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Thyroid hormone สุวัฒณี คุปติวุฒิ ตึกจุฑาธุช หอง 101 Aims Functional anatomy of thyroid gland Synthesis, secretion and metabolism of the thyroid hormones The mechanism of thyroid hormone action Role of thyroid hormone in development , growth and metabolism Thyroid hormone deficiency and excess in adult 1 Anatomy Relation of Thyroid gland Cross section of Thyroid gland Thyroid follicle C cell Thyroglobulin store in colloid of follicle Follicle cells 2 Thyroid gland contains numerous follicles Colloid is composed of thyroglobulin Thyroid follicle produce and secrete thyroxine (T4) and triiodothyronine (T3) C cell or parafollicular cell produce calcitonin Synthesis of Thyroid Hormone Uptake of Iodine by thyroid Coupling of Iodine to Thyroglobulin Formation of T3, T4 from MIT / DIT Storage of MIT / DIT in follicular space Re-absorption of MIT / DIT Release of T3, T4 into serum Breakdown of T3, T4 with release of Iodine 3 3 T Peroxidase Coupling COLLOID Reabsorption T Peroxidase Iodination 2 4 T Peroxidase 6 Deiodinase Thyroglobulin I 5 1 Iodine from diet I- Lysosome Iodine trap Na+/Isymporter BLOOD VESSEL Perchlorate / excess I2 p ci l ura o i h ylt rop ate rchlor ate/ pe n a y c thio T4 pro ci l ura o i l th T3 py 4 Uptake of Iodine by thyroid stimulated by Thyroid stimulationg hormone(TSH) Coupling of Iodine to Thyroglobulin Monoiodotyrosine (Thyroglobulin + one I-) Diiodotyrosine (Thyroglobulin + two I-) Thyroid Hormones T4 ( THYROXINE ) T3 ( TRIIODOTHYRONINE ) Formation of T3, T4 from MIT / DIT MIT + DIT = T3 (Triiodothyronine) DIT + DIT = T4 (Thyroxine) Catalyzed by thyroid peroxidase 5 Majority of circulating hormone is T4 98.5% T4 1.5% T3 D = deiodinase The affinity of the receptor for T3 > T4 ~ 10 times Thyroid H. are poorly soluble in water Thyroid binding protein: thyroid binding globulin (TBG), transthyrtein and albumin Increased TBG: - High estrogen states (pregnancy,HRT) - Liver disease (early) total Free Decreased TBG - Androgens or anabolic steroids - Liver disease total TSH Free TSH Decreased binding to TBG - Phenytoin (dilantin) - Salicylates 6 Regulation of of Thyroid Thyroid Hormone Hormone Secretion Secretion Regulation Iodine uptake Colloid endocytosis Growth of thyroid gl Thyroid Hormone Hormone Action Action Thyroid 7 Thyroid Hormone Hormone Action Action Thyroid Increase basal metabolism Stimulate cellular cellular respiration respiration -- Stimulate ¾ Increase oxidative phosphorylation enzymes in cells such as cytochromes, cytochrome oxidase uncoupling proteins (UCP 1-3) ¾ Increase activity of Na+/K+ pumps ¾ Increase RBC and 2,3 DPG enzyme O2 consumption body heat production Intermediary metabolisms Lipid metabolism - Lipolysis - Cholesterol clearance Carbohydrate metabolism - Blood glucose glucose absorption from GI tract gluconeogenesis glucogenolysis 8 Protein metabolism protein synthesis (normal level) Na+-K+ pump, myosin ATPase activity, amount of calcium both in skeletal and heart muscle Normal muscle function High level of thyroid hormone protein breakdown Inhibit creatine kinase Growth and development Maturation and differentiation effects Stimulating GH & IGF production Bone growth and bone resorption Promote growth and development of the fetal And neonatal brain - Regulate synpatogenesis, neural integration, myelination and cell migration Increase reflex response to stimuli 9 ------- Level of symphysis Normal Normal 22 years years Hypothyroid Hypothyroid 88 years years Dwarf-not Dwarf-not hypothyroid hypothyroid years 88 years Normal Normal years 88years Infantile body proportion (upper > lower portion) Cretinism = dwarfism + mental retardatyion Cretinism A Color Atlas of Endocrinology p66 10 Other function Increase number and affinity of β-adrenergic receptor Heart rate, contractility & cardiac output Vasodilatation Blood flow Decrease mucopolysaccharide synthesis hypothyroid Myxedema Maintain gonadal functions Before Rx After Rx 11 Thyroid Autoregulation Stabilize plasma T3 , T4 and TSH Organic I2 I- uptake TSH Response to TSH T3, T4 not I2 Organic I2 T3 T4 Organic I2 I- uptake Response to TSH T3, T4 not Wolff-Chaikoff effect Higher doses I- cause cessation of hormone formation z Decrease organification cause hypothyroid z This block is temporary. temporary Inorganic I- z Autoregulation fail Block total organification z Increasing doses of Iincrease hormone synthesis initially percent of I- Uptake z Dosage of stable iodide ( μg/rat) 12 Jod-Basedow z Aberration of the Wolff-Chaikoff effect z Excessive iodine loads induce hyperthyroidism Thyroid Thyroid Dysfunction Dysfunction Hyperthyroidism Hypothyroidism Goitre with Euthyroid - Puberty - Pregnancy with Hyperthyroid - Graves ’ disease with Hypothyroid - I2 deficiency - Goitrogen - Dyshormonogenesis 13 Hypothyroidism Decreased metabolic rate Weight gain, reduced appetite Dry and cold skin Weak, flabby skeletal muscles, sluggish Myxedema Apathetic, somnolent Coarse hair, rough dry skin Decreased iodide uptake Possible goiter Hyperthyroidism Increased metabolic rate Weight loss, increased appetite Warm flushed skin Weak muscles that exhibit tremors Exophthalmos Hyperactivity, insomnia Soft smooth hair and skin Increased iodide uptake Almost always develops goiter 14 Thyroid Antibodies Antibodies Thyroid Destructive Ab Antithyroid peroxidase (anti TPO) Antithyroglobolin (anti TG) Hypothyroidism (Hashimoto thyroiditis) Stimulating Ab Anti-TSH receptor (TSI) Hyperthyroidism (Graves’ disease) 15