ENDOCRINE

FUNCTION TESTS

MA. LOURDES TILBE, D,F,PSP

Objectives

Review hormone regulation in health and disease

Types of endocrine testing Basic principles behind test Considerations in patient preparation and

specimen handling Interpretion of tests applying acquired

knowledge

Endocrine System

Composed of different glands that secrete hormones directly in the blood

Some hormones are regulatory in nature Trophic hormones, releasing hormones

Synthesis and secretion of each hormone is under continous feedback control in normal physiologic conditions

HYPOTHALAMUS

PITUITARY GLAND

EFFECTOR ORGAN

Feed

back

External stimuli

Releasing hormones

Trophic hormones

Diagnosis of Endocrine Disorders

Normally, hormone concentration in circulation falls within a predictable range

Most hormones are conveniently measured by RIA or other immunoassays.

Direct measurement of individual hormones in plasma or serum allows for screening and establishing diagnosis of most endocrine disorders. Determine hyperfunction or hypofunction Localize the diseased organ

Effector organ (primary) Pituitary Gland (secondary) Hypothalamus (tertiary)

Endocrine disorders

1o excess high target organ hormones; low trophic hormone

1o deficiencylow target organ hormone; high trophic hormone

2o excess high trophic hormone and hormones of target gland

2o deficiency low trophic hormone and hormones of the target gland

3o deficiency low trophic hormone and hormones of the target gland

Assessment of Hormone Function

1. Direct measurement of hormone concentrationA. Basal serum hormone levelsB. Hormone measurement in the urine.

Urinary excretion of hormone or its metabolite Corrects for fluctuations in blood levels Integrates value over longer period

2. Dynamic testsA. Suppressive tests for hormone excess (DST; Glucose ST)B. Stimulation test for hormone deficiency (Insulin Induced

Hypoglycemia to evaluate Hypothal-PG axis3. Image Studies

Anterior PG Post. PG.

Ad. cortex

Thyroid

Gonads

Breast

Multiple tissues of the body

Hypothalamus

TSH

GH

PRL

LH

FSH

ACTH

Cortisol

Male testosterone

Female estrogens/progesterones

ADH

Oxytocin

T4

T3

RF

HYPOTHALAMIC HORMONES

HORMONE REGULATION PHYSIOLOGIC ACTION

Corticotropin Releasing H

Negative feedback by ACTH and adrenal cortisol

Stimulates secretion of ACTH

Thyrotropin RH Negative feedback by TSH and thyroid H

Stimulates secretion of TSH and prolactin

HORMONE REGULATION PHYSIOLOGIC ACTION

GH Inhibiting H Positive feedback by GH

Inhibits secretion of GH and TSH

Gonadotropin RH Negative feedback by FSH and LH

Stimulates secretion of FSH and LH

Prolactin IH Positive feedback by prolactin, TSH, FSH, LH and GH

Inhibits secretion of prolactin, TSH, FSH, LH and GH

Growth H RH(Somatocrinin)

Negative feedback by GH

Stimulates secretion of GH

ANTERIOR PITUITARY HORMONES

Adrenocorticotrophic H (ACTH)

Regulation: Corticotrophic releasing hormone (CRH) causes

secretion in response to biorhythms with circadian variation

Production is regulated by glucocorticoid concentration via the negative feedback mechanism

Physiologic action: Stimulate secretion of adrenocorticoids

Glucocorticoids (cortisol) Mineralocorticoid (aldosterone) Androgens)

Causes sedation, increased pain threshold, autonomic regulation of respiration, BP and HR

Adrenocorticotrophic H ( ACTH )

Episodic secretion in respose to 1. Falling levels of active glucocorticoids

Cortisol ( predominant) 90% inactive bound to CBG(Cortisol binding globulin)

2. Stress 3. Cycles of sleeping and waking

Display circadian rhythmPeak: bet 4 am and 8amnadir: at midnight

Adrenocorticotrophic H

Patient preparation: Stressful venipuncture inc levels

Specimen collection/handing: Collected in prechilled plastic tubes with EDTA or

heparin Place immediately on ice Store at -20 C within 15 min of collection

TSH or Thyrotropin

Regulation: TRH from hypothalamus causes secretion

in response to low levels of thyroid hormones (T3, T4)

Physiologic Function: Stimulates secretion of T3, T4

TSH

Serum TSH is single best screening test for thyroid fxn followed by FT4

Useful for evaluating both thyroid and pituitary function

Elevated serum level: sensitive and specific indicator of primary

HYPOTHYROIDISM Normal or decreased level: secondary or tertiary

hypothyroidism

Growth Hormone

AKA : somatotropin Most abundant hormone of ant PG

Growth Hormone

Regulation: GHRH and GHIH regulates its secretion in response to

exercise stress, hypoglycemia Amino acids testosterone estrogen levels

Physiologic Function: Promotes growth of soft tissue , cartilage and bone Stimulates Pr synthesis , fat and CHO metabolism

Growth Hormone

Increase GH gigantism in children acromegaly in adults

Decrease GH in children dwarfism

Secreted in pulsatile bursts with very short half life single random determination ( limited

usefulness) 24 hours hormone secretion level (better

measurement)

Growth Hormone

Patient preparation: Patient should be fasting Complete rest for 30 min before collection.

Spikes occur 3 hr after meals, stress, or exercise and 90 min after onset of sleep,

Specimen: Serum preferred; refrigerate immediately; stable at 2-8C

for 8 hr.

Prolactin Hormone

Biochemical properties similar with GH and placental GH

Main target organ: adult female mammary gland

Regulation: Regulated by TRH, dopamine

Physiologic Function: Increased in pregnancy, sucking Initiates lactation ; growth of mammary

tissues; controls osmolality, fat , CHO , Vit D metab and steroidogenesis in the ovary and testis

Effects : Suppresses ovulation Stimulates growth of prostate

Hypersecretion : Females: hypogonadism , infertility,

oligo/amenorrhea , galactorrhea Males: inhibits testosterone secretion, decrease

spermatogenesis , infertility and galactorrhea

Prolactin Hormone

Levels fluctuate; fluctuations occur Q 95 min,

Long half life ( approx 50 min ) Physiologically stimulated by :

Pregnancy, breast feeding, sleep, dietary Pr, hypoglycemia, exercise and stress

Prolactin Hormone

Patient Preparation: Collect 3-4 hr after awakening; levels increased during sleep and peak in early morning. Avoid emotional stress, exercise, ambulation, protein

ingestion ( can increase levels). Specimen:

fresh nonhemolyzed serum; stable at 4 C for 24 hr.

Follicle Stimulating and Luteinizining H

Regulated by GnRH from hypothalamus Controls the functional activity of gonads Exhibit episodic, circadian and cyclic variations– best to use

serial blood tests or timed urine collection Specimen:

Serum, plasma and urine acceptable; Stable 8 days at room temp; two weeks at 4C

HYPOTHALAMIC-PITUITARY FUNCTION TESTS

Hyperpituitarism

Most are due to benign tumors that are autonomous and do not respond to negative feedback control GHsecreted by pituitary adenoma is not suppressed by

glucose Exception to the rule of suppressibility:

Prolactinoma and Pit adenoma that secrete ACTH(Pituitary Cushing); both are partially autonomous

GH Excess: Acromegaly

1. Serum GH Elevated basal or random levels in most acromegalics Basal and random GH may also be inc in

Normal patients due to episodic secretion Malnourished patients Anorexia nervosa Patients on estrogen therapy

Best test to confirm acromegaly: Measurement of GH following a glucose load. GH is normally suppressed to <2ng/ml one hour after a 75 -

100g glucose load. Failure to suppress means a functioning pituitary adenoma

Pituitary Hyperpituitarism

2. Serum Somatomedin C Synthesized mainly in the liver Mediates most of the major growth promoting effects of GH Involved in negative feedback regulation of Normal GH secretion Serum level of SM-C is a good screening test for acromegaly

Basal SM-C is elevated in acromegaly Maybe elevated in adolescents during the peripubertal growth

spurt and during pregnancy

Hypopituitarism : GH deficiency

GH testing: Shd be routinely included in evaluating children with short stature Not indicated in adults suspected of hypopituitarism

Basal GH levels: not reliable to distinguish deficiency from normal;

Baseline measurement : fasting morning sample Factors that increase GH secretion:

Low serum glucose, dopamine, exercise

Laboratory diagnosis : Hypopituatarism : GH deficiency

Screening tests for GH deficiency: GH measurement after 15 min exercise Measurement of somatomedin:

Laron Dwarf: normal GH but low somatomedin

Stimulation Test to confirm GH deficiency

Stimuli 1. Insulin 2. Arginine 3. L-dopa 4. Clonidine

GH should be measured every 30 mins for 2-3 hours Normal: GH increment above baseline >5ng/ml or

a maximal GH>7ng/ml GH deficiency: failure to respond to at least two

independent stimuli; hypothalamic or pituitary gland dysfunction

Stimulation test:

Insulin induced hypoglycaemia to investigate suspected GH deficiency.

A reduced or absent response is seen in a GH deficient patient (B)

Insulin decreases plasma glucose concentrations and in a normal person this stimulates the release of GH (A)

Stimulation Test to confirm GH deficiency

GH stimulation test (After CRH): A CRH injection is given followed by

measurement of the blood level Normal: GH elevated Hypopituitarism: no response

PITUITARY GLAND

Measure Growth Hormone

Feed

back

Bolus injection of releasing hormone

HypothalamusHypothalamus

No response or delayed peak response (60 mins vs 20 mins)

ADRENAL FUNCTION TESTS

Hormones of Adrenal Gland :

Hormones of adrenal cortex (adrenal corticosteroids) : Glucocorticoid ( cortisol ) secreted by cells in zona

fasciculata – Mineralocorticoid ( aldosterone ) secreted by cells in z.

glomerulosa- Sex hormones (testosterone and estradiol ) secreted

by cells in zona reticularis Catecholamines (dopamine, epinephrine and

NE) secreted by chromaffin cells of adrenal medulla

Glucocorticoid (Cortisol)

Physiologic action: Affects metabolism of proteins, CHO and lipids Stimulates gluconeogenesis by the liver, inhibits the

effects of insulin and decrease the rate of glucose use in the cells

Regulation: Secreted in response to stress and ACTH Normally: secretion higher in early morning (6-8am) lower in the evening (4-6pm);

lowest at midnight Cortisol excess (Cushing’s Syndrome and in patients under

stress): loss of diurnal variation in secretion

Circadian rhythm of cortisol secretion

Feedback control of Adrenal Corticosteroid synthesis and release

Decreased blood levels of adrenal corticosteroids, stress

Hypothalamus secretes corticotrophin releasing hormone (CRH)

Ant Pit g gland secretes ACTH

Adrenal cortex secretes hormones (cortisol)

Hormone secretion suppressed via negative feedback

Corticosteroid Excess : Cushing Syndrome:

Hyperadrenalism with production of excess cortisol

Clinical Presentation: 1. Glucocorticoid Effects: “cushingoid

habitus”, bone dimineralization, glucose intolerance

2. Mineralocorticoid effects: HPN, edema, hypokalemic alkalosis

3. Sex steroid effects: hirsutism, acne, amenorrhea, gynecomastia

Cushing Syndrome: Causes

Exogenous glucocorticoid therapy (most common cause)

Other causes: 1. ACTH Producing pituitary adenoma (60%)

( Cushing disease) 2. Glucocorticoid producing adrenal neoplasm(20%)

(adenoma or carcinoma)

3. Ectopic ACTH-producing neoplasm(20%)

Tests for Adrenal Hormone Function

1. Serum cortisol -Secretion is episodic and pulsatile in response to ACTH -Single determination neither specific or sensitive -90-97% is bound to CBG or transcortin - Elevated in adrenal hyperfunction (Cushing’s Sx) - Decreased in adrenal hypofunction (Addison’s) - Diurnal rhythm of cortisol secretion is lost in Cushing Sx

and patients under stress

2. Urine Free Cortisol (UFC): **Glucocorticoids:

Degraded in the liver and excreted in the urine as Hydroxycorticosteroid (17-OHCS).

Urine 17 OHCS is an indirect measurement of excessive plasma Glucorticosteroid -indirect measure of the cortisol production rate

-Normal: <90ug/24hr - UFC> 250mg/24 hr is almost always due

to Cushing Sx

3. Dexamethasone Suppression Test• Dexamethasone: cortisol analoque that should

suppress ACTH in normal person and reduce cortisol.

Rapid DST for screening (low Dose DST) Administer 1 mg dexamethasone at 11pm; measure

8am the following day: Normal: Suppressed cortisol <5ug/dl No suppression in Cushing’s Sx: useful for screening

Dexamethasone Suppression Test

Normal person: dexamethasone will suppress ACTH secretion (feedback) and cortisol production is consequently reduced.

In pituitary- dependent Cushings only high doses may suppress ACTH secretion

Ectopic ACTH Syndrome: no suppression even to HDST

No suppression to low dose: Cushing Syndrome

Adrenal Function Test

1. Plasma ACTH level Increased : pituitary tumors ectopic ACTH producing tumors Decreased: cortisol producing tumors in

adrenals exogenous hormones

Adrenal Function Test

2. Overnight HIGH DOSE DST:

Procedure: Administer 8mg at 11pm measure serum cortisol 8am before and on the morning following dexamethasone

ACTH producing adenoma : Suppression of cortisol to 50% of basal

Adrenal neoplasm or ACTH syndrome: No suppression of cortisol

Primary Adrenal Insufficiency (Addison’s Disease)

Deficiency of all adrenal steroids Relatively rare Results from progressive destruction of

adrenals by local disease or systemic disorder

Adrenal Function Test for Adrenal Insufficiency

3. Metyrapone test

Metapyrone: Blocks 11 beta-hydroxylase in ad. cortex which reduces synthesis of cortisol hence stimulate synthesis of ACTH with proximal buildup of deoxycortisol in adrenal

Procedure: 1. Administer 3.0 mg metyrapone at midnight. 2. Measure cortisol and 11 deoxycortisol at 8am baseline and post-metyrapone

Metapyrone: Blocks 11 beta-hydroxylase in ad. cortex which reduces synthesis of cortisol hence stimulate synthesis of ACTH with proximal buildup of deoxycortisol in adrenal

deoxycortisol

11-β Hydroxylase

Cortisol

Metapyrone

Metyrapone Test: Normal response: fall in cortisol to <5ug/dl and

increase in ACTH, 11 deoxycortisol and urinary 17-OHCS

Cushing’s Dse: Increase in 11-deoxycortisol levels

Adrenal tumors/Ectopic ACTH: 11-deoxycortisol fails to increase

Failure of cortisol to fall invalidates the test Not routinely used, although maybe better than

High dose DST

Adrenal Function Test

Cortisone Stimulation (Cosyntropin); ACTH Stimulation Screening test; less time consuming; can be

done on OPD basis Cortrosyn (synthetic subunit of ACTH) have full

stimulating effect of ACTH in healthy individuals

- failure to respond : adrenal insufficiency

Procedure: 1. Get 4ml fasting blood venous sample at 8am 2. Administer cosyntropin IM/IV 3. Get 4ml samples at 30 and 60 mins after

Mineralocorticoid (Aldosterone)

Regulation: ALDOSTERONE (predominant mineralocorticoid) is

secreted by cells in the zona glomerulosa in response to ANGIOTENSIN (mainly); and by ACTH (not significant)

Clinical effects Retains Na and H20 accompanied by K

depletion leads to excess intravascular volume HPN

Aldosterone Elevated levels (primary aldosteronism)

Conn’s disease ( aldosterone producing adenoma) Elevated levels (secondary aldosteronism)

because of extenal stimuli or greater activity in the RAS: Salt depletion Potassium loading Cardiac Failure Nephrotic syndrom Diuretic abuse

Aldosterone

Decreased levels of aldosterone: Aldosterone deficiency Addison’s disease

Tests for hyperaldosteronism:

1. Basal level of plasma aldosterone

*limited diagnostic value 2. Urinary Aldosterone 3. Captopril Suppression Test

Angiotensin- converting enzyme inhibitor: decrease the renin-stimulated aldosterone production secondary aldosteronism; no response in primary aldosteronism

Test for hyperaldosteronism:

5. Aldosterone Suppression test (Isotonic Saline infusion)

Normal response suppress aldosterone release by decreasing renin

Primary aldosteronism lack of aldosterone suppression

6. Aldosterone Stimulation Test ( Sodium restricted from diet) Normal response renin level increasedPrimary aldosteronism slight or no response in renin level

Adrenal Insufficiency:

1. Serum cortisol decreased 2. Rapid ACTH stimulation test 3. Long ACTH stimulation test 4. Serum ACTH

Elevated in primary adrenal insufficiency Decreased in secondary and tertiary

5. Metapyrone test

PHEOCHROMOCYTOMA: Cathecolamine Excess

1. Increased cathecolamines at all times. Cathecolamines: either epinephrine or

norepinephrine is increased and should be assayed separately.

Plasma norepinephrine >750pg/ml or Epinephrine >100pg/ml are found in 90-95% of

patients 2. Urine test

Vanyllmandelic acid Total metanephrine Fractionated cathecholamines

PHEOCHROMOCYTOMA: Cathecolamine Excess

3. Clonidine Suppression test: Clonidine (alpha agonist) decrease

efferent symphathetic flow Normal: Norepinephrine level within N range Pheochromocytoma: exaggerated response

PHEOCHROMOCYTOMA: Patient Preparation

Blood should be drawn through a previously inserted catheter from a patient who is fasting, resting quietly and non-stressed.

If patient is to kept on antiHPN meds during resting The least interfering agents shld be used:

diuretics. Vasodilators, and alpha or Beta adrenergic blockers.

THYROID DISORDERS

Thyroid function

Hormone Regulation

TRH TSH iodine uptake, organification synthesis & release of thyroid hormone

T4/T3 Regulate: basal metabolism, thermogenesis,

lipogenesis fetal CNS development

Regulation of thyroid hormone secretion

>99% of thyroid hormones are carried in plasma bound to protein <1% is free & active

Thyroxin-binding protein (TBG) binds most of the T4 and T3 TBG is synthesed by liver, severe liver disease TBG

TT4 due to protein-bound T4 Estrogen (ex. Pregnancy) synthesis of TBG total T4

due to protein-bound T4 Albumin and pre-albumin also carry T4 and T3 in plasma

Thyroid Hormones

Thyroxine (T4) Thyroid gland t1/2: 8 days

Triiodothyronine (T3) 80% in Periphery

Liver/kidney remove iodine from T4 t1/2: 1-1.5 days

Binding Proteins

T4/T3 99% protein bound Prevents excess tissue uptake Maintains accessible reserve

T4

T3

20%

80%

Protein* binding + 0.03% free T4

Protein* binding + 0.3% free T3

(10-20x less than T4)

Total T4 60-155 nMTotal T3 0.7-2.1 nMT3RU/THBI 0.77-1.23

*TBG 75% TBPA 15% Albumin 10%

Thyroid Function Tests :

TSH T3 T4 FTI ( free thyroxine index ), FT4 ( free

thyroxine ) TRH TBG ( Thyroid binding globulin )

More T4 in serum (5.5 to 12.5 ug/dl) T3 in serum 9(100 to 200ng/dl)

T3 exerts the major hormone effects thus more phyiologically significant

T4 converted by peripheral nonthyroidal tissues to T3

T4 may have no direct effect until converted to T3

THYROID FUNCTION TESTS

THYROID STIMULATING HORMONE (TSH) Stimulated by TRH (from hypothalamus) Serum TSH is single best screening test for

thyroid fxn followed by FT4 Useful for evaluating both thyroid and pituitary

function Elevated serum level:

sensitive and specific indicator of primary HYPOTHYROIDISM

Normal or decreased level: secondary or tertiary hypothyroidism

Clinical Uses of TSH

Screening for euthyroidism Initial screening and diagnosis for

hyperthyroidism (dec. to undetectable levels except in rare TSH-secreting pituitary adenoma) and hypothyroidism

Useful in early or subclinical hypothyroidism before the patient develops clinical findings

Clinical uses of TSH

Differentiate primary (increased levels) from central [pituitary or hypothalamic] hypothyroidism (decreased levels)

Monitor adequate thyroid hormone replacement therapy in primary hypothyroidism

TSH increased in :

Primary untreated hypothyroidism Hypothyroidism receiving insufficient

thyroid hormone replacement therapy Hashimoto thyroiditis

THYROID FUNCTION TESTS: Total T4 and T3

1. TOTAL THYROXINE(T4) ANDTRIIODOTHYRONINE(T3) LEVELS

Total thyroxine (T4) is a good index of thyroid fxn when TBG are normal

T3 level- in cases of hyperthyroidisn with normal or low T4: T4; useful in monitoring therapy

THYROID FUNCTION TESTS:Total Thyroxine ( T4)

High: hyperthyroidism and acute thyroiditis

Low: hypothyroidism and chronic thyroiditis

Affected by concentration of binding proteins (TBG)

THYROID FUNCTION TESTS:Total Serum T3 ( Triiodothyronine )

Elevated proportionately to T4 in hyperthyroidism

Decreased in hypothyroidism T3 thyrotoxicosis ( 5% of ind.) T3

elevated while T4 is normal Not routinely measured except to

monitor tx of T3 thyrotoxicosis

THYROID FUNCTION TESTS: Thyroxine Binding Globulin

A glycoprotein: synthesized in the liver Principal serum carrier for T4 ( 75% ) and T3 Less than 1% of T3 and T4 are in the free form

which determines function Estrogen influences thyroxin binding Phenytoin, coumarin, heparin clofibrate and aspirin

compete with T3 & T4 for TBG binding sites Measurement is rarely indicated

T3 Uptake

Indirect measurement of unsaturated TBG in blood

Determination is expressed in arbitrary terms is inversely proportional to the TBG Low T3U is indicative of conditions where

there is elevated levels of TBG uptake

T3 Uptake

Hypothyroidism: insufficient T4 to saturate TBG unbound TBG is elevated and T3U values are low

Pregnant patients: TBG are increased proportionately more than T4 levels high levels of unbound TBG reflected in low T3U values

Useful only when T4 is done Used to calculate FTI or F7

T3 Uptake

Procedure: Known amount of radiolabeled T3 is added to

test serum Available binding sites in test serum combine

with labeled T3 inversely proportional to the amount of endogenous T4 already bound

Low endogenous T4 (hypothyroid) many TBG sites free to react with labeled T3—measured residual radiocativity is low

High endogenous T4 (hyperthyroid) few TBG sites free to react with labeled T3 measured residual radioactivity is high

Resin is used to measure residual radioctivity Low residual activity—numerous binding sites

unoccupied( low endogenous T4) High residual activity—few binding sites

unoccupied( high endogenous T4)

Results are expressed as % radioactivity left unbound Hyperthyroidism: both T4 and T3U high values Hypothyroidism: both T4 and T3U have low values

THYROID FUNCTION TESTS: FREE THYROXINE INDEX

Correlates better with clinical status in the presence of abnormalities in TBG Calculated as the product of absolute thyroid

hormone and the binding capacity of TBG FTI= Measured FT4 (T4 x Value of T3 Uptake)

(Reference Interval=1-4.2) Normal in pregnancy; low in hypothyroidism; high in hyperthyroidism

Thyroid Function Tests

HyperthyroidismHyperthyroidism HypothyroidismHypothyroidism

Total T3 & T4 in serumTotal T3 & T4 in serum IncreasedIncreased DecreasedDecreased

Free thyroxine indexFree thyroxine index IncreasedIncreased DecreasedDecreased

Serum TSHSerum TSH DecreasedDecreased IncreasedIncreased

Interpreting Thyroid Function Tests

Clinical patterns of thyroid disease

Hyperthyroidism- Lab: excessive levels of TH ( T3 , T4 ) ; S/sx: heat intolerance, palpitation, weight loss,

tachycardia tremors Causes: Graves Ds, toxic adenoma, toxic

goiter , TSH secreting pituitary adenoma

Hypothyroidism – Lab: decrease levels of TH S/sx: Bradycardia, cold sensitivity, dry

skin, muscle weakness , myxedema, cretinism

Causes : TG ablation and destruction ( primary ) ; pituitary hypofuncytion of TSH (secondary )

Laboratory Diagnosis of Thyroid Disease

1 thyroid dis. is abnormality in the thyroid gland TRH and TSH level just reflect N feedback response

2 thyroid dis. is really an abnormality in pituitary gland which cause error in amount of TSH produced T4 and T3 conc’n just reflect N feedback response

3 thyroid dis. is abnormality in hypothalamus causing error of TRH produced Both TSH and T4 & T3 levels just reflect N feedback response

Measuring trophic hormones and hormones of the peripheral endocrine gland

High TSH - Low T3/T4 1o

Hypothyroidism

Low TSH - High T3/T4 1o

Hyperthyroidism

Low TSH - Low T3/T4 2o

Hypothyroidism

“Euthyroid Sick Syndrome”

Severe illness often results in low serum levels of T3 and T4

Causes: 1. Decreased in serum pre albumin in severe

illness decrease in hormone binding capacity 2. Fall in amount of T4 deiodinatd to T3 with

increase in the metabolic pathways leadig to the inactive product reverse T3

Diagnosis: demonstrating normal TSH level.