
 Respiratory failure will ensue DIAGNOSIS
in severe cases and is
 This is confirmed by measuring the
exacerbated by development of
erythrocyte cholinesterase activity.
bronchorrhea and pulmonary  This may be decreased to 30-
edema. 50% in asymptomatic patients,
 The intermediate symptoms usually 10-20% in moderate poisoning
become established 2-4 days after and <10% in severe poisoning.
exposure when the symptoms and  Plasma cholinesterase activity is
signs of the acute cholinergic less specific but may also be
syndrome are no longer obvious. depressed.

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 Other investigations include:  Give continuous oxygen.
 Full blood count  Do not use respiratory
 Urea and electrolytes to rule stimulants as they cause harm
out electrolyte disturbances  Gain venous access and send
 Stool for microscopy, culture blood to the lab.
and sensitivity to rule out  Run IV normal saline
gastroenteritis.  Remove the clothes that may be
soiled.
TREATMENT  Mild cases require no specific
 Diagnosis treatment other than the removal of
 Assess for vital signs soiled clothing.
 Ascertain as far as possible, the  Atropine 2mg IV should be given
nature and quantity of the every 5-10 min until there are signs
poison and when it was taken. of atropinisation. The skin becomes
 Treatment is aimed at slowing flushed and dry, the pupils dilate
down, reducing or preventing and bradycardia (fast pulse) is
further absorption of poison and to abolished, frequency of
counteract the effects of the poison administration dependent of
already absorbed. severity.
 ABCs (Resuscitation)  Symptomatic patients should be
 Clear and secure the airway: give an oxime (pralidoxime,
pull the tongue forward, obidoxime or HI-6) to reactivate
remove dentures/foreign inhibited acetylcholinesterase.
bodies (e.g. food) and oral  Pralidoxime chloride 30mg/kg
secretion, hold the jaw forward by slow IV injection followed
and insert an oropharyngeal by an infusion of pralidoxime
airway if possible. mesylate 8-10 mg/kg per hour.
 Put the patient in a semi-prone
position with head down to
minimize the risk of aspiration
 Suction all secretions and
ensure patient is breathing
 Apply assisted ventilation with
an ambu bag

584
ALCOHOL INTOXICATION AND ALCOHOL
WITHDRAW

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GOUT
 These are a group of disorders of purine metabolism that are characterized by
serum uric acid elevation (hyperuricemia), urate deposits in articular or extra-
articular tissues.
 Elevation of serum uric acid alone is not sufficient for the diagnosis of gout, only
10% of patients with hyperuricemia develop gout.
ETIOLOGIC CLASSIFICATION OF HYPERURICEMIA
 Gout syndromes are characterized by either episodic or constant elevation of
serum uric acid concentration above 7mg/dl.
 Patients with elevated uric acid are mainly due to:
 Overproduction (10%): these patients synthesize greater than normal
amount of uric acid de novo. They have normal urinary excretion of uric
acid (>1000mg/day). Cause can be:
o Primary: purine pathway enzyme defect
o Secondary: increased cell turn over or cellular destruction with
 Alcohol use
 Hematologic malignancies
 Chronic hemolysis
 Cancer chemotherapy (tumor lysis syndrome)
 Reduced excretion (90%): decreased renal excretion of uric acid
(<700mg/dl)
o Drugs: diuretics, alcohol, Aspirin interfere with tubular handling of
urate
o Renal disease: chronic renal failure, lead nephropathy, inherited
disorders
 Conditions associated with gout:
 Obesity: Serum uric acid level rises with body weight
 Diabetes mellitus: more common in gout patients
 Hypertension: is more common in gout patients
 Hyperlipidemia
 Atherosclerosis

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CLINICAL FEATURES
 Clinical stages of gout include:
 Asymptomatic hyperuricemia: raised serum uric acid level without any
clinical evidences of deposition disease (i.e. arthritis, tophi, nephropathy or
uric acid stones)
o These patients have increased risk for nephrolithiasis or acute obstructive
uropathy
 Acute gouty arthritis: second and primary manifestation of gout.
o Extremely painful
o Acute onset arthritis
o Mostly affects middle aged or elderly men who had sustained
asymptomatic hyperuricemia for 20-30 years before first attack.
o Premenopausal women are not affected (probably due to effect of
estrogen on uric acid clearance) however, gout may be seen in
postmenopausal women who have hypertension especially.
o Onset in teens or 20s is unusual and when present is often associated with
primary or secondary causes of uric acid overproduction
o Precipitating events of an acute gouty attack:
 Dietary excess
 Trauma
 Surgery
 Excessive alcohol ingestion
 ACTH or glucocorticoid withdrawal
 Hypouricemic therapy
 Serious Medical illnesses e.g. myocardial infarction and stroke
o Presentation:
 Acute onset of severe, painful and tender joint swelling, affecting the
first metatarsophalangeal joint (called podagral)
 Other affected joint: tarsal joints, ankle and knee.
 Many attacks occur suddenly at night with rapid evolution of joints
with erythema, swelling, tenderness and warmth. Intense joint

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inflammation can extend in to the soft tissue and mimic cellulitis or
phlebitis
 Fever can occur in severe attacks.
 Polyarticular involvement can occur.
 Acute attacks usually resolve spontaneously in few days (3-10 days)
though some can extend over several weeks.
 The affected joint usually returns to normal between attacks and
patients do not have residual symptoms until the next episode
 Intercritical gout: this is the third stage of gout. It is asymptomatic after the
initial attack. Recurrence of new attacks may occur during this stage. Attacks
tend to become polyarticular and more severe over time. Some patients
develop chronic inflammatory arthritis without asymptomatic intervals
leading to a condition which may resemble rheumatoid arthritis.
 Chronic tophaceous gout: develops in untreated patients as the final stage of
gout. The tophus is a collection of urate crystal masses surrounded by
inflammatory cell and fibrosis. Typical locations for tophaceous deposits
include: Pinna of ear, the surfaces of chronically involved joints and
subchondral bone as well as extensor surface of the forearm, olecranon and
the intrapatellar and Achilles tendons.
 Renal complications: may arise at any stage of gout but nephrolithiasis is the
only common clinical presentation of renal involvement. Proteinuria and
impaired ability to concentrate urine related to urate deposition in the renal
interstitium have been described in gout patients.
DIAGNOSIS AND INVESTIGATIONS
 Acute gouty arthritis:
 Synovial fluid analysis: the demonstration of urate crystals, especial
intracellular crystals, in synovial fluid is diagnostic. Synovial fluid WBC of
10, 000-60 000/l with predominant neutrophils are common in acute
attacks.
 Serum uric acid: value often is not helpful in the clinical diagnosis of acute
gout. Serum uric acid concentration is normal in about 10% of patients at the
time of an acute attack and an elevated serum uric acid is non-specific of
acute gout. It can be used to assess the effectiveness of hyouricemic therapy.
 Chronic tophaceous gout
 Physical appearance: Tophi are firm movable and superficial located. If they
ulcerate a chalky material extrudes.

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 Radiologic findings: tophaceous deposits appear as well defined large
erosions (punched out erosions) of the subchrondral bone. These erosions are
common at the first Metatarsophalangeal joint (MTP) and at the base of the
head of phalanges however any joint area can be affected. Typically, gouty
erosions have an overhanging edge of subchondral new bone formation.
 Aspiration: tophi can be aspirate and crystals can be demonstrated.
MANAGEMENT
 Asymptomatic: treat underlying cause, no further treatment.
 Acute gouty arthritis: therapy most effective when started early after symptoms
begin.
 Colchicine: This has anti-inflammatory effect and if given early is effective
in 85% of patients.
o Dose: colchicine 0.6mg is given every hour until the relief of symptoms
of gastrointestinal toxicity occurs. It may also be given intravenously
during acute attack in patients who cannot take PO medication.
 NSAID: are used in high but quickly tapered doses. Drugs like Aspirin that
affect uric acid clearance should be avoided
o Ibuprofen: 800mg PO TDS
o Diclofenac: 25-50mg PO TDS
o Indomethacin: 25-50mg PO TDS
 Corticosteroids:
o Prednisolone 30-50mg/day as the initial dose and taper over 5-7 days.
Intra-articular injections of steroids can be used to treat acute gout of
single joint, particularly when the use of other agents is contraindicated.
 Drugs that alter serum uric acid concentration (e.g. allopurinol, probenecid)
should be avoided during acute attack because of lowering of serum uric acid
level induces the release of crystals into joint space and prolong the acute
attack
 Intercritical gout: prophylactic treatment with small dose of colchicine (0.6mg
OD or BD) or small doses of NSAIDs can be used to prevent new attacks.
 Chronic tophaceous gout: aim is to control hyperuricemia (reduce serum urate
level to <5mg/dl)
 Uricosuric agents: e.g. probenecid, facilitate the renal excretion of uric acid.
It can be used in patients who excrete less than 700mg of uric acid daily, who
have normal renal function and who have no history of urinary stones.
o Dose: Probenecid 200mg PO BD increased gradually as needed up to 2g.

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 Xanthine oxidase inhibitors: e.g. Allopurinol, competitively inhibit xanthine
oxidase. This drug is preferred in patients with urate excretion greater than
1000mg/day, creatinine clearance <30ml/min, tophaceous gout or history of
nephrolithiasis.
o Dose 300mg single morning dose initially and may be increased up to
800mg if needed.
o Dosage is reduced in the presence of renal failure to avoid toxicity.

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OSTEOARTHRITIS
 This is a degenerative bone and joint condition initially involving thinning of the
hyaline cartilage until the underlying bone is exposed and becomes damaged due
to direct stress.
 It can be:
 Primary (idiopathic) which is localized or generalized or
 Secondary which is usually localized.
 Nodal osteoarthritis is a primary osteoarthritis involving the hands.
RISK FACTORS
 Age>50 years
 Nodal OA:
 Post-menopausal women
 Family history
 Secondary:
 Mechanical strain from obesity, trauma or employment
 Joint disease: inflammatory arthritides
 Hemochromatosis
 Osteoporosis reduces the risk
CLINICAL FEATURES
Primary nodal OA Secondary OA
 Tender, swollen joints with reduce  Typically affects the knee, hip or
movement spine
 Typically affects the distal  Painful joint exacerbated by
interphalangeal joints (DIP), thumb movement and worse in the evening
carpometacarpal (CMC) joint, and knees  Joint gelling- stiffness after resting
 Muscle wasting and instability
 Squaring of hand due to thumb  Hip OA typically radiates to the groin
adduction and bone swelling at CMC and buttocks.
 Heberden’s nodes at the DIP and  Spin OA may compress a nerve and
Bouchard’s nodes at the PIP radiate down the leg
INVESTIGATIONS
 Diagnosis can be clinical- especially if patient >45 years old- and does not require
radiological evidence.
 X-ray can be useful to exclude other conditions and are needed in younger
patients or atypical histories. In osteoarthritis, may see ‘LOSS’:

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 L-loss of joint space (asymmetrical), reflecting thinning of the cartilage
 O-osteophytes, reflecting proliferation and ossification of cartilage in
unstressed areas
 S-subchondral sclerosis (thickening)
 S-Subchondral cysts, reflecting fluid-filled microfractures
 Bloods:
 CRP/ESR to rule out inflammatory cause.
MANAGEMENT
 Lifestyle and physical therapy:
 Exercise to improve strength and joint stability
 Reduce weight
 Walking aids
 Physio
 Pharmacological:
 Regular paracetamol +/- topical NSAID gel (knee or hands only), then move
up pain ladder if needed. Paracetamol is traditionally preferred for long-term
use over NSAIDs as it is safer but recent research question its efficacy.
 If adding/switching to NSAIDs PO (standard or coxib) stop topical NSAID
and give PPI. Unlike paracetamol, there is good evidence of efficacy.
 Further option: intra-articular steroid injections, topical capsaicin for hand or
knee OA.
 Glucosamine and chondroitin are not recommended
 Surgical: joint replacement

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RHEUMATOID ARTHRITIS
 This is a multisystemic inflammatory disease of unknown cause characterized by
persistent inflammatory synovitis usually involving peripheral joints in a
symmetrical distribution.
 It is an autoimmune disease in which IgG forms against cartilage and rheumatoid
factor (RF)- an IgM antibody forms against that IgG, leading to synovitis.
 This eventually leads to pannus (deposits in the synovial membrane) and joint
destruction, the hallmark of the disease.
 Rheumatoid arthritis is much more common in females (3:1).
 The prevalence increases with age. Peak onset around 50 years but any age can
be affected.
ETIOLOGY
 Cause remains unknown however genetic and environmental factors (infectious
agents) have been implicated.
 Genetic factors: genetic susceptibility to altered immune response may play
a role. The concordance rate among monozygoitic twins is 4 times and first
degree relatives of patients with RA have a very high chance of developing
RA. HLA-DR4 allogen has been associated with high incidence of RA.
 Infectious agent: May play a role in triggering an autoimmune reaction.
Infectious agents such as rubella, Mycoplasma, CMV and EBV virus may
play a role in the pathogenesis
CLINICAL FEATURES
 Onset:
 Insidious onset: in about 2/3 of patients, RA begins insidiously with
prodromal nonspecific symptoms such as fatigue, weight loss, anorexia,
generalized body weakness and vague musculoskeletal symptoms, for weeks
or months before the occurrence of specific joint symptoms.
 Acute onset: in about 10% of patients, RA has an acute onset, with rapid
development of polyarthritis, associated with constitutional symptoms
including fever, lymphadenopathy and splenomegaly.
 Patterns:
 Typical: Onset of symmetrical polyarthritis over weeks to months, it has a
relapsing-remitting course.
 Rare: persistent large joint monoarthropathy or palindromic RA, a recurrent
acute monoarthritis

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ARTICULAR (JOINT) MANIFESTATIONS
 Inflammatory features:
 Swollen, painful and stiff joints.
 Generalized joint stiffness is often seen after a period of inactivity. Morning
stiffness which lasts greater than 1 hour which is a feature of inflammatory
arthritis is a common complaint.
 Bilateral, symmetrical small joint involvement is typical for Carpal tunnel syndrome:
RA. this is caused by
 Commonly joints affected: compression of the
o Wrist joints, metacarpophalangeal joints and proximal median nerve due to
interphalangeal joint are often involved. The distal reduce size of the
interphalangeal joints are often spared. osseofibrous carpal
 Wrist joints: synovitis of wrist joint is very common tunnel, resulting from
in RA and may lead to limitation of movement, inflammation of the
deformity and median nerve entrapment (Carpal flexor retinaculum,
tunnel syndrome) arthritic changes in the
o The elbow and knee joint are also affected carpal bones, or
 Elbow joint involved may lead to flexion contracture inflammation or
 Knee joint is commonly involved with synovial thickening of the
hypertrophy, chronic effusion and frequent synovial sheaths of the
ligamentous laxity. Pain and swelling behind the flexor tendons. It leads
knee may be caused by extension of inflamed to pain and paresthesia
synovium in to popliteal space (Baker’s cyst) (tingling, burnng and
o Arthritis of the forefoot, ankles and subtalar joints can numbness) in the hand
produce severe pain with ambulation as well as a in the area supplied by
number of deformities. the median nerve and
o Axial involved is limited to cervical spines: atlantoaxial may also cause atrophy
ligament involvement in the cervical spine can lead to of the thenar muscles in
instability between C1 and C2 vertebrae and potential case of severe
neurologic complaints compression. There is
no paresthesia over the
 Joint deformities: with persistent inflammation, a variety of
thnar eminence skin
characteristic joint changes develop due to damage or
because this area is
weakening of ligaments, tendons and joint capsule. They are
supplied by the palmar
less common in the age of effective treatment. These include:
cutaneous branch of the
 Z-deformity: radial deviation at the wrist with ulnar
median nerve
deviation of the digits

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 Swan neck deformity: hyperextension of the Proximal interphalangeal joints
with compensatory flexion of distal interphalangeal joint
 Boutonier deformity: flexion contracture of proximal interphalangeal joints
and extension of distal interphalangeal joints
 Baker’s Cyst (from joint rupture)

EXTRAARTICULAR FEATURES
 Even though not all of them have clinical significance, they may be the major
evidence of disease activity and source of morbidity
 Most often the manifestations occur in patients who have high titer of rheumatoid
factor and patients who have more severe and established disease.
 Systemic symptoms (constitutional symptoms): fatigue, fever, weight loss.
 Neurological manifestations: the CNS is not directly affected
 Eye:
o Keratoconjunctivitis sicca (10-15%) these patients have a secondary
form of Sjogren syndrome.
o Scleritis or episcleritis occur less common but can lead to scleromalacia.
 Atlantoaxial subluxation: may lead to compression of spinal cord (cervical
myelopathy/radiculopathy)
 Peripheral nerves are affected through entrapment (Carpal tunnel syndrome)
or vasculitis related mononuritis multiplex. Tarsal tunnel syndrome may also
be seen.
 Cardiovascular
 Asymptomatic pericarditis (50% of patients on autopsy). It is often associated
with pleural effusion
 Pericardial effusion

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 Atherosclerosis
 Myocarditis and valvular dysfunction (mitral regurgitation)
 Rheumatoid vasculitis: this can affect nearly any organ system and is seen in
patients with severe RA, and high titers of circulating Rheumatoid factor.
o Peripheral nerves: distal sensory neuropathy or mononuritis multiplex
o Skin: cutaneous ulceration, dermal necrosis
o Digital gangrene
o Visceral infarction: MI, vasculitis involving the lungs, bowel, liver,
spleen, pancreas, kidneys etc.
 Hematological
 Anemia of chronic disease
 Methotrexate or sulfasalazine induced folate-deficiency anemia
 Thrombocytosis
 Felty’s syndrome: chronic RA with splenomegaly and neutropenia with an
occasional thrombocytopenia and anemia.
 Lungs:
 Pleuritis and pleural effusion. The pleural fluid is typically low in glucose.
 Interstitial pulmonary fibrosis
 Rheumatoid nodules may appear on the lung, single or multiple
 Obliterative bronchiolitis: fibrotic and inflammatory narrowing of
bronchioles
 Methotrexate pneumonitis
 Kidneys:
 Amyloidosis
 Glomerulonephritis
 Dermatological and mucosal:
 Sjogren’s
 Raynaud’s
 Rheumatoid nodules (most common feature-20-25%) on elbows and
sometimes lungs, meninges and eyes
 They are firm subcutaneous masses typically found in areas on
periarticular structures and on areas exposed to repetitive trauma e.g.
extensor surface of the forearm, the olecranon at the elbow, proximal
ulna, Achilles tendon and occiput.
 Pyoderma gangrenosum
 Erythema nodosum.
 Others: osteoporosis, hypothyroidism and cancer (lymphoma, lung if smoker)

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DIAGNOSIS
 History and examination
 Laboratory investigations
 Bloods
o Full blood count: normocytic normochromic anemia, leukocytosis and
thrombocytosis
o ESR: raised indicating chronic inflammation
o Rheumatoid factor: it is an autoantibody against the Fc component of
IgG. It is typically present in 60% of patients in the first year and 80% of
patients with long standing disease. Note 30-40% of patients with RA
may be sero-negative for RF (70% sensitivity)
o Anti-CCP- anti-cyclic Cetrullinated Peptide (more specific and
prognostic)
o Liver function tests, U + Es for baseline before DMARDs.
 Imaging: X-ray shows ‘LESS’
o L-loss of joint space
o E-erosion (high risk of progression)
o S-soft tissue swelling
o S-see through bones (Juxta-articular/periarticular osteopenia)
 Other investigations:
o Joint aspirate if diagnostic uncertainty of septic arthritis suspected.
o Urine: may contain blood and/or protein
o CXR to exclude lung disease.
AMERICAN REVISED CRITERIA FOR CLASSIFICATION OF
RA
 4 out of 7 needed to classify a patient as having RA:
 Morning stiffness lasting >1 hour
 Arthritis of 3 or more joint areas
 Arthritis of hand joints: Wrist, MCP, and PIP
 Symmetrical arthritis
 Rheumatoid nodules: subcutaneous nodules over bony prominences
 Serum rheumatoid factor
 Radiologic changes: periarticular bony erosion of RA is not excluded
 Patients with 2 or more criteria, the diagnosis of RA is not excluded.

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MANAGEMENT
 Goals of therapy:
 Short term: controlling pain and reducing inflammation without causing
undesired side effects.
 Long term: preservation of joint function and the ability to maintain lifestyle.
 Non-pharmacological
 Patient education
o Description of the illness: the chronicity of the disease
o Rest and exercise
 Patients should be advised to rest or splint acutely involved joints
 Exercise is advised to strengthen muscle surrounding involved joints,
when the arthritis is resolved.
 Physiotherapy and occupation therapy to reduce disability
 Pharmacological:
 First Line treatment
o NSAIDs are used to control symptoms and signs of local inflammatory
process. These agents are rapidly effective in alleviating pain and
symptoms but their effect on long term disease progression is minimal
o Drugs used:
 Aspirin 900 mg PO TDS
 Ibuprofen 400mg PO BD
 Diclofenac 50mg PO BD or TDS
 Indomethacin
o Side effects: dyspepsia, PUD, renal dysfunction, bone marrow toxicity
 Second line treatment: Low dose oral corticosteroids have potent anti-
inflammatory but they equally have predictable unwanted side effects.
o Systemic administration: given in severe progressive articular disease
and extra-articular involvement.
 Dose: start 5-10mg OD in the morning. If patient improves attempt
should be made to taper the dose.
o Local injection: steroids may be injected occasionally to joints which are
severely affected
 Third line treatment: Disease modifying antirheumatic drugs or slow acting
antirheumatic drugs (DMARDs)
o Drugs include: Methotrexate, Gold compounds, D-penicillamine,
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o Methotrexate is the most frequently used DMARD, which is relatively
rapid acting
 Dose: given in an intermittent low dose: 7.5 to 30mg once a week.
o Side effects: GI upset, oral ulcer, liver function abnormalities and
insidious liver fibrosis. Administration of folic acid may diminish the
frequency of some side effects.
o These are drugs which have no analgesic effect and generally require
weeks to month before anti-inflammatory effects are evident. Hence
NSAIDs should continue during the administration of DMARDs.
o They have the capacity to alter the course of RA.
o They are used in patients with RA who are not responding to NSAIDs
(with or without steroids)
o These drugs may be used singly mostly but they may be prescribed in
combinations in patients with bad prognosis or refractory diseases.
o The disease progression is delayed with these drugs and acute phase
reactants such as ESR and C-reactive protein frequently decline.
 Fourth line: Anti-cytokine agents
o These are biological agents that bind and neutralize TNF. These drugs
are effective in controlling signs and symptoms of RA in patients who
fail to respond with DMARDs.
 Fifth line: immunosuppressive therapy
o These include drugs such as Azathioprine, Cyclosporine, and
Cyclophosphamide. They have the same therapeutic effect as DMARDs
but they are not more effective than DMARDs. They are prescribed to
patients who fail to respond to DMARDs.
 Surgical:
 Early: synovectomy may decrease the inflammatory process in joint pain,
stiffness and swelling
 Late: arthroplasty or total joint replacement may be appropriate to relieve
pain or help restore function in structurally deformed joints.
ASSESSMENT OF RESPONSE
 Resolution of symptoms: reduction or disappearance of joint pain, stiffness and
swelling.
 Functional status: ability of the patient to perform daily activities and living
 Laboratory: anemia may be corrected and ESR declines

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PROGNOSTIC FACTORS
 Poor prognostic factors:
 Many persistently inflamed joints
 Poor functional status
 Low educational status of the patient
 Rheumatoid factor positivity
 HLA-DR4 positivity
 Extra-articular diseases
 Persistently elevated acute phase reactants (ESR, C-reactive protein)
 Radiologic evidence of erosion

SYSTEMIC LUPUS ERYTHEMATOSUS

 This is a chronic immune disorder characterized by multisystem involvement and
clinical exacerbations and remission.
 Circulating immune complexes and autoantibodies cause tissue damage and
organ dysfunction.
 SLE is 8-10 times more common among young women of child bearing age than
in men.
 It is common among black women than white women as well as among pregnant
women.
 SLE has a familial tendency and the concordance rate among identical twins is
50%.
ETIOLOGY
 No single cause has been identified, a mixture of environmental, genetic factors
and hormonal influences have been linked.
 Environmental factors: UV light, virus (e.g. EBV), smoking, toxins and drugs
(isoniazid, hydralazine, chlorpromazine, sulfasalazine, phenytoin,
procainamide, carbamazepine etc.)
 Genetic factors: there is genetic predisposition to SLE. HLA-DR2 and DR3
as well as complement deficiencies (C1q, C2, C4) have been implicated.
 Autoimmunity: loss of tolerance to autoantigens is central to the pathogenesis
 Hormonal influence: as the disease is more common in women of child
bearing age, estrogen may play a role in the pathogenesis.

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PATHOGENESIS
 When cells die by apoptosis, the cellular remnants appear on the cell surface as
small blebs which carry self-antigens.
 The antigens include nuclear constituents (e.g. DNA and histones) which are
normally hidden from the immune system.
 In people with SLE removal of these blebs by phagocytes is inefficient so that
they are transferred to lymphoid tissue where they can be taken up by antigen
presenting cells.
 The self-antigens from these blebs can then be presented to T cells which in
turn stimulate B-cells to produce autoantibodies directed against these antigens.
 Presence of self-antigens and failure of the immune system to inactivate B cells
and T cells which recognize these self-antigens (i.e. a breakdown of tolerance)
leads to:
 Development of autoantibodies that either form circulating complexes or
deposit by binding directly to tissues
 This leads to activation of complement and influx of neutrophils causing
inflammation in those tissues.
 Abnormal cytokine production: increased blood levels of IL-10 and alpha-
interferon are particularly closely linked to high activity of inflammation in
SLE.
CLINICAL FEATURES
 SLE can affect virtually all organs with a wide range of severity and a relapsing-
remitting course.

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 Note: Arthralgia and rashes are the most common clinical features while cerebral
and renal disease are the most serious
problems.
 Systemic symptoms: fatigue (90%),
weight loss, lymphadenopathy and fever
(50%)
 CNS (60%):
 Generalized manifestations: severe
headache, reactive depression,
psychosis (20%), seizures (20%) and
cognitive disturbances
 Focal: focal seizure, hemiparesis,
paraparesis, cranial nerve lesions,
ataxia, chorea may also be seen
 Peripheral nerves: some patients may
have sensory or sensorimotor
neuropathies.
 Cardiovascular (25%):
 Ischemic heart disease (5 times risk)
 Hypertension from renal
involvement
 Vasculitis
 Endocarditis Figure 64: Clinical features of SLE (Adapted from Kumar and
 Myocarditis Clark Clinical Medicine)
 Pericarditis
 Antiphospholipid syndrome (causes arterial and venous thrombosis)

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 Blood (75%):
 Anemia (normochromic normocytic or hemolytic-
Coombs positive)
 Leucopenia/Lymphopenia
 Thrombocytopenia
 Respiratory system (50%):
 Interstitial lung disease (fibrosing alveolitis)
 Pleurisy
 Pulmonary hemorrhage (causes hemoptysis and
anemia)
 Lupus pneumonitis
 Gastrointestinal (20%):
 Painless oral and nasal ulcers (30%)
Figure 65: Photosensitive malar
 Diarrhea and vomiting rash (Butterfly rash) (Image
 Dysphagia (10%) adapted from Kumar and Clark
 Abdominal pain Clinical Medicine)
 Splenomegaly (10%)
 Pancreatitis
 Intestinal vasculitis
 Genitourinary (50%): due to deposition of complement and IgG antibodies and
influx of neutrophils and lymphocytes.
 Lupus nephritis (50%): can cause 6 different types of glomerulonephritis
from minimal mesangial to advance sclerosis.
 Can manifest with proteinuria, casts, edema and later on chronic renal failure
(uremia)
 Musculoskeletal (90%):
 Joint/muscle pain
 Arthritis usually symmetrical, non-erosive polyarthritis with morning
stiffness but without swelling.
 Myalgia, tenosynovitis and tendon rupture
 Myositis and proximal myopathy
 Aseptic bone necrosis
 Skin (85%): due to deposition of complement and IgG antibodies and influx of
neutrophils and lymphocytes.
 Malar rash (60%)- Photosensitive malar butterfly rash (facial erythema over
the cheeks and nose)
 Photosensitivity (40%)

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 Discoid rash (20%)
 Alopecia
 Raynaud’s phenomena (50%)
 Purpura
 Urticaria
 Others:
 Eyes: Keratoconjunctivitis sicca (dry eyes), optic neuritis
 Recurrent abortions
INVESTIGATIONS
 Blood
 Full blood count: decreased hemoglobin (due to anemia of chronic disease
or Coomb’s positive hemolytic anemia), decreased WBC, Decreased
platelets
 ESR: elevated
 C-reactive protein: may be normal (or raised)
 U and Es + Creatinine: raised
 Clotting panel: increased aPTT in antiphospholid syndrome
 Serology:
o Antinuclear antibodies/ Antinuclear factor (ANA): are antibodies which
bind to elements of the cell nuclear. 95% sensitive (so screen with this
first) however they are 50% specific as they are mildly raised in 10% of
healthy population
o Double-stranded DNA (dsDNA) antibody is highly specific for SLE
(>90%) but only 60% sensitive. Especially associated with lupus
nephritis. Good for monitoring disease activity.
o Anti-smith (Sm) antibody: highly specific for SLE (>95%) but not
sensitive (30%)
o Anti-Ro and Anti-La antibody: can be seen in SLE, but commoner in
Sjogren’s syndrome
o Complements: C3 and C4 are low
 Other tests:
 Urinalysis: protein, blood, casts (red cells, tubular, granular)
 Imaging as per symptoms e.g. Chest X-ray if CVS or Respiratory symptoms
are present.

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DIAGNOSTIC CRITERIA
 4 out of 17 of SOAP B2RAI6N MD, including more than 1 clinical and 1 immune
criteria are needed for a diagnosis:
 Serositis (pleurisy, pericarditis)
 Oral or nasopharyngeal ulcer
 Arthritis
 Leuco-or lympho-Penia
 Blood disorders (up to 2): hemolytic anemia, decreased platelet count
 Renal disease: proteinuria or red cell casts
 Alopecia (non-scarring)
 Immune markers (up to 6): ANA, dsDNA, anti-Sm Antibodies,
Antiphospholipid antibodies, Decreased C3/C4 complements and Coomb’s
positive
 Neurocognitive symptoms: seizures or psychosis
 Malar rash
 Discoid rash
 Alternatively: a biopsy plus positive glomerulonephritis consistent with SLE plus
ANA or dsDNA antibodies is enough to warrant a diagnosis

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MANAGEMENT
 If SLE is believed to be due to be drug-induced, stop the drug
 Give Sun-block/Sunscreen lotions
 NSAIDs are used in full anti-inflammatory dose for fever, joint complaints and
Serositis
 Hydroxychloroquine (antimalarial medication) if joint/skin symptoms are not
controlled by NSAIDs e.g. 400mg/day PO for 6 months and then 200mg/day
 Corticosteroids

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 High dose prednisolone in life-threatening condition, 1mg/kg/day for 6
weeks, then taper. May be combined with other immunosuppressive
 Low dose prednisolone is of value in chronic disease.
 Cytotoxic drugs e.g. azathioprine and cyclophosphamide sometimes can be used
to treat severe refractory features of SLE particularly renal diseases.
Mild disease Moderate disease Severe disease
 Skin/joint  Cytopenias/hemolytic  Nephritis, severe CNS
involvement, oral anemia, Serositis, disease, vasculitis,
ulcers, Serositis mild pneumonitis, pulmonary
 NSAIDs mild myocarditis hemorrhage
 Topical  Moderately dosed  High dose
corticosteroids for systemic corticosteroids (≥1
skin disease corticosteroids mg/kg/day)
 Low-dose systemic (approximately  IV cyclophosphamide
corticosteroids 0.5mg/kg/day) (proven efficacy for
(<10mg/day)  Steroid-sparing agents nephritis, less
 Antimalarial such as azathioprine, established for other
medications (i.e. methotrexate (good indications
Hydroxychloroquine, for skin and arthritis)  Azathioprine
good for mild and mycophenolate  Mycophenolate
symptoms and skin mofetil. mofetil
disease)  IVIG (for antibody-
mediated cytopenias)
 Plasmapheresis (in
extreme
circumstances)

PROGNOSIS
 Early diagnosis and treatment decreased morbidity and mortality.
 Renal diseases and infectious complications are the major causes of death.
 CNS disease can lead to severe disability.
 Complications are as follows:
 Accelerated atherosclerosis, CAD
 Transitional cell carcinoma and hematologic malignancies if the patient
received cyclophosphamide
 Opportunistic infections

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METABOLIC DISTURBANCES
HYPERKALEMIA
 Normal potassium ECF concentration= 3.5-5.5 mEq/L
 Hyperkalemia is a serum potassium >5.5 mmol/L
 Causes:
 Trauma
 Crush injuries
 Burns
 Renal failure
 Excessive intake of potassium rich food and supplements
 Metabolic acidosis
 Addison’s disease
 Diuretic therapy (potassium sparing diuretics)
 Clinical features:
 Symptoms:
o Muscle weakness
 Signs:
o Ascending paralysis with respiratory failure
o Cardiac instability, ventricular fibrillation, cardiac arrest
o May have signs of acute kidney injury or metabolic acidosis
 Investigations:
 Serum potassium
o Mild hyperkalemia: 5.5-5.9
o Moderate hyperkalemia: 6.0-6.5
o Severe hyperkalemia: >6.5 and ECG changes
 ECG findings:
o Bradycardia
o Flat P waves
o Increased PR interval
o AV block
o Wide QRS complex
o Tall peaked symmetrical T waves

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MANAGEMENT
 Stop source of potassium (Oranges, bananas, ACEI, potassium sparing
diuretics, septrin, heparin, NSAIDs, Beta-blockers)
Mild hyperkalemia (5.5- Moderate hyperkalemia (6.0- Severe hyperkalemia (>6.5)
5.9) 6.5)
 Push Potassium out of  Protect the heart: 10mls  Protect the heart: 10mls
the body 10% Calcium Gluconate 10% Calcium Gluconate
 Furosemide over 10 mins. Effect is over 10 mins. Effect is
1mg/kg IV temporary but can be temporary but can be
(hydrate patient repeated after 15 minutes. repeated after 15 minutes.
first if dehydrated)  Push Potassium into cells  Push Potassium into cells
 Kayexalate/sodium  50mls 50% Dextrose  50mls 50% Dextrose
Resonium 15-30g with 10IU soluble with 10IU soluble
in 50-100ml 20% insulin over 15-20 insulin over 15-20
Sorbitol or with mins. May be given 2- mins. May be given 2-
lactulose PO/PR 4 hourly as required. 4 hourly as required.
 Consider Monitor serum glucose Monitor serum
hemodialysis if and potassium 2-4 glucose and potassium
refractory hourly 2-4 hourly
 10-20mg Nebulized  10-20mg Nebulized
Salbutamol (or 0.5mg Salbutamol (or 0.5mg
in 100ml of 5% in 100ml of 5%
glucose over 15 min- glucose over 15 min-
rarely used) rarely used)
 Push Potassium out of the  Push Potassium out of the
body body
 Furosemide 1mg/kg IV  Furosemide 1mg/kg
(hydrate patient first if IV (hydrate patient
dehydrated) first if dehydrated)
 Kayexalate  Kayexalate
(polystyrene (polystyrene
sulphonate) /sodium sulphonate)/sodium
Resonium 15-30g in Resonium 15-30g in
50-100ml 20% 50-100ml 20%
Sorbitol or with Sorbitol or with
lactulose PO/PR lactulose PO/PR
 Consider hemodialysis if  Consider hemodialysis
refractory if refractory

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HYPOKALEMIA
 This is a serum potassium <3.5, it may be associated with hypomagnesemia and
hypocalcemia.
 Causes:
 GIT losses (NG tube suctioning, vomiting, diarrhea)
 Renal losses (Renal disease)
 Metabolic alkalosis
 Potassium wasting diuretics
 Cushing’s disease (Sodium retention leads to potassium loss)
 Clinical features:
 Symptoms:
o Muscle weakness
o Fatigue
o Constipation
o Muscle cramps
 Signs:
o Paralytic ileus
o Ascending paralysis
o Reduced reflexes
o Tetany when associated with alkalosis
o Arrhythmias
 Investigations:
 Check potassium, other electrolytes and serum pH.
 ECG
o Flat or inverted T wave
o Prominent U wave
MANAGEMENT
 20mmol KCL in 250-500ml Normal saline over 1 hour. Check Potassium before
repeating dose and ECG monitoring.
 Consider 6-12ml (5-10mml/l) 20% MgSO4 or 2ml 50% diluted in 50ml over 1
hour.
 It cardiac arrhythmia or arrest give 2mmol KCL per minute IV for 5mins. Repeat
once only if necessary
 Oral Potassium supplements if potassium >3.0.

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HYPERNATREMIA
 Normal sodium ECF concentration= 135-145 mEq/L
 This is defined as a serum sodium >150 mmol/L
 Causes:
 Water loss more than electrolyte
 GIT losses
 Renal losses
 Diabetes insipidus
 Diabetes mellitus
 Increase in sodium
o Hyperaldosteronism
o Cushing’s
o Excessive saline or Sodium bicarbonate infusion
 Clinical features:
 Symptoms:
o Thirst
o Nausea and vomiting
o Weakness
o Malaise
o Muscle tremor
 Signs
o Dry mucous membranes and lips
o Oliguria
o Increased temperature and flushed skin
o Drowsiness
o Confusion
o Stupor
o Coma
o Convulsions
o Tremors
o Ataxia
 Investigations:
 Serum Sodium
 Urine Sodium

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MANAGEMENT
 Correct water deficit- rehydrate patient if dehydrated
 Stable/asymptomatic patients
 Take it easy
 Replace fluids orally
 Unstable/symptomatic patients
 IV fluids with NS, DNS
 Avoid 5% dextrose as sodium may drop too fast
 Rate of lowering serum sodium 0.5-1mmol/hr, aim for 12 mmol/L in
24hours and not more than this.
 Estimate the effect of 1 liter of any infusion on serum sodium
𝐼𝑛𝑓𝑢𝑠𝑖𝑜𝑛 𝑠𝑜𝑑𝑖𝑢𝑚−𝑆𝑒𝑟𝑢𝑚 𝑠𝑜𝑑𝑖𝑢𝑚
 Change in serum Sodium=
𝑇𝑜𝑡𝑎𝑙 𝑏𝑜𝑑𝑦 𝑤𝑎𝑡𝑒𝑟+1
 The answer is in mmol/L. The formula helps to calculate the infusion rate
so that you do not exceed 1 mmol/min.
HYPONATREMIA
 This is low serum sodium but treatment warranted with severe (<120mmol/L)
or acute
 Causes:
 Hypovolemic
o GI losses (NG tube suctioning, vomiting, diarrhea)
o Renal losses
o Diuretic therapies
 Euvolemic
o Hypothyroidism
o SIADH
o Adrenal insufficiency (Addison’s disease)
 Hypervolemic
o Congestive heart failure
o Cirrhosis
o Nephrotic syndrome
 Clinical features:
 Asymptomatic unless severe or acute
 Abdominal cramps, Nausea, vomiting, pitting edema over the sternum,
confusion, seizures, coma
 Investigations:

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 Serum sodium
 Urine sodium
 Serum and Urine osmolarity
MANAGEMENT
 CNS manifestations
 200ml 5% NaCl over 6 hours. Monitor serum sodium hourly.
 Aim to increase sodium to 120mmol/l at a rate of 0.5-1.0 mmol/l per hour
 If no CNS symptoms, do not use hypertonic saline.
 Once serum sodium is around 120 mmol/L, stop active therapy and restrict
fluid intake to approximately 500ml/day.
 Asymptomatic
 Can use conservative measure like fluid restriction may be enough
 SIADH
 Restrict fluid intake to 50-60% of estimated maintenance fluid requirements
(+/- 1L/day)
HYPERCALCEMIA
 Normal serum calcium: 2-2.5mmol/L
 Corrected serum Calcium >2.65mmol/L
 Causes
 Hyperparathyroidism
 Malignancy
 Sarcoidosis
 Drugs
 Vitamin D intoxication especially in renal patients
 Clinical features:
 Symptoms
o Polyuria
o Polydipsia
o Dysphagia
o Bone pain
o Renal colicky
o Muscle weakness
 Signs
o Confusion
o Hypotonia

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o Dysarthria
o Coma
o Seizures
 Investigations
 Serum Calcium, Urea + Electrolytes, Albumin, Magnesium, phosphate,
ALP, serum electrophoresis
 PTH
 X-rays
 ECG
o Short QT interval
o Wide QRS complex
o Flat T waves
o AV block
o May have fatal arrhythmias (frequent association with hypokalemia
increases risk of arrhythmias)
MANAGEMENT
 Hydrate with normal saline 500ml/hr until urine output >200ml/hr then reduce
100-200ml/hr.
 Furosemide 1mg/kg only when patient has been hydrated or if in cardiac failure
 Hemodialysis or peritoneal dialysis with low calcium dialysate. Hemodialysis is
preferred.
 Prednisolone 40mg daily especially for Vitamin D intoxication, sarcoidosis,
multiple myeloma, metastasis
 Pamidronate 60-90mg in 500-100ml NS infusion.

RADIOLOGY

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INTEPRETING X-RAYS chest wall and the dome of
each hemidiaphragm.
CHEST X-RAYS o On a lateral view the
GENERAL DETAILS costophrenic recesses are
 On all X-rays check the following seen in the region of the
details: anterior and posterior
 Check patient details: first costophrenic angles
name, surname, and date of formed by the chest wall
birth. and the dome of each
 Check orientation, position hemidiaphragm.
and side description: left, right,  Ideally the chest X-ray is taken in
erect, anterior-posterior, the posterior-anterior (PA)
posterior-anterior, supine, and direction at maximum inspiration
prone. with the heart close to the X-ray
 Check additional information: film to minimize magnification
inspiration and expiration. with respect to the thorax.
 Check for rotation: measure  A lateral may give additional
the distance from the medial information if the PA is abnormal.
end of each clavicle to the The cardiac structures and great
spinous process of the vertebra vessels can be seen on these X-
at the same level, which rays.
should be equal.  An Anterior posterior (AP) view is
 Check adequacy of inspiration: only taken in an emergency.
9 pairs of ribs should be seen
posteriorly in order to consider SPECIFIC RADIOLOGICAL
a chest X-ray adequate in CHECK LIST
terms of inspiration  Use the ABCDEFGH approach
 Check exposure: one needs to
be able to identify both A- AIRWAY
costophrenic angles and lung  Ensure that the trachea is visible
apices. and in the midline.
o On a PA view, the o Trachea gets pushed
costophrenic recesses are away from abnormalities
seen on each side as the such as pleural effusion
costophrenic angles or tension pneumothorax.
o The costophrenic angles
are formed by the lateral

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o Trachea gets pulled osteoblastic or osteolytic lesions in
towards abnormality clavicles, ribs, thoracic cage.
such as atelectasis.  Check the spine and humerus
o Trachea normally including osteoarthritic changes.
narrows at the vocal  At this time also check for soft
cords. tissues for subcutaneous air,
o View the carina, angle foreign bodies and surgical clips
should be between 60-  Take caution with nipple shadows,
100 degrees which may mimic intrapulmonary
o Beware of things that nodules:
may increase this angle o Compare side to side, if
e.g. left atrial on both sides the
enlargement, lymph node “nodules” in question are
enlargement and left in the same position, then
upper lobe atelectasis. they are likely to be due
o Check for tubes, to nipple shadows.
pacemaker wires, lines, C- CARDIAC
foreign bodies.  Check heart size and heart borders
o If an endotracheal tube is o Appropriate or blunted
in place, check the o Thin rim of air around
positioning, the distal tip the heart, think of
of the tube should be 3- pneumomediastinum
4cm above the carina.  Check aorta
 Check for a widened mediastinum o Widening, tortuosity,
o Mass lesions (e.g. tumor, calcification
lymph nodes)  Check valves
o Inflammation (e.g. o Calcification, valve
mediastinitis, replacements
granulomatous  Check superior vena cava, inferior
inflammation) vena cava, azygos vein
o Trauma and dissection o Widening, tortuosity
(e.g. hematoma, D- DIAPHRAGM
aneurysm of the major
 Right hemidiaphragm
mediastinal vessels)
o Should be higher than the
B- BONES left
 Check for fractures, dislocations,
subluxation (a partial dislocation),

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o If much higher, think of o The lingual abuts the left
effusion, lobar collapse, side of the heart
diaphragmatic paralysis  Identify the pattern of infiltration
o If you cannot see parts of o Interstitial pattern
the diaphragm, consider (reticular) versus alveolar
infiltrate or effusion (patchy or nodular)
 If film is taken in erect or upright pattern
position you may see free air under o Lobar collapse
the diaphragm if intra-abdominal o Look for air
perforation is present bronchograms, tram
E- EFFUSIONS tracking, nodules, kerley
 Effusion B lines
o Look for blunting of the o Pay attention to the
costophrenic angle apices
o Identify the major  Check for granulomas, tumor and
fissures, if you can see pneumothorax
them more obvious than G- GASTRIC AIR BUBBLE
usual, then this could  Check correct position
mean that fluid is  Beware of hiatus hernia
tracking along the  Look for fee air
fissure.  Look for bowel loops between
 Check out the pleura diaphragm and liver
o Thickening, loculations, H- HILUM
calcifications and  Check the position and size
pneumothorax bilaterally
F- FIELDS (LUNG FIELDS)  Enlarged lymph nodes
 Check for infiltrates  Calcified nodules
o Identify the location of  Mass lesions
infiltrates by use of
 Pulmonary arteries, if greater than
known radiological
1.5cm think about possible causes
phenomena e.g. loss of of enlargement
heart borders or the
contour of the diaphragm SILHOUETTE SIGN
o Remember that right  Can localize abnormalities on a PA
middle lobe abuts the film without need for a lateral
heart, but the right lower view.
lobe does not

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 The loss of clarity of a structure, causing subsequently a loss of
such as the hemidiaphragm or aeration.
heart border suggests that there is  The remaining air is gradually
adjacent soft tissue shadowing absorbed and the lung loses
such as consolidated lung. volume.
o The reason is that  Proximal stenosing bronchogenic
borders, outlines and carcinoma, mucous plugging, fluid
edges seen on plain retention in major airways, inhaled
radiographs depend on foreign body or malposition of an
the presence of two endotracheal tube are the most
adjacent areas of common reasons for a lung
different density. collapse.
o Roughly speaking, only 4  Tracheal displacement or
different densities are mediastinal sift towards the side of
detectable on plain films: the collapse is often seen.
air, fat, soft tissue and  Further findings are elevation of
calcium (5 if you include the hemidiaphragm, reduce vessel
contrast such as barium). count on the side of the collapse or
o If soft tissue densities lie herniation of the opposite lung
adjacent, then they will across the midline.
not be visible separately
(e.g. the left and right
ventricles). If, however
they are separated by air,
the boundaries of both
will be seen.

LUNG COLLAPSE
 A collapse usually occurs due to
proximal occlusion of a bronchus,

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COMMON PROCEDURES
PROCEDURE DOCUMENTATION
 Before you begin any procedure, stop and confirm:
 Consent has been obtained from the patient and the procedure has been
explained to the patient.
 Correct patient
 Correct procedure and Correct site
 No contraindications
 After you finish, document the procedure in the patient’s file: date, time,
procedure, indication, site, technique, quantity and quality of specimen,
complications.
 Examples:
 25/12/2020-10AM. A lumbar puncture was performed to rule out meningitis:
A 20g needle was inserted at L3-L4 using sterile technique. 5ml of clear fluid
was removed, normal pressure. A dipstick of the fluid revealed negative
leukocyte esterase. No complications occurred.

LUMBAR PUNCTURE (LP)

INDICATIONS
 Diagnostic:
 Meningitis
 Sub-arachnoid hemorrhage
 Demyelinating disorders
 Therapeutic: Cryptococcal meningitis to reduce ICP
 Patient presents with 2/4 of the following symptoms should have an urgent
LP performed:
(1) Fever (T>38.0oC)
(2) Headache
(3) Altered mental status (GCS<14) and
(4) Neck stiffness/Kernig/Brudzinski’s sign (Fever + headache alone are an
indication for LP if MPS is negative or patient already treated for malaria)

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CONTRAINDICATIONS
 Cardiorespiratory instability
 Increased intracranial pressure due to mass (papilledema, CT scan with mass)
 Skin infection over puncture site
 Bleeding disorders
TECHNIQUE
 Position the patient in either the lateral decubitus or upright sitting position. In
both positions the patient’s spine should be straight and as flexed as possible with
the forehead bent toward the knees. Position is very important for LP.
 Identify the puncture site. Palpate the top of the iliac crest and the vertebral
interspace located at the same level (L4- L5). Palpate L3-L4, L4-L5, L5-S1 and
mark the interspace that is most open. Note: Conus Medullaris is at L1-L2.
 Sterilize the puncture site around your mark with iodine solution and methylated
spirit.
 Using a sterile 20g needle (or spinal needle) and sterile gloves, enter the middle
of the interspace. Advance the needle slowly toward the umbilicus and parallel
to the ground. There will be some resistance and a give-in as the needle passes
through the ligamentum flavum.
 Once CSF is obtained, estimate the opening pressure based on the flow rate.
Collect fluid in at least 3 separate red bottles/tubes. Only the 2nd bottle needs to
be sterile to be sent for microbiology. Describe the appearance of the fluid in each
bottle/Tube.
 Place one drop of CSF on a urine dipstick and record results.
 Send the 1st bottle to chemistry (1ml) for total protein and glucose.
 Send the 2nd bottle (5 ml) to microbiology for gram stain, culture, sensitivity and
AFB (if indicated).
 Send the 3rd bottle to hematology for cell count and differential.
 Note: Blood should also be sent for estimation of serum glucose.
COMPLICATIONS
 Post LP headache (common, treat with caffeine)
 Nerve root injury (shooting pains, transient)
 Tonsillar herniation/Spinal hemorrhage (rare but severe)

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Feature Normal Bacterial meningitis Viral meningitis Tuberculous
meningitis
Pressure 50-250mm Normal/increased Normal Normal/increased
of water
Appearance Crystal Turbid Clear Cob-web appearance
clear
Cell count/ <10 RBCs Several thousands Several hundreds Several hundreds
microliter <5 WBCs (1000-5000 (10-2000 (50-5000
polymorphs) lymphocytes) lymphocytes)
Cell type None Granulocytes Lymphocytes Lymphocytes and
(Polymorphs) monocytes
Glucose 2/3 to ½ Decreased (<30mg/dl) Normal Decreased
blood < ½ blood glucose > ½ blood (<30mg/dl)
glucose glucose < ½ blood glucose
Protein 0.2-0.4 g/l Increased (>120mg/dl) Normal (0.4- Increased (>120
0.5-2.0g/l 0.8g/L) mg/dl)
0.5-3.0g/l
Lactate >3.5mmol/L <3.5 mmol/L >3.5mmol/L
dehydrogenase

THORACENTESIS
INDICATIONS
 Diagnostic:
 Should be performed for any patient with a moderate-large pleural effusion
who have not had a previous diagnostic thoracentesis.
 Therapeutic:
 For patient with respiratory distress due to large pleural effusion
 Patients with moderate-large exudative effusions.
CONTRAINDICATIONS
 Small pleural effusions (<1cm on lateral decubitus film)
 Bleeding disorders
 Cardiorespiratory instability
 Uncooperative patient
 Skin infection over the puncture site

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TECHNIQUE
 Position the patient. Have them sit on the edge of their bed while leaning over a
bedside table. The posterior approach
reduces risk of lung injury.
 Identify the puncture site by reviewing the
chest X-ray and percussing the level of the
effusion. Verify the presence and location
of the pleural fluid. Mark a puncture site 1-
2 intercostal spaces below this level at the
midline (in line with the tip of the scapula-
Midscapular line). Do not enter below the
8th intercostal space to avoid the abdominal
organs. Alternatively, the axillary
approach can be used entering at the mid-
axillary line between the 7th to 9th
intercostal space. Some experts
recommend using the intercostal space
below the upper limit of the dullness
 Sterilize the puncture site with iodine solution and methylated spirit. Infiltrate
using 1% lignocaine.
 Using a sterile 16 or 18g needle attached to a sterile syringe (5 or 10 ml) and
sterile gloves, insert the needle at the puncture site above the rib to avoid the
neurovascular bundle below the rib. Insert the needle slowly while drawing back
on the syringe. Stop inserting the needle when fluid starts to flow.
 Withdraw 5-10ml of fluid into the syringe for a diagnostic tap.
 Send 1ml to chemistry for total protein and
 4-5ml to microbiology for gram stain, culture, sensitivity and AFB (ZN
stain).
 Also send serum for total protein at the same time.
 Consider sending fluid for cytology if concerned for malignancy.
 For therapeutic tap, remove the needle but leave the plastic cannula in place and
attach it to IV tubing and a urine bag. Never drain more than 1 liter at a time to
prevent re-expansion edema.
 If more than 1 liter needs to be removed, clamp the IV tubing and wait 4-6 hours
before draining another 1 liter. This process can be repeated several times if
necessary.

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 An urgent CXR should be ordered post procedure if air is aspirated or the patient
develops cough, shortness of breath or chest pain.
 Note: patients with empyema or loculated pleural effusion should have chest
tubes or surgical drainage.
COMPLICATIONS
 Pneumothorax (common but usually mild, if signs of tension pneumothorax
consider immediate needle decompression)
 Hemothorax
Light’s Criteria: Exudate if any of the 3 are found
Transudate Exudate
Protein (Pleural/Serum) ≤0.5 >0.5
Lactate dehydrogenase ≤0.6 >0.6
(Pleural/Serum) Pleural LDH ≤ two thirds of Pleural LDH > two-thirds of
upper limit of serum LDH upper limit of serum LDH
Common causes  Hypoalbuminemia  Infection (Parapneumonic,
(Cirrhosis, Nephrotic TB, fungal, empyema)
syndrome)  Esophageal rupture
 Congestive heart failure  Pulmonary embolism
 Constrictive pericarditis  Neoplasms
 Myxedema  Autoimmune (Systemic lupus
(hypothyroidism) erythematosus)
 Ovarian tumors producing  Rheumatoid pleural effusion
right sided pleural effusion- Esophageal rupture
Meigs’ syndrome  Sub-diaphragmatic abscess
 Pancreatitis
 Uremic pleural effusion
 Hemothorax
 Chylothorax (thoracic duct
injury)
 Radiation and drugs
Note: in resource limited setting where LDH is often not available: Total protein
effusion >30g/L is often used to indicate an exudate effusion whilst that <30g/L is
a transudate

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PARACENTESIS
BACKGROUND
 Paracentesis is a procedure in which a needle or catheter is inserted into the
peritoneal cavity to obtain ascitic fluid for diagnostic or therapeutic purposes.
 Ascitic fluid may be used to help determine the etiology of ascites as well as to
evaluate for infection or presence of cancer.
INDICATIONS
 Diagnostic:
 Should be performed on any patient with ascites detectable by examination
who has not had a previous diagnostic paracentesis. The fluid evaluation
helps to determine etiology, differentiate transudative versus exudate, detect
the presence of cancerous cells or address other considerations.
 Suspected spontaneous bacterial peritonitis or secondary bacterial peritonitis.
 Refractory ascites
 Therapeutic:
 Only for patients with severe respiratory distress
 Abdominal pressure or pain secondary to ascites (abdominal compartment
syndrome due to massive ascites)

CONTRAINDICATIONS
 Acute abdomen requiring surgery is an ABSOLUTE CONTRAINDICATION
 Skin infection at puncture site
 Pregnancy
 Hypotension
 NOTE: Bleeding disorders (severe thrombocytopenia of <20 x 103/L and
coagulopathy with INR>2.0) are generally not a contraindication to paracentesis
(relative contraindication)
 Other relative contraindications:
 Distended urinary bladder
 Abdominal wall cellulitis
 Distended bowel
 Intra-abdominal adhesions

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EQUIPEMENT
 Dressing pack and adhesive tap
 Abundant supply of gauze pads
 Iodine/cleaning solution
 Sterile gloves
 10ml Syringe and 50ml Syringe
 21 Gauge (green) cannula or Grey cannula
 Urine bag
TEECHNIQUE
 Expose the patient’s abdomen fully and percuss out
ascitic fluid. Demonstrate shifting dullness and a fluid
thrill. Percuss either right or left iliac fossa- this is where
the drain will be inserted. Mark the position with a pen
if necessary.
 Position the patient either sitting up in bed or lying in
the left lateral decubitus position.
 Identify the puncture site. Use either 2 cm below the
umbilicus (lower risk of bleeding) or McBurney’s point
in the left lower quadrant (to prevent cecal perforation).
Avoid the lateral border of the rectus abdominis muscle.
 Confirm by percussion that there is fluid at the puncture
site. Sterilize the puncture site.
 Using a sterile 22g needle (18g for therapeutic paracentesis) attached to a sterile
5-10ml syringe and sterile gloves, enter the skin at the puncture site while pulling
the skin 2cm caudal in relation to the deep tissue (Z-line tract approach). This
helps to reduce skin leakage after the procedure. Advance the needle slowly while
drawing back on the syringe. Stop advancing the needle when fluid is obtained.
 For diagnostic tap, remove 5-10ml of fluid in the syringe. For therapeutic tap,
remove the needle and attach the plastic cannula to IV tubing and a urine bag.
Drain 2-6L as necessary to remove the patient’s symptoms.
 Send 1ml for chemistry for albumin and total protein. Send blood for albumin at
the same time. Send 5ml to microbiology for gram stain, culture and AFB (if
indicated) if concerned for Spontaneous bacterial peritonitis, send 1ml to
hematology for cell count and differential. Consider sending fluid for cytology if
concerned for malignancy.

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COMPLICATIONS
 Hemorrhage
 Hypovolemia and Hypotension (if too much fluid withdrawn)
 Renal dysfunction (post-paracentesis circulatory dysfunction) as the ascites re-
accumulates at the expense of the circulating volume (this is likely with >5L
removal and worse liver function)
 This is overcome by infusing albumin (8g/L of ascitic fluid removed)
 In practice up to 20L can be removed over 4-6 hours with albumin infusion.
 Skin leak
 Bowel/Bladder perforation
EVALUATION OF ASCITIC FLUID
 This is done with Serum-Ascitic Albumin Globulin Ratio (SAAG).
 This helps distinguish transudates from exudates in relation to ascitic fluid.
 SAAG= Serum Albumin Concentration- Ascitic Albumin concentration
 The SAAG correlates directly with portal pressure.
 Transudative ascites occurs when a patient’s SAAG is greater than or equal to
1.1g/dl (suspect portal hypertension as the cause of ascites). Causes include:
 Hepatic cirrhosis
 Alcoholic hepatitis
 Fulminant hepatic failure
 Heart failure (right sided), Tricuspid regurgitation, Constrictive pericarditis
 Portal vein thrombosis, hepatic veno-occlusive disease, Budd Chiari
syndrome
 Schistosomiasis
 Exudative ascites occurs when patient’s SAAG is lower than 1.1g/dl. Causes
include:
 Peritonitis (TB peritonitis)
 Inflammation of pancreas (pancreatitis) or biliary system
 Ischemic or obstructed bowel
 Peritoneal carcinomatosis (peritoneal cancer).
 Nephrotic syndrome

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COMMONLY USED DRUGS

ANTICOAGULANTS
 Blood coagulates by transformation of soluble fibrinogen into insoluble fibrin.
 Circulating protein interact in a “cascade” where clotting factors undergo limited
proteolysis to become active serine proteases.
 Anticoagulants decrease the formation of fibrin clots
 Oral anticoagulants inhibit the hepatic synthesis of clotting factors II, VII, IX and
X in the liver
 The endogenous anticoagulants protein C and protein S cause proteolysis of
factors Va and VIIIa.

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 Heparin blocks the clotting factors of the intrinsic pathway as such PTT is used
to monitor the intrinsic cascade and it increases the PTT
 Warfarin works on the liver not the factors already synthesized. It blocks
synthesis of vitamin K dependent clotting factors
Feature Heparin Warfarin (Coumadins)
Chemical Large polysaccharide, water Small molecule lipid soluble
nature soluble derivatives of vitamin K
Kinetics  Given parenterally (IV, SC),  Given orally
 Hepatic and reticuloendothelial  98% protein bound
elimination  When given orally it is
 Half-life=2h (short) metabolized by the liver
 No placental access  Half-life- 30+ hours
 Placental access (can cause
teratogenicity and bleeding in
the infant)
Mechanism Heparin catalyzes the binding of Decreases hepatic synthesis of
antithrombin III (a serine protease vitamin K dependent clotting
inhibitor) to factors IIa, IXa, X, factors (II, VII, IX and X).
XIa and XIIa resulting in their Coumarins prevent gamma-
rapid inactivation carboxylation by inhibiting vitamin
Works in vivo and in vitro K epoxide reductase. It has no effect
on factors already present. In vivo
effects only
Monitoring Partial thromboplastin time (PTT) Prothrombin Time (PT), INR
(international normalization ratio=
𝑃𝑇 𝑜𝑑 𝑡ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡
) INR should be
𝑃𝑇 𝑜𝑓 𝑡ℎ𝑒 𝑐𝑜𝑛𝑡𝑟𝑜𝑙
around 1.5-2.5
Antagonist Protamine sulfate- chemical Vitamin K (displaces warfarin from
antagonism, fast onset epoxide reductase)- increases
cofactor synthesis, slow onset, fresh
frozen plasma (fast)
Uses  Rapid anticoagulation  Longer-term anticoagulation
(intensive) for thromboses (controlled) for thromboses
 Emboli  Emboli
 Unstable angina  Post-MI
 DIC  Heart valve damage
 Open heart surgery  Atrial arrhythmias etc.

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Toxicity  Bleeding  Bleeding
 Osteoporosis  Skin necrosis (if low protein C
 Heparin-induced deficiency)
thrombocytopenia  Drug interaction (high plasma
(hypersensitivity type II protein bound, other drugs that
response, heparin binds to are highly protein bound could
platelet factor 4 leading to potential displace warfarin and
opsonization and destruction cause bleeding e.g.
by the platelets). LMW heparin sulphonamides, sulfonylureas,
(Enoxaparin) are less likely to NSAIDs other drugs deal with
cause heparin induced absorption as a Vitamin K
thrombocytopenia analogue it requires to be
 Hypersensitivity emulsified by bile so
cholestyramine and cholestipole
reduce absorption as they
decrease bile)
 Teratogenic (bone
dysmorphogenesis)
 Warfarin is contraindicated in
pregnancy.

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TEST YOURSELF
TRUE/FALSE QUESTIONS
1. Causes of inappropriate ADH secretion include:
A. Meningitis
B. Head injury
C. Lobar pneumonia
D. Small cell bronchial carcinoma
E. Phenothiazine therapy

2. Acute confusion in the elderly is likely to be the result of

A. Adverse drug reaction
B. Hypothermia
C. Bronchopneumonia
D. Myocardial infarction
E. Cerebral infarction

3. Common etiologies of adult community acquired bacterial meningitis includes

the following except:
A. Norcardia pneumonia
B. Neisseria meningitidis
C. Streptococcus pneumonia
D. Listeria monocytogenes
E. Cryptococcal infection

4. Migraine headache is often characterized by the following except:

A. Being throbbing
B. Being unilateral
C. Associated with projectile vomiting
D. May be associated with visual disturbances

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5. The most common cause of meningitis is:
A. Viral
B. TB
C. Bacterial
D. Malignancy
E. Fungal

6. Generalized seizure types include:

A. Localized
B. Absence
C. Tonic-Clonic
D. Myoclonic
E. Atonic

7. Meningitis may present with the following clinical features:

A. Fever
B. Reduced alertness
C. Photophobia
D. Headache
E. Shortness of breath

8. The following might precipitate seizures

A. Fever
B. Flickering light
C. Alcohol
D. Sleep deprivation
E. Laughter

9. Paralysis of the fourth cranial nerve produces:

A. Weakness of the inferior oblique muscle
B. Pupillary dilation
C. Impaired downward gaze
D. Elevation and abduction of the eye
E. None of the above.

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10.With respect to lumbar puncture:
A. Coagulation is a contraindication
B. Papilledema is an absolute contraindication
C. Can be therapeutic by reducing intracranial pressure
D. The less CSF is removed; the less likely coning is to occur

11.About Parkinsonism
A. Mainly results from reduction of dopaminergic transmission within the basal
ganglia
B. Intentional tremor and akinesia help in diagnosis
C. Family history is a risk factor
D. Neuropsychiatry symptoms might be present

12.Outcome of bacterial meningitis relates to:

A. Age of the patient
B. Time of first administration of antibiotics
C. CSF concentration of antibiotics
D. Development of antibiotics resistance during therapy

13.A 70-year-old woman complains of sudden onset of weakness of left arm and
leg, she also experiences difficulties in speech and loss of vision in one eye.
Although these symptoms were frightening, they improved within 10 hours and
she was feeling well when she came to the clinic. What is the likely diagnosis?
A. Patient has a minor stroke
B. Patient has motor neuron disease
C. Patient has Parkinson’s disease
D. Patient has Transient ischemic attack

14.Aseptic meningitis may be due to

A. Viral infection
B. TB
C. Partly treated bacterial infection
D. Lyme disease

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15.In a patient presenting with seizures
A. A screen for toxins may be indicated
B. Blood sugar is indicated
C. CSF studies is mandatory in HIV infected (if no contraindication), even in the
absence of symptoms or signs suggesting infection
D. Brain scan might be indicated

16.Differential diagnosis of seizure includes

A. Migraine
B. Syncope
C. Transient ischemic attack
D. Sleep walking

17.In motor neuron disease

A. The pathological hallmark is death of lower and upper motor neurons
B. Dementia is a component of Amyotrophic lateral sclerosis
C. Ocular motility is a late sign in Amyotrophic lateral sclerosis (ALS)
D. No treatment arrests the underlying process in ALS

18.Regarding the central nervous system (CNS) in HIV infection

A. Cytomegalovirus is the most common viral infection
B. Highly active anti-retroviral therapy significantly improves the survival of
patients with progressive multifocal leukoencephalopathy
C. The target sign on CT is pathognomic for tuberculoma
D. Gummas are the most frequent features of neurosyphilis

19.The following are true of CNS involvement in AIDS

A. HIV encephalopathy (HIVE) is the most common cause of neurological
disease
B. Progressive multi-focal leukoencephalopathy is associated with Jacob
Creutzfeldt papova virus (JC virus)
C. CMV encephalitis is easily differentiated from HIVE by its imaging
characteristics
D. Lumbar puncture is contraindicated in evaluating patients with AIDS and
CNS involvement

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20.In the evaluation of a confused patient, following should be considered
A. Motor neuron disease
B. Drug intoxication
C. Cerebral malaria
D. Post-seizure event

21.The risk factor for bronchogenic cancer are:

A. HIV
B. Asbestos
C. Radon gas
D. Cigarette smoking

22.Paraneoplastic manifestations of bronchial carcinoma include:

A. Cerebellar degeneration
B. Skin rash and proximal myopathy
C. Eaton-Lambert syndrome
D. Bone pain

23.A 68-year-old pub landlord and lifelong smoker is admitted with lethargy and
drowsiness. Laboratory tests reveal results consistent with syndrome of
inappropriate anti-diuretic hormone secretion (SIADH) and a chest radiograph
demonstrates a 3cm right upper lobe mass. He is due to undergo a CT guided
biopsy of the mass. What is the histological subtype most likely to be?
A. Bronchoalveolar cell carcinoma
B. Squamous cell carcinoma
C. Pulmonary hamartoma
D. Small (oat) cell carcinoma

24.The following tumor markers can be used as surrogate for bronchial carcinoma:
A. CA 125
B. CA 19-9
C. Neuron specific Enolase
D. Placental Alkaline phosphatase

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25.The following are contraindications to surgical resection in bronchial carcinoma:
A. Distant metastases
B. Pleural effusion (non-malignant)
C. Bilateral mediastinal lymphadenopathy
D. Esophageal involvement

26.Pancoast’s syndrome
A. Results from local extension of a tumor growing in the base of the lung
B. May result in involvement of the 8th cervical and 1st and 2nd thoracic nerves
C. Often with destruction of 4th and 5th ribs
D. May result in shoulder pain that characteristically radiates in the ulna
distribution of the arm

27.The following primary tumors can metastasis to the lungs:

A. Melanoma
B. Salivary gland tumor
C. Soft tissue sarcoma
D. Testicular cancer

28.A 60-year-old with congestive cardiac failure due to hypertensive heart disease,
who is also epileptic and HIV patient on HAART complains of breast
enlargement. Which of the following medications he is currently taking would
cause gynecomastia?
A. Calcium channel blockers
B. Spironolactone
C. Efavirenz
D. Sodium valproate

29.Which of the following statement is true about secondary diabetes?

A. A patient can be assumed not to be ketosis-prone
B. A patient is more than 85% likely to have clinical pancreatic exocrine
deficiency
C. Classical diabetic complications do not occur
D. Thiazide diuretics and beta-blockers can both impair insulin secretion

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30.Which of the following statement is true about hypoglycemia?
A. About 50% of patients who have had type 1 DM for 20 years or more develop
‘hypoglycemia awareness’.
B. Sweating and shaking are always late symptoms of insulin-induced
hypoglycemia
C. Metformin is responsible for as many cases of hypoglycemia as sulfonylureas
D. The symptoms characteristically come on over hours rather than minutes.

31.Which of the following is true about diabetic retinopathy?

A. Characteristically causes arterial-venous nipping
B. Should be referred to an ophthalmologist only if the patient has visual
symptoms
C. Inevitably causes blindness
D. May cause soft and hard exudates

32.The following will increase secretion of insulin

A. Ketone bodies
B. Vagal nerve stimulation
C. Amino acids
D. Glucagon

33.The following will decrease secretion of insulin

A. Glucagon
B. Alpha-agonist
C. Cortisol
D. Thyroxine

34.Complication of insulin include

A. Lipoatrophy
B. Lipohypertrophy
C. Hyperglycemia
D. Gynecomastia

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35.A 30-year-old HIV patient, Pre-HAART, is admitted with weight loss, diarrhea,
night sweats and cough. On TB treatment for 4 weeks and recently treated for
oral thrush. His BP 80/60, RR 24. Which other clinical signs are suggestive of a
possible cause of her low BP?
A. Clearly audible heart sound
B. Hyperpigmented palm creases and gums
C. A pulse of 70/minute with full volume
D. Normal JVP

36.Features of renal failure may include:

A. Loss of libido
B. Hyperparathyroidism
C. Delirium
D. Platelet dysfunction

37.A 28-year-old female presents with hematuria, proteinuria 2+, increased BP and
mild pedal edema and creatinine 60mmol/L. The doctor suspects a glomerular
disease. A urine microscopy was ordered. Which result is highly suggestive of a
glomerular disease
A. RBC casts
B. Hyaline casts
C. Muddy brown casts
D. Epithelial casts

38.The most likely clinical syndromes in the patient in Question 37 above

A. Nephrotic syndrome
B. Nephritic syndrome
C. Rapid progressively
D. Chronic glomerulonephritis

39.What is the Gold standard for making a definitive diagnosis in the above patient
in Question 37?
A. No need for further evaluation as long as the clinical syndrome is known
B. Kidney ultrasound
C. Histological diagnosis
D. 24-hour urine protein and creatinine

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40.In the diagnosis of Acute Kidney injury (AKI), diagnosis is usually based on the
following parameters:
A. Baseline creatinine, latest creatinine and/or urine output
B. Baseline GFR and latest GFR
C. A patient with AKI on dialysis is in stage 2
D. Urine output alone is not sufficient to make a diagnosis of AKI

41. A marathon runner was found fitting after taking 2L of water after a 10Km
marathon on a hot sunny day. What is the likely cause of seizures?
A. Hypernatremia
B. Dilutional hyponatremia
C. Pseudohyponatremia
D. Diabetic ketoacidosis

42.What will be the management of the patient in question 41?

A. Normal saline
B. 3% saline
C. Darrow’s
D. Ringer’s lactate

43.Cerebral blood flow is increased by:

A. Hypercapnia
B. Hypoxia
C. Alkalosis
D. Hypothermia
E. Polycythemia

44.Recognized features of pseudobulbar palsy include:

A. Inappropriate laughter
B. Dysarthria
C. An absent jaw jerk
D. Dysphagia
E. Fluctuating level of consciousness

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45.Guillan-Barre’ syndrome
A. Has an acute onset
B. Is typically associated with normal CSF protein
C. Presents with periods of loss of consciousness
D. Is characterized by bilateral motor weakness
E. Has a recognized association with carcinoma of the lung

46.Myasthenia gravis is characterized by

A. Dysphagia
B. Ptosis
C. Aplastic anemia
D. HLA antigen DR3
E. Morning stiffness

47.In the elderly stroke is significantly associated with

A. High serum cholesterol
B. Obesity
C. Polycythemia rubra vera
D. Myocardial infarction
E. Atrial fibrillation

48.Infarction in the territory of the anterior cerebral artery

A. Causes more severe hand then shoulder weakness on the affected side
B. Produces predominant weakness of the lower limb
C. Is most frequently seen after SAH after berry aneurysm rupture
D. Causes transcortical motor aphasia when affecting the dominant hemisphere
E. Usually occurs as a result of cerebral embolism

49.Characteristics features of occlusion of the left middle cerebral artery include

A. Hemiplegia with involvement of the leg more than the arm
B. Paralysis of conjugate gaze towards the left
C. Deep xanthochromia of CSF
D. Diplopia
E. Dementia

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50.Cases of SIADH include
A. Chest infection
B. Head injury
C. Chlopropamide
D. Addison’s disease
E. Liver cirrhosis

51.Which of the following is true about SAH?

A. It is common among elderly women and very rare in the young
B. Over 90% of SAH are due to untreated hypertension
C. Neck stiffness is very rare unless patient has meningitis
D. The presence of hypotension with tachycardia indicates raised intracranial
pressure
E. Nifedipine treatment is very important in the management

52.Which of the following are true about seizures?

A. Imipenem may cause seizures and should not be used to treat meningitis
B. These may occur in poisoning due to tricyclic antidepressants, mefenamic
acid or opioids
C. In Tenia solium infection, focal seizures can occur if cysts are present in the
brain
D. Pre-eclampsia is marked by seizures or coma in addition to other signs
E. In CKD, mental slowing, clouding of consciousness and rarely seizures may
occur

53.Which of the following are true about stroke?

A. In Zambia, cerebral hemorrhage accounts for more than 30% of acute strokes
B. In supratentorial strokes with homonymous hemianopia, patient cannot see on
the hemiplegic side
C. Vertigo, vomiting, dysphagia and Horner’s syndrome indicate occlusion of
the vertebrobasilar circulation
D. Pinpoint pupils and bilateral upgoing plantars could signal a brainstem stroke
E. Carotid endarterectomy should be considered for patient with more than 70%
stenosis

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54.In a patient with AIDS, Cryptococcal meningitis is
A. The commonest cause of meningitis
B. Characterized by abrupt onset of the classical features of a bacterial meningitis
C. Diagnosed by India ink stain of cerebrospinal fluid
D. Typically associated with negative CSF culture

55.Cryptococcal meningitis
A. Is caused only by Cryptococcus neoformans neoformans
B. Is more common than Cryptococcal pneumonia
C. Characteristically causes leucopenia
D. Only occurs in the immunosuppressed
E. Should be treated with ketoconazole

56.Amphotericin B is used in the treatment of

A. Visceral leishmaniasis
B. Dermatophyte infections of the nails
C. Azole resistant oral candida
D. Primary amoebic meningoencephalitis caused by Naegleria species
E. Cryptococcal meningitis

57.Common cause of blackouts include:

A. Drugs
B. Valvular heart disease
C. Myocardial infarction
D. Hypoglycemia
E. Alcohol ingestion

58.HIV infection is associated with

A. An RNA retrovirus
B. Involvement of CD4 lymphocytes
C. Viral half-life of 1-2 hours in plasma
D. A better prognosis in the presence of Kaposi’s sarcoma

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59.In HIV infection
A. 80% of vertically transmitted infections are transplacental
B. A child born to an infected mother has a 90% chance of acquiring HIV
C. Transmission can occur via breast milk
D. Risk of fetal transmission is unaffected by pre-partum antiviral agents

60.In the diagnosis of HIV infection

A. ELISA testing has a low false negative rate
B. Seroconversion invariably occurs in under 4 weeks
C. Antibody detection tests are particularly helpful in neonates
D. HIV-RNA is typically detected before anti-HIV antibodies

61.In the classification of HIV infection

A. Stage 1= acute seroconversion simulating glandular fever
B. Stage 2= persistent generalized lymphadenopathy
C. Stage 3= have absolute CD4 count >500/mm3
D. Kaposi’s sarcoma is stage 3 disease

62.Presenting features of HIV infection include

A. Hairy leucoplakia
B. Atypical pneumonia
C. Thrombocytopenic purpura
D. Pulmonary tuberculosis

63.Cryptosporidiosis in an HIV positive patient is

A. An AIDS-defining diagnosis if chronic
B. Likely to present with painless profuse diarrhea
C. Likely to self-limiting if the CD4 count is > 200 cells/mm3
D. Preventable by the use of boiled tap water

64.Pneumocystis carinii infection in an HIV positive patient is

A. The commonest cause of respiratory infection in African patients
B. Characterized by copious sputum production
C. Characterized by widespread fine pulmonary crackles
D. Excluded by the finding of a normal chest X-ray

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65.The following have been reported with initiation of HAART;
A. Immune reconstitution syndrome
B. Osteonecrosis
C. Diabetes Mellitus
D. Lipodystrophy syndrome

66.Side effects of Nucleoside reverse transcription inhibitor include;

A. Cough
B. Fever
C. Insomnia
D. Liver damage

67.The following are true;

A. Maraviroc is an antagonist of protease
B. A Fusion inhibitor is helpful in the treatment of HIV
C. Raltegravir is an inhibitor of HIV integrase
D. Stavudine has very few side effect

68.On protease inhibitor;

A. Should be used with caution in Diabetic Mellitus patient
B. Should not be used in patient with acute porphyria
C. Should be used with caution in patient with chronic hepatitis B
D. Should not be used in AIDS stage

69. About peptic ulcer disease

A. Gastrinoma should be suspected if there are multiple duodenal ulcers
B. Alcohol abuse is a risk factor for gastric ulcer
C. Peptic ulcer disease may lead to acute pancreatitis
D. Helicobacter pylori infection and NSAIDs are the two most common causes
of peptic ulcer disease
E. Biopsy must be performed in all patients with duodenal ulcer

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70.Patients with HIV stage 4 WHO may have the following conditions
A. Pulmonary tuberculosis
B. HIV encephalopathy
C. Esophageal candidiasis
D. Abdominal TB
E. Severe anemia

71.Regarding tuberculosis pericardial effusion

A. Pericardiocentesis is mandatory
B. Low dose prednisolone given during the first 2 months of treatment
C. Culture of pericardial fluid is confirmatory
D. Treatment is given for 12 months
E. Constrictive pericarditis is not a known complication

72.Signs of hypokalemia on ECG include:

A. Flattening of T wave
B. Prolonged QT interval
C. Tall U waves
D. J wave
E. Shortening of PR interval

73.Causes of hyperkalemia include

A. Addison’s disease
B. Diabetic ketoacidosis
C. Rhabdomyolysis
D. Renal puncture
E. Alkalosis

74.The most effective drug in control of hypertension in an emergency is

A. Nifedipine
B. Hydralazine
C. Sodium nitroprusside
D. Lasix
E. Methyldopa

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75.Optic neuritis is complication of:
A. Rifampicin
B. Isoniazid
C. Ethambutol
D. Pyrazinamide
E. Streptomycin

76.In community acquired pnemonias:

A. The commonest pathogen is Mycoplasma pneumoniae
B. Erythromycin is the first-line antibiotic for psittacosis
C. The serum urea correlates with severity of illness
D. Ciprofloxacin can be used as a single agent when the organisms is not known
E. The pneumococcal antigen can be identified in urine

77.Misoprostol is
A. H2 receptor antagonist
B. Synthetic prostaglandin analogue
C. Proton pump inhibitor
D. NSAID
E. Antacid

78.Microcytic anemia is a typical finding in:

A. Folic acid deficiency
B. Hemolytic anemia
C. Alcohol abuse
D. Primary sideroblastic anemia
E. Iron deficiency

79.Non-infectious causes of diarrhea:

A. Inflammatory bowel disease
B. Histoplasmosis
C. Bechets disease
D. Clostridium perfringens
E. Pseudomembranous colitis

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80.Causes of chronic liver disease
A. Alcohol
B. Methyldopa
C. Hepatitis B virus
D. Methotrexate
E. Idiopathic

81.The following is true of viral hepatitis:

A. Hepatitis C commonly presents with jaundice
B. Hepatitis C is fatal particularly in pregnancy
C. Hepatitis BeAg is a marker of viral replication
D. Hepatitis A is a risk factor for hepatoma
E. Hepatitis D occurs only in association with hepatitis C

82.The following are common causes of meningitis

A. Neisseria meningitidis
B. Haemophilus influenza
C. Listeria monocytogenes
D. Staphylococcus aureus
E. Gram negative bacilli

83.In the treatment of HIV infection

A. All useful drugs work via inhibition of reverse transcriptase
B. Reverse transcriptase inhibitors prevent replication in infected cells
C. Reverse transcriptase inhibitors prevent spread of infectious virus into
uninfected cells
D. Drug resistant strains of virus have not been recognized
E. Monotherapy is preferred

84.Recognized features of severe heart failure include

A. Tiredness
B. Weight loss
C. Epigastric pain
D. Nocturia
E. Nocturnal cough

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85.The pain of Myocardial ischemia
A. Is typically induced by exercise and relieved by rest
B. Radiates to the neck and jaw but not to the teeth
C. Rarely lasts longer than 10 seconds
D. Is easily distinguished from esophageal pain
E. Can easily be distinguished from pain arising from acute pancreatitis

86.Jone’s major criteria for the diagnosis of rheumatic fever

A. Migratory polyarthritis
B. Pancarditis
C. Chorea
D. Fever
E. Subcutaneous nodules

87.Adverse effects of corticosteroid therapy include:

A. Peptic ulceration
B. Hypertension
C. Avascular bone necrosis
D. Pseudogout
E. Insomnia

88.The typical features of type B viral hepatitis include:

A. Incubation period of 1 month
B. History of exposure to unsafe sex or drug abuse
C. Prodromal illness with polyarthralgia
D. Hepatic illness more severe than type A
E. Absence of progression to chronic hepatitis

89.Typical features of advanced hepatic cirrhosis include

A. Progressive hepatomegaly
B. Massive splenomegaly
C. Peripheral blood macrocytosis
D. Parotid gland enlargement
E. Central cyanosis

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90.Hepatic encephalopathy in cirrhosis is typically precipitated by:
A. Infection
B. Hypokalemia
C. Abdominal surgery
D. Gastrointestinal bleeding
E. Lactulose therapy

91.Hemoptysis is a clinical feature of

A. Carcinoma of lung
B. Bronchiectasis
C. Pulmonary tuberculosis
D. Primary pulmonary hypertension
E. Pulmonary embolism

92.A pleural effusion with a protein content 50g/L would be compatible with:
A. Congestive cardiac failure
B. Pulmonary infarction
C. Subphrenic abscess
D. Pneumonia
E. Nephrotic syndrome

93.Recognized causes of pyrexia of unknown origin (PUO)

A. Infective endocarditis
B. Renal cell carcinoma
C. Systemic lupus erythematosus
D. Tuberculosis
E. Drug fevers

94.The following would help distinguish between a kidney and a spleen in the left
upper quadrant
A. Dull percussion note over the mass
B. A well localized notched lower margin
C. Moves with respiration
D. A ballotable mass
E. A family history of renal failure

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95.The following are classified as high output states:
A. Hypertension
B. Sepsis
C. Hypothyroidism
D. Pregnancy
E. Arterial venous malformation

96.Clinical features of raised intracranial pressure:

A. Tachycardia and hypotension
B. Dizziness and lightheadedness
C. Headache aggravated by bending and straining
D. Behavioral and personality changes
E. Sixth or third nerve palsies

97.Recurrent headache could be due to

A. Migraine
B. Cluster
C. Glaucoma
D. Analgesia overdose
E. Tension headache

98.The definition of epilepsy includes being

A. Spontaneous
B. Intermittent
C. Having abnormal electrical discharge in some part of the brain
D. Diagnosis is predominantly clinical
E. A known epileptic and independent observer’s description being suggestive
of epilepsy

99.Migraine headache is often characterized by following except:

A. Being throbbing
B. Being unilateral
C. Associated with projectile vomiting
D. Associated with nervous tension
E. May be associated with visual disturbances

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100. CSF protein level is normal in the following types of meningitis?
A. Viral
B. TB
C. Bacterial
D. Malignant
E. Septicemia

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THIRD YEAR ESSAY QUESTIONS

1. HIV is a very common condition observed in the medical wards at Levy
Mwanawasa General hospital. Please answer the following questions:
a. What do you understand by immune reconstitution syndrome? (5 marks)
b. What are the central nervous system complications of HIV? (5 marks)
c. What are the renal complications of HIV? (5 marks)
d. What are the parameters of monitoring treatment? (5 marks)

2. 34-year-old male businessman present to you with a history of productive cough,

evening chills, night sweats, loss of appetite and loss of weight of the past 3 months.
He is newly diagnosed RVD with CD4 count of 3 cells/ml. His chest X-ray shows
a miliary picture and the safe lab markers are normal.
a. Which other investigations are you going to order- list 3 (3 marks)
b. List 5 differentials for the chest X-ray picture (5 marks)
c. If the diagnosis is Miliary TB, outline the management plan in the above patient
(4 marks)
d. List the common side effects of the antituberculosis- 2 for each (8 marks)

3. In relation to endocrine disorders, please answer the following:

a. Describe pathophysiology of Diabetic ketoacidosis (5 marks)
b. What are the causes of Addison’s disease (5 marks)?
c. What are the metabolic abnormalities with primary adrenal insufficiency? (5
marks)
d. What is a thyroid storm? (5 marks)

4. A 20-year-old female patient presented to emergency unit at Levy Mwanawasa

General Hospital with a history of progressive exercise intolerance. She has to use
extra pillows in order to get some peaceful sleep but she still wakes up often in the
middle of the night in gasps for breath. Professor Njelesani asks you to demonstrate
a cardiovascular exam and you on auscultation find a left parasternal diastolic
murmur loudest in expiration. Her BP is 110/50. You also find bibasal end-
inspiratory fine crackles and sacral edema.
a. What is your full diagnosis? (5 marks)
b. What other ‘special signs’ will you look out for? Name and describe 5 of them
(10 marks)

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c. What do you expect to see on her chest radiograph? (3 marks)
d. Give one differential for ‘bibasal end-inspiratory crackles’ (2 marks)

5. In relation to liver cirrhosis:

a. Please describe Child-purg score in relation to liver cirrhosis? (5 marks)
b. What are the poor prognostic indicators for liver cirrhosis? (5 marks)
c. What are the complications related to liver cirrhosis? (5 marks)
d. What is the pathophysiology of ascites related to liver cirrhosis? (5 marks)

6. In relation to hemato-oncology
a. What are the clinical features of iron-deficiency anemia? How do you make a
diagnosis? (5 marks)
b. Write short notes on the types of crises related to sickle cell disease? (5 marks)
c. What are the complications of multiple myeloma? (5 marks)
d. What are the complications of acute leukemias? (5 marks)

7. A young man is brought into the emergency department with history of vomiting,
increased urination and diarrhea of sudden onset after 30 minutes of spraying farm
products with unknown insecticides. On examination, he is semi-conscious,
frosting from the mouth, miosis and bradycardic with soiled clothing.
a. What is the most likely diagnosis? (2 marks)
b. What other signs might he present with? List 4 (4 marks)
c. Outline the pathophysiology of the above (4 marks)
d. What samples would you take to confirm diagnosis (4 marks)
e. Outline principle of management of the above young man (6 marks)

8. A 23-year-old African lady presents to a medical clinic with fatigue, weight loss,
anorexia, a photosensitive malar rash, oral ulcers, intermittent polyarthritis and
urinalysis reveals proteinuria. Anti-double stranded DNA is strongly positive.
a. What is the working diagnosis? (6 marks)
b. Briefly describe the immunopathology in this condition (8 marks)
c. Briefly describe hematological disorders in this conditions- List at least 3 (3
marks)
d. Describe briefly the CNS manifestation- at least 3 (3 marks)

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9. A 44-year-old coal miner presented with a 3-month history of polyuria and dyspnea
on exertion. He had developed a frontal headache the past 6 weeks and was
sweating profusely. He had recently noticed tingling in his hand which was worse
at night. On systemic enquire he admitted to loss of libido and impotence for 6
years. On examination he has coarse face, macrognathia, ‘spade’ hand and feet
with thick skin. Heart rate is 100/min regular with a BP of 200/100. Neurological
examination was grossly normal except for bi-temporal hemianopia and reduced
sensation to pin-prick over the thumb, index and ring fingers.
a. What is the diagnosis? (4 marks)
b. Give 2 possible causes of polyuria (4 marks)
c. What is cause of bi-temporal hemianopia (2 marks)
d. What is the cause of reduced sensation to pin-prick over the thumb, index and
ring fingers (4 marks)?
e. What single test would you use to confirm diagnosis (4 marks)
f. Give another test that will help in locating the cause of bi-temporal hemianopia?
(2 marks)

10. Write short notes on the following

a. Features of Nephrotic syndrome (5 marks)
b. Major differences between Nephrotic and Nephritic syndrome (5 marks)
c. Complication related to chronic renal failure (5 marks)
d. Hepatorenal syndrome (5 marks)

11.In relation to heart failure, please write short notes on the following include
definition, pathophysiology and clinical significance
a. Pulsus paradoxus
b. Systolic dysfunction
c. Paroxysmal nocturnal dyspnea
d. ‘A’ waves in relation to raised JVP
e. Please classify ‘3 types of Angina’ with symptoms

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FIFTH YEAR ESSAY QUESTIONS

1. You have been asked to evaluate a patient in the Department of Obstetrics and
gynecology. The consultation reads: “very urgent, come and manage our
patient with suspected acute renal failure”.

You find that she is 26 years old. She had given birth 10hours earlier by
spontaneous vaginal delivery to a mildly asphyxiated baby. She has not passed
urine since delivery. The Antenatal card shows she had no medical or
gynecological problems. Urinalysis was done twice during antenatal and was
reported normal. The midwife tells you that the labor was “very hectic” and
patient was difficult during delivery and hence “bled a lot”

Examination:
Drowsy, pulse 142/min, Blood pressure 85/55 mmHg, respiratory rate 29/min.
CVS-tachycardia, no murmurs, no gallop, RS- clear lung fields, GIT- normal.
There is no active bleeding per vagina and uterus is well contracted

Urinalysis
pH= 5.5
Specific gravity >1.030
Amino acids= trace
Glucose= trace
Casts=present
Hemoglobin, RBC, Albumin, White blood cells, nitrites= all negative

Glucometer random blood sugar= 6, Urea=26

Urgent bedside ultrasound shows normal kidneys

(a) What assessment needs to be done on this patient?

(b) Analyse the findings
(c) Plan your full management

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2. A male patient 45 years old was admitted yesterday to ICU with severe chest
pain. He is a known diabetic and hypertensive patient for more than 10 years.
Diagnosis of admitting doctor was Unstable angina. Doctor on call was
informed that patient suddenly changed his condition after a short episode of
breathlessness (though in the morning he appeared to be stable, pain free and
not on ventilation). The nurse reported the absence of pulse and unrecordable
BP.
On the monitor attached to the patient the fine oscillations seen.

(a) What condition is this?

(b) What is your immediate action?
(c) If the monitor still shows oscillations and pulse is absent on the carotid
arteries what do you do next?
(d) What is the possible diagnosis?
(e) How would you manage in post-resuscitation period?

3. A 20-year-old male patient presents to admission ward after being found

unconscious at home. The friend accompanying him says that he is a known
diabetic on “injections” that are kept in the fridge and that he has been unwell the
past 4 days with a febrile illness and is not sure whether he was getting his
injections or not.
Examinations: unconscious (GCS 8/14), moderately wasted, no generalized
lymphadenopathy, dehydrated, febrile and has Kaussmaul’s respiration.
You are the attending officer in Phase 5
Please, fully manage him (all the facilities are there i.e. labs etc.)
Answer in Bullet form…

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4. Daniel comes to the admission ward with complaints of weakness, nausea,
fatigability and poor appetite. He is a known HIV positive patient on HAART
(AZT,3TC and NVP) for over 2 years. His last CD4 was 200 cell/ml (at baseline
was 55 cells/ml). He was recently diagnosed to have sputum positive PTB at the
local clinic and started on anti-tuberculosis treatment.
(a) List two problems Daniel has and justify your answers (2 marks)
(b) List and justify investigations you would order (9 marks)
(c) Outline your management plan (9 marks)

5. A 22-year female lady (known cardiac patient) come in with history of weakness,
fever, malaise, sweating and painful sores on hands.
(a) List differential diagnosis? (4 marks)
(b) Write down the “Dukes criteria” (4 marks)
(c) What other signs would you look for and give the pathogenesis of the signs (6
marks)
(d) How would you manage this patient (6 marks)?

6. A 35-year-old Zambian man complains of easy fatigability of long-standing

duration. The following are his blood results.
WBC 5.3 x 109/L
RBC 1.2 x 1012/L
Hb 4g/dl
Platelets 20 x 109
Blood glucose 6 mmol/L
Sodium 137 mmol/L
Potassium 6.2mmol/L
Creatinine 1200 mol/L

(a) Comment on the results and their significance? (4 marks)

(b) What is your diagnosis? (4 marks)
(c) What will be the other clinical features of the patient with such results (6
marks)
(d) How would you confirm the definitive diagnosis (i.e. investigations and
justify)? (11 marks)

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7. Mr. Mabvuto Sakala is a 76-year-old male that arrives in AMEU at Levy
Mwanawasa General Hospital in an ambulance. As an intern doctor on duty he is
brought in your consultation room. He complains of shortness of breath for a
week which seem to have gotten worse today. He complains of also a persistent
dry cough especially at night.

He is known to be Diabetic and hypertensive on Losartan 50mg, Amlodipine

10mg and insulin therapy. He has no known drug allergies.
On assessment- Vitals BP: 218/110mmHg, RR-36b/min, Temp- 37.7, O2 Sat 95%
(Room oxygen), dusky nail beds, skin cool and moist with ankle edema. JVP is
10cm, Apex beat in the 6th intercostal space anterior axillary line with a
tachycardia and occasional ectopics. Rales noted right middle lobe and lower
lobes bilaterally.

The following are investigations done on the patient:

Sodium 135
Potassium 3.9
Hb 12.5
Creatinine 220 mol/L
CXR- bilateral pulmonary congestion with enlarged cardiac shadow
12 lead EKG: sinus tachycardia with occasional PVCS, Old anterior MI

(a) From the patient’s chief complain and your initial assessment, what is the
patient’s primary problem? (4 marks)
(b) Describe the pathophysiology of CHF (congestive heart failure) (6 marks)
(c) What are the signs and symptoms of heart failure in this patient? (2 marks)
(d) What factors contribute to the patient’s heart failure? (4 marks)
(e) What pharmacologic agents are used to improve performance in patients with
CHF? (4 marks)

8. A 65-year-old man present with a 6-week history of cough, progressive shortness

of breath and 10kg weight loss. He has 50-pack year smoking history and his
family doctor orders a chest X-ray and blood work.

The CXR shows a left lower lobe mass. His physical is normal. He is otherwise
healthy and takes no regular medication

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(a) List 4 differentials for above patient (8 marks)
(b) How would you further investigate this man in order to get a pathologist
diagnosis- List 5 (5 marks)
(c) If it is Bronchogenic carcinoma, what addition tests are required to properly
stage this patient- List 7 (7 marks)

9. Mrs. Banda is a 27-year-old woman (unemployed) who was referred from VCT
center after testing HIV positive 3 weeks ago. Her husband recently died from
Cryptococcal meningoencephalitis during his hospitalization he tested positive
for HIV causing her to pursue testing.

Her medical history has been unremarkable except being diagnosed with
extrapulmonary TB 4 months ago. She declined HIV test at the time of TB
diagnosis.

She is allergic to trimethoprim/Sulfamethoxazole which causes a diffuse

erythematous rash. Her physical examination is notable for a thin, well developed
woman with no acute distress. Her ENT exam reveals Candida on the tongue and
buccal mucosa. Heart, Lung and Abdomen examinations are normal.

Her Laboratory test

Hb- 11.7mg/dl
Platelets 167 000
HIV positive
CD4 4 410/L

(a) For this patient, what evidence (history, physical examination, and/or
laboratory data), support beginning antiretroviral therapy (ART) (4 marks)
(b) Do you identify any barriers to ARV adherence? List 3. What would you
recommend to address these barriers? (6 marks)
(c) What antiretroviral medication would initiate? (4 marks)
(d) What toxicities could be associated with the anti-retroviral therapy you chose?
2 for each (6 marks)

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10.Mr. Saili is a 74-year-old man who presents to your consultation room with his
wife complaining of shortness of breath and fever. His wife did bring records
from his last physician that he has Chronic Obstructive Pulmonary Disease
(COPD). After evaluation you make a diagnosis of acute exacerbation in COPD.
(a) What is the mechanism of airflow limitation in COPD? (4 marks)
(b) What is the role of inflammatory mechanisms in COPD? (4 marks)
(c) What are the organisms commonly associated with exacerbation of COPD?
(4 marks)
(d) What investigation would you order? (4 marks)
(e) How would you treat an acute exacerbation? (4 marks)

11.A 20-year-old young lady comes to the hospital complaining of fevers and oral
ulcers for a week. She reports having had fevers in the recent past. She says she
has no urinary symptoms. She feels tired and has no cardiac symptoms. She also
has noticed her hair is thinning out. The registrar suspects she has a connective
tissue disease.
(a) What else would you want to probe for in the history? (5 marks)
The patient is noted to have rash on her face that looks like a butterfly pattern and
she also has joint tenderness in the hands. Your registrar further suggests that this
could be Systemic Lupus Erythematosus (SLE).
(b) List the manifestations used in the criteria to make a diagnosis of SLE. (5
marks)
(c) What drugs can you use in a patient with SLE? (4 marks)

12.A 40-year-old HIV negative male patient presents to AMEU with four days of
Jaundice, upper abdominal pain, nausea, vomiting and headache. He is a patient
on sputum positive PTB on treatment for 6 weeks. He is currently on Rifampicin,
Isoniazid, Ethambutol and Pyrazinamide. The patient has no other pertinent past
medical history and uses no other medications.

On physical examination, he is alert and oriented with the following vital signs:
Blood pressure 113/62mmHg, heart rate 88b/min, respiratory rate 14
breaths/min, pulse oximetry 100% on room air, temperature 37.1 degree Celsius.

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His skin is jaundiced but without ecchymoses or petechiae. Eye examination
reveals scleral icterus.

Cardiovascular and pulmonary findings are unremarkable. His abdomen is soft,

but diffusely tender to palpation without and organomegaly, rebound, guarding
or rigidity.

Initial pertinent laboratory results include: AST> 2600 IU/L, ALT>2600 IU/L,
total bilirubin >20mg/dl, INR 3.7.
(a) What is the primary problem with this patient? (2 marks)
(b) How would you investigate this patient? List 4 important investigations (4
marks)
(c) How does Isoniazid (INH) cause hepatotoxicity? (6 marks)
(d) How would you manage this patient if it was purely due to INH? (8 marks)

13.Write short notes on:

(a) Diagnosis of Myocardial infarction (5 marks)
(b) Mechanism of diarrhea in Cholera (5 marks)
(c) Symptoms, signs and diagnosis of Organophosphate poisoning (5 marks)
(d) Treatment of organophosphate poisoning (5 marks)

14.The patient is a 41-year-old male who has a longstanding history of hypertension

and diabetes and presents with a complaint of pruritus, lethargy, lower extremity
edema, nausea and emesis. He denies any other medical illnesses.
On physical examination the patient is well-developed, well-nourished male in
moderate distress. Blood pressure 180/110, pulse 80, respirations 24 and he was
afebrile. Body weight 76.5kg. ENT exam was remarkable for fundoscopic
findings of AV nicking and copper wire changes consistent with hypertensive
injury. Cardiac exam had an S1, S2 and S4. The remainder of the exam was
remarkable for 2+ lower extremity edema and superficial excoriations of his skin
scratching.

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Laboratory data
Chemistry Normal Values Urinalysis
Sodium 133 136-146 mmol/L pH 6.0
Potassium 6.2 3.5-5.3 mmol/L Specific gravity
1.010
Chloride 100 98-108 mmol/L
Protein 1+
Total CO2 15 23-27 mmol/L Glucose negative
BUN 170 7-22 mg/dl Acetone negative
Creatinine 16.0 0.7-1.5 mg/dl Occult blood
negative
Glucose 108 70-110 mg/dl
Bile negative
Calcium 7.2 8.9-10.3 mg/dl Waxy casts
Phosphorus 10.5 2.6-6.4 mg/dl
Alkaline
306 30-110 IU/L
Phosphatase
Parathyroid
895 10-65 pg/ml
Hormone
Hemoglobin 8.6 14-17 gm/dl
Hematocrit 27.4 40-54 %

Mean cell volume 88 85-95 FL

24-hour urine protein and creatinine- volume 850ml, protein 600mg/dl and
creatinine 180 mg/dl.
Renal ultrasound- Right Kidney 9 x 6.0 cm, Left Kidney 9.2 x 5.8cm
Both kidneys illustrate hyperechogenicity and no hydronephrosis
(a) “Presents with a complaint of pruritus, Lethargy, lower extremity edema,
nausea and emesis.” What do these symptoms suggest to you? (2 marks)
(b) What are the fundus changes in a hypertensive? (4 marks)
(c) What are the fundus changes of a diabetic? (4 marks)
(d) What does S4 signify? What cardiac findings will you expect to find in a
hypertensive? (6 marks)

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(e) What is the significance of the finding “superficial excoriations of his skin
from scratching”? (2 marks)
(f) Why was a renal ultrasound ordered? (2 marks)

15.A 58-year-old woman comes to a physician’s office complaining of feeling

lightheaded for past week. She says she can feel her heart racing in her chest. She
mentions she has been staying up late for the past few weeks because of her
workload at work. The medical history reveals well controlled diabetes mellitus.

Physical examination reveals an anxious woman with pallor and mild

diaphoresis. Cardiac examination reveals an irregularly irregular beat. Vital signs
are as follows: Temperature: 36.1oC, Respiratory rate 22b/min, Heart rate 142
bpm, BP 118/55mmHg and Glucose 7.7 mmol/L

(a) What is the most likely diagnosis?

(b) What clinical and ECG abnormalities are most commonly associated with this
condition?
(c) What is the most appropriate treatment for this condition?
(d) How do Heparin and Warfarin work together to treat this condition?
(e) Why does paradoxical reaction sometimes occur after starting warfarin
therapy?

16.A 38-year-old male present to AFC with profuse diarrhea, low grade fever,
cough, shortness of breath for 3 days. On examination, BP: 85/40mmHg, HR:
110bpm, Temp 38.9oC, RR: 32/min. CXR: bilateral infiltrates
Part A

Labs: sodium= 140 mmol/L, chloride=110 mmol/L, bicarbonate= 12, pH= 7.30,
PCO2= 20
(a) What is the pH?
(b) What is the primary disorder?
(c) Is there any compensation>
(d) What is the anionic gap and what is the complete diagnosis?

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Part B
A 24-year-old female present with right flank pain and hematuria for 2 days’
duration
Lab results: Sodium= 138, Chloride= 115, bicarbonate= 12, pH=7.35,
Potassium=3.0
(a) What is the pH?
(b) What is the primary disorder?
(c) Is there any compensation?
(d) What is the anionic gap and what is the complete final diagnosis?

17.A 35 year-old previously health man presents with dyspnea, fevers, chills, and
night sweats for the past 2 months. He is a non-smoker with no concerning habits
or occupational exposures. His pulmonary function tests are as follows:

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(a) Describe the pattern of the abnormality, if one is present

(b) Grade the severity of the abnormality
(c) Generate a differential diagnosis for the observed abnormality
(d) Outline management of Acute severe asthma

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18.A 55-year old male presents with weakness in his legs and shortness of breath.
Sodium 142mmol/L, Potassium 2.5 mmol/L, urea 8 mmol/L, Glucose
9.6mmol/L, bicarbonate 35mmol/L
(a) What is the likely unifying diagnosis?
(b) What cause is suggested by the data?
(c) What 3 further investigations would you request?
(d) Name 5 reasons why this person may have limb weakness

19.A 28-year-old man comes to your office complaining of a 5-day history of

nausea, vomiting, diffuse abdominal pain, fever to 101oF and muscle aches. He
has lost his appetite, but he is able to tolerate liquids and has no diarrhea. He has
not significant medical history of family history and he has not travelled outside
the Lusaka. He admits to having 12 different lifetime sexual partners, denies
illicit drug use, and he drinks alcohol occasionally but not since this illness began.
He takes no medications routinely, but he has been taking acetaminophen,
approximately 30 tablets per day for 2 days for fever and body aches since this
illness began.

On Examination his temperature 38.9oC, heart rate 98 bpm and blood pressure
120/74 mmHg. He appears jaundiced, his chest is clear to auscultation and his
heart rhythm is regular without murmurs. His liver percusses 12cm and is smooth
and slightly tender to palpation. He has no abdominal distention or peripheral
edema.
Laboratory values are significant for a normal full blood count, creatinine
92mol/L, Alanine aminotransferase (ALT) 3440 IU/L, aspartate
aminotransferase (AST) 2705 IU/L, total bilirubin 24.5mg/dl, direct bilirubin
18.2mg/dl, alkaline phosphatase 349IU/L, serum albumin 3.0g/dl and
prothrombin time 14 seconds.

(a) What is the most likely diagnosis?

(b) What is the most important immediate diagnostic test?
In short notes interpret (in terms of progression and infectivity) the hepatitis B
profile tests seen below.

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20.A 28-year-old man comes to the emergency room complaining of 2 days of
abdominal pain and diarrhea. He describes his stools as frequent, with 10 to12
per day, small volume, sometimes with visible blood and mucus and preceded by
a sudden urge to defecate. The abdominal pain is crampy, diffuse and moderately
severe and it is not relieved with defecation.
In the past 6 to 8 months he has experienced similar episodes of abdominal pain
and loose mucoid stools but the episodes were milder and resolved within 24 to
48 hours. He has no other medical history and takes no medication. He has neither
traveled out of Zambia nor had contact with anyone with similar symptoms. He
works as an accountant and dose not smoke or drink alcohol. No member of his
family has gastrointestinal problems.

On Examination his temperature is 38oC, heart rate 98bpm, and blood pressure
118/74mmHg. He appears uncomfortable, is diaphoretic and is lying still on the
stretcher. His sclerae are anicteric and his oral mucosa is pink and clear without
ulceration. His chest is clear and his heart rhythm is regular, without murmurs.
His abdomen is soft and mildly distended, with hypoactive bowel sounds and
minimal diffuse tenderness but go guarding or rebound tenderness.
Laboratory studies are significant for a white blood cell (WBC) of 15, 800/mm3
with 82% polymorphonuclear leukocytes, hemoglobin 10.3g/dl, and platelet
count 754, 000/mm3. The HIV assay is negative. Renal function and liver
function tests are normal. A plain film radiograph of the abdomen shows a mildly
dilated air-filled colon with a 4.5cm diameter and no pneumoperitoneum or
air/fluid levels.

(a) What is the most likely diagnosis?

(b) What is your next step?
(c) How do you distinguish Amoebic dysentery from Shigella dysentery (please
answer in table form)?

21.A 30-year-old male patient was admitted to the emergency Room with history of
severe epigastric pain. His past medical history is unremarkable. He reports to
have been fine, in fact he was from having a copious meal with some wine with
his friends. You examined him and found a normal temperature but low blood
pressure of 86/55mmHg. He is conscious but in severe pain.
(a) Discuss the differential diagnosis?

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(b) What investigations would you do to confirm it?
(c) How would you classify this condition?
(d) Discuss the pathophysiology and common causes?
(e) Outline your management plan for this patient. Please fully manage him if all
the facilities were available.

22.A 35-year-old female teacher presents with 2 weeks’ complaint of general

fatigue. She had previously been well, her past medical history is unremarkable
and thought that it was work related fatigue. When it persisted, she came to see
you in the OPD.

You examined her and note that she is stable, not pale nor jaundiced but has
generalized lymphadenopathy and splenomegaly. The rest of examination is
unremarkable.

You obtain the following lab results:

WBC 98 x109/L with 90% lymphocytes
Monocyte 1%
Eosinophils 2%
RBC 4.28 x 1012/L
Hb 14.7
Platelet 240 x 109/L

(a) What is the possible diagnosis for this patient?

(b) What additional investigations are you going to order to confirm your
diagnosis?
(c) List 3 differentials
(d) Outline your management plan

23.A 27-year-old female with SLE is in remission. Last year she had a life-
threatening exacerbation of her disease. She is currently well controlled and her
treatment consists of azathioprine 75mg/d and prednisolone 5mg/d. She comes
for review and now strongly desires to become pregnant.
(a) Discuss the clinical manifestations of SLE
(b) Discuss the pathogenesis of SLE

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(c) What investigations do you do in SLE and discuss relevance?
(d) What advice would you give her on her desire to conceive?

24.A 20-year old male presents with a 3-day history of lethargy and generalized
malaise. He is confused and looks very unwell. His past medical history is
unremarkable and he is HIV negative. On examination, you found a rapid feeble
pulse with hypotension and cold extremities. He is tachypnoeic with clear lungs.
Abdominal examination is normal.

The following blood tests are obtained:

Blood gasses:
PH: 7.0
Bicarbonate 11mmol/L (22-30)
PCO2 20mmHg (35-45)

Electrolytes:
Potassium 2.7
Sodium 153
Chloride 124

Creatinine 70mol/L
Urea: 5.2 mmol/L
Glucose 52mmol/L

(a) What further history would you like to get from the bedside?
(b) Describe the acid-base balance
(c) What is the diagnosis?
(d) What electrolyte abnormalities does the patient have?
(e) What further tests would you order in this patient?
(f) How are you going to manage this patient?

25.A 25-year-old patient was admitted to the Emergency Room with easy
fatigability. His past medical history is remarkable for tooth extraction two weeks
ago. He also reports history of fever on and off. On examination his temperature
is 37.8oC and BP 120/80mmHg. He is pale with tinge of jaundice. His chest is

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clear and he has pansystolic murmur at the apex. Abdominal examination reveals
splenomegaly. Urinalysis shows red blood cells in urine.
(a) What is your working diagnosis?
(b) What investigations would you do to confirm it?
(c) What criteria is used to diagnose this condition?
(d) Outline your management plan for this patient. Please fully manage him if all
the facilities are available.

26.A 54-year-old man presents to his primary care provider with dyspnea and a
cough. He is a non-smoker with no relevant occupational exposures.

Lung function test results are as follows:

Pre-Bronchodilator (BD) Post-BD
Bronchodilator
Test Actual Predicted % Predicted Actual % change
FVC (L) 3.19 4.22 76 4.00 25
FEV1 (L) 2.18 3.39 64 2.83 30
FEV1/FVC (%) 68 80 71 4
(a) Describe the pattern of abnormality, if one is present
(a) Grade the severity of the abnormality
(b) What would be the management of this patient?

27.A 52-year-old woman with heart disease presents with shortness of breath, easy
fatigability and swollen feet. She has longstanding hypertension and takes
medicine when she feels unwell. She has been taking 2 bottles of wine on
weekends for the past 6 years but denies history of smoking. She feels her
condition is getting worse and can’t now climb stairs at her place. On examination
you noticed that her heart rate is 70 beats per minute irregular and her blood
pressure is 100/60mmHg. Her JVP is raised, her chest is clear but she has tender
hepatomegaly and pitting pedal edema. The doctor makes a diagnosis of heart
failure.

(a) List the common causes of heart failure in our settings

(b) What is the pathophysiology of heart failure?
(c) What two investigations would you do to confirm this diagnosis?

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(d) Which therapeutic modalities have been shown to improve survival in heart
failure?

28. A 23-year-old male patient is brought to the emergency room with history of
malaise and headache. Apart from history of palpitations and constipation, his
past medical history was apparently unremarkable. His blood pressure on
admission was 210/124mmHg. He had hyperpigmented lesions on the trunk. The
mini-mental test score was 8/10. Both heart sounds were normal and chest was
clear. He had tender liver and pitting edema of lower extremities. Fundal
examination revealed grade III retinopathy. Urinalysis shows protein +++ and
glucose trace. You obtain the following lab results: Hb 9g/dl, platelets 120 x
109/L, Urea 28 mmol/L, Sodium 138 mmol/L, potassium 7.4 mmol/L

(a) Discuss this patients’ clinical presentation and lab results

(b) What is the diagnosis?
(c) What further investigations would you order?
(d) Outline your management plan

29.Chanda a 24-year-old man is admitted complaining of headaches and confusion.

His headache had developed over the past 3 weeks and has become progressively
more severe. The headaches are now persistent and diffuse. He has lost 10Kg in
weight over 6 months and has recently become increasingly more confused. His
speech is slurred. While in AMEU he has a generalized tonic-clonic convulsion.

Examination reveals that he is wasted and weighs 55kg. His temperature is

38.5oC and has oral candidiasis but has no lymphadenopathy. Prior to the fit
neurological exam showed him to be disoriented in time place and person with
no focal neurological signs. Fundoscopy shows papilledema. The rest of the exam
is normal. You order an HIV test and comes out positive for HIV-1.

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(a) What would be the cause of this man’s headaches, confusion and fits? (name
3)
(b) What is his HIV WHO clinical stage?
(c) Why is his sodium low and why is he having papilledema?
(d) What further test should you order
A CT was done and the following Image was obtained

(e) What is the most likely diagnosis?

(f) How would you treat this man and include the dosing?

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THIS PAGE WAS INTENTIONALLY

LEFT BLANK

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ANSWERS TO TEST YOURSELF

TRUE/FALSE QUESTIONS
1. Causes of inappropriate ADH secretion include:
A. Meningitis-True
B. Head Injury-True
C. Lobar Pneumonia-True
D. Small cell bronchial Carcinoma-True
E. Phenothiazine Therapy-True

2. Acute confusion in the elderly is likely to be the result of

A. Adverse drug reaction-True
B. Hypothermia-True
C. Bronchopneumonia-True
D. Myocardial infarction-True
E. Cerebral infarction-True

3. Common etiologies of adult community acquired bacterial meningitis includes

the following except:
A. Norcardia pneumonia-True
B. Neisseria meningitidis-False
C. Streptococcus pneumonia-False
D. Listeria monocytogenes-True
E. Cryptococcal infection-True

4. Migraine headache is often characterized by the following except:

A. Being throbbing-False
B. Being unilateral-False
C. Associated with projectile vomiting-False
D. May be associated with visual disturbances-False

5. The most common cause of meningitis is:

A. Viral-True
B. TB-True
C. Bacterial-True
D. Malignancy-False
E. Fungal-True

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6. Generalized seizure types include:
A. Localized-False
B. Absence-True
C. Tonic-Clonic-True
D. Myoclonic-True
E. Atonic-True

7. Meningitis may present with the following clinical features:

A. Fever-True
B. Reduced alertness-True
C. Photophobia-True
D. Headache-True
E. Shortness of breath-False

8. The following might precipitate seizures

A. Fever-True
B. Flickering light-True
C. Alcohol-True
D. Sleep deprivation-True
E. Laughter-True

9. Paralysis of the fourth cranial nerve produces:

A. Weakness of the inferior oblique muscle-False
B. Pupillary dilation-False
C. Impaired downward gaze-True
D. Elevation and abduction of the eye-True
E. None of the above-False

10.With respect to lumbar puncture:

A. Coagulation is a contraindication-True
B. Papilledema is an absolute contraindication-True
C. Can be therapeutic by reducing intracranial pressure-True
D. The less CSF is removed; the less likely coning is to occur-True

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11.About Parkinsonism
A. Mainly results from reduction of dopaminergic transmission within the basal
ganglia-True
B. Intentional tremor and akinesia help in diagnosis-False
C. Family history is a risk factor-True
D. Neuropsychiatry symptoms might be present-True

12.Outcome of bacterial meningitis relates to:

A. Age of the patient-True
B. Time of first administration of antibiotics-True
C. CSF concentration of antibiotics-True
D. Development of antibiotics resistance during therapy-True

13.A 70-year-old woman complains of sudden onset of weakness of left arm and
leg, she also experiences difficulties in speech and loss of vision in one eye.
Although these symptoms were frightening, they improved within 10 hours and
she was feeling well when she came to the clinic. What is the likely diagnosis?
A. Patient has a minor stroke-True
B. Patient has motor neuron disease-False
C. Patient has Parkinson’s disease-False
D. Patient has Transient ischemic attack-True

14.Aseptic meningitis may be due to

A. Viral infection-True
B. TB-True
C. Partly treated bacterial infection-True
D. Lyme disease-True

15.In a patient presenting with seizures

A. A screen for toxins may be indicated-True
B. Blood sugar is indicated-True
C. CSF studies is mandatory in HIV infected (if no contraindication), even in
the absence of symptoms or signs suggesting infection-True
D. Brain scan might be indicated-True

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16.Differential diagnosis of seizure include
A. Migraine-True
B. Syncope-True
C. Transient ischemic attack-True
D. Sleep walking-True

17.In motor neuron disease

A. The pathological hallmark is death of lower and upper motor neurons-True
B. Dementia is a component of Amyotrophic lateral sclerosis-True
C. Ocular motility is a late sign in Amyotrophic lateral sclerosis (ALS)-False
D. No treatment arrests the underlying process in ALS-True

18.Regarding the central nervous system (CNS) in HIV infection

A. Cytomegalovirus is the most common viral infection-True
B. Highly active anti-retroviral therapy significantly improves the survival of
patients with progressive multifocal leukoencephalopathy-True
C. The target sign on CT is pathognomic for tuberculoma-True
D. Gummas are the most frequent features of neurosyphilis-True

19.The following are true of CNS involvement in AIDS

A. HIV encephalopathy (HIVE) is the most common cause of neurological
disease-False
B. Progressive multi-focal leukoencephalopathy is associated with Jacob
Creutzfeldt papova virus (JC virus)-True
C. CMV encephalitis is easily differentiated from HIVE by its imaging
characteristics-False
D. Lumbar puncture is contraindicated in evaluating patients with AIDS and
CNS involvement-False

20.In the evaluation of a confused patient, following should be considered

A. Motor neuron disease-True
B. Drug intoxication-True
C. Cerebral malaria-True
D. Post-seizure event-True

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21.The risk factor for bronchogenic cancer are:
A. HIV-True
B. Asbestos-True
C. Radon Gas-True
D. Cigarette Smoking-True

22.Paraneoplastic manifestations of bronchial carcinoma include:

A. Cerebellar Degeneration-True
B. Skin rash and proximal Myopathy-True
C. Eaton-Lambert Syndrome-True
D. Bone Pain-True

23.A 68-year-old pub landlord and lifelong smoker is admitted with lethargy and
drowsiness. Laboratory tests reveal results consistent with syndrome of
inappropriate anti-diuretic hormone secretion (SIADH) and a chest radiograph
demonstrates a 3cm right upper lobe mass. He is due to undergo a CT guided
biopsy of the mass. What is the histological subtype most likely to be?
A. Bronchoalveolar cell Carcinoma-False
B. Squamous cell Carcinoma-False
C. Pulmonary Hamartoma-False
D. Small (oat) cell Carcinoma-True

24.The following tumor markers can be used as surrogate for bronchial carcinoma:
A. CA 125-False
B. CA 19-9-False
C. Neuron specific Enolase-True
D. Placental Alkaline Phosphatase-False

25.The following are contraindications to surgical resection in bronchial carcinoma:

A. Distant Metastases-True
B. Pleural effusion (non-malignant)-False
C. Bilateral mediastinal Lymphadenopathy-True
D. Esophageal Involvement-True

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26.Pancoast’s syndrome
A. Results from local extension of a tumor growing in the base of the Lung-False
B. May result in involvement of the 8th cervical and 1st and 2nd thoracic Nerves-
True
C. Often with destruction of 4th and 5th Ribs-False
D. May result in shoulder pain that characteristically radiates in the ulna
distribution of the Arm-True

27.The following primary tumors can metastasis to the lungs:

A. Melanoma-True
B. Salivary gland Tumor-True
C. Soft tissue Sarcoma-True
D. Testicular Cancer-True

28.A 60-year-old with congestive cardiac failure due to hypertensive heart disease,
who is also epileptic and HIV patient on HAART complains of breast
enlargement. Which of the following medications he is currently taking would
cause gynecomastia?
A. Calcium channel Blockers-True
B. Spironolactone- True
C. Efavirenz-True
D. Sodium Valproate-True

29.Which of the following statement is true about secondary diabetes?

A. A patient can be assumed not to be Ketosis-Prone-False
B. A patient is more than 85% likely to have clinical pancreatic exocrine
Deficiency-True
C. Classical diabetic complications do not occur- False
D. Thiazide diuretics and beta-blockers can both impair insulin Secretion-True

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30.Which of the following statement is true about hypoglycemia?
A. About 50% of patients who have had type 1 DM for 20 years or more develop
‘hypoglycemia awareness’-True
B. Sweating and shaking are always late symptoms of insulin-induced
Hypoglycemia-False
C. Metformin is responsible for as many cases of hypoglycemia as
Sulfonylureas-False
D. The symptoms characteristically come on over hours rather than Minutes-
False

31.Which of the following is true about diabetic retinopathy?

A. Characteristically causes arterial-venous Nipping-False
B. Should be referred to an ophthalmologist only if the patient has visual
Symptoms-False
C. Inevitably causes Blindness-False
D. May cause soft and hard Exudates-True

32.The following will increase secretion of insulin

A. Ketone bodies- True
B. Vagal nerve Stimulation-True
C. Amino Acids-True
D. Glucagon-False

33.The following will decrease secretion of insulin

A. Glucagon-True
B. Alpha-Agonist-True
C. Cortisol-True
D. Thyroxine-True

34.Complication of insulin include

A. Lipoatrophy-True
B. Lipohypertrophy-True
C. Hyperglycemia-False
D. Gynecomastia-False

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35.A 30-year-old HIV patient, Pre-HAART, is admitted with weight loss, diarrhea,
night sweats and cough. On TB treatment for 4 weeks and recently treated for
oral thrush. His BP 80/60, RR 24. Which other clinical signs are suggestive of a
possible cause of her low BP?
A. Clearly audible heart Sound-False
B. Hyperpigmented palm creases and Gums-True
C. A pulse of 70/minute with full Volume-False
D. Normal JVP-False

36.Features of renal failure may include:

A. Loss of libido- True
B. Hyperparathyroidism- True
C. Delirium-True
D. Platelet Dysfunction-True

37.A 28-year-old female presents with hematuria, proteinuria 2+, increased BP and
mild pedal edema and creatinine 60mmol/L. The doctor suspects a glomerular
disease. A urine microscopy was ordered. Which result is highly suggestive of a
glomerular disease
A. RBC Casts-True
B. Hyaline Casts-False
C. Muddy brown Casts-False
D. Epithelial Casts-False

38.The most likely clinical syndromes in the patient in Question 37 above

A. Nephrotic Syndrome-False
B. Nephritic Syndrome-True
C. Rapid Progressively-True
D. Chronic Glomerulonephritis-True

39.What is the Gold standard for making a definitive diagnosis in the above patient
in Question 37?
A. No need for further evaluation as long as the clinical syndrome is Known-
False
B. Kidney Ultrasound-False
C. Histological Diagnosis-True
D. 24-hour urine protein and Creatinine-False

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40.In the diagnosis of Acute Kidney injury (AKI), diagnosis is usually based on the
following parameters:
A. Baseline creatinine, latest creatinine and/or urine output- True
B. Baseline GFR and latest GFR-True
C. A patient with AKI on dialysis is in stage 2- False
D. Urine output alone is not sufficient to make a diagnosis of AKI-False

41. A marathon runner was found fitting after taking 2L of water after a 10Km
marathon on a hot sunny day. What is the likely cause of seizures?
A. Hypernatremia-False
B. Dilutional Hyponatremia-True
C. Pseudohyponatremia-False
D. Diabetic Ketoacidosis-False

42.What will be the management of the patient in question 41?

A. Normal Saline-False
B. 3% Saline-True
C. Darrow’s-False
D. Ringer’s Lactate-False

43.Cerebral blood flow is increased by:

A. Hypercapnia- True
B. Hypoxia- False
C. Alkalosis-False
D. Hypothermia-False
E. Polycythemia- False

44.Recognized features of pseudobulbar palsy include:

A. Inappropriate Laughter-False
B. Dysarthria-True
C. An absent jaw Jerk-False
D. Dysphagia-True
E. Fluctuating level of Consciousness-False

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45.Guillan-Barre’ syndrome
A. Has an acute Onset-False
B. Is typically associated with normal CSF protein- False
C. Presents with periods of loss of Consciousness-False
D. Is characterized by bilateral motor Weakness-True
E. Has a recognized association with carcinoma of the Lung-False

46.Myasthenia gravis is characterized by

A. Dysphagia-True
B. Ptosis-True
C. Aplastic Anemia-False
D. HLA antigen DR3-True
E. Morning Stiffness-False

47.In the elderly stroke is significantly associated with

A. High serum Cholesterol-True
B. Obesity-True
C. Polycythemia rubra vera-True
D. Myocardial Infarction-True
E. Atrial Fibrillation-True

48.Infarction in the territory of the anterior cerebral artery

A. Causes more severe hand then shoulder weakness on the affected Side-False
B. Produces predominant weakness of the lower Limb-True
C. Is most frequently seen after SAH after berry aneurysm Rupture-True
D. Causes transcortical motor aphasia when affecting the dominant Hemisphere-
True
E. Usually occurs as a result of cerebral Embolism-True

49.Characteristics features of occlusion of the left middle cerebral artery include

A. Hemiplegia with involvement of the leg more than the Arm-False
B. Paralysis of conjugate gaze towards the Left-True
C. Deep xanthochromia of CSF-True
D. Diplopia-False
E. Dementia-False

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50.Causes of SIADH include
A. Chest Infection-True
B. Head injury- True
C. Chlopropamide-True
D. Addison’s Disease-False
E. Liver Cirrhosis-False

51.Which of the following is true about SAH?

A. It is common among elderly women and very rare in the Young-True
B. Over 90% of SAH are due to untreated Hypertension-False
C. Neck stiffness is very rare unless patient has Meningitis-False
D. The presence of hypotension with tachycardia indicates raised intracranial
Pressure-False
E. Nifedipine treatment is very important in the Management-True

52.Which of the following are true about seizures?

A. Imipenem may cause seizures and should not be used to treat Meningitis-True
B. These may occur in poisoning due to tricyclic antidepressants, mefenamic
acid or Opioids-True
C. In Tenia solium infection, focal seizures can occur if cysts are present in the
Brain-True
D. Pre-eclampsia is marked by seizures or coma in addition to other Signs-False
E. In CKD, mental slowing, clouding of consciousness and rarely seizures may
Occur-True

53.Which of the following are true about stroke?

A. In Zambia, cerebral hemorrhage accounts for more than 30% of acute Strokes-
False
B. In supratentorial strokes with homonymous hemianopia, patient cannot see on
the hemiplegic Side-True
C. Vertigo, vomiting, dysphagia and Horner’s syndrome indicate occlusion of
the vertebrobasilar Circulation-True
D. Pinpoint pupils and bilateral upgoing plantars could signal a brainstem Stroke-
False
E. Carotid endarterectomy should be considered for patient with more than 70%
Stenosis-True

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54.In a patient with AIDS, Cryptococcal meningitis is
A. The commonest cause of Meningitis-True
B. Characterized by abrupt onset of the classical features of a bacterial
Meningitis-False
C. Diagnosed by India ink stain of cerebrospinal Fluid-True
D. Typically associated with negative CSF culture- False

55.Cryptococcal meningitis
A. Is caused only by Cryptococcus neoformans neoformans- False
B. Is more common than Cryptococcal pneumonia- True
C. Characteristically causes leucopenia- False
D. Only occurs in the Immunosuppressed-True
E. Should be treated with Ketoconazole-False

56.Amphotericin B is used in the treatment of

A. Visceral leishmaniasis- True
B. Dermatophyte infections of the nails- True
C. Azole resistant oral Candida-True
D. Primary amoebic meningoencephalitis caused by Naegleria Species-True
E. Cryptococcal Meningitis-True

57.Common cause of blackouts include:

A. Drugs-True
B. Valvular heart Disease-True
C. Myocardial Infarction-True
D. Hypoglycemia-True
E. Alcohol Ingestion-True

58. HIV infection is associated with

A. An RNA retrovirus- True
B. Involvement of CD4 lymphocytes- True
C. Viral half-life of 1-2 hours in plasma- False
D. A better prognosis in the presence of Kaposi’s sarcoma- False

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59.In HIV infection
A. 80% of vertically transmitted infections are transplacental-False
B. A child born to an infected mother has a 90% chance of acquiring HIV-False
C. Transmission can occur via breast Milk-True
D. Risk of fetal transmission is unaffected by pre-partum antiviral Agents-False

60.In the diagnosis of HIV infection

A. ELISA testing has a low false negative rate- True
B. Seroconversion invariably occurs in under 4 Weeks-False
C. Antibody detection tests are particularly helpful in Neonates-False
D. HIV-RNA is typically detected before anti-HIV Antibodies-True

61.In the classification of HIV infection

A. Stage 1= acute seroconversion simulating glandular Fever-True
B. Stage 2= persistent generalized Lymphadenopathy-False
C. Stage 3= have absolute CD4 count >500/mm3-False
D. Kaposi’s sarcoma is stage 3 Disease-False

62.Presenting features of HIV infection include

A. Hairy Leucoplakia-True
B. Atypical pneumonia- True
C. Thrombocytopenic purpura- True
D. Pulmonary tuberculosis- True

63.Cryptosporidiosis in an HIV positive patient is

A. An AIDS-defining diagnosis if chronic- True
B. Likely to present with painless profuse diarrhea- True
C. Likely to self-limiting if the CD4 count is > 200 cells/mm3- True
D. Preventable by the use of boiled tap water- True

64.Pneumocystis carinii infection in an HIV positive patient is

A. The commonest cause of respiratory infection in African Patients-True
B. Characterized by copious sputum Production-False
C. Characterized by widespread fine pulmonary Crackles-True
D. Excluded by the finding of a normal chest X-Ray-False

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65.The following have been reported with initiation of HAART;
A. Immune reconstitution syndrome- True
B. Osteonecrosis- True
C. Diabetes Mellitus- True
D. Lipodystrophy syndrome- True

66.Side effects of Nucleoside reverse transcription inhibitor include;

A. Cough-False
B. Fever-False
C. Insomnia-False
D. Liver Damage-True

67.The following are true;

A. Maraviroc is an antagonist of Protease-False
B. A Fusion inhibitor is helpful in the treatment of HIV-False
C. Raltegravir is an inhibitor of HIV Integrase-True
D. Stavudine has very few side effect- False

68.On protease inhibitor;

A. Should be used with caution in Diabetic Mellitus Patient-True
B. Should not be used in patient with acute porphyria- True
C. Should be used with caution in patient with chronic hepatitis B-True
D. Should not be used in AIDS Stage-False

69.About peptic ulcer disease

A. Gastrinoma should be suspected if there are multiple duodenal Ulcers-True
B. Alcohol abuse is a risk factor for gastric Ulcer-True
C. Peptic ulcer disease may lead to acute Pancreatitis-True
D. Helicobacter pylori infection and NSAIDs are the two most common causes
of peptic ulcer Disease-True
E. Biopsy must be performed in all patients with duodenal Ulcer-False

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70.Patients with HIV stage 4 WHO may have the following conditions
A. Pulmonary Tuberculosis-True
B. HIV Encephalopathy-True
C. Esophageal Candidiasis-True
D. Abdominal TB-True
E. Severe Anemia-False

71.Regarding tuberculosis pericardial effusion

A. Pericardiocentesis is Mandatory-False
B. Low dose prednisolone given during the first 2 months of Treatment-True
C. Culture of pericardial fluid is Confirmatory-True
D. Treatment is given for 12 Months-False
E. Constrictive pericarditis is not a known Complication-False

72.Signs of hypokalemia on ECG include:

A. Flattening of T Wave-True
B. Prolonged QT Interval-True
C. Tall U Waves-True
D. J wave -False
E. Shortening of PR Interval-True

73.Causes of hyperkalemia include

A. Addison’s Disease-True
B. Diabetic ketoacidosis- True
C. Rhabdomyolysis-True
D. Renal Puncture-True
E. Alkalosis-False

74.The most effective drug in control of hypertension in an emergency is

A. Nifedipine-False
B. Hydralazine-True
C. Sodium Nitroprusside-True
D. Lasix-False
E. Methyldopa-False

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75.Optic neuritis is complication of:
A. Rifampicin-False
B. Isoniazid-False
C. Ethambutol-True
D. Pyrazinamide-False
E. Streptomycin-False

76.In community acquired pnemonias:

A. The commonest pathogen is Mycoplasma pneumoniae-False
B. Erythromycin is the first-line antibiotic for Psittacosis-False
C. The serum urea correlates with severity of illness- True
D. Ciprofloxacin can be used as a single agent when the organisms is not Known-
True
E. The pneumococcal antigen can be identified in Urine-True

77.Misoprostol is
A. H2 receptor Antagonist-False
B. Synthetic prostaglandin Analogue-True
C. Proton pump Inhibitor-False
D. NSAID-False
E. Antacid-False

78.Microcytic anemia is a typical finding in:

A. Folic acid deficiency- False
B. Hemolytic anemia- False
C. Alcohol Abuse-False
D. Primary sideroblastic Anemia-True
E. Iron Deficiency-True

79.Non-infectious causes of diarrhea:

A. Inflammatory bowel Disease-True
B. Histoplasmosis-False
C. Bechets Disease-True
D. Clostridium perfringens-False
E. Pseudomembranous Colitis-True

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80.Causes of chronic liver disease
A. Alcohol- True
B. Methyldopa-True
C. Hepatitis B Virus-True
D. Methotrexate-True
E. Idiopathic-True

81.The following is true of viral hepatitis:

A. Hepatitis C commonly presents with Jaundice-True
B. Hepatitis C is fatal particularly in Pregnancy-True
C. Hepatitis BeAg is a marker of viral Replication-True
D. Hepatitis A is a risk factor for hepatoma-False
E. Hepatitis D occurs only in association with hepatitis C-False

82.The following are common causes of meningitis

A. Neisseria meningitidis-True
B. Haemophilus Influenza-True
C. Listeria monocytogenes-True
D. Staphylococcus Aureus-True
E. Gram negative Bacilli-True

83.In the treatment of HIV infection

A. All useful drugs work via inhibition of reverse transcriptase- False
B. Reverse transcriptase inhibitors prevent replication in infected Cells-True
C. Reverse transcriptase inhibitors prevent spread of infectious virus into
uninfected Cells-False
D. Drug resistant strains of virus have not been Recognized-False
E. Monotherapy is Preferred-False

84.Recognized features of severe heart failure include

A. Tiredness-True
B. Weight Loss-True
C. Epigastric Pain-True
D. Nocturia-True
E. Nocturnal Cough-True

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85. The pain of Myocardial ischemia
A. Is typically induced by exercise and relieved by Rest-True
B. Radiates to the neck and jaw but not to the Teeth-True
C. Rarely lasts longer than 10 Seconds-False
D. Is easily distinguished from esophageal Pain-False
E. Can easily be distinguished from pain arising from acute Pancreatitis-False

86.Jone’s major criteria for the diagnosis of rheumatic fever

A. Migratory Polyarthritis-True
B. Pancarditis-True
C. Chorea-True
D. Fever-False
E. Subcutaneous Nodules-True

87.Adverse effects of corticosteroid therapy include:

A. Peptic Ulceration-True
B. Hypertension-False
C. Avascular bone Necrosis-True
D. Pseudogout-True
E. Insomnia-True

88. The typical features of type B viral hepatitis include:

A. Incubation period of 1 month- True
B. History of exposure to unsafe sex or drug Abuse-True
C. Prodromal illness with polyarthralgia-True
D. Hepatic illness more severe than type A-True
E. Absence of progression to chronic Hepatitis-False

89.Typical features of advanced hepatic cirrhosis include

A. Progressive Hepatomegaly-False
B. Massive Splenomegaly-True
C. Peripheral blood macrocytosis-True
D. Parotid gland Enlargement-True
E. Central Cyanosis-False

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90.Hepatic encephalopathy in cirrhosis is typically precipitated by:
A. Infection-True
B. Hypokalemia-True
C. Abdominal Surgery-True
D. Gastrointestinal Bleeding-True
E. Lactulose Therapy-False

91.Hemoptysis is a clinical feature of

A. Carcinoma of Lung-True
B. Bronchiectasis-True
C. Pulmonary Tuberculosis-True
D. Primary pulmonary Hypertension-True
E. Pulmonary Embolism-True

92.A pleural effusion with a protein content 50g/L would be compatible with:
A. Congestive cardiac Failure-False
B. Pulmonary Infarction-False
C. Subphrenic Abscess-True
D. Pneumonia-True
E. Nephrotic Syndrome-False

93.Recognized causes of pyrexia of unknown origin (PUO)

A. Infective Endocarditis-True
B. Renal cell Carcinoma-True
C. Systemic lupus Erythematosus-True
D. Tuberculosis-True
E. Drug Fevers-True

94.The following would help distinguish between a kidney and a spleen in the left
upper quadrant
A. Dull percussion note over the Mass-True
B. A well localized notched lower Margin-True
C. Moves with Respiration-True
D. A ballotable Mass-True
E. A family history of renal Failure-False

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95.The following are classified as high output states:
A. Hypertension-False
B. Sepsis-True
C. Hypothyroidism-False
D. Pregnancy-True
E. Arterial venous Malformation-True

96.Clinical features of raised intracranial pressure:

A. Tachycardia and hypotension-False
B. Dizziness and lightheadedness-True
C. Headache aggravated by bending and straining-True
D. Behavioral and personality changes-True
E. Sixth or third nerve palsies-True

97.Recurrent headache could be due to

A. Migraine-True
B. Cluster-True
C. Glaucoma-True
D. Analgesia overdose-False
E. Tension headache-True

98.The definition of epilepsy includes being

A. Spontaneous-True
B. Intermittent-True
C. Having abnormal electrical discharge in some part of the brain-True
D. Diagnosis is predominantly clinical-True
E. A known epileptic and independent observer’s description being suggestive
of epilepsy-True

99.Migraine headache is often characterized by following except:

A. Being throbbing-False
B. Being unilateral-False
C. Associated with projectile vomiting-False
D. Associated with nervous tension-True
E. May be associated with visual disturbances-False

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100. CSF protein level is normal in the following types of meningitis?
A. Viral-True
B. TB-False
C. Bacterial-False
D. Malignant-False
E. Septicemia-True

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THIRD YEAR ESSAY QUESTIONS

1. HIV is a very common condition observed in the medical wards at Levy
Mwanawasa General hospital. Please answer the following questions:
a. What do you understand by immune reconstitution inflammatory syndrome?
(5 marks)
Answer:
Immune reconstitution inflammatory syndrome is a condition seen in some
cases of AIDS or immunosuppression, in which the immune system begins to
recover, but then responds to previously acquired opportunistic infection with
an overwhelming inflammatory response that paradoxically makes the
symptoms of infection worse.
The suppression of CD4 T cells by HIV causes a decrease in the body’s normal
response to certain infections. Not only does this make it more difficult to fight
infection it may mean that a level of infection that would normally produce
symptoms is instead undetected (subclinical infection) If the CD4 count rapidly
increases (Due to effective treatment of HIV) a sudden increase in the
inflammatory response produces nonspecific symptoms such as fever and in
some cases a worsening of damage to the infected tissue.
There are 2 common IRIS scenarios. The first is the ‘unmasking’ of an occult
opportunistic infection and the second is the ‘paradoxical’ symptomatic relapse
of a prior infection despite microbiologic treatment success.

b. What are the central nervous system complications of HIV? (5 marks)

Answer:
 Progressive multifocal leukoencephalopathy
 Unexplained nerve palsy
 HIV encephalitis
 Aseptic meningitis
 CNS lymphoma
 Immune reconstitution inflammatory syndrome of the CNS (CNS-IRIS)
 HIV related stroke
 Acute demyelinating polyneuropathy
 Peripheral neuropathies

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c. What are the renal complications of HIV? (5 marks)
Answer:
 Acute kidney injury
 HIV associated nephropathy
o Thrombotic microangiopathy
o HIV related tubulointerstitial injury
o Immune complex-mediated glomerular disease (nephritic syndrome)
o Nephrotic syndrome
 Comorbid chronic kidney disease

d. What are the parameters of monitoring treatment? (5 marks)

Answer:
 CD4 count
o Should be measured at time of diagnosis before commencement of
therapy and every 1-3 months after initiating antiretroviral treatment and
then every 3-4 months (when CD4 count is above 350 cells for at least 12
months).
o Measure CD4 if new clinical staging events develop.
 Viral Load
o Desirable but not entirely essential prior to initiating therapy
o Viral load should be assessed to confirm clinical or immunological failure
where possible prior to switching treatment regimen.
o By 4 weeks’ therapy the viral load should have dropped by at least 1 log10
copies/mL and by 12-24 weeks should be below 50 copies/mL.
o Once stable on therapy the viral load should be routinely done every 3-4
months.
 Baseline hemoglobin level, white blood cell count, Liver enzyme, Urea &
electrolytes, creatinine, blood glucose and lipid profile.
o This should be assessed before and after initiation of therapy

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2. 34-year-old male businessman present to you with a history of productive cough,
evening chills, night sweats, loss of appetite and loss of weight of the past 3 months.
He is newly diagnosed RVD with CD4 count of 3 cells/ml. His chest X-ray shows
a miliary picture and the safe lab markers are normal.
a. Which other investigations are you going to order- list 3 (3 marks)
Answer:
 Erythrocyte sedimentation rate
 Sputum microscopy with Ziehl-Neelsen stain (Acid-fast bacilli), culture and
sensitivity
 Sputum for GeneXpert

b. List 5 differentials for the chest X-ray picture (5 marks)

Answer:
 Miliary tuberculosis
 Histoplasmosis
 Sarcoidosis
 Pneumoconiosis
 Pulmonary siderosis
 Bronchoalveolar carcinoma

c. If the diagnosis is Miliary TB, outline the management plan in the above patient
(4 marks)
Answer:
 Assess sensitivity of bacilli to the first line drugs
 Treatment duration is for 9-12 months.
o 2 months’ intensive phase with Rifampicin, isoniazid, pyrazinamide and
ethambutol
o 7-10 months’ continuation phase with rifampicin and isoniazid
 Give isoniazide with vitamin B6.
 Since CD4 <50 cell/ml also start antiretroviral treatment immediately.
o Triple therapy according to current national guidelines.

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d. List the common side effects of the antituberculosis drugs- 2 for each (8 marks)
Answer:
 Rifampicin
o Hepatotoxicity, Acute renal failure
o Orange/red discoloration of body fluids
o Stevens-Johnson syndrome
 Isoniazid
o Hepatotoxicity and jaundice
o Sideroblastic anemia
o Peripheral neuropathy
 Pyrazinamide
o Hepatotoxicity
o Hyperuricemia and gout
 Ethambutol
o Optic neuritis
o Color blindness, loss of visual acuity, peripheral neuritis
o Thrombocytopenia
 Streptomycin
o Ototoxicity (hearing impairment)
o Mild skin rash

3. In relation to endocrine disorders, please answer the following:

a. Describe pathophysiology of Diabetic ketoacidosis (5 marks)
Answer:
This is mainly a complication of type 1 diabetes mellitus but can sometimes
also arise in type 2 diabetes mellitus.
Any event that decreases insulin availability or causes stress that increases the
insulin demand (e.g. infection, poor compliance with insulin or discontinuation
of insulin, dehydration, stress- trauma, surgery or emotional crisis, and excessive
alcohol ingestion) will lead to severe insulin deficiency and excessive release of
the stress hormones glucagon, cortisol, epinephrine and growth hormone.
This results in:
 Increased production of glucose by the liver and increase glycogen degradation
to glucose
 Decreased glucose uptake and utilization

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 Lipolysis: enhanced break down of free fatty acids and subsequent ketogenesis.
This increases blood levels of ketone bodies such as acetoacetate, beta-
hydroxybutyric acid, and acetone resulting in metabolic acidosis.
The above biochemical processes result in significant hyperglycemia and
ketoacidosis, which is responsible for the clinical manifestations of diabetic
ketoacidosis:
 Volume depletion (dehydration) due to osmotic diuresis- dry tongue and
buccal mucosa, poor skin turgor and hypotension
 Kaussmaul’s respiration: deep and fast breathing resulting from metabolic
acidosis
 Nausea and vomiting with abdominal pain
 Acetone (‘fruity’) odor of breath: due to acetone
 Mental status changes: lethargy and confusion which may lead to coma in
severe DKA
 Cerebral edema: especially in children

b. What are the causes of Addison’s disease (5 marks)?

Answer:
 Acute causes:
o Waterhouse-Friderichsen syndrome- Infection with Neisseria meningitidis
o Sudden withdrawal of long term corticosteroid treatment
 Chronic causes:
o Primary adrenal insufficiency
o Chronic
- Tuberculosis of adrenal cortex
- AIDS
- Systemic amyloidosis
- Hemochromatosis
- Sarcoidosis
- Fungal infection
- Autoimmune adrenalitis

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c. What are the metabolic abnormalities with primary adrenal insufficiency? (5
marks)
Answer:
 Hyperkalemia
 Hypercalcemia
 Increased urea
 Hyponatremia
 Hypoglycemia

d. What is a thyroid storm? (5 marks)

Answer:
This is a severe life-threatening form of hyperthyroidism. It is characterized by
excessive thyroid hormones in the blood (e.g. from performing a thyroidectomy
of a hyperthyroid patient) accompanied with signs and symptoms consistent
with thyrotoxicosis:
o Tachycardia, arrhythmias and cardiac failure
o Restlessness
o Fever
o Confusion
o Agitation
o Weakness
o Dyspnea
o Diarrhea
o Shock
It is also known as thyroid crisis.

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4. A 20-year-old female patient presented to emergency unit at Levy Mwanawasa
General Hospital with a history of progressive exercise intolerance. She has to use
extra pillows in order to get some peaceful sleep but she still wakes up often in the
middle of the night in gasps for breath. Professor Njelesani asks you to demonstrate
a cardiovascular exam and you on auscultation find a left parasternal diastolic
murmur loudest in expiration. Her BP is 110/50. You also find bibasal end-
inspiratory fine crackles and sacral edema.
a. What is your full diagnosis? (5 marks)
b. What other ‘special signs’ will you look out for? Name and describe 5 of them
(10 marks)
c. What do you expect to see on her chest radiograph? (3 marks)
d. Give one differential for ‘bibasal end-inspiratory crackles’ (2 marks)

5. In relation to liver cirrhosis:

a. Please describe Child-purg score in relation to liver cirrhosis? (5 marks)
Answer: this is a scoring system in cirrhosis used liver cirrhosis to determine 1
year, 5 years and 10-year survival
SCORE 1 2 3
Ascites None Mild Moderate/severe
Encephalopathy None Mild Marked
Bilirubin (mol/L) <34 34-50 >50
Albumin (g/L) >35 28-35 <28
Prothrombin time <4 4-6 >6
(Seconds over
normal)

Once the total score is added the survival rates are as follows
Grade % SURVIVAL
(SCORES) 1 YEAR 5 YEARS 10 YEARS
<7 82 45 25
7-9 62 20 7
10+ 42 20 0

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b. What are the poor prognostic indicators for liver cirrhosis? (5 marks)
Answer:
 Blood tests
o Low albumin (<28g/l)
o Low serum sodium (<125 mmol/L)
o Prolonged prothrombin time >6s above normal value
o Raised creatinine >130mol/L
 Clinical
o Persistent jaundice
o Failure of response to therapy
o Ascites
o Hemorrhage from varices particularly with poor liver function
o Neuropsychiatric complications developing with progressive liver failure
o Small liver
o Persistent hypotension
o Etiology e.g. alcoholic cirrhosis if the patient continues drinking

c. What are the complications related to liver cirrhosis? (5 marks)

Answer:
 Portal hypertension
 Gastrointestinal hemorrhage
 Ascites
 Portosystemic encephalopathy
 Hepatocellular carcinoma
 Bacteremia and infections
 Renal failure

d. What is the pathophysiology of ascites related to liver cirrhosis? (5 marks)

Answer:
Ascites with liver cirrhosis is associated with many factors including:
 Decreased synthetic ability of the liver due to fibrosis of parenchyma: there is
a decrease in the synthesis of proteins which contribute to oncotic pressure
which opposes hydrostatic pressure (which forces fluid out of the vascular
space). In liver cirrhosis there is hyperproteinemia and a resultant decrease in
oncotic pressure leading to an imbalance in the starling forces across the blood
vessels. The hydrostatic pressure exceeds the oncotic pressure and more fluid
leaves the vascular compartment into the interstitium leading to ascites.

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 Severe sinusoidal portal hypertension: which results in congestion and an
increase in hydrostatic pressure in the venous system leading to transudation
of fluid.

8. In relation to hemato-oncology
a. What are the clinical features of iron-deficiency anemia? How do you make a
diagnosis? (5 marks)
Answers:
 Clinical features:
o Pica
o Brittle nails
o Koilonychia
o Atrophic glossitis
o Brittle hair
o Angular stomatitis
o Palpitations, lightheadedness, dizziness, headaches, fatigue, tinnitus and
syncope
 Diagnosis:
o Clinical features: History and examination (as above)
o Full blood count
- Hemoglobin and red blood cell count- reduced
- Mean corpuscular volume-reduced (<80fL)
- Mean corpuscular hemoglobin- reduced (<27 pg)
- Mean corpuscular hemoglobin concentration- reduced
o Peripheral smear
- Hypochromic cells
- Poikilocytosis
- Target cells
o Iron studies
- Decreased serum iron
- Decreased ferritin
- Decreased percentage saturation
- Increased total iron binding capacity
o Investigations to establish cause:
- Stool for occult blood
- Stool for ova and parasites

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- Chest x-ray to exclude pulmonary hemosiderosis
- Upper and lower GI radiologic and endoscopic studies
- Urinalysis for hematuria or hemosiderinuria
b. Write short notes on the types of crises related to sickle cell disease? (5 marks)
Answer:
The crises include:
 Splenic sequestration crisis
o There is pooling of red cells in the spleen and hypovolemia leading to
circulatory collapse.
o There is severe hemolysis, rapid splenomegaly and a high reticulocyte
count.
o This is common in childhood before multiple infarcts occur that lead to
a fibrotic non-functioning spleen.
 Hyper hemolytic crisis
o This is due to excessive hemolysis of red blood cells.
o Presents as pre-hepatic jaundice.
 Aplastic crisis
o This happens following infection with erythrovirus B19 (previously
called Parvovirus B19) which invades proliferating erythroid progenitors.
o There is a rapid fall in hemoglobin with no reticulocytes in the peripheral
blood because of the failure of the marrow.
 Vaso-occlusive crisis
o This is due to vaso-occlusion of the blood vessels as a result of sickling
of red blood cells.
o When this happens in the hands and feet dactylitis ensures. Severe pain
can also be felt in other bones such as femur, humerus, vertebrae, ribs,
pelvis.
o One of the feared complications that may arise from a vaso-occlusive
crisis in the lungs is acute chest syndrome due to pulmonary infarction.
Patient may present with shortness of breath, fever, cough and chest pain.
o Blockage of splanchnic vasculature results in recurrent abdominal pains.
c. What are the complications of multiple myeloma? (5 marks)
Answer:
 Anemia
 Pancytopenia
 Bleeding disorders- retinal bleeds
 Heart failure

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 Bone marrow failure
 Infections
 Spinal cord compression
 Pathological fractures
 Carpal tunnel syndrome
 Nephrotic syndrome
 Chronic kidney disease

d. What are the complications of acute leukemias? (5 marks)

Answer:
 Anemia
 Bone marrow failure
 Pancytopenia
 Bleeding disorders
 Infections

9. A young man is brought into the emergency department with history of vomiting,
increased urination and diarrhea of sudden onset after 30 minutes of spraying farm
products with unknown insecticides. On examination, he is semi-conscious,
frosting from the mouth, miosis and bradycardic with soiled clothing.
a. What is the most likely diagnosis? (2 marks)
Answer: Organophosphate poisoning
b. What other signs might he present with? List 4 (4 marks)
Answer:
 Muscle fasciculation and tremors
 Muscle weakness and Flaccid paralysis of limbs, respiratory and extraocular
muscles
 Sweating
 Seizures, with slurred speech
c. Outline the pathophysiology of the above (4 marks)
Answer:
 Organophosphate are absorbed through inhalation as well as the skin. The
irreversibly bind and inhibit the enzyme acetylcholinesterase both centrally
and peripherally resulting in accumulation of acetylcholine and subsequent
overstimulation of muscarinic receptors (resulting in sweating) as well as
nicotinic receptors (Resulting in muscle fasciculation, tremor, muscle

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weakness and flaccid paralysis) including receptors in central nervous system
resulting in seizures with slurred speech
d. What samples would you take to confirm diagnosis (4 marks)
Answer:
 Blood for erythrocyte cholinesterase activity or plasma for cholinesterase
activity (this may be decreased to 30-50% in asymptomatic patients, 10-20%
in moderate poisoning and <10% in severe poisoning)- This confirms
diagnosis of organophosphate poisoning.
 Full blood count
 Urea and electrolytes to rule out electrolyte disturbances
 Stool for microscopy, culture and sensitivity to rule out gastroenteritis
e. Outline principle of management of the above young man (6 marks)
Answer:
 Ensure Airway is patent by suctioning all the secretions
 Ensure patient is breathing and chest is rising (assess for possible need to
intubate)
 Obtain venous access and start running fluids (normal saline)
 Change and remove soiled clothing
 Insert a urinary catheter and monitor urine output
 Start Atropine 2mg IV every 3-5 min to reduce increased secretions,
rhinorrhea and bronchorrhea
 Give Pralidoxime (to reactivate inhibited acetylcholinesterase)
o Pralidoxime chloride 30mg/kg slow IV injection followed by an
infusion of pralidoxime mesylate 8-10mg/kg per hour.

10. A 23-year-old African lady presents to a medical clinic with fatigue, weight loss,
anorexia, a photosensitive malar rash, oral ulcers, intermittent polyarthritis and
urinalysis reveals proteinuria. Anti-double stranded DNA is strongly positive.
a. What is the working diagnosis? (6 marks)
Answer: Systemic lupus erythematosus
b. Briefly describe the immunopathology in this condition (8 marks)
c. Briefly describe hematological disorders in this conditions- List at least 3 (3
marks)
d. Describe briefly the CNS manifestation- at least 3 (3 marks)

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11. A 44-year-old coal miner presented with a 3-month history of polyuria and dyspnea
on exertion. He had developed a frontal headache the past 6 weeks and was
sweating profusely. He had recently noticed tingling in his hand which was worse
at night. On systemic enquire he admitted to loss of libido and impotence for 6
years. On examination he has coarse face, macrognathia, ‘spade’ hand and feet
with thick skin. Heart rate is 100/min regular with a BP of 200/100. Neurological
examination was grossly normal except for bi-temporal hemianopia and reduced
sensation to pin-prick over the thumb, index and ring fingers.
a. What is the diagnosis? (4 marks)
b. Give 2 possible causes of polyuria (4 marks)
c. What is cause of bi-temporal hemianopia (2 marks)
d. What is the cause of reduced sensation to pin-prick over the thumb, index and
ring fingers (4 marks)?
e. What single test would you use to confirm diagnosis (4 marks)
f. Give another test that will help in locating the cause of bi-temporal hemianopia?
(2 marks)

12. Write short notes on the following

a. Features of Nephrotic syndrome (5 marks)
Answer:
 Proteinuria >3.5g/day.
 Hypoalbuminemia- due to proteinuria.
 Edema (peri-orbital, generalized edema especially early morning)- due to
decreased oncotic pressure
 Hypercoagulable state- due to loss of anti-thrombin III and overproduction
of fibrinogen by the liver.
 Recurrent infections (with encapsulated organisms)- due to loss of
immunoglobulins (hypogammaglobinemia) and low molecular weight
complement proteins e.g. C3b.
 Hyperlipidemia and lipiduria- increased cholesterol, increased low,
intermediate & very low density lipoproteins, decreased high density
lipoproteins.

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b. Major differences between Nephrotic and Nephritic syndrome (5 marks)
Answer:
FEATURE NEPHROTIC NEPHRITIC
SYNDROME SYNDROME
Proteinuria > 3.5g/day <3.5g/ day
Signs and Symptoms Edema Hematuria
Hypoalbuminemia Hypertension
Hypogammaglobinemia Edema
Hypercoagulable states Oliguria
Hyperlipidemia Azotemia
Frothy urine RBC casts in urine
Etiology Primary:  Idiopathic
 Minimal change disease  Lupus nephritis
 Focal segmental  IgA nephropathy
glomerulosclerosis  Poststreptococcal
 Membranous glomerulonephritis
nephropathy
 Membranoproliferative
glomerulonephritis
Secondary:
 Diabetes mellitus
 Hypertension
 Collagen vascular disease
 Amyloidosis

c. Complication related to chronic renal failure (5 marks)

Answer:
1. Metabolic acidosis: due to accumulation of organic acids
2. Electrolyte imbalance: hyperkalemia, hypocalcemia, hyperphosphatemia
3. Uremia
4. Cardiovascular:
o Hypertension: due to fluid overload
o Congestive heart failure: due to fluid overload
o Pericarditis: due to accumulation of toxins. Pericardial effusions are
often hemorrhagic
5. Hematological:

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o Anemia (normocytic normochromic): due to decreased production
of erythropoietin
o Bleeding tendency (platelet dysfunction)- GI bleeding, intracranial
hemorrhage
6. Pulmonary edema: due to fluid overload and increased pulmonary capillary
permeability
7. Endocrine
o Men: impotence and oligospermia due to decreased levels of plasma
testosterone.
o Women: amenorrhea, inability to carry pregnancy to term
8. Renal osteodystrophy- hyperphosphatemia, hypocalcemia
o Osteitis fibrosis cystica: due to osteoclastic bone resorption of
especially terminal phalanges, long bones and distal end of clavicles
o Renal rickets (Osteomalacia)
o Osteosclerosis: enhanced bone density in the upper and lower
margins of vertebrae

d. Hepatorenal syndrome (5 marks)

Answer: Hepatorenal syndrome is a condition consisting of rapid deterioration
of kidney function in individuals with cirrhosis or fulminant liver failure.
Vigorous diuresis, paracentesis and sepsis may predispose to Hepatorenal
syndrome. Typically, the kidneys are histologically normal with the capacity of
regaining normal function in the event of recovery of liver function. There is
severe cortical vasoconstriction.
It is characterized by declining GFR, oliguria, low urine sodium (<10mg/l),
normal urinary sediment and azotemia often with disproportionately high levels
of blood urea nitrogen and creatinine.
Diagnosis is made after pre-renal causes of renal failure is excluded.
Management includes volume expansion to rule out volume depletion, low
dose vasopressin, octreotide or norepinephrine may be given and liver
transplantation is the accepted management.

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101. In relation to heart failure, please write short notes on the following include
definition, pathophysiology and clinical significance
a. Pulsus paradoxus:
Answer:
 This refers to an abnormally large decrease in stroke volume, systolic
blood pressure and pulse wave amplitude during inspiration. The normal
fall in pressure is less than 10mmHg. In pulsus paradoxus it drops more
than 10mmHg.
 It is characteristic of cardiac tamponade and severe airway obstruction
(e.g. chronic obstructive pulmonary disorders, asthma, sleep apnea and
croup)
 In airway obstruction, it is due to accentuation of change in intrathoracic
pressure with respiration. In cardiac tamponade, compression of the right
heart prevents the normal increase in flow through the right heart on
inspiration, which exaggerates the usual drop in venous return to the left
heart and produces a marked fall in BP (>10mmHg fall during inspiration)
b. Systolic dysfunction
Answer:
 Systolic dysfunction denotes heart failure due to reduced ejection fraction
and an enlarged ventricular chambers. It can involve either of the ventricle.
In left ventricular systolic dysfunction the cardiac output to the systemic
circulation is markedly impaired and so this results in a back flow of blood
into the pulmonary circuit and resultant signs and symptoms such as
dyspnea, paroxysmal nocturnal dyspnea and orthopnea. In right ventricular
systolic dysfunction, the cardiac output to the pulmonary vasculature is
reduce and there is a backflow into the systemic circuit resulting in ankle
edema, sacral edema or generalized edema. Systolic dysfunction is seen in
both congestive heart failure and dilated cardiomyopathy.

c. Paroxysmal nocturnal dyspnea

Answer:
 This refers to attacks of severe shortness of breath and coughing generally
occurring at night. It usually awakens the person from sleep and may be
quite frightening.
 In paroxysmal nocturnal dyspnea fluid shifts from the interstitial tissues of
the peripheries into the circulation within 1-2 hours of lying down.

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Pulmonary edema follows causing the patient to wake and sit upright,
profoundly breathless.
 It is indicative of severe heart failure

d. ‘A’ waves in relation to raised JVP

Answer:
 The ‘a’ wave is produce by atrial systole and is increased with right
ventricular hypertrophy secondary to pulmonary hypertension or
pulmonary stenosis.
 Giant cannon waves occur in complete heart block and ventricular
tachycardia.

e. Please classify ‘3 types of Angina’ with symptoms

Answer:
 The 3 types of angina include:
o Stable angina pectoris
o Unstable angina pectoris
o Prinzmetal/vasospastic angina
 Stable angina
o This is characterized by a short-lasting ‘crushing’ like chest feeling/
Chest pain (not lasting more than 20 minutes) during exertion. The
pain may radiate to the left arm, left jaw, epigastric area and even
the back.
o It is due to a fixed obstruction of one or more of the coronary
arteries. The lumen is 70% occluded.
o Due to the fixed obstruction, the blood supply cannot increase and
the heart becomes vulnerable to ischemia whenever there is
increased demand such as that produced by physical activity,
emotional stress or excitement or any other cause of increased
cardiac workload.
o Ischemia is limited to the subendocardial myocardium
 Unstable angina
o This is characterized by an unstable coronary atheromatous plaque
which can undergo severe acute changes making it highly
thrombogenic.
o The chest pain (not lasting longer than 20 minutes) occurs with
increased frequency duration and it can be precipitated by

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progressively less effort. The pain may radiate to the left arm, left
jaw, epigastric area and even the back.
o Ischemia initially involves subendocardial myocardium but can be
transmural if obstruction is complete
 Prinzmetal angina
o This is characterized by spastic constriction of the coronary arteries
resulting in complete occlusion of blood flow.
o Symptoms are not associated with exertion or any atheromatous
plaque.
o Ischemia to myocardium is transmural.

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714
FIFTH YEAR ESSAY QUESTIONS
1. You have been asked to evaluate a patient in the Department of Obstetrics and
gynecology. The consultation reads: “very urgent, come and manage our
patient with suspected acute renal failure”.

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You find that she is 26 years old. She had given birth 10hours earlier by
spontaneous vaginal delivery to a mildly asphyxiated baby. She has not passed
urine since delivery. The Antenatal card shows she had no medical or
gynecological problems. Urinalysis was done twice during antenatal and was
reported normal. The midwife tells you that the labor was “very hectic” and
patient was difficult during delivery and hence “bled a lot”

Examination:
Drowsy, pulse 142/min, Blood pressure 85/55 mmHg, respiratory rate 29/min.
CVS-tachycardia, no murmurs, no gallop, RS- clear lung fields, GIT- normal.
There is no active bleeding per vagina and uterus is well contracted

Urinalysis
pH= 5.5
Specific gravity >1.030
Amino acids= trace
Glucose= trace
Casts=present
Hemoglobin, RBC, Albumin, White blood cells, nitrites= all negative

Glucometer random blood sugar= 6, Urea=26

Urgent bedside ultrasound shows normal kidneys

(a) What assessment needs to be done on this patient?

Answer:
Blood investigations:
o Full blood count: assess the level of RBCs, WBCs Hemoglobin
and platelets
o Cross match
o Liver function tests and liver enzymes to exclude Hepatorenal
syndrome
o Serum electrolyte (check potassium levels especially and also
calcium, and phosphate)
o Creatinine
o Arterial blood gases for metabolic acidosis
Urine

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o Urine chemistry: urine sodium (if <1% indicates prerenal failure, if
>2% indicates renal causes)
o Urine microscopy and culture

(b) Analyse the findings

Answer:
The woman is anuric given that she has not passed urine over 10hours
(urine output <0.5ml/kg/hr for more than 6 hours- Stage 1 acute kidney
injury), in addition she has bleed a lot leading to hypovolemia (and shock)
as evidenced by the drowsiness, a systolic blood pressure less than
90mmHg (blood pressure was 85/55mmHg) with a tachycardia of
142b/min. Furthermore, the woman is tachypnic with a respiratory rate of
29/min however, with the chest being clear on auscultation as per
examination findings pulmonary edema seems unlikely. From the findings
of the urinalysis there is an increase in specific gravity (normal 1.010 to
1.030) indicating there is no intrinsic damage to the nephron, the cast cells
may be suggestive of acute tubular necrosis due to the hypoperfusion
brought about by the massive blood loss during delivery. Lastly the rise in
urea signifies the decrease in the excretory function of blood urea
nitrogenous waste and so they tend to accumulate in the blood stream.

Working Diagnosis: Acute tubular necrosis (AKI) 2o Postpartum

hemorrhage

(c) Plan your full management

Answer:
o Cannulate and Catheterize the patient
o Avoid/stop nephrotoxic drugs (beta blockers, ACE inhibitors,
ARBs, aminoglycosides-gentamicin, streptomycin, penicillin,
NSAIDs or corticosteroids)
o Cross match and transfuse with packed cells (depending on the level
of RBC or Hemoglobin)
o Administer intravenous fluids (normal saline) while awaiting blood
 Fluid challenge as patient is dehydrated. 250-500ml of saline
over 30 minutes.
 Reassess after fluid challenge if still dehydrated (give fluids
until JVP visible and systolic BP >100mmHg).

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 Once fluid replete, continue fluids at 20ml + previous hour’s
urine output/hour
 If overloaded, consider urgent dialysis.
o Monitor:
 Blood pressure
 Fluid input and output
 Urine output
 Daily weighing
 Electrolytes (especially potassium) and acid base status
 ECG monitoring
o If any signs of infection place patient on antibiotics
o Treat any complications that arise
 Hyperkalemia
 Protect myocardium: 10ml of 10% Calcium gluconate given in 5 minute. Dose
can be repeated after 15 minutes
 Push potassium into cells: 10IU insulin and 50ml of 50% dextrose IV over 10-
15mings with regular check of glucose and/or salbutamol 0.5mg in 100ml of 5%
glucose over 15 minutes.
 Push Potassium out of cells: polystyrene sulphonate resins: 15g orally TDS with
laxatives 30g rectally followed 9hour later by an enema
 Hemodialysis or peritoneal dialysis if above fails
 Pulmonary edema: IV diuretics (Furosemide)
o Consult renal unit
o Dialysis if patient refractory to above management or develops
acidosis, Fluid overload (pulmonary edema) refractory to
conventional dose of diuretic, electrolyte imbalance (hyperkalemia)
and uremia

2. A male patient 45 years old was admitted yesterday to ICU with severe chest
pain. He is a known diabetic and hypertensive patient for more than 10 years.
Diagnosis of admitting doctor was Unstable angina. Doctor on call was
informed that patient suddenly changed his condition after a short episode of
breathlessness (though in the morning he appeared to be stable, pain free and

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not on ventilation). The nurse reported the absence of pulse and un-recordable
BP.
On the monitor attached to the patient the fine oscillations seen.

(a) What condition is this?

Answer: Ventricular fibrillation

(b) What is your immediate action?

Answer:
 Check if patient is unresponsive by shaking him/her and shouting into one
ear.
 If no response:
o Call for help
o Ensure airway is patent (remove any dentures or foreign bodies,
suction secretions)
o Perform a jaw thrust or chin lift to keep head in “sniffing air in the
morning” position
o Endotracheal intubation and ensure oxygenation
o Gain venous access and start an intravenous infusion in a large
peripheral or central vein
o Perform chest compression: 30 cardiac compressions with 2
effective breaths (30:2)
o Attach patient to defibrillator

(c) If the monitor still shows oscillations and pulse is absent on the carotid arteries
what do you do next?
Answer: Defibrillation with unsynchronized shock of 150-200J biphasic (or
360 J monophasic) via paddles or self-adhesive pads followed immediately
by 2 minutes of cardiopulmonary resuscitation.

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(d) What is the possible diagnosis?
Answer: Pulseless ventricular tachycardia

(e) How would you manage in post-resuscitation period?

Answer:
 Ensure patient’s airway is patent and patient is breathing.
 Get full history and complete physical examination full neurological and
cardiovascular exam
 Monitor vitals: Blood pressure, pulse, O2 Saturation
 Monitor U+Es, creatinine.
 Do lipid profile, FBC
 Controlled oxygenation and ventilation
 12-Lead ECG
 Treat precipitating cause:
o Insulin for the diabetes (monitor blood glucose levels)
o ASA 75mg PO OD to prevent thrombi formation
o Antihypertensives (Beta blocker) to control BP
 Temperature control and monitoring, keep temperature between 32-34oC
 Resuscitate if patient when necessary

3. A 20-year-old male patient presents to admission ward after being found

unconscious at home. The friend accompanying him says that he is a known
diabetic on “injections” that are kept in the fridge and that he has been unwell the
past 4 days with a febrile illness and is not sure whether he was getting his
injections or not.
Examinations: unconscious (GCS 8/14), moderately wasted, no generalized
lymphadenopathy, dehydrated, febrile and has Kaussmaul’s respiration.
You are the attending officer in Phase 5
Please, fully manage him (all the facilities are there i.e. labs etc.)
Answer in Bullet form…
Answer:
 Admit to high dependency unit or ICU
 Ensure Airway is patent, suction any secretions and ensure patient is breathing
 Keep patient warm.
 Gain venous access with 2 large bore cannulae, send blood for:
 Full blood count

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 Urea, Electrolytes (Sodium, potassium, bicarbonate, chloride, calcium and
magnesium), Creatinine
 Liver enzymes and liver function tests
 Serum glucose (also perform a random blood sugar)
 Serum ketones
 Arterial blood gases
 Cross match
 Also send blood and urine cultures as well as perform and chest X-ray
 Catheterize the patient and insert an NGT
 Perform a urinalysis
 Check vitals: (1 hourly for first 8 hours)
 Blood pressure
 Temperature
 Respiratory rate
 Pulse
 Oxygen saturation
 Continuous ECG monitoring
 Start fluids normal saline
 If SBP <90mmHg give 500ml of normal saline in 15 minutes repeat as
necessary. Give 1L in 30 minutes
 If/When SBP >90mmHg give normal saline:
o 1L in 1 hour
o 1L in 2 hours
o 1L in 4 hours
o 1L in 8 hours
 When blood sugar <14mmol use 5% dextrose
 Give insulin (0.1IU/kg/hr) as an intravenous infusion. Check random blood
sugar (RBS) hourly. When blood glucose between 10-14mmol/L use
0.05IU/Kg/hr
 When patient becomes conscious and can take oral feeds calculate total
insulin usage and give TDS soluble insulin SC for each meal
 Alternatively, 6IU SC every hour (8IU if obese)
 Aim for 3-6mmol/L per hour drop of blood glucose from baseline
 Blood glucose (RBS) should be less than 8.9mmol/L
 Monitor glucose hourly for first 8 hours
 Check potassium:

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 If >5.5 mmol/L do not give potassium chloride
 If 3.5-5.5 mmol/L give 20mmol of KCl to second bag of fluids
 If <3.5mmol/L give 40mmol of KCl to second bag of fluids
 Cover on antibiotics (Ceftriaxone 1g BD)
 Give sodium bicarbonate 600ml of 1.4% or 100ml of 8.4% in large cannulated
vein if pH<7.0
 Monitor:
 For signs of pulmonary edema
 Urine output (check hourly for first 8 hours)
 Electrolytes (check at baseline then hourly till 6 hours and then at 12 hours
and 24 hours)
 Glucose (check hourly for first 8 hours)
 Blood gases (check at 0, 2 and 6 hours)
 Vitals (check hourly for first 8 hours)
 Take full history after patient gains consciousness, counsel on diabetes
management and its complications. Adapt patient’s regimen to fit their needs.

4. Daniel comes to the admission ward with complaints of weakness, nausea,

fatigability and poor appetite. He is a known HIV positive patient on HAART
(AZT, 3TC and NVP) for over 2 years. His last CD4 was 200 cell/ml (at baseline
was 55 cells/ml). He was recently diagnosed to have sputum positive PTB at the
local clinic and started on anti-tuberculosis treatment.
(a) List two problems Daniel has and justify your answers (2 marks)
Answer:

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 Treatment failure this is because despite Daniel being on treatment for 2
years he has clinical symptoms that show signs of deteriorating status, a
poor rise in CD4 count and the presence of an opportunistic infection.
 Poor compliance and adherence to treatment as justified by the rise of CD4
count from baseline over the past 2 years on treatment coupled with the
emergence of pulmonary TB. This may also contribute to the treatment
failure. Furthermore, there may be a poor response to treatment probably
due to resistance of HIV to the anti-retroviral drugs.
 AZT may have caused bone marrow suppression leading to the decrease
in WBC and the onset of PTB.

(b) List and justify investigations you would order (9 marks)

Answer:
 Liver enzymes/Biochemistry: AST and ALT as the anti-TB drugs are
hepatotoxic
 Urea, Electrolytes and Creatinine: To assess kidney function before
changing Antiretroviral therapy regimen, as well as continuation of anti-
TB treatment. Calculate creatinine clearance
 Full blood count to assess WBC (infection) and look out for pancytopenia
(RBC and platelets) which may indicate Zidovudine induced bone marrow
suppression.
 Viral load: to assess the level of viremia and effectiveness of treatment
 Chest X-ray- to assess for pulmonary involvement as well as rule out any
other pulmonary pathologies and for comparison with prior radiographs
for any radiological improvement.
 Repeat sputum microscopy, culture and sensitivity to assess effectiveness
of the TB therapy
 Lumbar puncture for CSF analysis and biochemistry as well CT scan of
the head if possible to rule out CNS opportunistic infections

(c) Outline your management plan (9 marks)

Answer:
 Admit
 Continue Anti-tuberculous treatment-4FDCs (intensive phase for 2 months
on Rifampicin, Isoniazid, Pyrazinamide and Ethambutol and Continuation
phase for 4 months on Rifampicin and Isoniazid)
 Repeat sputum and Chest X-ray after 14 days of TB treatment

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 After patient stabilizes, change anti-retroviral drugs to ABC + 3TC (or
FTC) + DTG (avoid TDF since patient is on Rifampicin, increase DTG to
50mg BD)
 Keep hydrated and daily monitoring of urine output
 Monitor Creatinine, Liver function tests weekly
 Counsel patient on treatment adherence, compliance and side-effects of
drugs
 Discharge via psychosocial counseling when patient improves and review
in clinic after 2 weeks.

5. A 22-year female lady (known cardiac patient) come in with history of weakness,
fever, malaise, sweating and painful sores on hands.
(a) List differential diagnosis? (4 marks)
Answer:
 Infective endocarditis
 Systemic lupus erythematosus
 Reactive arthritis
 Disseminated gonococcal infection

(b) Write down the “Dukes criteria” (4 marks)

Answer:
 Major criteria:
o Positive blood cultures for typical microorganisms from 2 separate
blood cultures
o Positive echocardiogram findings: definitive vegetation, abscess,
new partial dehiscence of prosthetic valve, new valvular
regurgitation
 Minor criteria:
o Predisposition: predisposing heart condition or IV drug abuse
o Microbiologic evidence: Positive culture but not meeting major
criterion (e.g. 1 positive culture)
o Echocardiogram consistent with IE but not meeting major criterion
(i.e. positive echo for other abnormality)
o Fever greater than 38 degrees Celsius
o Embolic phenomena: Embolism, CNS hemorrhage, conjunctival
hemorrhage, Janeway lesion

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o Immunologic phenomena: glomerulonephritis, rheumatoid factor,
Osler’s nodes, Roth’s spots, false positive VDRL test
 For diagnosis:
o 2 major
o 1 major plus 3 minor
o 4 minor

(c) What other signs would you look for and give the pathogenesis of the signs (6
marks)
Answer:

(d) How would you manage this patient (6 marks)?
Answer:
 Admit patient
 Investigate:
o Blood culture
o Echocardiography
o Chest X-ray
o ECG
o Full blood count
o Urinalysis and microscopy
o U/E, LFTs
 Bed rest
 Antibiotics for 4-6 weeks (IV antibiotics for at least 2 weeks):
o Crystalline penicillin 3-4 million IU IV every 4 hours for 4-6 weeks’
plus
o Gentamicin 1mg/kg IV TDS for 2 weeks
 Treat any heart failure and arrhythmias than ensue
 Refer for Surgery: for debridement, repair or valve replacement if medical
therapy fails or complications ensue.

6. A 35-year-old Zambian man complains of easy fatigability of long-standing

duration. The following are his blood results.
WBC 5.3 x 109/L
RBC 1.2 x 1012/L
Hb 4g/dl

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Platelets 20 x 109
Blood glucose 6 mmol/L
Sodium 137 mmol/L
Potassium 6.2mmol/L
Creatinine 1200 mol/L

(a) Comment on the results and their significance? (4 marks)

Answer:
(b) What is your diagnosis? (4 marks)
(c) What will be the other clinical features of the patient with such results (6
marks)
(d) How would you confirm the definitive diagnosis (i.e. investigations and
justify)? (11 marks)

7. Mr. Mabvuto Sakala is a 76-year-old male that arrives in AMEU at Levy

Mwanawasa General Hospital in an ambulance. As an intern doctor on duty he is
brought in your consultation room. He complains of shortness of breath for a
week which seem to have gotten worse today. He complains of also a persistent
dry cough especially at night.

He is known to be Diabetic and hypertensive on Losartan 50mg, Amlodipine

10mg and insulin therapy. He has no known drug allergies.
On assessment- Vitals BP: 218/110mmHg, RR-36b/min, Temp- 37.7, O2 Sat 95%
(Room oxygen), dusky nail beds, skin cool and moist with ankle edema. JVP is
10cm, Apex beat in the 6th intercostal space anterior axillary line with a
tachycardia and occasional ectopics. Rales noted right middle lobe and lower
lobes bilaterally.

The following are investigations done on the patient:

Sodium 135
Potassium 3.9
Hb 12.5
Creatinine 220 mol/L
CXR- bilateral pulmonary congestion with enlarged cardiac shadow
12 lead EKG: sinus tachycardia with occasional PVCS, Old anterior MI

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(f) From the patient’s chief complain and your initial assessment, what is the
patient’s primary problem? (4 marks)
(g) Describe the pathophysiology of CHF (congestive heart failure) (6 marks)
(h) What are the signs and symptoms of heart failure in this patient? (2 marks)
(i) What factors contribute to the patient’s heart failure? (4 marks)
(j) What pharmacologic agents are used to improve performance in patients with
CHF? (4 marks)

8. A 65-year-old man present with a 6-week history of cough, progressive shortness

of breath and 10kg weight loss. He has 50-pack year smoking history and his
family doctor orders a chest X-ray and blood work.

The CXR shows a left lower lobe mass. His physical is normal. He is otherwise
healthy and takes no regular medication
(d) List 4 differentials for above patient (8 marks)
(e) How would you further investigate this man in order to get a pathologist
diagnosis- List 5 (5 marks)
(f) If it is Bronchogenic carcinoma, what addition tests are required to properly
stage this patient- List 7 (7 marks)

9. Mrs. Banda is a 27-year-old woman (unemployed) who was referred from VCT
center after testing HIV positive 3 weeks ago. Her husband recently died from
Cryptococcal meningoencephalitis during his hospitalization he tested positive
for HIV causing her to pursue testing.

Her medical history has been unremarkable except being diagnosed with
extrapulmonary TB 4 months ago. She declined HIV test at the time of TB
diagnosis.

She is allergic to trimethoprim/Sulfamethoxazole which causes a diffuse

erythematous rash. Her physical examination is notable for a thin, well developed

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woman with no acute distress. Her ENT exam reveals Candida on the tongue and
buccal mucosa. Heart, Lung and Abdomen examinations are normal.

Her Laboratory test

Hb- 11.7mg/dl
Platelets 167 000
HIV positive
CD4 4 410/L

(e) For this patient, what evidence (history, physical examination, and/or
laboratory data), support beginning antiretroviral therapy (ART) (4 marks)
(f) Do you identify any barriers to ARV adherence? List 3. What would you
recommend to address these barriers? (6 marks)
(g) What antiretroviral medication would initiate? (4 marks)
(h) What toxicities could be associated with the anti-retroviral therapy you chose?
2 for each (6 marks)

10.Mr. Saili is a 74-year-old man who presents to your consultation room with his
wife complaining of shortness of breath and fever. His wife did bring records
from his last physician that he has Chronic Obstructive Pulmonary Disease
(COPD). After evaluation you make a diagnosis of acute exacerbation in COPD.
(f) What is the mechanism of airflow limitation in COPD? (4 marks)
(g) What is the role of inflammatory mechanisms in COPD? (4 marks)
(h) What are the organisms commonly associated with exacerbation of COPD?
(4 marks)
(i) What investigation would you order? (4 marks)
(j) How would you treat an acute exacerbation? (4 marks)

11.A 20-year-old young lady comes to the hospital complaining of fevers and oral
ulcers for a week. She reports having had fevers in the recent past. She says she
has no urinary symptoms. She feels tired and has no cardiac symptoms. She also
has noticed her hair is thinning out. The registrar suspects she has a connective
tissue disease.
(d) What else would you want to probe for in the history? (5 marks)

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The patient is noted to have rash on her face that looks like a butterfly pattern and
she also has joint tenderness in the hands. Your registrar further suggests that this
could be Systemic Lupus Erythematosus (SLE).
(e) List the manifestations used in the criteria to make a diagnosis of SLE. (5
marks)
(f) What drugs can you use in a patient with SLE? (4 marks)

12.A 40-year-old HIV negative male patient presents to AMEU with four days of
Jaundice, upper abdominal pain, nausea, vomiting and headache. He is a patient
on sputum positive PTB on treatment for 6 weeks. He is currently on Rifampicin,
Isoniazid, Ethambutol and Pyrazinamide. The patient has no other pertinent past
medical history and uses no other medications.

On physical examination, he is alert and oriented with the following vital signs:
Blood pressure 113/62mmHg, heart rate 88b/min, respiratory rate 14
breaths/min, pulse oximetry 100% on room air, temperature 37.1 degree Celsius.
His skin is jaundiced but without ecchymoses or petechiae. Eye examination
reveals scleral icterus.

Cardiovascular and pulmonary findings are unremarkable. His abdomen is soft,

but diffusely tender to palpation without and organomegaly, rebound, guarding
or rigidity.

Initial pertinent laboratory results include: AST> 2600 IU/L, ALT>2600 IU/L,
total bilirubin >20mg/dl, INR 3.7.
(e) What is the primary problem with this patient? (2 marks)
(f) How would you investigate this patient? List 4 important investigations (4
marks)
(g) How does Isoniazid (INH) cause hepatotoxicity? (6 marks)
(h) How would you manage this patient if it was purely due to INH? (8 marks)

13.Write short notes on:

(e) Diagnosis of Myocardial infarction (5 marks)
(f) Mechanism of diarrhea in Cholera (5 marks)

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(g) Symptoms, signs and diagnosis of Organophosphate poisoning (5 marks)
(h) Treatment of organophosphate poisoning (5 marks)

14.The patient is a 41-year-old male who has a longstanding history of hypertension

and diabetes and presents with a complaint of pruritus, lethargy, lower extremity
edema, nausea and emesis. He denies any other medical illnesses.
On physical examination the patient is well-developed, well-nourished male in
moderate distress. Blood pressure 180/110, pulse 80, respirations 24 and he was
afebrile. Body weight 76.5kg. ENT exam was remarkable for fundoscopic
findings of AV nicking and copper wire changes consistent with hypertensive
injury. Cardiac exam had an S1, S2 and S4. The remainder of the exam was
remarkable for 2+ lower extremity edema and superficial excoriations of his skin
scratching.

Laboratory data
Chemistry Normal Values Urinalysis
Sodium 133 136-146 mmol/L
Potassium 6.2 3.5-5.3 mmol/L pH 6.0
Specific gravity
Chloride 100 98-108 mmol/L
1.010
Total CO2 15 23-27 mmol/L Protein 1+
BUN 170 7-22 mg/dl Glucose negative
Creatinine 16.0 0.7-1.5 mg/dl Acetone negative
Occult blood
Glucose 108 70-110 mg/dl
negative
Calcium 7.2 8.9-10.3 mg/dl Bile negative
Phosphorus 10.5 2.6-6.4 mg/dl Waxy casts
Alkaline
306 30-110 IU/L
Phosphatase
Parathyroid
895 10-65 pg/ml
Hormone
Hemoglobin 8.6 14-17 gm/dl
Hematocrit 27.4 40-54 %
Mean cell volume 88 85-95 FL

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24-hour urine protein and creatinine- volume 850ml, protein 600mg/dl and
creatinine 180 mg/dl.
Renal ultrasound- Right Kidney 9 x 6.0 cm, Left Kidney 9.2 x 5.8cm
Both kidneys illustrate hyperechogenicity and no hydronephrosis
(g) “Presents with a complaint of pruritus, Lethargy, lower extremity edema,
nausea and emesis.” What do these symptoms suggest to you? (2 marks)
(h) What are the fundus changes in a hypertensive? (4 marks)
(i) What are the fundus changes of a diabetic? (4 marks)
(j) What does S4 signify? What cardiac findings will you expect to find in a
hypertensive? (6 marks)
(k) What is the significance of the finding “superficial excoriations of his skin
from scratching”? (2 marks)
(l) Why was a renal ultrasound ordered? (2 marks)
15.A 58-year-old woman comes to a physician’s office complaining of feeling
lightheaded for past week. She says she can feel her heart racing in her chest. She
mentions she has been staying up late for the past few weeks because of her
workload at work. The medical history reveals well controlled diabetes mellitus.

Physical examination reveals an anxious woman with pallor and mild

diaphoresis. Cardiac examination reveals an irregularly irregular beat. Vital signs
are as follows: Temperature: 36.1oC, Respiratory rate 22b/min, Heart rate 142
bpm, BP 118/55mmHg and Glucose 7.7 mmol/L

(f) What is the most likely diagnosis?

(g) What clinical and ECG abnormalities are most commonly associated with this
condition?
(h) What is the most appropriate treatment for this condition?
(i) How do Heparin and Warfarin work together to treat this condition?
(j) Why does paradoxical reaction sometimes occur after starting warfarin
therapy?

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16.A 38-year-old male present to AFC with profuse diarrhea, low grade fever,
cough, shortness of breath for 3 days. On examination, BP: 85/40mmHg, HR:
110bpm, Temp 38.9oC, RR: 32/min. CXR: bilateral infiltrates
Part A

Labs: sodium= 140 mmol/L, chloride=110 mmol/L, bicarbonate= 12, pH= 7.30,
PCO2= 20
(e) What is the pH?
(f) What is the primary disorder?
(g) Is there any compensation>
(h) What is the anionic gap and what is the complete diagnosis?

Part B
A 24-year-old female present with right flank pain and hematuria for 2 days’
duration
Lab results: Sodium= 138, Chloride= 115, bicarbonate= 12, pH=7.35,
Potassium=3.0
(e) What is the pH?
(f) What is the primary disorder?
(g) Is there any compensation?
(h) What is the anionic gap and what is the complete final diagnosis?

17.A 35 year-old previously health man presents with dyspnea, fevers, chills, and
night sweats for the past 2 months. He is a non-smoker with no concerning habits
or occupational exposures. His pulmonary function tests are as follows:

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(e) Describe the pattern of the abnormality, if one is present

(f) Grade the severity of the abnormality
(g) Generate a differential diagnosis for the observed abnormality
(h) Outline management of Acute severe asthma

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18.A 55-year old male presents with weakness in his legs and shortness of breath.
Sodium 142mmol/L, Potassium 2.5 mmol/L, urea 8 mmol/L, Glucose
9.6mmol/L, bicarbonate 35mmol/L
(e) What is the likely unifying diagnosis?
(f) What cause is suggested by the data?
(g) What 3 further investigations would you request?
(h) Name 5 reasons why this person may have limb weakness

19.A 28-year-old man comes to your office complaining of a 5-day history of

nausea, vomiting, diffuse abdominal pain, fever to 101oF (38.3o C) and muscle
aches. He has lost his appetite, but he is able to tolerate liquids and has no
diarrhea. He has not significant medical history of family history and he has not
travelled outside the Lusaka. He admits to having 12 different lifetime sexual
partners, denies illicit drug use, and he drinks alcohol occasionally but not since
this illness began. He takes no medications routinely, but he has been taking
acetaminophen, approximately 30 tablets per day for 2 days for fever and body
aches since this illness began.

On Examination his temperature 38.9oC, heart rate 98 bpm and blood pressure
120/74 mmHg. He appears jaundiced, his chest is clear to auscultation and his
heart rhythm is regular without murmurs. His liver percusses 12cm and is smooth
and slightly tender to palpation. He has no abdominal distention or peripheral
edema.
Laboratory values are significant for a normal full blood count, creatinine
92mol/L, Alanine aminotransferase (ALT) 3440 IU/L, aspartate
aminotransferase (AST) 2705 IU/L, total bilirubin 24.5mg/dl, direct bilirubin
18.2mg/dl, alkaline phosphatase 349IU/L, serum albumin 3.0g/dl and
prothrombin time 14 seconds.

(a) What is the most likely diagnosis?

Answer: Acute hepatic failure 20 acetaminophen induced toxicity (? Viral
Hepatitis)

(b) What is the most important immediate diagnostic test?

Answer: Plasma paracetamol concentration estimate

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20.A 28-year-old man comes to the emergency room complaining of 2 days of
abdominal pain and diarrhea. He describes his stools as frequent, with 10 to 12
per day, small volume, sometimes with visible blood and mucus and preceded by
a sudden urge to defecate. The abdominal pain is crampy, diffuse and moderately
severe and it is not relieved with defecation.
In the past 6 to 8 months he has experienced similar episodes of abdominal pain
and loose mucoid stools but the episodes were milder and resolved within 24 to
48 hours. He has no other medical history and takes no medication. He has neither
traveled out of Zambia nor had contact with anyone with similar symptoms. He
works as an accountant and dose not smoke or drink alcohol. No member of his
family has gastrointestinal problems.

On Examination his temperature is 38oC, heart rate 98bpm, and blood pressure
118/74mmHg. He appears uncomfortable, is diaphoretic and is lying still on the
stretcher. His sclerae are anicteric and his oral mucosa is pink and clear without
ulceration. His chest is clear and his heart rhythm is regular, without murmurs.
His abdomen is soft and mildly distended, with hypoactive bowel sounds and
minimal diffuse tenderness but go guarding or rebound tenderness.
Laboratory studies are significant for a white blood cell (WBC) of 15, 800/mm3
with 82% polymorphonuclear leukocytes, hemoglobin 10.3g/dl, and platelet
count 754, 000/mm3. The HIV assay is negative. Renal function and liver
function tests are normal. A plain film radiograph of the abdomen shows a mildly
dilated air-filled colon with a 4.5cm diameter and no pneumoperitoneum or
air/fluid levels.

(a) What is the most likely diagnosis?

Answer: Dysentery (most likely bacillary)

(b) What is your next step?

Answer:
 Stool for microscopy/culture and sensitivity.
 Give oral rehydration salts and analgesics
 Cover on Ciprofloxacillin 500mg BD for 3 days
 If bacillary dysentery continue Cipro
 If amoebic switch to metronidazole 800mg PO TDS followed by
diloxanide furoate 500mg TDS for 10 days.

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(c) How do you distinguish Amoebic dysentery from Shigella dysentery (please
answer in table form)
Answer:
Feature Bacillary dysentery Amoebic dysentery
(Shigella)
Causative organism Usually Shigella but can Entamoeba histolytic
also be caused by
enterohemorrhagic
E.coli, Vibrio
parahemolyticus,
Campylobacter jejuni
Onset Acute Chronic
Fever High grade Low grade
Dehydration Frequent Moderate
Number of stools Over 10 motions per day 6-8 motions per day
Amount Small Relatively copious
Odor Odorless Offensive
Color Bright red Dark red
Nature Blood and mucus no Blood and mucus mixed
feces with feces
Nature of lesion Suppurative due to Necrotic due to
diffusible toxins proteolytic ferment
Depth of ulcer Shallow Deep
Margin of ulcer Uniform, clear-cut Ragged and undermined
(sharp)
Intervening mucosa Inflamed Normal
Type of necrosis Karyolysis (Ghost cell Pyknotic (Pyknotic body
(cellular level) and ring nucleus) and mouse eaten cell)
Liver abscess Rare Common
Cellular response Polymorphonuclear Mononuclear

21.A 30-year-old male patient was admitted to the emergency Room with history of
severe epigastric pain. His past medical history is unremarkable. He reports to
have been fine, in fact he was from having a copious meal with some wine with
his friends. You examined him and found a normal temperature but low blood
pressure of 86/55mmHg. He is conscious but in severe pain.

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(f) Discuss the differential diagnosis?
(g) What investigations would you do to confirm it?
(h) How would you classify this condition?
(i) Discuss the pathophysiology and common causes?
(j) Outline your management plan for this patient. Please fully manage him if all
the facilities were available.

22.A 35-year-old female teacher presents with 2 weeks’ complaint of general

fatigue. She had previously been well, her past medical history is unremarkable
and thought that it was work related fatigue. When it persisted, she came to see
you in the OPD.

You examined her and note that she is stable, not pale nor jaundiced but has
generalized lymphadenopathy and splenomegaly. The rest of examination is
unremarkable.

You obtain the following lab results:

WBC 98 x109/L with 90% lymphocytes
Monocyte 1%
Eosinophils 2%
RBC 4.28 x 1012/L
Hb 14.7
Platelet 240 x 109/L

(e) What is the possible diagnosis for this patient?

(f) What additional investigations are you going to order to confirm your
diagnosis?
(g) List 3 differentials
(h) Outline your management plan

23.A 27-year-old female with SLE is in remission. Last year she had a life-
threatening exacerbation of her disease. She is currently well controlled and her
treatment consists of azathioprine 75mg/d and prednisolone 5mg/d. She comes
for review and now strongly desires to become pregnant.
(e) Discuss the clinical manifestations of SLE

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(f) Discuss the pathogenesis of SLE
(g) What investigations do you do in SLE and discuss relevance?
(h) What advice would you give her on her desire to conceive?

24.A 20-year old male presents with a 3-day history of lethargy and generalized
malaise. He is confused and looks very unwell. His past medical history is
unremarkable and he is HIV negative. On examination, you found a rapid feeble
pulse with hypotension and cold extremities. He is tachypnoeic with clear lungs.
Abdominal examination is normal.

The following blood tests are obtained:

Blood gasses:
PH: 7.0
Bicarbonate 11mmol/L (22-30)
PCO2 20mmHg (35-45)

Electrolytes:
Potassium 2.7
Sodium 153
Chloride 124

Creatinine 70mol/L
Urea: 5.2 mmol/L
Glucose 52mmol/L

(g) What further history would you like to get from the bedside?
(h) Describe the acid-base balance
(i) What is the diagnosis?
(j) What electrolyte abnormalities does the patient have?
(k) What further tests would you order in this patient?
(l) How are you going to manage this patient?

25.A 25-year-old patient was admitted to the Emergency Room with easy
fatigability. His past medical history is remarkable for tooth extraction two weeks
ago. He also reports history of fever on and off. On examination his temperature
is 37.8oC and BP 120/80mmHg. He is pale with tinge of jaundice. His chest is

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clear and he has pansystolic murmur at the apex. Abdominal examination reveals
splenomegaly. Urinalysis shows red blood cells in urine.
(e) What is your working diagnosis?
(f) What investigations would you do to confirm it?
(g) What criteria is used to diagnose this condition?
(h) Outline your management plan for this patient. Please fully manage him if all
the facilities are available.

26.A 54-year-old man presents to his primary care provider with dyspnea and a
cough. He is a non-smoker with no relevant occupational exposures.

Lung function test results are as follows:

Pre-Bronchodilator (BD) Post-BD
Bronchodilator
Test Actual Predicted % Predicted Actual % change
FVC (L) 3.19 4.22 76 4.00 25
FEV1 (L) 2.18 3.39 64 2.83 30
FEV1/FVC (%) 68 80 71 4
(b) Describe the pattern of abnormality, if one is present
(c) Grade the severity of the abnormality
(d) What would be the management of this patient?

27.A 52-year-old woman with heart disease presents with shortness of breath, easy
fatigability and swollen feet. She has longstanding hypertension and takes
medicine when she feels unwell. She has been taking 2 bottles of wine on
weekends for the past 6 years but denies history of smoking. She feels her
condition is getting worse and can’t now climb stairs at her place. On examination
you noticed that her heart rate is 70 beats per minute irregular and her blood
pressure is 100/60mmHg. Her JVP is raised, her chest is clear but she has tender
hepatomegaly and pitting pedal edema. The doctor makes a diagnosis of heart
failure.

(e) List the common causes of heart failure in our settings

(f) What is the pathophysiology of heart failure?
(g) What two investigations would you do to confirm this diagnosis?

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(h) Which therapeutic modalities have been shown to improve survival in heart
failure?

28. A 23-year-old male patient is brought to the emergency room with history of
malaise and headache. Apart from history of palpitations and constipation, his
past medical history was apparently unremarkable. His blood pressure on
admission was 210/124mmHg. He had hyperpigmented lesions on the trunk. The
mini-mental test score was 8/10. Both heart sounds were normal and chest was
clear. He had tender liver and pitting edema of lower extremities. Fundal
examination revealed grade III retinopathy. Urinalysis shows protein +++ and
glucose trace. You obtain the following lab results: Hb 9g/dl, platelets 120 x
109/L, Urea 28 mmol/L, Sodium 138 mmol/L, potassium 7.4 mmol/L

(a) Discuss this patients’ clinical presentation and lab results

Answer:
This is a patient that is having chest complaints (palpitations) with a very high
blood pressure (210/124 mmHg- severe hypertension) suggesting a
hypertension as an underlying condition. The fact that he is having headaches
with a mini-metal test score of 8/10 is highly suggestive of hypertensive
encephalopathy and the brain involvement as end-organ damage as a
complication of the hypertension. Furthermore, the other target organ that
seems to be involved are the kidneys as evidenced by the proteinuria 3+, lower
extremity pitting edema, the rise in urea (28 mmol/L), and the rise in
potassium (7.4mmol/L). Additionally, the factor that he is having malaise,
headache, hyperpigmented lesions on the trunk, a tender liver and constipation
could signify an infectious process with Typhoid fever being very likely
though it would require further investigations to justify. The patient also has
a low Hemoglobin and platelets

(b) What is the diagnosis?

Answer: Hypertensive emergency

(c) What further investigations would you order?

Answer:
 Blood:
o RDT for malaria
o Widal antigen test: to rule out typhoid fever

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o Blood culture: to rule out any underlying infection, or sepsis
o Clotting panel to rule out any underlying coagulopathy
o Lipid profile: check for serum cholesterol, triglycerides, LDLs and
HDLs
o Liver function test: to check for the integrity of the liver
o Cross match: because of low hemoglobin and platelets
 Imaging
o Abdominal X-ray: to rule out intestinal obstruction
o Abdominal ultrasound: to visualize and rule out any liver, kidney or
abdominal pathology
o ECG and ECHO in view of the palpitations and extremely high
blood pressure to check on the functionality of the heart. The ECG
also to look out for arrhythmias due to hyperkalemia

(d) Outline your management plan

Answer:
 Admit patient
 Control blood pressure
o Hydralazine 10mg IV stat followed by 5mg IV every 30 minutes
until diastolic pressure is less than 110mmHg (or Labetalol 50mg
IV over at least a minute repeated after 5 minutes if necessary with
a maximum dose of 200mg)
 Note: sodium nitroprusside 0.5-8micrograms/kg/min
continuous IV infusion till diastolic BP<110mmHg
o Add furosemide 40mg IV stat dose
o When diastolic blood pressure <110mmHg give Nifedipine 20mg
PO BD
o Check blood pressure before each administration of hydralazine
o Daily blood pressure measurements and daily weighing
 For the hyperkalemia give
o 10mls of 10% calcium gluconate in 10 minutes to protect the heart.
Repeat effect after 15 minutes
o 50mls of 50% dextrose over with insulin 10IU intravenously over
15minutes repeat after 2-4 hours if potassium is still raised
o Give furosemide 1mg/kg IV
o If present Kayexalate can be used
o Continuous ECG monitoring

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o Continuous potassium monitoring
o If above measures failure refer for hemodialysis
 Cover on antibiotics: ceftriaxone 1g IV BD while awaiting blood culture
and Widal antigen test results
 Repeat Urinalysis, Urea, electrolytes and creatinine after blood pressure
controlled. Serial measurements if they are still deranged
 Before discharge counsel patient on diet (DASH diet), reduced salt intake,
exercise and lifestyle modification
 Discharge on Nifedipine 20mg PO BD and review in a week to check
blood pressure and look out for any other new developments.

29.Chanda a 24-year-old man is admitted complaining of headaches and confusion.

His headache had developed over the past 3 weeks and has become progressively
more severe. The headaches are now persistent and diffuse. He has lost 10Kg in
weight over 6 months and has recently become increasingly more confused. His
speech is slurred. While in AMEU he has a generalized tonic-clonic convulsion.

Examination reveals that he is wasted and weighs 55kg. His temperature is

38.5oC and has oral candidiasis but has no lymphadenopathy. Prior to the fit
neurological exam showed him to be disoriented in time place and person with
no focal neurological signs. Fundoscopy shows papilledema. The rest of the exam
is normal. You order an HIV test and comes out positive for HIV-1.

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(a) What would be the cause of this man’s headaches, confusion and fits? (name
3)
Answer:
 Cryptococcal meningitis
 CNS Toxoplasmosis
 Neurosyphilis
 Tuberculous meningitis

(b) What is his HIV WHO clinical stage?

Answer: WHO Stage 4

(c) Why is his sodium low and why is he having papilledema?

Answer:
The low sodium may be attributed to the CNS opportunistic infection that
causes release of ADH (syndrome of inappropriate ADH secretion) which
retains water resulting in a Euvolemic type of hyponatremia and because of
the CNS opportunistic infection and reabsorption of water there is increased
intracranial pressure leading to papilledema.

(d) What further test should you order

Answer:
 Lumbar puncture for:
o CSF microscopy, culture and sensitivity
o CSF biochemistry
 Rapid diagnostic test for malaria
 Rapid plasma reagin (RPR) for syphilis
 Serum cortisol
 CT/MRI of the brain
A CT was done and the following Image was obtained

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(e) What is the most likely diagnosis?

Answer: CNS Toxoplasmosis
(f) How would you treat this man and include the dosing?
Answer:
 Regimen one: Loading dose of pyrimethamine 200mg (loading dose
200mg, then 50mg daily) combined with sulfadiazine (2-4g/day) and
folinic acid (10-20mg/day)
 Regimen two: Fansidar (Pyrimethamine 25mg + Sulfadoxine 500mg) +
Folinic acid 10-20mg/day
o Dose: 525mg (2 tabs) PO BD for 2 days and then 1-tab PO/day, if
patient is very critical add Doxycycline 100 PO BD.
 Note: Clindamycin and pyrimethamine may be used in patients allergic to
sulphonamide
o Regimen 3: Pyrimethamine and Folinic acid plus Clindamycin
450mg 8 hourly
 Duration of treatment is 6 weeks or 3 weeks after complete resolution of
lesions on CT.
 Continue suppressive therapy for life: Pyrimethamine 25mg/day +
Sulfadiazine 2g/day + folinic acid 5-10mg/day.

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HAART should be initiated as soon as the patient is clinically stable,
approximately 2 weeks after acute treatment has begun to minimize the risk
of IRIS.

Also administer: dexamethasone 8mg IV stat and then 4mg IV DIQ till the
suppressive/maintenance therapy: Fansidar 1 tab per day should be continued.
Suppressive therapy (Secondary prophylaxis) can be stopped when the CD4
count is more than 200 for 6 months.

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INDEX

ATN. See Acute tubular necrosis

A Autoimmune hepatitis, 325

Acute interstitial nephritis, 311

Acute kidney injury, 301 B
Acute tubular necrosis, 308
Acute tubulointerstitial necrosis. See Acute tubular Bed side urinalysis. See Urinalysis
necrosis Bruit, 47
AKI. See Acute kidney injury Budd-Chiari syndrome, 306
Alcoholic cirrhosis, 329
Alcoholic fatty liver, 328 C
Alcoholic hepatitis, 328
Alcoholic liver disease, 328 Cardiomyopathies, 92
Alpha-1 antitrypsin deficiency, 260 Cardiovascular examination, 35
Anemia, 200 Cholangiocarcinoma, 304
Ascites, 296 Chronic hepatitis, 276

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Chronic Kidney Disease, 323 Hypertrophic cardiomyopathy, 96
Chronic liver disease, 276
CKD. See Chronic Kidney disease
Congestive cardiomyopathy. See Dilated cardiomyopathy
I
Convulsion, 418
Intrarenal failure. See Intrarenal uremia
Cushing’s syndrome, 346
Intrarenal uremia, 306
Iron deficiency anemia, 206
D

Demographic data, 17
J
Diabetes mellitus, 360
Jaundice, 264
Dilated cardiomyopathy, 94
Dipstick. See Urinalysis
Drug induced hepatitis, 327 K

KDIGO Staging, 301

E

End-stage renal disease. See Chronic Kidney Disease L

Epilepsy, 418
ESRD. See Chronic Kidney Disease Liver, 298
Liver cirrhosis, 278
Liver disease, 298
F Liver tumors, 302
Fulminant hepatic failure, 274
M
G Malaria, 485
Megaloblastic anemia, 139
Glomerulopathies, 302
Metabolic liver disease, 257
Glomerulopathy, 302
Mitral stenosis, 50
Murmur, 47
H

HAV. See Hepatitis A virus

N
HBV. See Hepatitis B virus
Nephritic syndrome, 317
HCC. See Hepatocellular carcinoma
Nephrotic syndrome, 304, 305
HCV. See Hepatitis C virus
New York Heart Association Functional classification, 35
HDV. See Hepatitis D virus
Non-Alcoholic fatty liver disease, 330
Hepatic encephalopathy, 286
Non-verbal communication, 8
Hepatitis A virus, 309
Hepatitis B virus, 313
Hepatitis C virus, 319 P
Hepatitis D virus, 321
Hepatitis E virus, 321 Pain, 15
Hepatitis G virus, 322 Physical examination, 27
Hepatocellular carcinoma, 302 Portal hypertension, 291
Hepatoma. See Hepatocellular carcinoma Porto-pulmonary hypertension, 290
Hepatopulmonary syndrome, 290 Postrenal failure. See Postrenal uremia
Hepatorenal syndrome, 300 Postrenal uremia, 311
Hereditary hemochromatosis, 257 Pre-renal failure. See Pre renal uremia
HEV. See Hepatitis E virus Pre-renal uremia, 302
HGV. See Hepatitis G virus Primary benign liver tumors, 302
History taking, 16

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Internal medicine
Tuberculosis, 216
R

Rapidly progressive glomerulonephritis, 321 U

Renal papillary necrosis, 311
Restrictive cardiomyopathy, 99 Urinalysis, 309
RIFLE classification, 301 Urinary Tract Infection, 337
UTI. See Urinary Tract Infection

S
V
SBP. See Spontaneous bacterial peritonitis
Secondary liver tumors, 305 Valvular heart disease, 50
Seizure, 418 Variceal hemorrhage, 292
Sideroblastic anemia, 129 Verbal communication, 8
SOCRATES, 15 Viral hepatitis, 308
Spontaneous bacterial peritonitis, 299

W
T
Wilson Disease, 262
Thalassemia, 130

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