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Thyroid

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  1. Thyroid Roger L. Bertholf, Ph.D. Associate Professor of Pathology Director of Clinical Chemistry & Toxicology

  2. Thyroid hormones Tetraiodothyronine (T4, Thyroxine) 3,5,3´ Triiodothyronine (T3) 3,3´,5´ Triiodothyronine (reverse T3)

  3. Effects of thyroid hormones • Calorigenic ( O2 consumption) • Growth, development, sexual maturation, CNS maturation •  HR and contraction •  Protein synthesis, C(H2O)n metabolism, lipid turnover •  Sensitivity of -adrenergic receptors to catecholamines • Brain, retina, lungs, spleen, testes appear to be unaffected by thyroid hormones

  4. Regulation of thyroid hormones TRH TSH T4 (T3) T3 (rT3)

  5. T1 T2 T4 T3 T3 T4 Thyroglobulin Thyroglobulin T4 T4 T4 TBG Alb TBPA Thyroid hormone production Follicle Colloid TPO Iodide (I-) NIS* I- (40X) Thyroglobulin TSH *Sodium/Iodide Symporter protein

  6. Thyroid hormone synthesis Thyroglobulin Free thyroxine

  7. Peripheral T4 metabolism

  8. Peripheral thyroxine metabolism • T4 production is exclusively thyroidal • 70-90% of T3 is produced extrathyroidally • 95-98% of rT3 is produced extrathyroidally • Most peripheral de-iodination occurs in the liver • T3 accounts for most of the thyroid hormone activity in peripheral tissues • 3-4 times more potent than T4 • Some researchers have questioned whether T4 has any intrinsic biological activity • rT3 is biologically inactive

  9. T3 T4 TBG T3 Alb T4 T4 T3 TBPA Circulating thyroid hormones 99.97% T4 fT4 (0.03%) fT3 (0. 3%) Only free hormone is active! 99.7% T3

  10. Affinities of thyroid binding proteins TBG TBPA Alb >>> >> 68% of T4 80% of T3 Low conc. (0.27 M) High affinity (K=1010) 54 kDa 11% of T4 9% of T3 Low conc. (4.6 M) Low affinity (K=107) 15.5 kDa 20% of T4 11% of T3 High conc. (640 M) Low affinity (K=105) 66 kDa A small fraction of thyroid hormones is bound to lipoproteins

  11. Increased protein binding •  TBG • Genetic, NTI (HIV, hepatitis, estrogen-producing tumors, AIP), pregnancy, drugs •  Prealbumin (TBPA) (euthyroid thyroxine excess) • Albumin variant (familial dysalbuminemia hyperthyroxinemia) • T4 autoantibodies

  12. Decreased protein binding •  TBG • Genetic, NTI (NS), drugs, nephrosis •  Prealbumin (TBPA) •  TBG binding capacity (competing drugs such as salicylate and phenytoin)

  13. Thyroglobulin (Tg) • 660 kd protein that is the intra-thyroidal carrier of thyroid hormones • Synthesized in the thyroid follicular cells; secreted into the lumen • Stored mostly in the colloid • Synthesis, colloidal uptake, and proteolysis (to release T4 and T3) regulated by TSH

  14. Thyrotropin (TSH) • One of several hormones synthesized in the anterior pituitary • Others are LH, FSH, Prolactin, ACTH, GH •  (common with LH, FSH, hCG) and  subunits • MW=30 kDa • Binds to a TSH receptor on the thyroid follicular cells to activate adenylyl cyclase/cAMP protein kinase A and Ca++ protein kinase C pathways

  15. Sick Euthyroid Healthy Sick T3 T3 Peripheral T4 rT3 rT3

  16. Sick Euthyroid rT3 TSH Normal range fT4 Concentration  T4 T3 Mild Moderate Severe Recovery Phase of illness

  17. Hypothyroidism • A deficiency in thyroid hormone activity • Occurrence as high as 15%, with ♀preference • Myxedema is severe form • Untreated congenital hypothyroidism results in severe developmental deficits • Can be structural or functional • 1°= deficiency in thyroid hormone production • 2° (or “central) = pituitary or hypothalamic failure • Hypothalamic failure sometimes called “3°”

  18. Primary Hypothyroidism • Iodine deficiency (most common worldwide) • Hashimoto’s thyroiditis (most common in developed countries) • Autoimmune (α-TG or α-TPO) • Non-goitrous causes • Radioactive I2 therapy/exposure; surgical ablation • Congenital (1 per 3500 to 4000 live births)

  19. Secondary Hypothyroidism • Pituitary (TSH) or hypothalamic (TRH) failure. • Isolated TSH deficiency is rare; usually associated with panhypopituitarism. • Sheehan’s Syndrome • Endocrine-inactive adenomas • Other space-occupying lesions

  20. Stages of Hypothyroidism

  21. Hyperthyroidism (thyrotoxicosis) • Increased thyroid hormone production • Graves’ Disease (most common; α-TSH receptor) • Toxic multi-nodular goiter • Solitary toxic adenoma or pituitary adenoma • Normal thyroid hormone production • Thyroiditis (thyroid hormone leakage) • Thyrotoxicosis facticia • Metastatic thyroid carcinoma or struma ovarii

  22. Stages of Hyperthyroidism

  23. Summary of thyroid autoantibodies

  24. Effects of Drugs on Thyroid Hormones

  25. Laboratory Evaluation of Thyroid Function nl TSH Euthyroid ND   Hyperthyroid? Hypothyroid? Borderline fT4 if N, T3 fT4, T3 TRH? fT4