Thyroid hormone

THYROID HORMONEM. ARAVINDMBBS I YEAR

DSMCH PERAMBALUR

OBJECTIVES

Iodine metabolism Thyroid hormone metabolism Function of thyroid hormone Abnormalities of thyroid function Hyperthyroidism Hypothyroidism Goiter Thyroid function tests

IODINE METABOLISM

SOURCES: drinking water, fish, cereals, vegetables, iodinated salt

Commercial: sea weeds RDA: 150-200 microgram/day DISTRIBUTION: Total body content:25-30mg (found in all

cells) 80%- thyroid gland Blood- 5-10 microgram/dL FUNCTION: formation of T3 & T4

GOITROUS BELTS: In most parts of the world, iodine is a scarce

component of the soil. Upper regions of the mountains contain less iodine

GOITROGENS: Ingredients in food stuffs, which prevent

utilization of iodine Seen in cassava, maize millet, bamboo

shoots, sweet potatoes, beans Cabbage & tapioca (thiocynate- inhibits

iodine uptake) Mustard seed (thiourea – iodination of

thyroglobulin)

THYROXINE METABOLISM

STEP 1: UPTAKE OF IODINE BY THYROID GLAND

Inhibited by thiocynate & perchlorate which compete for carrier mechanism

Stimulated by TSH Rx congenital iodine trapping defect-

large doses of iodine

STEP:2 OXIDATION OF IODINE IN THYROID

Stimulated by TSH Inhibited by antithyroid drugs (thiourea,

thiouracil, methimazole) Rx- inborn error of iodine oxidation

defect- T4 administration From the follicular cells, iodine is

transported into the follicular cavity by an iodine chloride pump called pendrin

STEP: 3 IODINATION OF Tgb IN ACINI

Tgb – SYNTHESIS- thyroid follicles (endoplasmic reticulum & Golgi apparatus)

Large protein about 5000 aas (600kD) 10% carbohydrates 115 tyrosine residues (35 – iodinated) Stored in follicle 3- monoiodotyrosine & 3,5 diiodotyrosine

are produced

STEP: 4 COUPLING IN FOLLICULAR CELLS

Tyrosine + I = MIT MIT + I = DIT DIT + MIT = T3 (formed by de-iodination of

outer ring of T4 by 5’ deiodinase) (1 molecule of thyroxine for every 10 molecules) (peripheral cells)

MIT + DIT = reverse T3 (1% - negligible biological activity)(formed b inner ring deiodination by 5deiodinase)

DIT +DIT = T4 (99%) Attached to Tgb Rx – inborn error give T4

STEP:5 STORAGE

Thyroid- only endocrine gland to store appreciable amounts of hormone

Tgb 8 T4 residues per molecule Thyroid acini Several months (4) Signs & symptoms of thyroid hormone

deficiency donot occur for 4 months

STEP 6: UTILIZATION

Follicular cell sends foot-like extensions called pseudopods, which close around the thyroglobulin-hormone complex. This process is mediated by a receptor-like substance called megalin, which is present in the membrane of the follicular cell.

Psudopods convert thyroglobulin-hormone complex into small pinocytic vesicles. (pinocytosis)

STEP 7: HYDROLYSIS Lysosomes fuse with these vesicles Proteinases digest Tgb (proteolysis) &

release thyroid hormones Stimulated by TSH Inhibited by iodide(KI is used as an

adjuvant in hyperthyroidism) In a genetic disorder abnormal Tgb is

produced, resulting in deficient proteolysis and deficiency of thyroxine

ROLE OF IODINE

When the dietary level of iodine is moderate, the blood level of thyroid hormones is normal.

However, when iodine intake is high, the enzymes necessary for synthesis of thyroid hormones are inhibited by iodine itself, resulting in suppression of hormone synthesis

This effect of iodide is called Wolff-Chaikoff effect

STEP 8: RELEASE

Diffuse through base of the follicular cell and enter the blood stream

STEP 9: SALVAGING OF IODINE

MIT & DIT are not released into blood These iodotyrosine residues are

deiodinated by an enzyme iodotyrosine deiodinase, resulting in the release of iodine

The iodine is reutilized by follicular cells for further synthesis of thyroid hormones

During congenital absence of iodotyrosine deiodinase, MIT & DIT are excreted in urine & the symptoms of iodine def develop

Rx- give iodine

STEP 10: TRANSPORT OF THYROID HORMONES

3 types of proteins total protein bound iodine (PBI) is 10

microgram/dL out of which T4 constitutes 8 microgram/dL

THYROXINE BINDING GLOBULIN: (one third) 80%- T4, 60%- T3

Transthyretin(TTR) or thyroxine binding prealbumin: one fourth

Albumin: one tenth

STEP 11: CATABOLISM HALF LIFE: T4- 4-7 days (is a prohormone which is

deiodinated to T3) T3- 1 day (biologically more active) Deiodination takes place in the peripheral

tissues by deiodinase (Se containing enz) Conjugated with glucoronic acid – excreted

through bile Lesser extent through urine Deamination: T4 – tetraiodothyroacetic

acid(Tetrac), T3- triiodothyroacetic acid (triac)

These are only one fourth as active as parent compound

MECHANISM OF ACTION

METABOLIC EFFECTS

Acts on almost all the tissues BMR- increases CALORIGENIC EFFECT OR THERMOGENESIS:

1 mg of T4 produce 1000 kcal by uncoupling oxidative phosphorylation.

Body temp increases called thyroid hormone induced thermogenesis

Normal functioning of CNS Erythropoietic activity It causes the muscle to work with more

vigour

PROTEIN MET: increased RNA synthesis- increased protein synthesis. Higher concentration of T3 causes protein catabolism and negative nitrogen balance

CARBOHYDRATE MET: Increased gluconeogenesis,

glycogenolysis, glucose uptake. Glucose tolerance test shows rapid absorption

FAT MET: mobilize fat from adipose tissue increases FFA level in blood. Decreases plasma cholesterol, phospholipids, triglyceride levels (increasing its excretion from liver into bile)

HYPERTHYROIDISM

CAUSES: Graves disease Thyroid adenoma Pituitary adenoma Excessive intake of thyroid hormones Increased affinity of binding protein Increase in binding protein T4 toxicosis (T4 increase, T3 low)

TYPES

PRIMARY HYPERTHYROIDISM: due to diseases of thyroid gland (Grave’s disease, adenoma, functioning metastatic thyroid carcinoma, TSH receptor mutation, excess iodine)

SECONDARY HYPERTHYROIDISM: due to diseases of pituitary or hypothalamus (TSH secreting pituitary adenoma)

SIGNS AND SYMPTOMS

Exophthalmus Increased rate of metabolism Intolerance to heat Weight loss Sweating Fine tremors emotional disturbances Anxiety/ excess worries / paranoid

thoughts diarrhoea

HYPOTHYROIDISM MYXEDEMA- in adults characterised by

generalised edematous appearance CAUSE: Deficiency of iodine Deficiency of TSH/ TRH Diseases of thyroid gland Iodine deficiency Hashimoto’s thyroiditis(autoimmune

thyroiditis)

SIGNS AND SYMPTOMS Swelling of the face Bagginess under the eyes Non pitting type of edema Atherosclerosis (inc cholestrol) Arteriosclerosis Hypertension Increase in body weight Fatigue and muscular sluggishness Mental sluggishness Cold intolerance Constipation Anemia

anaemic

CRETINISM

Hypothyroidism in children characterised by stunted growth

CAUSE Congenital absence of thyroid gland Lack of iodine in the diet Genetic defect CONGENITAL HPOTHYROIDISM (incidence: 1:4000)

SIGNS AND SYMPTOMS Sluggish movements and croaking sound Skeletal growth is affected Tongue becomes so big and hangs down

with dribbling saliva Big tongue obstructs swallowing and

breathing Guttural breathing-sometimes choke the

baby Mental retardation Different parts of the body are

disproportionate Reproductive functions are affected sleepiness

EUTHYROID GOITER

CAUSE: iodine def CHARACTERISTICS: Raised TSH level would produce

continued stimulation of gland leading to hyperplasia & goiter

Hormone levels

NON THYROIDAL ILLNESS

In acutely ill patients, T3,T4, TSH are found to be lowered

It is advisable to postpone the thyroid function in acutely ill patients till they recover completely in order to get a correct picture of the functional status of the thyroid gland

GOITER Enlargement of the thyroid gland Goiter in hyperthyroidism- toxic goiter Inc secretion of thyroid hormone caused by

tumour Goiter in hypothyroidism- nontoxic goiter (hypothyroid goiter) enlargement of thyroid

gland without increase in hormone secretion ENDEMIC COLLOID GOITER- iodine def IDIOPATHIC NON-TOXIC GOITER- goitrogens,

def of enz- peroxidase, iodinase, deiodinase

THYROID FUNCTION TESTS

ASSAY OF HORMONES T3 & T4 Radio immuno assay (RIA) Enzyme linked immuno sorbent assay

(ELISA) Chemiluminescent immunoassay (CLIA) Fluorescent immuno assay (FIA) HYPERTHYROIDISM- T3,T4 TSH HYPOTHYROIDISM- T3,T4 TSH Due to hypothalamic/ pituitary defect-

T3,T4,TSH

fT3 & fT4

Free hormones are active forms which can be measured accurately by CLIA / FIA

fT4- 0.35% fT3-0.3% Variations in binding proteins donot affect

the free hormone levels therefore more reliable in diagnosing true hyper & hypofunction

PLASMA TSH

P hypothyroidism- TSH S hypothyroidism- TSH (T3, T4) P hyperthyroidism- (T3,T4 )TSH S hyperthyroidism- (T3, T4) TSH

BINDING PROTEINS

Since sensitive and accurate tests are there to measure free T3 and T4, this test is only of historical importance

TRH RESPONSE TEST

HYPERTHYROIDISM: negative feedback effect of high T4 overpowers the stimulant effect of TRH. TSH T3,T4

P HYPOTHYROIDISM: TSH (exaggerated response)

HYPOPITUITARISM: TSH,T3,T4

CHOLESTEROL HYPOTHYROIDISM- increased cholesterol

level(cholesterol carrying lipoprotein degradation is decreased)

It is not diagnostic, because hypercholesterolinemia is also seen in DM,obstructive jaundice, hypertension, nephrotic syndrome

It is useful in monitoring the effectiveness of the therapy

RADIOACTIVE IODINE UPTAKE

Dose of 131I is given intravenously, after few hours, the patient is monitored at the neck region by a movable gamma-ray counter.

NORMAL VALUES- 25% within 2 hours, 50% within 24 hours

HYPERTHYROIDISM- increased uptake

HYPOTHYROIDSM- decreased uptake

THYROID SCANNING

24 hours after administering the dose of 131I intravenously, the patient is placed under the scanner, which detects the radioactive emissions from the neck region.

Approximate size & shape of the thyroid gland is produced

Hyperthyroidism- heavily shaded areas Thyroid cancer- silent nodule (iodine

uptake is defective)

DETECTION OF THYROID ANTIBODIES

In Grave’s disease, thyroid stimulating immunoglobulin (TSIg) also known as long acting thyroid stimulator (LATS) is seen in circulation

They bind to TSH receptor which is not under feed back control

It is significant because the prevalence of autoimmune disease is on the increase

In thyroid cancer- antithyroglobulin antibodies

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