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THE THYROID

THE THYROID. The Thyroid Gland.

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THE THYROID

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  1. THE THYROID

  2. The Thyroid Gland • The thyroid is a small (25 grams) butterfly-shaped gland located at the base of the throat. The largest of the endocrine glands, it consists of two lobes joined by the isthmus. The thyroid hugs the trachea on either side at the second and third tracheal ring, opposite of the 5th, 6th and 7th cervical vertebrae. It is composed of many functional units called follicles, which are separated by connective tissue. • Thyroid follicles are spherical and vary in size. Each follicle is lined with epithelial cells which encircle the inner colloid space (colloid lumen). Cell surfaces facing the lumen are made up of microvilli and surfaces distal to the lumen lie in close proximity to capillaries.

  3. The Thyroid Gland • Formation of the thyroid gland occurs during weeks 7-9 of gestation as an epithelial proliferation of the floor of the pharinx at the site of foramen cecum linque. The gland riches its final position by week 9 descending along the thyro-glosal duct. • Weeks 7-9 : thyroid formation begins • Week 10 : TSH and T4 are detectable • Week 17 : structural maturity of the thryoid gland • Week 20 : type 2 and type 3 deiodinase are present • Weeks 18 – 40 : • TRH present • TSH is present and controls thyroid hormone production • Fetal thyroid response to TSH - thyroid hormone to TRH and TSH hormone feed established

  4. Thyroid anatomy

  5. Microscopic appearance of thyroid follicles

  6. Thyroid hormones in the body

  7. Thyroid hormones synthesis The thyroid is stimulated by the pituitary hormone TSH to produce two hormones, Thyroxine (T4) and triiodothyronine (T3)  in the presence of iodide. Hormone production proceeds by six steps: • Dietary iodine is transported from the capillary through the epithelial cell into the lumen NIS and Pendrin. • Iodine is oxidized to iodide by the thyroid peroxidase enzyme (TPO) and is bound to tyrosine residues on the thyroglobulin molecule to yield monoiodotyrosine (MIT) and diiodotyrosine (DIT). • TPO further catalyzes the coupling of MIT and DIT moieties to form T4 and/or T3. • The thyroglobulin molecules carrying the hormones are taken into the epithelial cells via endocytosis in the form of colloid drops. • Proteolysis of the iodinated hormones from thyroglobulin takes place via protease/peptidase action in lysosomes and the hormones are released to the capillaries. • Any remaining uncoupled MIT or DIT is deiodinated to regenerate iodide and tyrosine residues.

  8. Iodine metabolism in normal thyroid cells TSH signaling via the TSH receptor (which is shown at the bottom of the thyrocyte on the left) controls thyroid hormone synthesis, and it can increase expression of NIS in the basolateral membrane of thyrocytes. As shown in the thyrocyte on the right, NIS takes up iodide from the blood. The proteins involved in efflux of iodide at the apical membrane are not known, and the roles of AIT and pendrin are unclear. As shown in the left-hand thyrocyte, iodide is organified in the tyrosyl residues of Tg in a reaction catalyzed by TPO, in the presence of H2O2, which is produced by DUOX. Tg contains MIT, DIT, T3, and T4 and is stored in colloid until T3 and T4 need to be released into the blood.

  9. ClO4-, SCN- organification NaI symporter (NIS) and pendrine Propylthiouracil (PTU) blocks iodination of thyroglobulin Thyroid peroxidase (TPO) ION TRANSPORT BY THE THYROID FOLLICULAR CELL BLOOD I- COLLOID I-

  10. Iodination of Tyr residues of Tg TSH TSH receptor TPO THYROGLOBULIN SYNTHESIS IN THE THYROID FOLLICULAR CELL COLLOID

  11. T4 T3 DIT MIT I- TSH TSH receptor THYROID HORMONE SECRETION BY THE THYROID FOLLICULAR CELL COLLOID

  12. OH OH I I I I I O O NH2 NH2 I I OH OH O O 3,5,3’-Triiodothyronine (T3) THYROID HORMONES Thyroxine (T4)

  13. Thyroid hormone transport • bound to thyroxine-binding globulin (TBG): 70% • bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA):10-15% • Paralbumin: 15-20% • unbound T4 (fT4): 0.03% • unbound T3 (fT3): 0.3%

  14. FEEDBACK REGULATION THE HYPOTHALAMIC-PITUITARY-THYROID AXIS Hormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known astrophic hormones. Key players for the thyroid include: TRH - Thyrophin Releasing Hormone TSH - Thyroid Stimulating Hormone T4/T3 - Thyroid hormones

  15. Control of thyroid function TRH Thyrotropin releasing hormone is produced by the hypothalamus and functions to stimulate the anterior pituitary to release TSH. TRH is a small tripeptide that acts in conjunction with somatostatin and dopamine to regulate the synthesis and release of TSH in a dose dependent manner. Dysfunction at this stage in the stimulatory cascade results in decreased TSH production and hence hypothyroidism, termed a tertiary thyroid disorder. While thyroid hormones T4 and T3 down-regulate TSH in a classic feedback inhibition scheme, TRH production is also inhibited the these thyroid hormones, albeit to a lesser degree, in the hypothalamus.

  16. Control of thyroid function TSH Thyroid stimulating hormone (TSH) or thyrotropin is a glycoprotein with a molecular weight of approximately 28,000 daltons, synthesized by the basophilic cells (thyrotropes) of the anterior piyuitary TSH is composed of two noncovalently linked subunits designated alpha and beta. Although the alpha subunit of TSH is common to luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG), the beta subunits of these glycoproteins are hormone specific and confer biological as well as immunological specificity. Both alpha and beta subunits are required for biological activity. TSH stimulates the production and secretion of the metabolically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3), by interacting with a specific receptor on the thyroid cell surface. T3 and T4 are responsible for regulating diverse biochemical processes throughout the body which are essential for normal development and metabolic and neural activity.

  17. THYROID HORMONES ACTIONS

  18. NH2 NH2 I OH I OH OH “Step up” “Step down” I O O O I T4 I I OH I R OH I R I O O I T3 rT3 I OH I R O 3,3’-T2 R = THYROID HORMONE METABOLISM

  19. THYROID HORMONE DEIODINASES • Three deiodinases (D1, D2 & D3) catalyze the generation and/disposal of bioactive thyroid hormone. • D1 & D2 “bioactivate” thyroid hormone by removing a single “outer-ring” iodine atom. • D3 “inactivates” thyroid hormone by removing a single “inner-ring”iodine atom. • All family members contain the novel amino acid selenocysteine (SeC) in their catalytic center.

  20. extracellular domain A B E intracellular domain COOH D C NH2 EXISTS AS A DIMER BASIC ORGANIZATION OF THE SELENODEIODINASES

  21. BASICS OF THYROID HORMONE ACTION IN THE CELL

  22. SPECIFIC ACTIONS OF THYROID HORMONE: METABOLIC • Regulates of Basal Metabolic Rate (BMR). • Increases oxygen consumption in most target tissues. • Permissive actions: THincreases sensitivity of target tissues to catecholamines, thereby elevating lipolysis, glycogenolysis, and gluconeogenesis.

  23. SPECIFIC ACTIONS OF THYROID HORMONE: DEVELOPMENT • TH is critical for normal development of the skeletal system and musculature. • TH is also essential for normal brain development and regulates synaptogenesis, neuronal integration, myelination and cell migration. • CRETINISM is the term for the constellation of defects resulting from untreated neonatal hypothyroidism.

  24. THYROID HORMONES MECHANISM OF ACTIONS • Passive diffusion or active transport? • Deiodination of T4 to T3 • T3 binds to specific nuclear receptor • Nuclear receptor activation increases RNA and protein synthesis • Increased Na/K aATP-ase and ATP turn-over • Increased oxigen consumption in mitochondrias • Calorigenic effects

  25. THYROID HORMONES ACTIONS • Increase basal metabolic rate • Increase heat production through stimulation of Na/K ATP-ase • Stimulate protein synthesis • Regulate long bone growth synergistic with GH • Stimulate neuronal maturation • Increase number of cathecolamine receptors • TH are essential for normal development and differentiation of all cells of the human body • Increase lipid catabolism / lypolisis • Increase glucose uptake and metabolism • Growth, development, body temperature, energy metabolism regulation

  26. Thyroid hormones are responsible for neuronal mielinization

  27. EXAMPLES OF THYROID DISEASES Hyperthyroidism Hypothyroidism

  28. EXAMPLES OF THYROID DISEASES Juvenile Hypothyroidism Congenital Hypothyroidism

  29. Normal ultrasound appearence of the thyroid gland

  30. Calculation of thyroid volume Formula of a rotationg elipsoid a = AP diameter AP b = Transverse diameter c = longitudinal diameter I a x b x c x  / 6 II a x b x c x 0.479 III a x b x c x 0.53 IV a x b x c x 0.5

  31. Malignant thyroid nodule

  32. Thyroid scintigraph

  33. Thyroid scintigraph with 123I The nodule on the right lobe appears to be hypofunctioning (cold nodule).

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