Prof.Dr.Arzu SEVEN

Thyroid hormone biosynthesis involves thyroglobulin and iodide metabolism

THYROİD HORMONES 1- Concentration of iodide In the follicular epithelial cells, against a strong electrochemical gradient Energy-dependent process, linked to ATPase – dependent Na + - K + pump Thyroidal I - transporter (controlled by TSH) İodide in thyroid/iodide in serum ratio reflects the activity of this transporter (25/1) İodide transporter is inhibited by perchlorate and thiocyanate

2- Oxidation of I - by thyroid peroxidase (TPO) in the peroxisome to iodine As an oxidizing agent, TPO requires H2O2, produced by NADPH-dependent enzyme (like cytocrome c reductase). Antithyroid drugs-thiourea-inhibit I - oxidation 3- Iodination of tyrosine (organification) oxidized ioide reacts with tyrosyl residues in thyroglobulin (involves TPO) to form MIT or DIT

Thyroglobulin: Prohormone Precursor and storage form of T4 and T3 Large, iodinated and glycosylated protein Composed of 2 subunist Contains 115 tyrosine residues Thyroglobulin is synthesized in the basal portion of the cell. It is stored in the extracellular colloid

4- Coupling of iodotyrosyls (catalysed by TPO, inhibited by antithyroid drugs ) DIT + DIT  T4DIT + MIT  T3 In the thyroglobuli n molecule

5-Thyroglobulin (Tgb) hydrolysis stimulated by TSH (or cAMP) inhibited by I - İncrease in microvilli on the apical membrane  phagocytosis + pinocytosis, bring Tgb back into the follicular cell Phagosomes + lysosomes  phagolysosomes in which acid proteases and peptidases hydrolyse Tgb into amino acids and iodothyronines

T3 and T4 are discharged from the basal portion of cell by facilated process into blood MIT DIT ~ 70% of iodide in Tgb exists in inactive precursors (MIT, DIT),~ 30% in T4 and T3 Tyrosine deiododinase I-I-

When iodine supplies are sufficient  T4/T3: 7/1 In iodine deficiency, T4/T3, DIT/MIT Daily iodide requirement: µg

Transport of thyroid hormones Thyroxine binding globulin (TGB) 70% Albumin 25% Thyroxine binding prealbumin (TBPA) 5% TBG, a glycoprotein, binds nearly all T4 and T3 noncovalently TBG is produced in liver Its synthesis is, increased by estrogens,decreased by androgens or glucocorticoid therapy and in liver disease Phenytoin and salicylates compete with T3 and T4 to bind to TBG

The small, unbound (free) fraction is responsible for biological activity Free T4 and T3 is a measure of thyroid hormone status, represents <1% of total T4 and T3 T4: 8µg/dl (100nmol/L), t 1/2 : 6.5 days T3: 0,15µg/dl(2 nmol/L), t 1/2 : 1.5 days

5’_deiodination converts T4 to T3 This process may occur in the thyroid gland, in target tissues or in other peripheral tissues Since T3 binds to thyroid receptors in target cells with 10 times the affinity of T4, T3 is the metabolically active form. T4 may be regarded as a prohormone

About 80% of T4 is metabolized by deiodination with equal amounts of T3 or rT3 20% of T4 is conjugated with sulfate or glucuronic acid and deactivated by deamidation or decarboxylation Among deiodinases 1 and 2 (DI1,DI2),DI2 is particularly important in controlling nuclear T3 levels.

DI3 is a major metabolic catabolic enzyme; it catalyzes removal of iodide from 3 rather than 5 position to form rT3 rT3 is biologically inactive and similarly de_iodinates and inactivates T3 rT3 is a very weak agonist, made in relatively larger amounts in severe chronic disease (sick euthroid syndrome) in carbohydrate starvation and in the fetus Propylthiouracil and propranolol decrease T4  T3 conversion

FUNCTON Thyroid hormones bind to specific,high_affinity receptors in target cell nucleus They are accelerator pedal of metabolism  increase whole basal metabolic rate They regulate gene expresssion, tissue differentiation, general development, enhance protein synthesis, cause (+) nitrogen balance Thyroid hormones increase Na/K dependent ATP ase activity, increase mitochondrial metabolism T3 and glucocorticoids enhance GH gene transcription  GH production

Clinical disorders of thyroid function Thyroid disease is common, affects almost 3% of the population,9 times as many women as men are affected Autoimmune in origin(mostly) Antibodies may arise against several components of thyroid cells, including the peroxidase rich microsomes

Hypothyroidizm Develops slowly İt is therefore easily missed clinically Clinical biochemistry has an important role in diagnosis

Clinal features: Lethargy and tiredness Cold intolerance Weight gain Dryness and coarsening of skin and hair Hoarseness Slow relaxation of muscles and tendon reflexes Anemia, dementia, constipation,bradycardia Muscle stiffness, carpal tunnel syndrome, subfertility and galactorrhoea

High cholesterol (down regulaton of LDL receptors on liver) Aoutoimmune destruction of thyroid gland (Hashimoto’s disease) Radioiodine or surgical treatment of hyperthyroidism

Rare causes include Transient hypothyroidism (lithium carbonate treatment) TSH deficiency (panhypopituitarism) Congenital defects such as blocks in T4 andT3 synthesis or endorgan resistance Severe iodine deficiency

diagnosis Primary hypothyroidism is failure of the thyroid gland itself, it is one of the most commonly encountered endocrine problem Elevated TSH is usually diagnostic Secondary hypothyroidism failure of pituitary to secrete TSH is much less common TRH test will be included in the protocol to investigate pituitary or hypothalamic causes

Congenital hypothyroidism A condition which, unless treated within 3 months of birth, results in permanent brain damage Hypothyroid children have delayed skeletal maturation, short stature and delayed puberty: delays in treatment result in cretinism high blood TSH is diagnostic

Hyperthyroidism(thyrotoxicosis) Overactivity of thyroid gland Clinical features:  Weight loss,despite normal appetite  Sweating and heat intolerance  Fatigue  Palpitation, sinus tachycardia or atrial fibrillation  Agitation and tremor  Generalized muscle weakness-proximal myopathy

 Angina and heart failure  Diarrhea  Oligomenorrhea and subfertility  Goitre  Eyerlid retraction and lid lag

causes Graves disease (diffuse toxic goitre) Toxic multinodular goitre Solitary toxic adenoma Thyroiditis Exogenously adminstrated iodine and iodine containing drugs Excessive T3 and T4 ingestion

 Most common  Autoimmune disease  Antibodies to TSH receptor on the surface of thyroid cells appear to mimic pituitaary hormone action  Regulatory controls of T4 synthesis and secretion are lacking of thyroid hormones in blood inhibit TSH secretion Most commonAutoimmune disease Antibodies to TSH receptor on the surface of thyroid cells appear to mimic pituitary hormone action Regulatory controls of T4 synthesis and secretion are lacking,high concentrations of thyroid hormones in blood inhibit TSH secretion GRAVES DISEASE

diagnosis Supressed TSH (undetectable) + raised thyroid hormone confirm primary hyperthyroidism Free T4 assays are routinely used, as first time test of thyroid dysfunction TSH secretion is very sensitive to changes in free T4 Free T4 assays are invaluable in diagnosis when TBG are altered (pregnancy, oral contraceptive use,nephrotic syndrome)