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Thyroid Anatomic prominence; one of first endocrine glands to be correlated with clinical condition caused by malfunction Releases two types of hormones: I. T3: triiodothyronine (59% iodine) T4: thyroxine (65% iodine) Important in growth and development; regulate energy metabolism; maintain body temperature II. Calcitonin: important in regulating calcium metabolism Thyroid Thyroid gland unique- stores large amounts T3 and T4 T3 and T4 synthesized and stored as amino acid residues in thyroglobulinprotein, constitutes vast majority thyroid follicular colloid Thyroid Hormones (T3 and T4) Active form: L–isomers Iodine essential part of both hormones T3 59% iodine T4 65% iodine T3 more potent than T4 Bind to specific cell surface receptors on sensitive targets; leads to increased uptake of glucose and amino acids T3 also binds to cytoplasmic binding protein leads to increased protein synthesis Starvation: decreasesT3 and T4 receptors Thyroid Gland Thyroid consists of follicles (vesicles) made up of thyroid follicular cells; thyroglobulin associated with inner surface of follicle thyroglobulin thyroid follicular cell (glycoprotein) colloid Thyroid follicle (cuboid epithelial cells) Thyroid Gland Thyroglobulin (TG)- synthesized at colloid/cell interface T3 and T4 synthesized and stored as amino acid residues in TG Thyroid Hormone Synthesis 1. Uptake of Iodide (iodide trapping) 2. Iodide organification (oxidation and iodination) 3. Coupling of MIT and DIT 4. Secretion of thyroid hormones 5. Conversion of T4 to T3 1. Uptake of Iodide Iodide trapping; iodide concentration in blood normally very low; thyroid concentrates and stores iodide Uptake involves transport of iodide from blood into thyroid follicular cell Autoregulatory control: decreased iodide storage increased uptake Uptake stimulated by TSH from anterior pituitary Inhibited by monovalent anions: perchlorate, thiocyanate, pertechnetate 2. Iodide Organification Oxidation and iodination of iodide Occurs in thyroid follicular cell Thyroid peroxidase: oxidizes iodide to iodine Heme containing enzyme; utilizes hydrogen peroxide derived from oxidation of NADPH as an oxidant; inhibited by: thionamides Iodine rapidly iodinates tyrosine residues in thyroglobulin forming MIT (mono-iodotyrosine) and DIT (di-iodotyrosine) 3. Coupling of MIT and DIT Coupling reaction involves oxidation by thyroid peroxidase MIT + DIT T3 DIT + DIT T4 Stored in thyroglobulin in colloid matrix Synthesis: T4/T3 = 5:1; mostly T4 released Inhibited by thionamides 4. Secretion of T4 and T3 Proteolysis releases T4 and T3 stored within thyroglobulin (TG) Endocytosis of TG/colloid from follicular lumen Fusion with lysosomal granules containing proteolytic enzymes Breakdown of TG and release of T4 and T3 MIT and DIT deiodinated; iodine reutilized T4 and T3 reversibly bind to specific serum proteins thyroxine binding globulin and transthyretin; protect against metabolism 5. Conversion of T4 to T3 80% T4 converted to T3 De-iodination of T4 (thyroxine) to active T3 (triiodothyronine) and to reverse T3 (inactive) Very low levels free T4 and T3 in blood (0.04% T4, 0.4 % T3) T4 and T3 mostly bind to thyroxine binding globulin (TBG): acidic glycoprotein, higher affinity for T4 than T3 Other T4 and T3 binding proteins (transthyretin): decreased affinity Regulation of Thyroid Hormone Synthesis Pituitary-Hypothalamus Autoregulation Abnormal stimulators Pituitary-Hypothalamus (-) Hypothalamus TRH (-) Anterior Pituitary TSH Thyroid adenyl cyclase T4 and T3 Thyroid Regulation Autoregulation Increased iodine decreased iodide uptake and organification (conversion to iodine) Abnormal stimulators Graves disease: production of thyroid stimulating immunolglobulin (antibody) by lymphocytes; mimics action of TSH; longer duration action; autoimmune disease Tumors: thyrotoxicosis- excessive hormone production Effects of Thyroid Hormones Growth and Development Calorigenic Effects Cardiovascular Effects Metabolic Effects Growth and Development Thyroid hormone (TH) regulates optimal growth and development of all body tissue; stimulates protein synthesis presumably by increasing DNA transcription; TH critical for nervous, skeletal and reproductive tissues Cretinism: deficiency in iodine; failure of thyroid to develop; dwarfism, mental retardation, pale skin, slow heart rate, low body temperature normal development-requires early diagnosis and treatment Calorigenic Effect Thyroid hormones increase resting or basal metabolic rate of whole organism Most sensitive tissues: heart, skeletal muscle, liver, kidneys Thyroid hormones increase body temperature Alterations in body temperature regulate TH production Cold Increased T3 and T4 production Cardiovascular Effects Thyroid hormones: increase heart rate increase force of contraction increased cardiac output Mechanism: Direct effect: binding to thyroid hormone receptors in heart; not just response to increased in basal metabolism Indirect effect: Increased number of beta receptors in heart Metabolic Effects Stimulate metabolism of cholesterol to bile acids Increase binding of LDL by liver Increase carbohydrate metabolism Increase glucose uptake Thyroid Hyperfunction Signs and Symptoms Increased body temperature Increased motor activity Increased sympathetic nervous system activity Skin- flushed, warm Weak muscles; fatigue Increased heart rate; arrhythmias; CHF Increased appetite Nervousness; jittery Increased basal metabolic rate; decreased cholesterol and triglycerides Menstrual irregularities; decreased fertility Thyroid Hyperfunction Excessive secretion thyroid hormones Difuse Toxic Goiter (Graves Disease) -Characterized by thyrotoxicosis and opthalmopathy -Most common in young, middle age females -Autoimmune disease -IgG antibodies to TSH receptors- activate receptors increased T3 and T4 release -Genetic defect in TSH: increase TH increase Ts-Ig Toxic Nodular Goiter (Plummer’s Disease) -Occurs in older patients -Arises from long-standing nontoxic goiter Treatment of Hyperthyroidism Agents that interfere with production of T3 and T4 Agents that modify tissue responses to T3 and T4 Destruction of thyroid gland: surgery; radiation Thyroid Hyperfunction Treatment Antithyroid drug therapy Thyroidectomy 131Iodine Thyroid Storm (thyrotoxic crisis) life threatening; need immediate treatment: propanolol Anti-thyroid Hormone Drugs Goitrogens: agents that decrease production of TH Thionamides -methimazole (10x more potent) -propylthiouracil -carbimazole (UK) Accumulate in thyroid Thionamides Mechanism of Action Inhibit thyroid peroxidase catalyzed reactions: – Block iodine organification – Coupling of MIT and DIT Inhibit peripheral de-iodination of T3 and T4 Block synthesis T3 and T4 not release, therefore slow onset of action Thionamides Therapeutic Use – Hyperthyroidism Untoward Effects – Relatively low incidence (3 – 12%) – Most occur early – Agranulocytosis (<1%) Anti-thyroid Hormone Drugs Anion Inhibitors Monovalent anions: resemble Iodide; competitve inhibitors inhibit transport of iodide into thyroid overcome by increased Iodide – Perchlorate (ClO4-) – Pertechnetate (TcO4-) – Thiocyanate (SCN-) Therapeutic use: Diagnostic Anti-thyroid Hormone Drugs Iodides - Oldest remedy - Paradoxical action - Observe effects within 24 hours - Maximum effects: 10 –15 days - Effects temporarily - Inhibit TH release*, inhibit organification of iodide - Decreased size and vascularity of hyperplastic gland - No longer used alone (thionamides) Radioactive Iodine (131I) - Rapidly absorbed (orally) - Concentrated in thyroid - Emits b radiation destruction of thyroid gland (painless) - Short half life (8 d) - Widely used to treat hyperthyroidism - Disadvantage: delayed hypothyroidism -Alternative: 123I; emits x-rays; used for thyroid scans; half life = 13 hr Iodinated Contrast Media Ipodate and Iopanoic Acid -Inhibit conversion T4 3 T in liver, kidney, pituitary and brain -Used in adjunct therapy Adrenoceptor Blocking Agents Many symptoms of thyrotoxicosis mimic sympathetic stimulation Need to use agents that rapidly deplete catacholamines or b-blockers Block physiologically effects of sympathetic nervous system stimulation Guanethidine Propanolol Thyroid Hypofunction Thyroid hormone deficiency (Gull’s Disease) Hypothyroidism: mild Myxedema: more severe symptoms Degeneration or atrophy thyroid gland may be associated with goiter Hashimoto’s Thyroiditis: autoimmune destruction of thyroid gland; most common in US Thyroid Hypofunction: Signs and Symptoms Pale puffy skin Droopy eyelids Decreased peripheral vascular resistance Decreased heart rate and cardiac output bradycardia Decreased appetite Lethargy, slowing of mental processes Decreased kidney and reproductive function (infertility) Decreased basal metabolism Children: mental retardation, dwarfism Diagnosis and Treatment of Hypothyroidism Diagnosis: decreased T4 production; presence of anti-thyroid antibody (autoimmune) Treatment: Replacement therapy with levothyroxine (T4); Stable, long half-life (7 d), converted to T3; used to treat hypothyroidism, myedemia, coma, cretinism, simple goiter, nodular goiter