EVALUATION OF CREATINE KINASE AS A DIAGNOSTIC

TOOL FOR
THYROID FUNCTION

DISSERTATION SUBMITTED FOR

M.D GENERAL MEDICINE

BRANCH – I

MAY2018

THE TAMIL NADU

Dr. M G R MEDICAL UNIVERSITY, CHENNAI

TAMIL NADU, INDIA

1
 CERTIFICATE FROM THE DEAN

This is to certify that the dissertation entitled “EVALUATION OF CREATINE KINASE

AS A DIAGNOSTIC TOOL FOR THYROID FUNCTION” is the bonafide work of Dr. N.EZHILin

partial fulfilment of the University regulations of the TamilNadu Dr. M.G.R Medical

University, Chennai for M.D General Medicine Branch I examination to be held in May

2018.

Dr. D. MARUTHUPANDIAN M.S, FICS,

FAIS
The Honorable Dean
Madurai Medical College
Govt. Rajaji Hospital
Madurai

2
 CERTIFICATE FROM THE HOD

This is to certify that the dissertation entitled “EVALUATION OF CREATINE KINASE

AS A DIAGNOSTIC TOOL FOR THYROID FUNCTION” is the bonafide work of Dr. N.EZHILin

partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R Medical

University, Chennai for M.D General Medicine Branch I examination to be held in May 2018.

Dr. V.T. THEOPHILUS PREMKUMAR, M.D.,

H.O.D & Professor of Medicine
Department Of General Medicine,
Government Rajaji Hospital,
Madurai Medical College, Madurai.

3
 CERTIFICATE FROM THE GUIDE

This is to certify that the dissertation entitled “EVALUATION OF CREATINE KINASE

AS A DIAGNOSTIC TOOL FOR THYROID FUNCTION” is the bonafide Work ofDr. N.EZHILin

partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R Medical

University, Chennai for M.D General Medicine Branch I examination to be held in May 2018.

Dr. G. BAGIALAKSHMI, M.D.,

Professor of Medicine,
Department Of General Medicine,
Government Rajaji Hospital,
Madurai Medical College, Madurai.

4
 DECLARATION

I, Dr. N.EZHILsolemnly declare that this dissertation“EVALUATION OF CREATINE

KINASE AS A DIAGNOSTIC TOOL FOR THYROID FUNCTION”is a bonafide record of work

done by me at the Department of General Medicine, Govt. Rajaji Hospital, Madurai under

the guidance of Dr.G.BAGIALAKSHMI, MD, Professor. Department of General Medicine

Madurai Medical College. Madurai.

This Dissertation is submitted to the Tamil Nadu Dr. M.G.R Medical University in

partial fulfilment of the rules and regulations for the award of M.D GENERAL MEDICINE

DEGREE BRANCH–I examination to be held in May 2018.

DATE:

PLACE: MADURAI (Dr. N.EZHIL)

5
 ACKNOWLEDGEMENT

I would like to thank our respected DeanProf. Dr. D.MARUTHUPANDIANM.S,

FICS, FAIS, Madurai Medical College for permitting me to utilize the facilities of

Madurai Medical College and Government Rajaji Hospital for this dissertation.

I wish to express my respect and sincere gratitude to my beloved teacher

and Head of the Department, Prof. Dr. V.T. THEOPHILUS PREMKUMAR, M.D.,

and Professor of Medicine for his valuable guidance and encouragement during

the study and also throughout my course period.

I would like to express my deep sense of gratitude, respect and thanks to

my beloved Unit Chief and Professor of Medicine, Prof.Dr.G.BAGIALAKSHMI,

M.D., for her valuable suggestions, guidance and support throughout the study

and also throughout my course period.

I am greatly indebted to the Professors, Dr. R. BALAJINATHAN M.D., Dr.

M. NATARAJAN M.D, and Dr.J. SANGUMANI M.D, Dr.DHARMARAJ M.D.

andDr.R.PRABHAKARAN, M.D., for their valuable suggestions throughout

thecourse of the study.

I sincerely thank the Assistant ProfessorsDr.P.SARAVANAN M.D.,

Dr.S.KRISHNASAMY PRASAD M.D. for their guidance and suggestions in this

dissertation work.

I sincerely thank all the staffs of department of medicine for the timely

help rendered to me whenever and wherever needed.

6
 I extend my thanks to all my friends, batch mates, my junior and senior

colleagues who have stood by me and supported me throughout my study and

course period.

Finally, I thank all the patients, who form the most vital part of my work,

for their extreme patience and co-operation without whom this project would

have been a distant dream and I pray to God for their speedy recovery.

7
 CONTENTS

Sl. PAGE
CONTENTS
NO NUMBER

1 INTRODUCTION 1

2 AIM OF THE STUDY 29

3 REVIEW OF LITERATURE 30

4 MATERIALS AND METHODS 52

5 RESULTS AND ANALYSIS 56

6 CONCLUSION 74

7 ANNEXURES

I. PROFORMA

II. MASTER CHART

III. ABBREVIATIONS

IV. BIBLIOGRAPHY

V. ETHICAL COMMITTEE CERTIFICATE

VI. ANTI-PLAGIARISM CERTIFICATE

8
 INTRODUCTION

Thyroid disorders are one of the most common endocrinological

disorders among general population. Thyroid gland secretes T3(tri iodo

thyronine), T4(thyroxine) hormones, which plays a role in basal metabolic rate,

growth, development and tissue differentiation.

ANATOMY OF THYROID

Thyroid gland consists of

 A midline isthmus lying parallel just below the cricoidcartilage

 Right and left, two lateral lobes that extend superiorly, infront of neck

giving the look of a butterfly.

 The gland is fully enclosed by pre tracheal fascia, under the strapmuscle,

which makes the gland move up with deglutition.

HISTOLOGY OF THYROID

 Thyroid gland is divided by thin fibrous septa into pseudolobules

 These pseudolobules are composed of vesicles otherwise

calledfollicles or acini, are densely surrounded by a capillary

network.

 Follicular walls are surrounded by cuboidal epithelium

 Protenaceous colloidal material is filled within the lumen offollicles

which contain the unique protein called thyroglobulin.

9
 The peptide sequences of T4 and T3 are stored and synthesized

ascomponent of thyroglobulin.

DEVELOPMENT OF THYROID

 Develops from the ectoderm of the floor of the pharynx with

somecontribution from the lateal pharyngeal pouches.

 The thyroglossal duct, which extends from the foramen caecumnear the

base of the tongue to the isthmus of the thyroid arise fromdescent of the

midline thyroid anlagen.

 The posterior aspect of the thyroid gland becomes associated withthe

parathyroid gland and the para follicular C cells, during thedevelopment,

which are derived from ultimo-bronchial body,which become

incorporated into its substance.

 While they experience malignant transformation, the C cells are

thesource of the calcitonin and gives to medullary thyroid carcinoma.

 At about 10-12 weeks of intra uterine life, the foetal thyroid beginsto

concentrate and organify iodine.

 Maternal TSH and T4 do not cross the placenta, but the maternalTRH

crosses the placenta.

 The major source of thyroid hormone in the foetal life is T4 fromthe

foetal thyroid.

 The functional unit is foetal pituitary – thyroid axis which isdistinct

from that of mother.

10
PHYSIOLOGY OF THYROID GLAND

Thyroid secretes three hormones – thyroxin (T4), triiodothyronine(T3)

and clacitionin. Thyroid follicles secrete the first two hormones,have similar

biological activity and the term “thyroid hormones” ispertinent to these 2

hormones only. Calcitonin is chemically andbiologically dissimilar entirely and

is secreted from parafollicular C cells. It regulates calcium metabolism and it is

considered along with parathormone.

Thyroid hormone contains iodine. Iodine enters the thyroid in theform

of inorganic or organic iodide is oxidized by a peroxidise enzyme atthe cell –

colloidal interface. Subsequent reactions results in formation ofthyroxin. The

only source of T4 is thyroid gland. Thyroid secretes 20% ofT3; extra glandular

tissues produce the remaining amount by theperipheral conversion of T4 into

T3.

CHEMISTRY AND SYNTHESIS OF THYROID HORMONE

Both T4 and T3, which is a condensation product of 2 molecules

oftyrosine are iodine containing derivatives of thyronine.Thyroxine (T4) - 3, 5,

3’, 5’ – tetraiodothyronineT3 - 3, 5, 3’ – triiodothyronineThyroid hormones are

synthesized and stored in thyroid folliculesas part of thyroglobulin molecule

which is a glycoprotein synthesized inthyroid cells, contains 10% of sugar,

MW 660 KDa. There are 5 steps insynthesis of thyroid hormones.

11
1. IODIDE UPTAKE OR IODIDE TRAPPING : Iodine fromperipheral

circulation is taken into the follicles by active transportprocess called Na

+ I – symporter or NIS. Iodine content of follicleregulates the iodide

trap. Meagre storage activates and largestorage inhibits this trap. This

method is mediated by TSH.Percholarate, thiocyanates and nitrates

inhibits this trapping.

2. OXIDATION AND IODINATION : “Iodide trapped by follicularcells is

transported by one another transporter across the apicalmembrane called

as “pendrin” and oxidized by thyroid peroxidaseenzyme present in

follicular membrane and forms iodinium ions(I+) or hypoiodous acid

(HOI) or enzyme linked hypoiodate (E-OI)with the help of H2O2.These

various forms of iodine bound avidly with thyroglobulin and forms

monoiodothyrosine (MIT) and diiodotyrosine (DIT).

3. COUPLING : Pairs of iodinated tyrosine residues forms T3 and T4by

coupling with one another. Coupling belongs to oxidativereaction and is

catalysed by the same thyroid peroxidise. Oxidationand Coupling, both

reactions are regulated by TSH.

4. STORAGE AND RELEASE : Tyrosil residues are stored asthyroid

colloid. These materials are taken back into follicular cellsby

endocytosis and undergo lysosomal proteolysis then realised asT4 and

T3. This colloidal uptake and proteolysis are mediated byTSH. At rest,

follicles filled with colloid has flat or cuboidal epithelium and TSH

stimulated follicles have columnar cells, colloid emptied.

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 5. PERIPHERAL COVERSION OF T4 TO T3: Conversion

occurspredominantly in kidney and liver. One third of T4

undergoesconversion and most of T3 in plasma is derived from liver.

Targetorgans take up T3 for metabolic functions except brain

andpituitary which take up T4 and converts in to T3 by their owncellular

mechanisms.

RELATION BETWEEN T3 AND T4

 Normally thyroid secretes more amount of T4 compared to T3. Butthis

difference is reduced in iodine deficient state.

 Normally T4 is the major circulating form because it is avidly

boundwith plasma proteins 15 times more.

 T3 is five times more potent than T4.

 T3 acts very faster than T4.

 Peak effect of T3 comes earlier (1-2 days), but peak effect of T4comes

later (6-8 days).

 T3 is more tightly bound to the nuclear receptors than T4 and the

T4receptor complex is not able to activate or depress the

genetranscription.

 About one third of T4 is converted in to T3 in peripheral tissues, inliver

and kidney, by D1 type of 5’ Deiodinase (D1 type 5’ DI) andreleased in

to circulation. But in addition, T3 is generated within thetarget cells like

skeletal muscles, brain, pituitary and heart, by anotherenzyme type

13
 called type 2 deiodinase (D2 type 5’ DI). T4 is convertedin to

metabolically active T3 or inactive reverse T3 (r T3).

 T4 and T3 metabolized in liver by conjugation with glucuronate

andsulfate. Enzyme inducers such as phenobarbitone, Carbamazepine

andphenytoin increase the metabolic clearance of the hormones

withoutdecreasing the proportion of free hormones in the circulation.

 Finally, T3 is an active form. T4 is a transport form i.e.precursor ofT3.

 Normal daily secretion of T3-10-30 mcgm. T4-60-90 mcgm.

 T3 and T4 bound with 3 plasma proteins – they are

 Thyroxin binding globulin (TBG)

 Thyroxin binding pre albumin (Transthyretin)

 Albumin

 Plasma t 1⁄2 of T3 is 1-2 days; of T4 is 6-7 days. The half life is

increased in hypothyroidism and shortened in hyperthyroidism due to

enhanced and blunted metabolism respectively.

 Thyroid is the only source of T4”.

LABORATORY EVALUATION

Measurement of Thyroid Hormones

The TSH levels change dynamically in response toalterations of T4 and

T3. The first approach to thyroid testing is to firstfind out whether TSH is

normal, suppressed or elevated. With very rareexceptions, a normal TSH level

excludes a primary abnormality ofthyroid function. The enhanced sensitivity

14
and specificity of TSH assayshave greatly improved laboratory assessment of

thyroid function.

Immune chemi-lluminometric assays (ICMAs) for TSH aresensitive

enough to discriminate between the suppressed values that occurwith

thyrotoxicosis and the lower limit of the reference range. Extremelysensitive

(fourth –generation) assays can detect TSH levels 0.004 mU/L,are enough. The

TRH stimulation test is now obsolete because of thewidespread availability of

the TSH ICMA. Also there is often a failure ofTSH to rise after an intravenous

bolus of 200-400 mcg.

The finding of an abnormal TSH level should then be followed

bycirculating thyroid hormone levels to correctly diagnose

hypothyroidism(elevated TSH) or hyperthyroidism (Suppressed TSH).

Radioimmunoassays are widely available for serum totalT4 and totalT3. T4

andT3 are highly protein-bound. Medications, illness, genetic factors etc.

Can influence protein binding. So the free or unbound hormone

levels,which correspond to the biologically available hormone pool should

bemeasured next.

This is because total thyroid hormone level is not affected bychanges in

serum binding protein affinity. Serum TSH level is the firstline of investigation

in the diagnosis of primary hypothyroidism andhyperthyroidism. However the

test is not diagnostic in secondary thyroiddysfunction.

15
Thyroid hormones level in various clinical conditions

CONDITION FREE T3 FREE T4 TSH

Subclinical
Normal Normal Increased
hypothyroidism

Subclinical
Normal Normal Low
hyperthyroidism

Primary
Increased Increased Undetectable
hyperthyroidism

Primary
Low or normal Low High
hypothyroidism

Secondary

Hyperthyroidism Increased Increased Increased/normal

(TSHoma)

Secondary
Low/normal Low Low/normal
Hypothyroidism

T3 toxicosis Well increased Normal Undetectable

16
 But the thyroid hormonal assays are prone for alteration and interaction

in various clinical conditions. None of these parameters have provento be ideal

as their measured levels tend to vary in conditions like pregnancy, use of oral

contraceptives, protein wasting diseases, liver disease, certain drugsand

heparin, etc. The inherent limitations of these parameters necessitate the

establishment of alternate markers and enzymes like transaminases,

lactatedehydrogenase (LDH) and creatine (CK). Among these, CK has shown

promising results as a diagnostic tool for thyroid disease. Serum CK was first

used as a diagnostic aid inprogressive muscular dystrophy. It has since then

become important clinical marker for muscle damage. The serum CK levels in

healthy individuals dependon age, race, lean body mass and physical activity.

Musculoskeletal disorders often accompany thyroid dysfunction. In addition to

well-known observationthat musculoskeletal disorders are common in patients

with hypothyroidism, they are also observed in thyrotoxicosis and level of CK

is altered in both theseconditions.

17
 METABOLIC
INCREASED DECREASED
PROCESS

Androgens,

Heroin, Estrogens, Glucocoricoids,

Binding proteins
Clofibrate Phenytoin,

Carbamazepine

T4 synthesis / release Iodine Lithium, Iodide

Frusemide,

Amiodarone,

T4 / T3 binding in mefenamic acid, beta

serum blockers,

glucocorticoids,

Salicylates

Rifampicin
T4 metabolism
Anticonvulsants

Phenytoin,

TSH secretion Amiodarone Glucocoticoids,

dopamine agonists

18
REFERENCE VALUES

T3-77-135ng/dl

T4- 5.5- 12.5mcg/dl

TSH- 0.5-5.5mIU/L

CPK- 50-150 U/L

Maternal Thyroid Function During Pregnancy

Normal pregnancy entails substantial changes in thyroid function in all

animals. These phenomena have been studied most extensively in humans, but

probably are similar in all mammals. Major alterations in the thyroid system

during pregnancy include:

 Increased blood concentrations of T4-binding globulin: TBG is one of

several proteins that transport thyroid hormones in blood, and has the

highest affinity for T4 (thyroxine) of the group. Estrogens stimulate

expression of TBG in liver, and the normal rise in estrogen during

pregnancy induces roughly a doubling in serum TBG concentratrations.

 Increased levels of TBG lead to lowered free T4 concentrations, which

results in elevated TSH secretion by the pituitary and, consequently,

enhanced production and secretion of thyroid hormones. The net effect

of elevated TBG synthesis is to force a new equilibrium between free

and bound thyroid hormones and thus a significant increase in total T4

and T3 levels. The increased demand for thyroid hormones is reached by

about 20 weeks of gestation and persists until term.

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 Increased demand for iodine: This results from a significant pregnancy-

associated increase in iodide clearance by the kidney (due to increased

glomerular filtration rate), and siphoning of maternal iodide by the fetus.

The World Health Organization recommends increasing iodine intake

from the standard 100 to 150 ug/day to at least 200 ug/day during

pregnancy.

 Thyroid stimulation by chorionic gonadotropin: The placentae of

humans and other primates secrete huge amounts of a hormone called

chorionic gonadotropin (in the case of humans, human chorionic

gonadotropin or hCG) which is very closely related to luteinizing

hormone. TSH and hCG are similar enough that hCG can bind and

transduce signalling from the TSH receptor on thyroid epithelial cells.

Toward the end of the first trimester of pregnancy in humans, when

hCG levels are highest, a significant fraction of the thyroid-stimulating

activity is from hCG. During this time, blood levels of TSH often are

suppressed, as depicted in the figure to the right. The thyroid-stimulating

activity of hCG actually causes some women to develop transient

hyperthyroidism.

 Hyperestrogenemic states, including pregnancy, cause an increase in

serum T4-binding globulin (TBG) concentrations and an increase in the

proportion of TBG molecules with greater anodal mobility on isoelectric

focusing, indicating greater sialic acid content. The possible causal

relationship between the degree of sialylation and accumulation of TBG

20
 in serum was explored by measuring the in vivo half-lives (t½) of TBGs

with different isoelectric points. TBG in unfractionated serum and its

major peaks, isolated by chromatofocusing and defined by their

isoelectric points on isoelectric focusing were each injected iv into rats.

The resulting TBG concentrations, measured by specific RIA in serum

samples obtained at intervals after injection, were used for the

calculation of the t½. TBG in serum from a pregnant woman had a

significantly longer t½ of 17.2 ± 1.2 h (mean ± SD) compared to those

of 13.3 ± 1.5 and 12.9 ± 0.9 h for TBG in serum from a man and a

nonpregnant woman, respectively. TBG peaks II, III, IV, and V, with

increasing anodal mobility, had progressively longer t½ values of 11,

13, 15, and 33 h, respectively. However, TBG peaks of the same

mobility on IEF isolated from serum of pregnant or nonpregnant

subjects had similar t½values. Neither the TBG concentration nor

estrogen had a direct effect on the rate of TBG clearance. Indeed, the t½

of TBG from a subject with inherited TBG excess was not different

from that of TBG from a nonpregnant woman or a man. Chronic

treatment of rats with estradiol did not alter the rate of clearance of

injected human TBG. Finally, the more heavily sialylated anodal bands

of purified but unfractionated serum TBG, analyzed by Western blots,

survived longer in the circulation of a rat.

 These results indicate that the rate of in vivo metabolism of TBG is

dependent on its sialic acid content. The increased proportion of TBG

21
 molecules with higher sialic acid content thus contributes to the increase

in the serum TBG concentration in hyperestrogenemic states”.

THYROXINE-BINDING GLOBULIN

TBG is a glycoprotein with a molecular mass of about 54 kDa, about

20% of which is carbohydrate, encoded by a 3.8-kb transcript located on the X

chromosome. The protein sequence of TBG resembles that of the serpin family

of serine antiproteases. Because there is one iodothyronine binding site per

TBG molecule, the T4 or T3 binding capacity of TBG in normal human serum

is equivalent to its concentration, which is approximately 270 nmol/L

(1.5 µg/dL). The half-life of the protein in plasma is about 5 days. A congenital

deficiency of TBG is common, occurring in 1/5000 newborns, and is associated

with the complete absence of the protein in males. l-Asparaginase blocks the

synthesis of TBG, which accounts for the low T4concentrations in patients

receiving this agent.

The glycosylation of TBG influences its clearance from the plasma and

its behavior during isoelectric focusing. In estrogen-treated patients, there is an

increase in the prevalence of the more acidic bands of TBG. The more highly

sialylated TBG is cleared more slowly from plasma than is the more positively

charged TBG, because sialylation inhibits the hepatic uptake of glycoproteins.

Sera from pregnant patients, women receiving oral contraceptives, and patients

with acute hepatitis have increased fractions of acidic TBG. Patients with

inherited TBG excess have normal amounts of highly sialylated TBG, as do

men and nonpregnant women. Because TBG is the principal T4- and T3-

22
binding protein, changes in TBG or its binding are paralleled by changes in

total plasma T4 and T3 even though T4 and T3production is little changed.

Another post-translational modification affecting TBG occurs in septic

patients or following cardiopulmonary bypass surgery. TBG is subjected to

cleavage by a serine protease released from polymorphonuclear leukocytes,

resulting in the release of a 5-kDa carboxy-terminal loop with a consequent

decrease in affinity for T4. An analogous reaction has been described for

cortisol-binding globulin, which releases cortisol at the site of inflammation. It

has been postulated that the released T4might play a critical role in the

response to injury perhaps by providing a supply of iodine for antibacterial

purposes. The cleaved TBG of approximately 49 kDa circulates, and because it

binds T4 with lower avidity, it may explain the increased ratio of free to bound

T4 in acute illness, even when TBG saturation studies or immunoassays

indicate TBG concentration is normal

THYROID FUNCTION TEST IN CRITICALLY ILL

The metabolic support of the critically ill patient is a relatively new

target of active research and little is as yet known about the effects of critical

illness on metabolism. The nonthyroidal illness syndrome, also known as the

low T3 syndrome or euthyroid sick syndrome, describes a condition

characterized by abnormal thyroid function tests encountered in patients with

acute or chronic systemic illnesses. The laboratory parameters of this syndrome

include low serum levels of triiodothyronine (T3) and high levels of reverse

T3, with normal or low levels of thyroxine (T4) and normal or low levels of

23
thyroid-stimulating hormone (TSH). This condition may affect 60 to 70% of

critically ill patients. The changes in serum thyroid hormone levels in the

critically ill patient seem to result from alterations in the peripheral metabolism

of the thyroid hormones, in TSH regulation, in the binding of thyroid hormone

to transport-protein and in receptor binding and intracellular uptake.

Medications also have a very important role in these alterations. Hormonal

changes can be seen within the first hours of critical illness and, interestingly,

these changes correlate with final outcome. Data on the beneficial effect of

thyroid hormone treatment on outcome in critically ill patients are so far

controversial. Thyroid function generally returns to normal as the acute illness

resolves.

DRUG INDUCED THYROID DYSFUNCTION

“Drug-induced thyroid dysfunction should be considered when thyroid

function test results are inconsistent with the clinical scenario or when a patient

is taking a medication known to commonly disrupt thyroid function. Pseudo-

abnormalities in thyroid function tests should be differentiated from true

thyroid dysfunction. Certain drugs or agents can cause either or both of these

abnormalities and understanding their potential thyroidal effects will help the

clinician to appropriately manage the patient.

The use of certain drugs or agents have the potential to interfere with

various steps of thyroid hormone metabolism which results in hypothyroidism

or hyperthyroidism:

24
  Thyroid hormone absorption (in patients already taking levothyroxine

[LT4] therapy)

 Hypothalamic and pituitary regulation of thyroid hormone production

 Thyroid hormone synthesis and production

 Binding of T4 and T3 (triiodothyronine) to serum carrier proteins,

mainly thyroxine binding globulin (TBG)

 Thyroid hormone pharmacokinetics

 Thyroid hormone pharmacodynamics (e.g. interference with the

conversion of T4 to T3 in peripheral target organs)

Thyroid dysfunction can be transient or permanent, depending on the

specific drug or agent, status of iodine nutrition, and presence or absence of

any pre-existing autonomous thyroid nodules, subclinical thyroid dysfunction,

and thyroid autoantibodies.

Because primary hypothyroidism (e.g. Hashimoto's disease) or

hyperthyroidism (e.g. Graves' disease, toxic multinodular goiter, silent

thyroiditis) are common, the distinction between drug-induced and primary

thyroid dysfunction cannot always be easily made. Clinical judgment should

dictate whether the suspected drug should be withdrawn and how the thyroid

dysfunction should be further investigated and treated.

25
General considerations regarding drug-induced hypothyroidism

The clinical presentation of drug-induced hypothyroidism is

indistinguishable from other causes of hypothyroidism. The types of drug-

induced hypothyroidism are:

 Impaired levothyroxine absorption arising from use of calcium, iron,

bile acid sequestrants, coffee, sulcralfate, aluminum hydroxide, and

sevelamer (to minimize this, patients should be encouraged to take their

levothyroxine in the morning on an empty stomach to reduce the risk of

interaction)

 Transient hypothyroidism, similar to the hypothyroid phase of painless

thyroiditis (silent lymphocytic thyroiditis), which normalizes after

withdrawal of the drug or agent

 Permanent hypothyroidism (with or without detectable thyroid

autoantibodies)

 Similarly, symptoms and signs resulting from drug-induced

hyperthyroidism are indistinguishable from causes of spontaneous

hyperthyroidism. The types of drug-induced hyperthyroidism are:

 Transient hyperthyroidism, similar to the hyperthyroid phase of painless

thyroiditis (silent lymphocytic thyroiditis)

 Hyperthyroidism due to Graves' disease (with or without positive TSH

receptor antibodies)

 Hyperthyroidism arising from an iodine load in a patient with thyroid

nodules

26
Use of certain drugs may result in altered thyroid hormone metabolism and

require higher doses of replacement LT4 to achieve a normal TSH.

 Increased hepatic enzymes from certain antiepileptic medications

(phenobarbital, carbamazepine or phenytoin) and the antibiotic,

rifampicin, may reduce the half-lives of T4 and T3

 Imatinib (a tyrosine kinase inhibitor used to treat certain cancers) is

thought to increase the hepatic metabolism of thyroid hormone

 Drugs that increase thyroxine binding globulin (TBG) levels (e.g.

estrogens) will reduce the availability of FT4

 Amiodarone impairs the peripheral de-iodination of T4, and therefore,

the conversion of T4 to T3

 Glucocorticoids and some beta blockers at high doses can also inhibit

T4 toT3 de-iodination, although these changes are not usually clinically

relevant”

Creatine (CK) - also known as creatine phospho (CPK) or phospho-

creatine - is an enzyme expressed by various tissues and cell types. CK

catalyses the change of creatine and utilizes adenosine triphosphate (ATP) to

create phosphocreatine (PCr) and adenosine diphosphate (ADP). This CK

enzyme reaction is reversible and thus ATP can be generated from PCr and

ADP.

In tissues and cells that consume ATP rapidly, especially skeletal

muscle, but also brain, photoreceptor cells of the retina, hair cells of the inner

ear, spermatozoa and smooth muscle, PCr serves as an energy reservoir for the

27
rapid buffering and regeneration of ATP in situ, as well as for intracellular

energy transport by the PCr shuttle or circuit. Thus creatine is an important

enzyme in such tissues.

Clinically, creatine is assayed in blood tests as a marker of damage of

CK-rich tissue such as in myocardial infarction (heart attack), rhabdomyolysis

(severe muscle breakdown), muscular dystrophy, autoimmune myositides, and

acute kidney injury.

Contents

TYPES

In the cells, the "cytosolic" CK enzymes consist of two subunits, which

can be either B (brain type) or M (muscle type). There are, therefore, three

different isoenzymes: CK-MM, CK-BB and CK-MB. The genes for these

subunits are located on different chromosomes: B on 14q32 and M on 19q13.

In addition to those three cytosolic CK isoforms, there are two mitochondrial

creatine isoenzymes, the ubiquitous and sarcomeric form. The functional entity

of the latter two mitochondrial CK isoforms is an octamer consisting of four

dimers each.

28
 While mitochondrial creatine is directly involved in formation of

phospho-creatine from mitochondrial ATP, cytosolic CK regenerates ATP

from ADP, using PCr. This happens at intracellular sites where ATP is used in

the cell, with CK acting as an in situ ATP regenerator.

Gene Protein

CKB creatine, brain, BB-CK

CKBE creatine, ectopic expression

CKM creatine, muscle, MM-CK

CKMT1A, CKMT1B creatine mitochondrial 1; ubiquitous mtCK; or mtCK

CKMT2 creatine mitochondrial 2; sarcomeric mtCK; or mtCK

Isoenzyme patterns differ in tissues. Skeletal muscle expresses CK-MM

(98%) and low levels of CK-MB (1%). The myocardium (heart muscle), in

contrast, expresses CK-MM at 70% and CK-MB at 25–30%. CK-BB is

predominantly expressed in brain and smooth muscle, including vascular and

uterine tissue.

29
 FUNCTIONS

The mitochondrial creatine is present in the mitochondrial

intermembrane space, where it regenerates phosphocreatine (PCr) from

mitochondrially generated ATP and creatine (Cr) imported from the cytosol.

Apart from the two mitochondrial CK isoenzyme forms, that is, ubiquitous

mtCK (present in non-muscle tissues) and sarcomeric mtCK (present in

sarcomeric muscle), there are three cytosolic CK isoforms present in the

cytosol, depending on the tissue. Whereas MM-CK is expressed in sarcomeric

muscle, that is, skeletal and cardiac muscle, MB-CK is expressed in cardiac

muscle, and BB-CK is expressed in smooth muscle and in most non-muscle

tissues. Mitochondrial mtCK and cytosolic CK are connected in a so-called

PCr/Cr-shuttle or circuit. PCr generated by mtCK in mitochondria is shuttled to

cytosolic CK that is coupled to ATP-dependent processes, e.g. ATPases, such

as acto-myosin ATPase and calcium ATPase involved in muscle contraction,

and sodium/potassium ATPase involved in sodium retention in the kidney. The

bound cytosolic CK accepts the PCr shuttled through the cell and uses ADP to

regenerate ATP, which can then be used as energy source by the ATPases (CK

is associated intimately with the ATPases, forming a functionally coupled

microcompartment). PCr is not only an energy buffer but also a cellular

transport form of energy between subcellular sites of energy (ATP) production

(mitochondria and glycolysis) and those of energy utilization (ATPases). Thus,

CK enhances skeletal, cardiac, and smooth muscle contractility, and is involved

in the generation of blood pressure.

30
LABORATORY TESTING

CK is often determined routinely in a medical laboratory. It is used

specifically in patients with chest pain but this test has been replaced by

troponin. Normal values at rest are usually between 60 and 174 IU/L, where

one unit is enzyme activity, more specifically the amount of enzyme that will

catalyze 1 μmol of substrate per minute under specified conditions

(temperature, pH, substrate concentrations and activators.) This test is not

specific for the type of CK that is elevated.

Creatine in the blood may be high in health and disease. Exercise

increases the outflow of creatine to the blood stream for up to a week, and this

is the most common cause of high CK in blood. Furthermore, high CK in the

blood may be related to high intracellular CK such as in persons of African

descent. Finally, high CK in the blood may be an indication of damage to CK-

rich tissue, such as in rhabdomyolysis, myocardial infarction, myositis and

myocarditis. This means creatine in blood may be elevated in a wide range of

clinical conditions including the use of medication such as statins; endocrine

disorders such as hypothyroidism; and skeletal muscle diseases and disorders

including malignant hyperthermia, and neuroleptic malignant syndrome.

Furthermore, the isoenzyme determination has been used extensively as

an indication for myocardial damage in heart attacks. Troponin measurement

has largely replaced this in many hospitals, although some centers still rely on

CK-MB.

31
32
 AIM OF THE STUDY

 To evaluate the role of creatine (CK) as a diagnostic tool in thyroid

disorders

 To show that increased CK in hypothyroidism is not only because of

prevalence of muscular dystrophy in hypothyroidism but also due to role

of free T3 in gene expression, resulting in elevated CK in

hypothyroidism and low CK in hyperthyroidism.

 To correlate elevated CK to subclinical myopathy in hypothyroidism

33
 REVIEW OF LITERATURE

The decreased serum levels of triiodothyroinine (T3) and thyroxine (T4)

in hypothyroid patients is well established but whether there is any correlation

of creatinephospho kinase (CPK) with hypothyroidism is not well established.

There is a paucity of reference on this study. Therefore a study of serum CPK

and thyroid profile was carried out in thyroid diseases by the dept of

biochemistry, ajmer which was published in Indian journal of biochemistry. “In

hypothyroid patients T3, T4 levels in serum were found to be lowered with an

increase level of thyroidstimulating hormone (TSH) associated with marked

rise in serum CPK level. In hyperthyroid patients serum levels ofT3, T4 were

found to be increased with decrease in TSH with significant decrease in

creatine phospho level. Serum creatine phospho levels thus show an inverse

relation with serum T3, T4 levels”.

Lima GH et al, evaluated retrospectively 6,230 laboratory results of

TSH and CPK from 2007 to 2011. From these, 3,369 had free T4 results. They

evaluated the correlation between CPK and TSH and the pathological states of

the thyroid. A positive correlation was found between serum CPK and TSH,

and a negative correlation between CPK and FT4. CPK was lower in the group

with hyperthyroidism, and greater in that with hypothyroidism.

A study by Goldman J, Matz R, Mortimer R, Freeman R on the title

“High elevations of creatine phosphokinase in hypothyroidism isoenzyme

analysis, described six hypothyroid patients with extreme elevations (17- to

34
160-fold) of CPK levels. Enzyme analysis showed only MM isoenzyme in four

cases and MM plus trace MB isoenzyme in two patients. Hypothyroidism

should, therefore, be considered when elevated CPK levels, even extreme, are

found. Isoenzyme analysis in such a case will show primarily an MM pattern,

although trace MB fraction can also be seen. This isoenzyme pattern suggests

that the sources of the CPK elevations is skeletal muscle.

A study by KMDS Panag*, Gitanjali*, Sudeep Goyal** significant

increase in CK levels was found as compared to control group (190 ± 40 IU/l in

hypothyroid patients and 100 ± 70 IU/l in control group). A negative

correlation was also found between FT3 and CK (r = –0.51; p < 0.005). In

patients of hyperthyroidism, the levels of CK were found to be on the lower

side. It was concluded that CK measurements may be useful as alternative

diagnostic tool for the diagnosis of thyroid function disorders, which may be

not only because of prevalence of muscular dystrophies in thyroid disorders but

also due to role of FT3 in gene expression.

Serum CK was first used as a diagnostic aid in progressive muscular

dystrophy. It has since then become important clinical marker for muscle

damage. The serum CK levels in healthy individuals depend on age, race, lean

body mass and physical activity. Musculoskeletal disorders often accompany

thyroiddysfunction. In addition to well-known observation that musculoskeletal

disorders are common in patientswith hypothyroidism, they are also observed

in thyrotoxicosis and level of CK is altered in both these conditions. In recent

years, studies have been conducted to establish a relationship of CK levels in

35
thyroid diseases. Skeletal muscle is affected by hypothyroidism more

profoundly in cases of overt hypothyroidism and less so when subclinical

hypothyroidism is present. Thus, it follows that assay of CK activity in serum

may prove to be valuable in screening of thyroid disorders and in the present

study, we tried to evaluate the role of CK as an alternative diagnostic tool in

patients of thyroid disorder. The study was done at GGS Govt. Medical

College, Faridkot, Punjab. The study group comprised of 100 patients

randomly selected from patients coming for thyroid function tests in the

biochemistry diagnostic laboratory. There were 60 hypothyroid cases and 40

hyperthyroid cases. Fifty age, sex and socioeconomic status matched persons

were taken as controls. Exclusion criteria was taken to rule out other diseases

which can alter the results of study like cardiovascular, neuromuscular

involvements, recent cerebral stroke, gross hepatic or renal dysfunction and

pulmonary infarction. All patients were screened for any drug history,

especially drugs which can affect CK or thyroid hormone levels. Recent history

of intramuscular injections, strenuous exercise was ruled out.

A study by Klein I, Mantell P, Parker M, Levey GS on the title

Resolution of abnormal muscle enzyme studies in hypothyroidism, followed

Seven patients with increased thyroid stimulating hormone (TSH) and elevated

CPK levels during replacement by oral l-thyroxine or l-thyroxine plus

triiodothyronine. Data in three patients demonstrate a fairly constant rate of fall

in CPK with a half-time for disappearance of approximately ten to 12 days. The

36
normalization of muscle enzymes often precedes the correction of elevations in

TSH.

A study by Finsterer J1, Stöllberger C, Grossegger C, Kroiss A on the

title “Hypothyroid myopathy with unusually high serum creatine kinase values,

showed that depending on the degree of hormone deficiency, skeletal muscle

involvement may occur in hypothyroidism. Usually, hypothyroid myopathy is

associated with creatine kinase values <5,000 U/l. they reported a 54-year-old

man suffering from increasing fatigability, hoarseness, gait disturbances and a

creatine kinase of 9,000 (normal: <80 U/l). He presented with bradyphrenia,

macroglossia, dysarthria, myxedema, monoparesis, reduced deep tendon

reflexes and stocking-type sensory disturbances. Free triiodthyronine was 0.25

pg/ml (normal: 0.6-1.9 pg/ml), free thyroxine <0.1 ng/dl (normal: 0. 6-1.8

ng/dl) and the thyroid-stimulating hormone >48.0 (normal: 0. 1-4.0 IU).

Clinical neurologic examination and electromyography were compatible with

myopathy and polyneuropathy. Other causes of myopathy, except

hypothyroidism, were excluded. After L-thyroxine therapy (1.7 microg/kg

BW/day) during 3 months, the patient's symptoms and signs vanished, except

for sensory disturbances, and creatine kinase values and electromyography

became normal. Severe hypothyroidism may be associated with highly elevated

creatine kinase and myopathy. Adequate therapy leads to complete recovery,

including myopathy.

Madhu SV1, Jain R, Kant S, Prakash V, Kumar V in the study

“Myopathy presenting as a sole manifestation of hypothyroidism”, Myopathy

37
as the sole manifestation of hypothyroidism is rare although muscle weakness,

aches and cramps, stiffness and delayed tendon jerk relaxation are the usual

features of hypothyroid associated myopathy. We describe a patient with

primary hypothyroidism, presenting solely with a clinical picture of myositis

with very high levels of creatine (CPK), which normalised after 12 weeks of

treatment with levothyroxine

Aslam H1, Sayeed MA1, Qadeer R1, Afsar S presented a case of

Hypothyroidism simulating as polymyositis. Polymyositis-like syndrome in

hypothyroidism is a rare condition characterised by proximal muscle weakness

and elevated muscle enzymes. Patients with this condition can initially be

misdiagnosed as having polymyositis due to similar characteristics of both

diseases; however a response to thyroxine is the main differentiating feature.

This report highlights the case of a 30-year-old male who had severe myalgia

and proximal muscle weakness. In addition to raised creatinine (CPK) levels,

his biochemical profile showed hypothyroidism. Initially thought to be

suffering from polymyositis, improvement in both clinical and biochemical

profile with thyroxine led to the diagnosis of polymyositis-like syndrome

associated with hypothyroidism

KMDS Panag*, Gitanjali*, SudeepGoyal** studied the correlation of

thyroid function test with CPK.Sixty hypothyroid and 40 hyperthyroid patients

were compared with 50 age, sex and sociocoeconomic status matched healthy

controls. In hypothyroid patients, significant increase in CK levels was found

as compared to control group (190 ± 40 IU/l in hypothyroid patients and 100 ±

38
70 IU/l in control group). A negative correlation was also found between FT3

and CK (r = –0.51; p < 0.005). In patients of hyperthyroidism, the levels of CK

were found to be on the lower side

G.Rupa, G.Assalatha, N.Geetha, in the title “AN APPROACH TO

EARLY DETECTION OF THYROID DYSFUNCTION ASSOCIATED

WITH MYOPATHIES” the results are as follows.Inhypothyroid patients,

T3/T4 serum levels were found lowered with increased TSH levels(100%)

along with marked rise in CPK levels(84%) whereas hyperthyroid cases

showed an increase(T3/T4 serum levels) with decrease in TSH( 96%) and CPK

levels; and thus confirming, an inverse relation between Serum CPK levels and

T3/T4 levels.

Hence concluded that, Hypothyroidism reduces ability of muscles to

maintain its energetic economy leading to myopathy causing elevation of CPK

levels while a decrease in thegeneration of enzyme is the cause in

hyperthyroidism.

A study by shimada sl, kasai k studied A clinical evaluation of the

increased serum myoglobin: creatine phosphokinase and lactic dehydrogenase

in patients with thyroid disorders “Since muscle dysfunction is frequently

associated with a hypothyroid state, many clinical reports have indicated that

serum enzyme activities derived from the muscle such as creatine

phosphokinase (CPK), lactic dehydrogenase (LDH) and glutamic-oxaloacetic

transamynase (GOT) are elevated. These enzyme activities in the serum of

hyperthyroidism, euthyroidism and hypothyrodism have been known to have a

39
good inverse correlation with protein-bound iodine (PBI). Therefore, as part of

a study of the relationship between thyroid states and muscle tissue, values of

serum myoblobin (Mb) were measured by RIA. The values of Mb in untreated

hyperthyroidism were significantly lower (P<0.01) and, in untreated

hypothyroidism, Mb values were significantly higher (p<0.001) than in normal

subjects. There was a significant inverse correlation (p<0.01) between T4 or T3

concentration and Mb levels in these subjects. The relationship found between

either Mb and LDH or Mb and CPK was also studied in the present study, and

it was found that Mb significantly correlated to both LDH and CPK (P<0.001).

Abnormalities of these enzyme levels in serum returned to the normal range

rapidly after the correction of the abnormal thyroid states in each patient””

A study by kedzia A, kryziak R, madej A, okopien B on the title “Is

every case of muscle damage during hypolipemic therapy the side effect of this

therapy? A case report”showed that “Hypolipemic agents, both statins and

fibrates, may cause a spectrum of side-effects, including the transient increase

in creatine phosphokinase (CPK) activity. Muscle injury may present as

common myalgia, non-specific myositis with normal CPK levels, myopathy

and in the most serious cases, as rhabdomyolysis. Muscle damage is much

more probably in patients with concomittant kidney and liver diseases,

hypothyroidism, and serious infections or after some injuries or a heavy

physical effort. On the other hand, one of the most common causes of

secondary hypercholesterolemia and myopathy is hypothyroidism. This

condition, which may enhance the risk of muscle damage in the course of

40
hypolipemic treatment, may sometimes present with an atypical clinical

presentation, making its diagnosis challenging. In this article, we present the

case of a 50-year-old male physical worker presented with marked

dyslipidemia, in whom myopathy was diagnosed during therapy with

hypolipemic agents. Cessation of the treatment resulted in the only moderate

reduction of CPKactivity. Only just the introduction of thyroid hormone

supplementation led to regression of symptoms and normalization of

abnormalities found in laboratory examinations including remarkable

improvement in lipid profile. After several months of observation we consider

that hypolipemic treatment probably revealed previously occult autoimmune

thyroid disease in this patient”.

In accordance with the article Hypothyroid myopathy. Clinico-

pathologic study of 20 cases “20 patients afflicted with primary

hypothyroidism were studied in order to evaluate the association of clinical or

sub-clinical myopathy, detected by neurophysiological (electromyography)

(EMG) or neuropathological methods (muscular biopsy with enzymatic study).

70% of the patients had muscular weakness (moderate in 30% and severe in

40%) of the scapular and pelvic muscles. 60% of the patients had muscular

cramps. There was no myodema nor muscular atrophy or hypertrophy. Seric

CPK was high in 70% of the cases. EMG was myopathic in 65%. All cases

with weakness registered EMG alterations. The histological findings were

import findings were important. The enzymatic techniques showed alterations

of the fiber subtypes in 90% of the cases.

41
 The type I fibers had sarcolemmal and mitochondrial accumules in 85%

and 70% had areas without oxidative activity, similar to "core". In this study,

we did not find any correlation between the evolution time of hypothyroidism,

hormonal levels, CPK increase, and muscular weakness. The EMG was

myopathic in cases with severe weakness, however, in patients with moderate

weakness it could also prove abnormal. There was no correlation between the

electric myopathic pattern, CPK levels and thyroid hormones.

A study by Heffron JJ, Mitchell G in the topic” Diagnostic value of

serum creatine phosphokinase activity for the porcine malignant hyperthermia

syndrome” showed that “Serum creatine phosphokinase (CPK) activity was

measured in 10 German Landrace pigs from 11 to 28 weeks of age. A

pronounced age dependence of serum enzyme activity was observed, peak

activity occurring at 19 weeks of age. At the end of the growth period, when

the pigs were challenged with halothane to detect the malignant hyperthermia

syndrome, 3 pigs were found to be susceptible. Singificant increases in the

serum enzyme levels in the susceptible pigs were observed only at 11 and 28

weeks of age. Serum enzyme levels measured during the rapid phase of growth

could not be used to predict the malignant hyperthermia syndrome. Elevated

serum CPK levels were also observed in two litters of Large White and

Landrace x Large White pigs, breeds known to be stress-resistant. No pigs in

these litters were susceptible to halothane, even though CPK levels were

similar to those of the German Landrace pigs. The results indicate that serum

42
CPK levels can be used as evidence of predisposition to the malignant

hyperthermia syndrome but cannot be relied on as a single ultimate test.”

The ROC curves demonstrated a significant discriminatory ability of

both increased total CPK and decreased CPK-MB% ratio for the diagnosis of

E.

Determination of CPK isoenzyme fractions can significantly enhance

the diagnostic value of total maternal CPK in the prediction of ectopic

pregnancy.

SPECIFIC CONSIDERATIONS WHEN INTERPRETING TFT

THYROID FUNCTION TESTS IN HYPOTHYROIDISM

43
44
THYROID FUNCTION TESTS IN HYPERTHYROIDISM

45
Clinical context/thyroid status

As a general rule, thyroid function tests should only be requested when

there are specific clinical features that require a primary disorder of

hypothalamic–pituitary–thyroid function to be ascertained. Measuring TH

and/or TSH concentrations when there is a low index of suspicion for HPT

dysfunction risks the possibility of TFTs that confound, and a train of

inappropriate investigations and management (e.g. in non-thyroidal illness).

Accordingly, when apparently anomalous TFTs occur, the first step is to

reappraise the patient's clinical status as this will help guide further

management. Importantly, many clinical laboratories provide generic reference

ranges for T4, T3 and TSH, despite increasing evidence that this may not be

appropriate, with, for example, ethnicity, iodine intake, gender, age, and body

mass index influencing the reference range of serum TSH, while pregnancy is

associated with major changes in both TH and TSH concentrations.

Non-thyroidal illness

A common pitfall in the interpretation of thyroid function tests is to

overlook the confounding effects of ‘non-thyroidal illness’ (NTI). NTI (or sick

euthyroid syndrome) is a relatively common finding following any acute or

chronic illness, and is defined by the absence of an intrinsic abnormality of

HPT function – rather it is considered a secondary adaptive change. Whether it

is a beneficial response (e.g. to reduce metabolic rate) or a maladaptive

response (with potential benefit from TH replacement therapy) has been much

46
debated, but compelling evidence for the use of T3 or T4 therapy in the

majority of patients with NTI is currently lacking.

Changes in TH (especially T3) and TSH may be seen as early as 24 h

after the onset of non-thyroidal illness, and have been observed in subjects with

poor nutrition/starvation, sepsis, burns, malignancy, myocardial infarction,

post-surgery, and with chronic liver and renal disease. NTI can be

characterized by a variety of abnormal TFT patterns, which may evolve/change

with progression or resolution of the underlying primary disorder. Many

commercial assays for free TH typically return low (or low-normal) FT4 and

FT3, with normal or low (but rarely fully suppressed) TSH. However, elevated

FT4 may also be found, and it is not uncommon for the same sample to yield

markedly discordant FT4 concentrations when run on different assay platforms,

reflecting methodological differences/limitations. Where total TH

concentrations are measured, reductions in TT4, and in particular TT3, are

common even in mild NTI, and are usually more marked than the

corresponding decreases in free hormone concentrations (likely reflecting

reduced serum TH binding capacity in acute and chronically ill patients,

secondary to a fall in TH binding protein concentrations and/or impaired T4/T3

binding). The magnitude of T4 decrease has been reported to correlate with a

less favourable outcome, and mortality can be as high as 80% when TT4 drops

below 26 nmol/L . When measured, reverse T3 (rT3) is usually raised.

In subjects with acute, major psychiatric illness, raised T4 with non-

suppressed TSH is sometimes observed, but usually resolves spontaneously

47
within a short time frame (<2 weeks); in others, TSH may be elevated or

suppressed but without accompanying abnormalities of T4 or T3.

There remains considerable debate regarding the precise mechanisms

underpinning NTI, with changes noted at all levels in the pathway of TH

synthesis/secretion, transport, cellular uptake and action. These include, but are

not restricted to: reduced hypothalamic TRH secretion from paraventricular

nuclei ; impaired pituitary TSH secretion; decreased TH binding capacity in

serum ; reduced tissue/cellular uptake of T4 and T3; altered deiodinase activity

with reduced DIO1, but increased DIO2 and DIO3 (although findings in DIO3

knockout and DIO1/DIO2 knockout mice suggest altered deiodinase activity

may be a consequence, rather than a cause, of the changes that occur in T4 and

T3) ; and altered thyroid hormone receptor expression/signalling (e.g. reduced

in skeletal muscle) .

The mediators of such changes are also much debated, but pro-

inflammatory cytokines (including IL-1, IL-6, TNF-α) have been implicated in

NTI in a variety of infectious, inflammatory and neoplastic states. In addition,

the reduction in leptin levels that accompanies malnutrition may directly impair

hypothalamic TRH secretion. A role for excess endogenous glucocorticoids has

also been postulated, while the use of exogenous corticosteroid therapy and

dopamine (see below) in critically ill patients may further suppress pituitary

TSH release.

During recovery from intercurrent illness, TH and TSH concentrations

return to normal, although in some patients TSH may become overtly elevated

48
for a short period of time. This rise in TSH typically precedes the increase in

T4 and T3 concentrations, suggesting that it is required for the restoration of

euthyroidism .It is important to be aware of this transient phenomenon in order

to avoid inappropriate diagnosis and treatment.

Pregnancy

Pregnancy has a significant impact on HPT physiology and may be

associated with marked changes in serum thyroid hormone and thyrotropin

concentrations. Under normal circumstances, about two thirds of circulating T4

is bound to TBG. During pregnancy TBG levels rise as a consequence of

oestrogen-induced increased hepatic synthesis, together with reduced

degradation. Accordingly, serum total T4 and T3 concentrations increase to

approximately 150% of non-pregnant values – this occurs during the first half

of pregnancy and is maintained thereafter until parturition. Free T4

concentrations also change during pregnancy: in the first trimester a transient

rise is often observed and has been ascribed to the stimulatory effects of high

circulating levels of human chorionic gonadotrophin (hCG) acting on the TSH

receptor (TSH concentrations are correspondingly reduced, or even partially

suppressed). In its most extreme form (hyperemesis gravidarum), affected

women may become overtly thyrotoxic with a fully suppressed TSH. In this

setting, it is important to distinguish gestational hyperthyroidism from other

common causes of thyrotoxicosis (e.g. Graves' disease) as the management of

these conditions differs significantly. Measurement of anti-TSH receptor

antibody (TRAb) titres can be particularly helpful.

49
 As hCG levels decline, FT4 decreases and this has been shown to be a

genuine effect rather than the result of analytical interference. FT4

concentrations are often lower than those observed in the non-pregnant state,

which may lead to concern regarding the possibility of central thyroid

dysfunction if values are compared with non-pregnant reference ranges.

Changes in FT3 broadly parallel those of FT4. TSH levels are restored as hCG

levels fall in the second and third trimester.

In addition to the effects of fluctuating hCG levels and rising TBG, a

number of other mechanisms have been proposed to contribute to the

alterations in thyroid status observed in pregnancy, including an increased

circulating plasma volume, enhanced DIO3 activity (placental origin: increased

T4 & T3 degradation) and increased urinary iodine clearance (leading to goitre

in iodine-deficient regions)

Levothyroxine therapy

Although clinical and biochemical euthyroidism is readily restored in

the majority of patients treated with levothyroxine (L-T4), an important

subgroup manifests apparently anomalous TFTs, which can be a source of

considerable frustration and confusion both for patient and clinician alike.

Even after careful consideration of all of these factors, discrimination

between an as yet unidentified cause of true thyroxine malabsorption and poor

L-T4 compliance can prove difficult. In these circumstances, a formal

thyroxine absorption test may help resolve the issue.

50
Drug therapy

An array of commonly prescribed drugs may result in altered thyroid

function/status, either by modulating the HPT axis itself, or through

downstream effects on thyroid hormone transport or metabolism.

Altered TBG concentrations

In subjects with an intact HPT axis, drugs affecting TBG synthesis

typically result in changes in total but not free serum thyroid hormone

concentrations, although transient alterations in FT4 and FT3 have occasionally

been observed. Also, extreme changes in TBG concentrations can potentially

affect some FT4 assays (Moran, Gurnell, Halsall & Chatterjee, unpublished

observation). It is important to note that in patients on fixed dose L-T4 therapy,

an increase or decrease in the total number of serum T4 and T3 binding sites

necessitate an adjustment in levothyroxine dosage to maintain euthyroidism.

51
 Drugs that are recognised to increase serum TBG concentrations include

oral (but not transdermal) oestrogen, raloxifene, tamoxifen, mitotane,

fluorouracil, methadone and heroin. In contrast, androgens, chronic

glucocorticoid therapy and nicotinic acid have all been shown to inhibit TBG

synthesis.

T4 and T3 displacement from TH binding proteins

In contrast to the situation described above, where quantitative changes

in binding proteins bring about changes in total but not free TH concentrations,

the presence of agents in serum that are capable of displacing T4 and T3 from

their binding sites can alter hormone delivery and clearance and distort

diagnostic tests for FT4 and FT3. A number of commonly prescribed drugs

have been shown to bring about competition for TH binding sites on TBG,

albumin and transthyretin, including furosemide (especially with doses >80

mg/day and when given intravenously) aspirin, nonsteroidal anti-inflammatory

agents, phenytoin and heparin.

The effect of heparin on serum free TH measurements merits particular

consideration given the increasingly widespread use of low molecular weight

heparin thromboprophylaxis in modern medical and surgical practice. The

potential for heparin to raise free TH concentrations was first noticed by Schatz

and colleagues in 12 patients undergoing haemodialysis. To investigate this

further, they administered intravenous heparin to nine healthy controls and five

subjects with hypothyroidism, and were able to show a prompt (within 2–15

min) rise (up to five-fold) in FT4 concentrations, which could not be replicated

52
by adding a similar concentration of heparin to the sample in vitro, thus

confirming that this phenomenon is initiated in vivo.

Subsequent studies have shown that in heparin-treated subjects, serum

non-esterified fatty acid (NEFA) concentrations may increase markedly as a

consequence of heparin-induced activation of endothelial lipoprotein lipase in

vivo, leading to increased NEFA generation in vitro during sample storage or

incubation. In the presence of normal serum albumin concentrations, NEFA

concentrations >2–3 mmol/L exceed normal serum binding capacity, resulting

in direct competition for T4 and T3 binding sites on TBG either by NEFAs

themselves or as a result of displacement of other ligands from the albumin

sites that normally limit their free concentration.

Not surprisingly, this artefact is more pronounced when serum

triglyceride concentrations are elevated, in the presence of hypoalbuminaemia,

and with laboratory methods that require long incubation periods. Indeed, in

the presence of sufficient triglyceride substrate, even very low dose intravenous

heparin (equivalent to that used to maintain the patency of an indwelling

cannula), and subcutaneous low molecular weight heparin (LMWH)

prophylaxis can lead to FT4 (and FT3) elevation.

Moreover, the heparin effect has been observed with a variety of assay

platforms including equilibrium dialysis, ultracentrifugation, and direct

immunoassay.

53
 Ideally therefore, measurement of FT4 and FT3 is best avoided in

patients receiving heparin therapy. However, when indicated, taking a blood

sample more than 10 h after the last injection of heparin, and analysing it

without delay, can help reduce the risk of artifactual hyperthyroxinaemia,

although clinicians should bear in mind that small rises in free TH may be

inevitable in predisposed individuals. Alternatively, measurement of total TH

levels, together with TSH and TBG, can help confirm the patient's euthyroid

status when displacement is suspected.

54
 MATERIALS AND METHODS

STUDY POPULATION

This study is done in Madurai medical college, Madurai. This study

group comprises of50 patients randomly coming for TFT to endocrinology

OPD. There were 30 hypothyroid, 20 hyperthyroid patients. 25 age, sex,

socioeconomic status matched persons were taken as controls.

All patients are interviewed and clinically examined.

Informed consent will be obtained from all subjects for clinical

examination. Patient confidentiality will be maintained.

Inclusion criteria

All adult patients with newly detected hypothyroidism and

hyperthyroidism based on T3, T4, TSH were taken into this study

Exclusion criteria

• Cardiovascular disease

• Neuro muscular involvement

• Recent stroke

• Pulmonary infarction

• Drugs affecting CK and thyroid hormone levels

• Recent IM injections and exercise

• Abnormal Liver function test, and

• Abnormal Renal function test.

55
ANTICIPATED OUTCOME

The levels of CK are likely to be elevated in hypothyroidism, reduced in

hyperthyroidism as compared to normal individuals

DATA COLLECTION

A previously designed profoma will be used to collect the demographic

and clinical details of the patients. A thorough clinical examination and

laboratory investigations will be done after obtaining consent from the patient.

LABORATORY INVESTIGATIONS

• T3, T4, TSH

• Creatine phosphokinase

• ECG

• Renal function test

• Liver function test

DESIGN OF STUDY

Prospective observational study.

PERIOD OF STUDY

6 MONTHS (March 2017- August 2017)

COLLABORATING DEPARTMENTS

Department of biochemistry

Department of endocrinology

ETHICAL CLEARANCE: obtained

56
CONSENT: Individual written and informed consent.

ANALYSIS: STATISTICAL ANALYSIS.

CONFLICT OF INTEREST: NIL

FINANCIAL SUPPORT: NIL

PARTICIPANTS

50 patients randomly coming for TFT to endocrinology OPD. 25 age,

sex, socioeconomic status matched persons coming to medicine OPD were

taken as controls

PROFORMA

Name:

Age / Sex:

Occupation:

Presenting complaints:

H/o fatigability, H/o cold intolerance, H/o constipation ,

H/o palpitations, weight loss, tremors

H/o swelling of legs/abdominal distension, H/o burning micturition, H/o

jaundice

Past History:

H/o DM, HT, CKD, DRUG INTAKE, Thyroid disorders, Alcohol intake

Clinical Examination:

57
General Examination

Consciousness, Pallor, jaundice, Clubbing, Lymphadenopathy, hydration status

Vitals:

PR

BP

RR

SpO2

Systemic examination:

CVS:

RS:

ABDOMEN:

CNS:

Laboratory investigations

• T3, T4, TSH

• Creatine phosphokinase

• ECG

• Renal function test

• Liver function

58
 RESULTS AND ANALYSIS

This is a prospective observation study, data was collected for controls

from medicine OPD in govt rajaji hospital, Madurai. Data from cases were

selected from endocrinology OPD

This study group comprises 30 hypothyroid, 20 hyperthyroid patients

and 25 age and sex matched controls. Sample distribution in the study group is

shown in table 1 and figure 1

Their sex distribution is shown in figure 2,3,4

Sample size distribution in the study group{table 1}

Table 1

Number of Number of
Diagnosis Number of male
sample female
16
Hyperthyroid (1) 19 3

25
Hypothyroid (2) 31 6

22
Control (3) 25 3

63
Total 75 12

59
Figure 1

60
Sex Distribution – Figure 2

61
Figure 3

62
Sex Distribution- Figure 4

63
 The data was collected and entered into excel sheet. The descriptive and

inferential statistics was done using SPSS software. The data was segregated

based on the diagnosis into 3 categories: hypothyroidism, hyperthyroidism and

control. The summary of description for each diagnostic category was given

below.

Descriptive statistics of the data {Table 2}

Mean of
Mean Mean of Mean of Mean of
Diagnosis N CPK
age T3 T4 TSH

35.53 78.26
Hyperthyroid 20 159.16 38.21 0.07

32.84 1.99 48.48

Hypothyroid 30 43.68 195.81

33.32 98.08 7.59 2.39 90.44

Control 25

REFERENCE VALUES

T3-77-135ng/dl

T4- 5.5- 12.5mcg/dl

TSH- 0.5-5.5mIU/L

CPK-50-150 U/L

64
 On inferential analysis, the data (T3, T4, TSH, CPK) under each

diagnostic category (hyperthyroid, hypothyroid and control) was checked for

normality, and depending on whether the data is normally distributed or not,

selection of analysis was done. When the bivariate data was normally

distributed, Pearson correlation was done and when the bivariate data was not

distributed normally, spearman rank correlation was done between T3, T4,

TSH and CPK and tabulated individually.

HYPERTHYROIDISM ANALYSIS

The data was analyzed through SPSS and Shapiro-Wilk test of normality

was done for T3, T4, TSH and CPK. From Shapiro-Wilk test, TSH and CPK

were normally distributed as significance value is more than0.05 but T3 and T4

were not as the significance value is less than 0.05.

Test of normality for T3, T4, TSH and CPK for sample with hyperthyroidism.

Table - 3

Tests of Normality

Shapiro-Wilk

Statistic Df Sig.

T3 .860 20 .010

T4 .776 20 .001

Tsh .906 20 .063

Cpk .963 20 .632

65
 Pearson correlation was done between TSH and CPK, whereas

Spearman correlation was done between T3, T4 and CPK.

Table - 4

Correlation co-efficient table for T3, T4, TSH and CPK for sample with

hyperthyroidism.

Variables T3 T4 TSH

CPK -0.629** -0.513* 0.467*

* p<0.05

** p<0.001

Figure 5

From the table… showing the correlation coefficient of different

variables indicates that there is strong negative correlation between T3, T4 and

CPK (r=-.629 and r=-.513) at p < 0.001 and p < 0.05 level of significance

66
respectively. Whereas, there is a strong positive correlation between TSH and

CPK values (r=.467) at p < 0.05 level of significance in this given sample.

HYPOTHYROIDISM

The data was analyzed through SPSS and Shapiro-Wilk test of normality

was done for T3, T4, TSH and CPK. From Shapiro-Wilk test, T3 and TSH

were not normally distributed whereas, T4 and CPK were normally distributed.

Table - 5

Test of normality for T3, T4, TSH and CPK for sample with

hypothyroidism.

Shapiro-Wilk

Statistic Df Sig.

T3 .911 30 .014

T4 .958 30 .254

tsh .920 30 .024

cpk .975 30 .657

Pearson correlation was done between T4 and CPK, whereas Spearman

correlation was done between T3, TSH and CPK.

67
 Table - 6

Correlation co-efficient table for T3, T4, TSH and CPK for sample with

hypothyroidism

Variables T3 T4 TSH

CPK -.727** -.605** .715**

** P<0.001

Figure 6

From the above table showing the correlation coefficient of different

variables indicates that there is very strong negative correlation between T3, T4

and CPK (r=-.727 and r=-.605) both at p < 0.001 level of significance.

Whereas, there is a strong positive correlation between TSH and CPK values

(r=.715) at p < 0.001 level of significance in this given sample.

68
CONTROL….

The data was analyzed through SPSS and Shapiro-Wilk test of normality

was done for T3, T4, TSH and CPK. From Shapiro-Wilk test, T3, T4, TSH and

CPK were normally distributed as significance value is more than0.05

Table - 7

Test of normality for T3, T4, TSH and CPK for sample with control

Shapiro-Wilk

Statistic Df Sig.

T3 .936 25 .121

T4 .946 25 .199

tsh .946 25 .205

cpk .974 25 .752

Pearson correlation was done to compare between T3, T4, TSH and

CPK as all the data were normally distributed

Table - 8

Correlation co-efficient table for T3, T4, TSH and CPK for sample with

control

Variables T3 T4 TSH

CPK .002 .197 .144

69
 From the above table… showing the correlation coefficient of different

variables indicates that there is no correlation between T3, T4, TSH and CPK

(r= 0.002; r= 0.197; r= 0.144 respectively)

Distribution of CPK normality, increase, decrease in hypothyroidism

and hyperthyroidism were studied and tabulated so as to analyse their

usefulness as a diagnostic tool.

CPK in hypothyroidism

30 cases of newly detected hypothyroid patients were included in the

study and Evaluated. About 73.33% of hypothyroid cases had elevated CPK

levels. 26.67% of hypothyroid cases had normal CPK values.{figure 7}

Figure 7

70
CPK in hyperthyroidism

20 newly diagnosed hyperthyroid patients were taken into our study and

evaluated. 85% of cases had normal CPK values and 15% of cases had low

CPK values.

Figure 8

71
CPK in controls

Figure 9

Out of the 25 age and sex matched controls, 23 persons had normal

CPK, 1 person had elevated CPK and one person had less than normal CPK

value.

72
 DISCUSSION

Based on the results of the study mean age of study population is 34 yrs.

Controls were age and sex matched.pearson correlation was done between

TSH and CPK and showed a strong positive correlation (i-e as TSH increase in

hypothyroidism CPK proportionally increases)

Spearman correlation was done between T3 T4 and CPK, correlation

coefficient was calculated which established a negative correlation between T3

T4 and CPK. The statistical significance of the results were analyzed with chi-

square method.

In this study neuromuscular disorders were excluded, but still CPK

values were high, this may be due to subclinical myopathy or the role of T3 in

gene expression of CPK which explains its elevation even in the absence of

muscle disease.

Similar study was done by KMDS panag, geetanjali, sudeep goyal from

department of biochemistry. The study showed similar results but ths study was

performed in a larger population and they correlated CPK with FT3.

Hekimsoy et al in a study conducted in 2005, found that skeletal muscle

is affected by

Hypothyroidism more profoundly in cases of overt hypothyroidism as

compared tosubclinical hypothyroidism. Also, there was positive correlation

between CK and TSH (r= 0.432; p = 0.04), a negative correlation was found

between FT3 and CK (r = –0.556, p = 0.002). It was concluded that CK

73
measurements may be useful as alternative diagnostic tool for the diagnosis of

thyroid function disorders, which may be not only because of prevalence of

muscular dystrophies in thyroid disorders but also due to role of FT3 in gene

expression.

Giampietro et al in 1984, found myoglobin and CK to be the best

indicators of hypothyroid myopathy, since they are sensitive for the early

detection of muscle involvement due to metabolic disorder and are closely

correlated to the metabolic condition of patients. Scott et al in a study

conducted in 2002 showed that thyroid hormone replacement therapy resulted

in resolution of clinical symptoms and a marked reduction in CK levels in a

patient with progressive proximal weakness and serum CK level of over 29,000

IU/l. Such a high serum CK level in a patient with hypothyroidism underscores

the importance of assessing thyroid function in patients with weakness,

regardless of serum CK levels, even when systemic symptoms and signs of

hypothyroidism are minimal or absent. In casestudies, patients with

hypothyroidism solely presented with symptoms of myositis and very high

74
levels of CK which resolved after treatment for hypothyroidismand in a patient

of Grave’s disease, patient developed myalgia with high level of CK after total

thyroidectomy, the features were normalized after treatment and again

reappeared after treatment was stopped. These studies clearly show that

muscular involvement was there in thyroid disorders. In hypothyroid patients

with decrease in serum T3, there is significant increase in CK and this may be

in fact used as a parameter for screening hypothyroid patients.

75
LIMITATIONS OF THE STUDY

• The sample size is less

• The ratio of control: case is less. If the control population was more

the power of the study would have been improved

• Isoenzymes of CPK could not be done

• Too many exclusion criterias

76
 CONCLUSION

Its concluded from the above study that CPK may be used as a

supportive marker to diagnose hypothyroidism, especially in situations where

measured thyroid hormone levels are likely to vary like pregnancy, oral

contraceptives, drugs like heparin, protein wasting diseases etc.

It also shows the inverse correlation between T3 T4 and CPK which

may be explained by the role of T3 in gene expression.

77
FUTURE RECOMMENDATIONS

 Molecular studies are required to prove the role of T3 in gene

expression

 Large study population may show that CPK decreases in

hyperthyroidism at par with other studies

 Quantitative range of CPK elevation in hypothyroidism may be studied

further, so that CPK may be used as a screening tool to assess

hypothyroidism in a cases of myopathy.

78
 PROFORMA

Name:

Age / Sex:

Occupation:

Presenting complaints:

H/o fatigability, H/o cold intolerance, H/o constipation ,

H/o palpitations, weight loss, tremors

H/o swelling of legs/abdominal distension, H/o burning micturition, H/o

jaundice

Past History:

H/o DM, HT, CKD, drug intake, Thyroid disorders, Alcohol intake

Clinical Examination:

General Examination:

Consciousness, Pallor, jaundice, Clubbing, Lymphadenopathy, hydration status

Vitals:

PR

BP

RR

SpO2

Systemic examination:

CVS:

RS:

ABDOMEN:

79
CNS:

Laboratory investigations:

• T3, T4, TSH

• Creatine phosphokinase

• ECG

• Renal function test

• Liver function

80
 ANNEXURE

MASTER CHART

CASE AGE SEX T3 T4 TSH CPK DIAGNOSIS

pavithra 34 F 149 18.5 0.12 66 hyper
karuppaye 45 F 189 85 0.001 38 hyper
madhana 20 F 147 25.3 0.09 97 hyper
thennamal 45 F 168 42 0.015 104 hyper
gurupriya 28 F 158 27.1 0.096 78 hyper
Latha 35 F 145 15 0.12 56 hyper
kanmani 30 F 186 100 0.001 45 hyper
pandian 36 M 149 20.5 0.072 124 hyper
meenakshi 28 F 156 19.6 0.06 59 hyper
thirumagal 42 F 165 47 0.045 82 hyper
podhumponnu 52 F 184 96 0.001 47 hyper
savithri 45 F 145 26 0.08 96 hyper
ilamaaran 40 M 168 54 0.02 75 hyper
Ilaki 34 F 146 18.4 0.1 106 hyper
maheswari 28 F 170 52 0.002 51 hyper
abdulrahim 24 M 150 17.4 0.12 88 hyper
Pappa 31 F 147 18.5 0.2 96 hyper
padmasri 36 F 158 28 0.01 75 hyper
Rakku 42 F 144 15.6 0.1 104 hyper
Ponni 33 F 140 12.6 0.1 70 hyper
Jagan 40 M 41 1.05 76 300 hypo
maragadham 48 F 60 4.12 12 298 hypo
kanaga 25 F 52 3.1 44 82 hypo
manikam 33 M 60 2.1 25 145 hypo
kaliammal 39 F 14 0.21 100 320 hypo

81
lakshmi .p 41 F 22 1.5 78 254 hypo
Sangeetha 36 F 51 4.2 48 178 hypo
Lathamary 19 F 44 1.4 70 204 hypo
Lathiffa 23 F 56 2.8 30 140 hypo
mariyabeevi 37 F 67 2.65 15 67 hypo
Nancy 27 F 39 3.2 56 186 hypo
Rani 33 F 60 1.25 28 240 hypo
Abinaya 26 F 15 0.06 96 284 hypo
Ganesan 29 M 9 0.01 100 310 hypo
Chandra 39 F 41 1.5 58 168 hypo
Jesika 25 F 52 1.9 45 175 hypo
Jeslin 40 M 54 3.4 18 98 hypo
Nivetha 20 F 65 2.5 22 80 hypo
Saroja 41 F 32 0.96 65 254 hypo
Christi 37 F 33 1.45 42 178 hypo
Mupudathi 30 M 35 1.56 74 240 hypo
Hariharan 38 M 65 3.4 14 52 hypo
Salma 22 F 45 2.4 42 196 hypo
Catherine 38 F 10 0.12 100 408 hypo
Preethi 18 F 32 0.56 50 225 hypo
meenakshi .m 29 F 64 1.5 14 194 hypo
marudhayee 40 F 12 1.8 86 250 hypo
Karthika 35 F 56 2.1 32 190 hypo
Nirmala 52 F 65 3.3 10 128 hypo
Tessy 25 F 45 4.2 28 156 hypo
CONTROLS
Habiba 39 F 94 6.2 2.12 120 euthyroid
Kulanthai 48 M 89 8.4 2.2 86 euthyroid
Deepa 27 F 116 7.5 1.4 90 euthyroid
Ananthi 36 F 102 6.3 1 78 euthyroid

82
Lalitha 24 F 109 6.6 3.45 112 euthyroid
naachal 44 F 115 9.4 2 48 euthyroid
rahman 28 M 79 8.9 1.34 130 euthyroid
indurani 36 F 86 7.9 2.56 118 euthyroid
Ramya 30 F 114 8.5 1.67 98 euthyroid
kavitha 25 F 100 6.8 3.08 76 euthyroid
seeniammal 41 F 94 6.3 4.12 102 euthyroid
shanmugam 36 M 86 11.4 1.56 88 euthyroid
Kani 33 F 104 5.9 3.56 65 euthyroid
amirtham 40 F 125 6.5 2.12 95 euthyroid
catherine 21 F 94 7.2 2.34 100 euthyroid
sankari 31 F 84 10.3 1.98 114 euthyroid
velthai 54 F 102 5.2 3.12 56 euthyroid
roobini 25 F 95 4.5 3.45 97 euthyroid
Esaki 24 F 120 9.2 4.34 156 euthyroid
Akila 18 F 85 11.4 1.82 84 euthyroid
papathi 48 F 96 5.8 2.34 78 euthyroid
ramani 25 F 80 7.6 3.5 52 euthyroid
fathima 38 F 83 10.2 1.08 78 euthyroid
Rani 28 F 115 5.6 2.34 65 euthyroid
rajeswari 34 F 85 6.2 1.34 75 euthyroid

83
 ABBREVIATIONS

TSH - Thyroid stimulating hormone

T3 - Triiiodothyronine

T4 - Tetraiodothyronine

TH - Thyroid hormone

r T3 - Reverse triiodothyronine

CPK - Creatine phosphokinase

FT3 - Free T3

FT4 - Free T4

CK - Creatine kinase

TFT - Thyroid function test

TBG - Thyroid binding globulin

NEFA - Non esterified fatty acid

L-T4 - Levothyroxine

HPT - Hypothalamo pituitary thyroid

DIO - Deiodinase

NTI - Non thyroidal illness

EMG - Electromyography

ICMA - Immune chemiillumminometric assay

84
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