Dr. Mohammed Kalimi Thyroid Physiology

Iodide Turnover Input = Output 500 μg Iodide = Renal excretion =480 μgI- (Daily dietary) Stool excretion= 20 μg I -

Biosynthesis of TH 1. Iodide pump or trap: Transport of iodide into the gland against electro chemical gradients by Na+ -I- cotransport (symport) ↑ Na-K ATPase and TSH Inhibition by Sodium thiocyanate and Perchlorate

T/S Ratio Normal T/S 20:1 TSH stimulation 100:1 Hypophysectomized (no TSH) 1:1

Biosynthesis of TH 2. Conversion of Iodide to Iodine 2I -  I2 H2O2 sustrate and thyroid peroxidase enzyme ↑ TSH and inhibited by PTU and methimazole

Biosynthesis of TH 3. Organification: Formation of MIT and DIT by iodination of tyrosyl residue of TG 4. Coupling: MIT + DIT = T3 DIT + DIT = T4 Organification and coupling are caralyzed by thyroid peroxidase and require hydrogen peroxide and TSH

TH Synthesis and Release

Administration of large quantities of Iodide (2 mg or more)  TH synthesis due to  expression of Na-I symporter  enzyme peroxidase genes

T3 and T4 Plasma bound T4 = 99.97% Plasma free T4 = 0.03% Plasma bound T3 = 99.7% Plasma free T3 = 0.3%

T3 and T4 Ten times (of the total) T3 in the blood is free Compared to T4 Plasma half life of T3 = 1 day Plasma half life of T4 = 7 days T3 is two to three times more biologically potent than T4

TH blood binding proteins Thyroxine binding globulins (TBG): binds to about 70% total T4 and 50% total T3 Thyroxine binding prealbumin (TBPA): binds 20% of total T4 ( no binding to T3) Albumin : binds 10% of total T4 and 50% of total T3

Degradation of T4 1. Conversion of T4 to T3 (T4  5’ Deiodinase T3) about 35% 2. Conversion of T4 to rT3 (T4  5 Deiodinase  rT3) about 45% 3. T4 metabolised by cojugation or oxidative deamination : about 20%

Reverse T3 Physiological role unknown Levels ↑ with chronic illness, calorie deprivation, β blockers and corticosteroids

Thyroid Physiology Acts on most tissues Action –slow in onset and long in duration TH is not necessary for life, improves quality of life

TH Actions 1. Growth and Development 2. Metabolic 3. Neural 4. Cardiovascular

TH Actions Normal growth (↑GH)and development (bone, skeletal and brain) Congenital deficiency ; cretinism Dwarf stature (bone remains infantile ), mental retardation

TH Actions Metabolic: ↑ BMR, ↑ O2 consumption, ↑ heat production, ↑ mitochondrial ATP synthesis. Acute response to cold by ↑ BMR, ↑ heat production, ↑ catecholamines, ↑ lipolysis, ↑ cardiac adjustments, ↑ muscular activity Chronic cold: ↑ conversion of T4 to T3

TH Actions ↑ Carbohydrate, protein and lipid metabolism ↑ Gluconeogenesis, ↑ Glycolysis, ↑ absorption of carbohydrates from the GI tract Negative nitrogen balance (↑ protein turnover) ↑ Lipolysis, FFA synthesis and oxidation  Total cholesterol and LDL

TH Actions Neural: Promotes normal neuronal development Cardiovascular effects: ↑ heart rate and strength of the heart beat, ↑ ventilation and cardiac output ↑ Cardiac β receptors

TH Mechanism of Action

TRH Tripeptide Synthesized and released from hypothalamus ↑ T3,T4,  anterior pitutary TRH receptors,  TSH

TSH α subunit identical with LH, FSH, hCG β subunit is specific to TSH Plasma T1/2= 1 hour Plasma TSH levels = 0.5-5.0 μU/ml ↑ TSH, ↑ cold, ↑ TRH, ↑ leptin  TSH, sleep, fasting and ↑ somatostatin

Goiter ( enlargement of TH gland) Prolonged and excessive TSH stimulation of TH gland Euthyroid Goiter: Iodide deficiency, ↑ TSH to compensate  TH Hyperthyroid Goiter: over secretion of TSI (thyroid stimulating immunoglobulin) which mimics TSH, ↑ TSI, ↑TH Hypothyroid Goiter: Administration of drugs such as PTU, perchlorate, thiocyanate, TH,↑ TSH

TH : Clinical tests Measurement of plasma total T3 and Total T4 Measurement of TSH Normal values= 0.5-5.0 micro units/ mL of blood Elevation in serum TSH is the most sensitive measure for primary hypothyroidism

TH: Clinical tests TSH above 5.0 (hypothyroidism) treatment with thyroxine TSH below 0.5 (hyperthyroidism), radiation treatment plus thyroxine (T4)

TH Clinical In deficiency state: Hypothyroidism Overactivity: Hyperthyroidism

Hypothyroidism Primary disease: Thyroid failure (surgical, immune or iodide destruction of thyroid gland) Secondary disease: Pituitary (TSH deficiency) or hypothalamus (TRH deficiency)failure Defective TH receptors Myxedema Cretinism

Symptoms of hypothyroidism Decreased BMR , decreased pulse rate and vitality Increased plasma cholesterol and LDL Growth failure, weight gain, constipation Dry scaly thickened skin, cold intolerance Sluggishness, hoarse voice, lethargic, puffy eyelids, enlragement of tongue Depression and insomnia

Hyperthyroidism Graves’ disease (Thyrotoxicosis) ↑ TSI, ↑ T3,T4,  TSH

Symptoms of hyperthyroidism ↑ BMR  Plasma Cholesterol and LDL ↑ Cardiac output, ↑ heart rate and ↑cardiac beta receptors, congestive heart failure ↑ Body heat, sweating and vasodialation Osteoporosis (negative calcium balance) Hyperkinetic and psychotic behavior ↑ GI malfunctions and weight loss Neuro muscular-fatigue,hyperactive reflexes Eye discomfort, marked protrusion of eyes (exophthalamos)

Pregnancy and TH Pregnancy, ↑ Estrogen, ↑TBG, ↑Total plasma T3 and T4