Lect 13 Thyroid PDF

THYROID Dr. Sassan Hafizi  THIS LECTURE THYROID GLAND — Location and histology of the thyroid — Formation, storage, and release of thyroid hormones — Control of thyroid hormone secretion — Actions of thyroid hormones — Thyroid diseases and treatment THYROID  T...

THYROID Dr. Sassan Hafizi  THIS LECTURE THYROID GLAND — Location and histology of the thyroid — Formation, storage, and release of thyroid hormones — Control of thyroid hormone secretion — Actions of thyroid hormones — Thyroid diseases and treatment THYROID  THYROID GLAND ¢ 2 lobes connected by isthmus — Greek: “shield-like” (Wharton 1656) ¢ Relatively large endocr. gland – 18-60g in adults ¢ Location: caudal to larynx, adherent to front of trachea ¢ Able to concentrate iodine from blood stream HISTOLOGY OF THYROID GLAND ¢ Follicle (acinus) - sac of stored hormone (colloid) ¢ Surrounded by acinar cells that produce iodine-containing thyroid hormones: — Thyroxine (T4; tetraiodothyronine) — Triiodothyronine (T3) ¢ Inactive gland – acinar cells are thin, flattened ¢ Overactive/hyperactive gland – acinar cells are tall, columnar ¢ Other cells: parafollicular cells — produce calcitonin (other topic) SUMMARY OF HORMONES BY CHEMICAL CLASS PRODUCTION OF THYROID HORMONE IODINATION OF TYROSYL RESIDUES BY THE THYROPEROXIDASE–H2O2 COMPLEX  PRODUCTION OF THYROID HORMONE 1. Follicular cells — Trap iodide, active, against steep concn grad ¢ Na+/I- symporter (NIS) and I-/Cl- porter (pendrin, PDS) — Synthesise glycoprotein thyroglobulin (TGB) — Release TGB into colloid 2. Iodination of tyrosine in colloid 3. Formation of T3 & T4 by coupling:  SYNTHESIS OF THYROID HORMONES Thyroid hormones formed within the structure of thyroglobulin (TGB): ¢ 40/125 Tyr residues in TGB available for iodination — Proportion related to I- concn ¢ Tyr in TGB is iodinated to form monoiodotyrosine (MIT) ¢ MIT is iodinated to form diiodotyrosine (DIT) ¢ Coupling then occurs: MIT+DIT = T3; DIT+DIT = T4 Thyroid hormones  PRODUCTION OF THYROID HORMONE 1. Follicular cells — Trap iodide, active, against steep concn grad ¢ Na+/I- symporter (NIS) and I-/Cl- porter (pendrin, PDS) — Synthesise glycoprotein thyroglobulin (TGB) — Release TGB into colloid 2. Iodination of tyrosine in colloid 3. Formation of T3 & T4 by coupling: — MIT (T1) + DIT (T2) — Extracellular “depot” of hormone 4. Uptake & digestion of colloid containing TGB by follicle cells (TGB degraded) 5. Secretion of thyroid hormone into blood — 80-90% T4, 10-20% T3 — Only 0.03% T4 & 0.3%T3 free (unbound) ¢ Most bound to thyroxine-binding globulin (also transthyretin, albumin) CONTROL OF THYROID HORMONE SECRETION CONTROL OF THYROID HORMONE SECRETION — Thyrotropin-releasing hormone (TRH) from hypothalamus — Thyroid-stimulating hormone (TSH) from anterior pituitary (thyrotroph cells):  1 Low blood levels of T3 and T3 or low metabolic rate stimulate release of Hypothalamus TRH 2 TRH, carried by hypophyseal portal veins to anterior pituitary, 5 Elevated stimulates T3inhibits release of TSH release of by thyrotrophs TRH and TSH TSH (negative feedback) Anterior 3 TSH released into blood stimulates pituitary thyroid follicular cells 4 T3 and T4 released into Thyroid blood by follicle follicular cells Actions of Thyroid Hormones: Increase basal metabolic rate Stimulate synthesis of Na+/K+ ATPase Increase body temperature (calorigenic effect) Stimulate protein synthesis ACTIONS OF THYROID HORMONES ¢ T3 & T4 cause: — ↑ Metabolic rate — ↑ Protein synthesis — ↑ Breakdown of fats — ↑ Use of glucose for ATP production ¢ Calcitonin — From the parafollicular cells Responsible for building of bone — Other topic “C” cells IMPORTANCE OF THYROID HORMONES ¢ Administration of thyroid hormones: — ­ BASAL METABOLIC RATE (BMR) in adults ¢ Concentration of circulating thyroid hormones relatively constant — Contrast to most other hormones ¢ Essential for normal growth and development ¢ In adult, virtually every body tissue requires thyroid hormones — Principal site of action is cell nucleus  ACTIONS OF THYROID HORMONES ¢ Calorigenic - increases oxygen consumption of most tissues ¢ Effect on nerves - brain maturation during foetal development ¢ Synergistic with catecholamines (adr., noradr.) - ­ heart rate ¢ Effect on carbohydrates - increase uptake from GI tract ¢ Growth & development - need for correct growth ¢ Effect on skeletal muscle - need for muscle strength ¢ Effect on heart muscle - heart v. sensitive to thyroid hormones ¢ Cholesterol lowering - lowers blood cholesterol THYROID HORMONE PROPERTIES ¢ Thyroid secretes mostly T4 (80 μg/d) in adult human (T3, 4 μg/d) ¢ T3 probably the true hormone — more active — faster turnover — better T3 receptor binding ¢ T3 activates T3 receptor in cell nucleus, turning on protein synthesis ¢ T4 largely a prohormone — Easily converted to T3 (deiodinase) — Up to 80% T4 converted to T3 outside thyroid (liver, kidney, spleen) PROPERTIES OF THYROID HORMONES T3 T4 T½ in blood 2 days 6 days Start of action (nucleus) 4h 24h Maximum effect 2-3 days 10 days % bound in blood 99.8 99.98 Free level in plasma 0.4 ng/dl 2 ng/dl Total level in plasma 0.15 μg/dl 8 μg/dl O2 consumption in 3-5x effect of T4 on humans a molar basis THE EFFECT OF EQUIMOLAR DOSES OF T3 AND T4 ON BASAL METABOLIC RATE IN A HYPOTHYROID SUBJECT Thyroid disease states  HYPOTHYROIDISM - Symptoms ¢ ¯ BMR ¢ Slow pulse ¢ Feel cold, want extra clothing ¢ Weight gain ¢ Sluggishness ¢ Coarse skin ¢ => ⑧ Myxoedema  GOITRE ¢ Thyroid is dependent upon constant supply of dietary iodide ¢ In iodine deficiency, gland swells in response — Gland appears nodular with irregular outline — Grossly enlarged — Treatable with iodine in diet — More common inland and before iodised salt  CAUSES OF HYPOTHYROIDISM ¢ Common, mainly females ¢ Simple goitre — Usually due to iodine lack in diet — Naturally occurring goitrogens, eg cassava (not soaked) ¢ Acquired hypothyroidism — Autoimmune attack on thyroid e.g. Hashimoto's PRIMARY thyroiditis (antibodies against thyroid cells or TGB) hypothyroidism TSH is high ¢ Congenital hypothyroidism 2ndary due to — Irreversible brain damage pituitary or ¢ Cretinism (described by Fagge, 1871) hypothalamic ¢ Severely stunted physical & mental growth disease — Usually due to genetic defect e.g. incomplete TSH is low development, or complete absence of thyroid TREATMENT OF HYPOTHYROIDISM ¢ Replacement therapy: — Levothyroxine sodium (T4) – generally 100μg/day (oral) — Liothyronine sodium (T3) - 20-60 μg/day (oral or inject) ¢ Increase dose slowly until reach equilibrium ¢ Monitor therapy via blood T4 & TSH levels ¢ Caution in patients with heart disease HYPERTHYROIDISM CAUSES OF HYPERTHYROIDISM ¢ Overactivity of thyroid gland (­ T3 & T4) ¢ ¯ TSH Usually due to: ¢ Graves’ disease (aka exophthalmic goitre) — Autoimmune disease ¢ Auto-IgGs stimulate the TSH receptor on follicular cells — 80% of cases ¢ Thyroid toxic adenoma HYPERTHYROIDISM (THYROTOXICOSIS) – SIGNS AND SYMPTOMS ­ BMR b-adrenergic overactivity Goitre (thyroid growth due to lack of –ve feedback) Weight loss Anxious, irritable Restless, cannot sleep & easily fatigue Hyperphagia (excess eating) Heat intolerance, increased body temperature Excess sweating, warm soft skin Increase irregular heart rate Tremours in fingers Some get protruding eyes (exophthalmia) Fine hair Rapid growth in children Nails thin & brittle Menstrual irregularities Marty Feldman Diarrhoea TREATMENT OF HYPERTHYROIDISM ¢ AIMS are to: ¢ Block coupling (inhibit thyroid peroxidase, e.g. oral carbimazole in UK) ¢ Block conversion of T4 to T3 (propylthiouracil) ¢ Block TGB synthesis ¢ 2 regimes: “titration” (18 months) or “block and replace” (6 months) ¢ ANTITHYROID DRUGS (preferred in