Thyroid hormone synthesis
- 1. THYROID GLAND AND THYROID METABOLIC HORMONES
- 2. LEARNING OBJECTIVES By the end of this lecture you should be able to: • Describe physiologic anatomy of thyroid gland. • Describe various steps involved in synthesis of thyroid hormones. • Enumerate various functions of TSH. • Describe difference between T4 and T3. • Describe how T4 is converted to T3 • Describe how thyroid hormone is transported in circulation.
- 3. ANATOMY OF THE THYROID GLAND
- 4. FOLLICLES: THE FUNCTIONAL UNITS OF THE THYROID GLAND Follicles Are the Sites Where Key Thyroid Elements Function: • Thyroglobulin (Tg) • Tyrosine • Iodine • Thyroxine (T4) • Triiodotyrosine (T3)
- 5. THYROID SECRETESTWO METABOLIC HORMONES: 1. THYROXINE (T4 ) 2. TRIIODOTHYRONINE (T3)
- 6. STEPS OF THYROID HORMONE SYNTHESIS T4 and T3
- 7. Biosynthesis of T4 and T3 • Dietary iodine (I) ingestion • Active transport and uptake of iodide (I-) by thyroid gland. • Synthesis of Thyroglobulin by ER Of thyroid follicular cells • Oxidation of I- and iodination of thyroglobulin (Tg) tyrosine residues • Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3 • Proteolysis of Tg with release of T4 and T3 into the circulation
- 8. Dietary iodine (I) ingestion Iodine Sources • Available through certain foods: seafood, bread, dairy products, iodized salt, or dietary supplements, as a trace mineral • The recommended minimum intake is 150 g/day 1mg/week
- 9. ACTIVE TRANSPORT AND I- UPTAKE BY THE THYROID Dietary iodine reaches the circulation as iodide anion (I-) I- accumulation in the thyroid is an active transport process that is stimulated by TSH
- 10. Iodide Active Transport is Mediated by the Sodium-Iodide Symporter (NIS) • NIS is a membrane protein that mediates active iodide uptake by the thyroid • It functions as a I- concentrating mechanism “iodide trapping” for T4 and T3 biosynthesis
- 18. OXIDATION OF I- AND IODINATION OF TYROSINE RESIDUES—“ORGANIFICATION” OF THYROGLOBULIN. • I- must be oxidized to be able to iodinate tyrosyl residues of Tg. • Iodination of the tyrosyl residues then forms monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are then coupled to form either T3 or T4 • Both reactions are catalyzed by TPO
- 20. Thyroperoxidase (TPO) • TPO catalyzes the oxidation steps involved in I- activation, iodination of Tg tyrosyl residues, and coupling of iodotyrosyl residues • TPO has binding sites for I- and tyrosine • TPO uses H2O2 as the oxidant.
- 21. Storage of Thyroglobulin • Each thyroglobulin molecule contains up to 30 thyroxine molecules and a few T3 molecules. • The thyroid hormones are stored in the follicles to supply the body with of thyroid hormones for 2 to 3 months.
- 22. RELEASE OF THYROXINE AND TRIIODOTHYRONINE FROM THE THYROID GLAND
- 23. PROTEOLYSIS OF TG WITH RELEASE OF T4 AND T3 • T4 and T3 are synthesized and stored within the Tg molecule • Proteolysis is an essential step for releasing the hormones • To liberate T4 and T3, Tg is resorbed into the follicular cells in the form of colloid droplets, which fuse with lysosomes to form phagolysosomes • Tg is then hydrolyzed to T4 and T3, which are then secreted into the circulation
- 25. ION TRANSPORT BY THE THYROID FOLLICULAR CELL I- I- organification Propylthiouracil (PTU) blocks iodination of thyroglobulin COLLOID BLOOD NaI symporter (NIS) Thyroid peroxidase (TPO) ClO4 -, SCN-
- 26. Conversion of T4 to T3 in Peripheral Tissues
- 27. Production of T4 and T3 • T4 is the primary secretory product of the thyroid gland, which is the only source of T4 93% • The thyroid secretes approximately 70-90 g of T4 per day.
- 28. T4: A Prohormone for T3 • T4 is biologically inactive in target tissues until converted to T3 • T3 is the biologically active hormone responsible for the majority of thyroid hormone effects
- 29. Sites of T4 Conversion • The liver is the major extrathyroidal site for conversion ofT4 to T3 • Some conversion also occurs in the kidney and other tissues
- 31. Carriers for Circulating Thyroid Hormones • More than 99% of circulating T4 and T3 is bound to plasma carrier proteins – Thyroxine-binding globulin (TBG), binds about 75% – Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA), binds about 10%-15% – Albumin binds about 7% – High-density lipoproteins (HDL) , binds about 3% • Carrier proteins can be affected by physiologic changes, drugs, and disease
- 32. Free Hormone Concept • Only unbound (free) hormone has metabolic activity and physiologic effects –Free hormone is a tiny percentage of total hormone in plasma (about 0.03% T4; 0.3% T3)
- 33. Thyroid-Stimulating Hormone (TSH) • Regulates thyroid hormone production, secretion, and growth • Is regulated by the negative feedback action of T4 and T3. • TSH stimulates active transport and i- uptake by the thyroid
- 34. Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism
- 35. Changes in TBG Concentration Determine Binding and Influence T4 and T3 Levels • Increased TBG – Total serum T4 and T3 levels increase – Free T4 (FT4), and free T3 (FT3) concentrations remain unchanged • Decreased TBG – Total serum T4 and T3 levels decrease – FT4 and FT3 levels remain unchanged
- 36. Drugs and Conditions That Increase Serum T4 and T3 Levels by Increasing TBG • Drugs that increase TBG – Oral contraceptives and other sources of estrogen – Methadone – Clofibrate – 5-Fluorouracil – Heroin – Tamoxifen • Conditions that increase TBG – Pregnancy – Infectious/chronic active hepatitis – HIV infection – Biliary cirrhosis – Acute intermittent porphyria – Genetic factors
- 37. Drugs and Conditions That Decrease Serum T4 and T3 by Decreasing TBG Levels or Binding of Hormone to TBG • Drugs that decrease serum T4 and T3 – Glucocorticoids – Androgens – L-Asparaginase – Salicylates – Mefenamic acid – Antiseizure medications, eg, phenytoin, carbama-zepine – Furosemide • Conditions that decrease serum T4 and T3 – Genetic factors – Acute and chronic illness