Thyroid physiology
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Thyroid physiology
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Health & Medicine
This PPT gives the students the basic physiology of the Thyroid gland. It is the only Endocrine gland that can be palpable with your hands. Very useful to M.B.B.S; B.D.S as well as PG students.
Uthamalingam MuraliFollow
Thyroid physiology
- Objectives Formation of Thyroid hormones Peripheral Conversion Hormonal transport Actions of Thyroid hormones Regulation of Thyroid hormones
- Thyroid Essential for: Development & Regulation of Metabolism Constant supply is essential for Normal growth Brain development Maintenance of metabolism Functional activity of many organs
- 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)
- Iodine Necessary – synthesis – thyroid hormones. Iodine → iodide & absorbed SI – stomach & jejunum 90-95% - absorbed iodide taken up by thyroid
- Iodine Sources Available through certain foods (eg, seafood, bread, dairy products, eggs), iodized salt, or dietary supplements, drinking water as a trace mineral The recommended minimum intake is 0.1mg/day
- Biosynthesis of T4 and T3 1. Iodide Trapping Dietary iodine (I) ingestion Active transport and uptake of iodide (I- ) by thyroid gland – First step Dehalogenase enzyme Thiocyanates + Perchlorates ≠ block
- Biosynthesis of T4 and T3 2. Oxidation Iodide → Inorganic iodine Thyroperoxidase (TPO) enzyme Thioamides ≠ block Sulphonamides / PAS / Carbimazole / PT
- Biosynthesis of T4 and T3 3. Binding - Iodination Binding with tyrosine Formation of iodotyrosines Thyroperoxidase (TPO) enzyme Iodine + tyrosine ═ MIT & DIT Thiourea groups ≠ block Carbimazole
- Biosynthesis of T4 and T3 4. Coupling 2 molecule – DIT ═ T4 1 molecule ═ T3 Dehalogenase enzyme Thiourea groups ≠ block Carbimazole
- Biosynthesis of T4 and T3 5. Proteolysis / Hydrolysis Hormones + globulin ═ colloid ( Tg ) Stored in thyroid gland Proteolysis of Tg with release of T4and T3into the circulation - required
- Plasma iodide enters through the sodium iodide symporter (NIS). •Thyroglobulin (Tg), a large glycoprotein, is synthesized within the thyroid cell. •Thyroid peroxidase (TPO) sits on the lumenal membrane. It iodinates specific tyrosines in Tg, creating mono-and di- iodotyrosines. •The iodotyrosines combine to form T3 and T4 within the Tg protein
- TSH TSH receptor Iodination of Tyr residues of Tg COLLOID TPO THYROGLOBULIN SYNTHESIS IN THE THYROID FOLLICULAR CELL
- In response to TSH, pseudopodia form and endocytose colloid. •In the cell, colloid droplets fuse with lysosomes and thyroid hormone is cleaved enzymatically from Tg. •T4 and T3 are released into the circulation. •TSH stimulates iodide trapping, as well as thyroid hormone synthesis and secretion
- Active Transport and I- Uptake by the Thyroid Dietary iodine reaches the circulation as iodide anion (I- ) The thyroid gland transports I- to the sites of hormone synthesis I- accumulation in the thyroid is an active transport process that is stimulated by TSH NIS is a membrane protein that mediates active iodide uptake by the thyroid
- 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-
- 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 T4and 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 T4and T3, which are then secreted into the circulation
- THYROID HORMONE SECRETION BY THE THYROID FOLLICULAR CELL COLLOID TSH TSH receptor DIT MIT I- T4 T3
- Production of T4 and T3 T4 is the primary secretory product of the thyroid gland, which is the only source of T4 The thyroid secretes approximately 70-90 µg of T4per day T3 is derived from 2 processes The total daily production rate of T3is about 15-30 µg About 80% of circulating T3comesfrom deiodination of T4 in peripheral tissues About 20% comes from direct thyroid secretion
- Sites of T4 Conversion The liver is the major extrathyroidal T4 conversion site for production of T3 Some T4to T3 conversion also occurs in the kidneys / heart / muscle and other tissues
- Peripheral Conversion - process Although T4 is the principal hormone from Thyroid, T3 is the main hormone for regulation of metabolism T3 is produced by de-iodination of T4, by the enzymes T4 -5’De-iodinase Type I & Type II Type I T4 -5’De-iodinase is found in the Liver & Kidneys. It is responsible for the production of ⅔ of the total T3 in the body Type II T4 -5’De-iodinase is responsible for most of the T3 found in the Pituitary, Brain & Brown Fat T3 either enters the cell or locally produced, which is transported into the nucleus Type III – which converts T4 → rt3 which is biologically inactive
- 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.
- O OH NH 2 I I I IOH O T4 I I OH O R 3,3’-T2 I I I OH O R T3 “Step up” I I IOH O R rT3 “Step down” THYROID HORMONE METABOLISM O OH NH 2 R =
- Thyroxine (T4 ) 3,5,3’,5’ tetraiodo-L-thyronine THYROID HORMONES •Derived entirely from the thyroid gland •Is a pro-hormone
- THYROID HORMONES *Is the biologically active thyroid hormone *•20% of plasma T3 comes from thyroidal secretion •80% comes from T4 5’-deiodination in peripheral organs
- T3 & T4 Iodinated aminoacids With in thyroid, integral part of TG, in which they are synthesized & stored In plasma, circulate as free amino acids in equilibrium with THBP Free forms: Penetrate cells-induce & stimulate Oxygen consumption, Body heat, Metabolism of CHO/Fat/Protein Stimulates feedback mechanisms with Pituitary
- T4 Disposition Normal disposition of T4 About 41% is converted to T3 38% is converted to reverse T3 (rT3), which is metabolically inactive 21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile Normal circulating concentrations T4 4.5-11 µg/dL T3 60-180 ng/dL (~100-fold less than T4)
- 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
- 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) Total hormone concentration Normally is kept proportional to the concentration of carrier proteins Is kept appropriate to maintain a constant free hormone level
- Thyro-Globulin It is a dimeric Glyco-Protein M.wt: 660000 Contains about 120 Tyrosyl units 30% of Tyrosyl will undergo iodination After the synthesis of the Hormones and its intracellular transport, exophytic residues discharge their contents in the Folliclle TG accumulates in the lumen Colloid, which fills the Follicular lumen is almost exclusively composed of Iodinated TG
- Thyroid Physiology Hormone Binding proteins are the principal factors influenzing total hormone concentration, which is normally maintained at a level appropriate for the concentration of carrier proteins, to maintain a constant free hormone level Various factors may cause changes in the concentrations of TBG & changes in TBG level may alter the total hormone concentration, irrespective of the metabolic status or free hormone level TBG estimation is a more accurate indicator of the Thyroid Hormone dependant metabolic state
- 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
- 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
- Drugs and Conditions that Decrease Serum T4 and T3 by Decreasing TBG Levels or Binding of Hormone to TBG Drugs that decrease serum T4and T3 Glucocorticoids Androgens L-Asparaginase Salicylates Mefenamic acid Antiseizure medications, eg, phenytoin, carbama-zepine Furosemide Conditions that decrease serum T4and T3 Genetic factors Acute and chronic illness
- ACTIONS BMR due to O2, Heat, Temp & Heat intolerance. Optimum level is necessary for balanced growth & maturation Stimulates Lipogenesis & Lipolysis, Lowers serum Cholesterol by enhancing Excretion thro’ Faeces Conversion to Bile Acids Catecholamine effect Brain / retina / lungs / spleen & testes are unaffected by thyroid hormones
- ACTIONS Site Actions Outcomings Brain Effects on activity & mood Hyperactivity & Mood changes Pituitary ↓TSH release ↓TSH level Heart Rate; changes in proteins Tachycardia, Arrhythmia, Failure Liver LDL Receptors, Cholesterol synthesis, Cholesterol excretion & conversion to Bile acids ↓Cholesterol Muscle Changes in Protein Myopathy Bone Osteoblastic & 2º Osteoclastic activity Osteoporosis
- ACTION OF THYROID HORMONES Parameter/ organ system Action Developmental Essential for normal neural and skeletal development Calorigenesis Oxygen consumption Basal Metabolic Rate Intermediary Metabolism Protein Synthesis Synthesis/ Degradation of cholesterol Lipolysis Glycogenolysis Cardiovascular Heart rate and myocardial contractility Sympathetic Nervous System Sensitivity to catecholamines Catecholamine receptors in cardiac muscle Amplification of catecholamine effects at postreceptor site Endocrine Steroid hormone release Hematopoietic Erythropoiesis 2,3 DPG production Maintain hypoxic and hypercapnic drives Musculo skeletal Bone turnover Urinary hydroxy proline excretion Increased rate of muscle relaxation
- REGULATION OF THYROID HORMONE SECRETION Classic feed back loop that involves pituitary and hypothalamus Intrinsic thyroid autoregulatory process
- FEEDBACK REGULATION THE HYPOTHALAMIC-PITUITARY-THYROID AXIS Hormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones. Key players for the thyroid include: TRH - Thyrophin Releasing Hormone TSH - Thyroid Stimulating Hormone T4/T3 - Thyroid hormones
- TSH TSH (Thyroid Stimulating Hormone or Thyrotrophin) Normal Level = 0.5 to 4.5 μUnits/ML Normal daily production & degradation is 40 to 150 μUnits Circardian rhythm-raise 2 hours after sleep, peak from 2 to 4 AM Initial effect of TSH is in Iodide transport Glycoprotein Like LH / FSH / HCG, TSH also has α & β subunits α subunits of all the said hormones are identical β subunits of each are responsible for biological & immunological specificities TSH is required for normal production & secretion of T3 & T4 Mostly influezed by tonic stimulation by TRH and feedback inhibition by T3 & T4 T3 regulates the transcription of the GENES for both the subunits of TSH
- Effects of TSH Iodine binding to TG coupling of MIT & DIT Activation of Exocytosis Transfer of proteins into the follicles Secretion of T3 & T4 Major factor in the growth of thyroid Iodine & Drugs blocking the binding of Iodine to TG cause↓ TSH & diffuse enlargement of Thyroid When TSH is low or absent (Hypophysectomy, inactive TSH) the Thyroid gland in size↓ Prolonged TSH administration will the ↑ weight of the Thyroid Gland Chronic TSH leads to: proliferation of capillaries & fibroblasts rather than Follicles
- TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP. TSH increases metabolic activity that is required to synthesize Thyroglobulin (Tg) and generate peroxide. TSH stimulates both I- uptake and iodination of tyrosine resides on Tg. TSH REGULATION OF THYROID FUNCTION
- TRH Tripeptide- (pyroglutamyl-histidyl-proline amide) First Hypothalamic hormone isolated Produced at Supra-Optic & Para-Ventricular Nuclei Passes thro’ their axons to median eminence and stored Reach the Pituitary via hypophyseal portal vessels & binds to receptor sites Increases the synthesis & secretion of TSH Increases the synthesis & secretion of Prolactin Tonic stimulation of TSH producing cells
- Auto-Regulation In Humans, the Wolff-Chaikoff’s block(acute block of Iodide binding) is induced by elevated plasma iodide level to ≥ 25 μGm% Aftert the critical level of iodide, there is a progressive inhibition of iodide binding to tyrosyl residues in TG Iodide adminisration leads to: ↓Iodine containing compounds from thyroid ↓ serum T3 & T4 ↓in Hypervascularity Seen in ↓in Hyperplasia Hyperthyroidism May induce Hyperthyroidism May cause Nodularity in Goitres
- WOLFF CHAIKOFF’S EFFECT TSH independent manner by availability & glandular content of iodide Iodide depletion enhances iodide transport & stimulate hormone synthesis In the presence of excess iodide, iodide causes suppression of both transport & hormone synthesis
- Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism
- CALCITONIN Secreted By: Parafollicular cells of Thyroid gland Regulation: Negative feedback mechanism High calcium levels in blood stimulated secretion & vice versa Action: Decrease blood level of ionic Ca2+ & PO4 by inhibiting bone reabsorption by osteoclasts and uptake of Ca & PO4 in bone matrix.
- ANTI THYROID COMPOUNDS PROCESS AFFECTED EXAMPLES OF INHIBITORS Active Transport of Iodide Complex anions: Perchlorate, fluoborate, pertechnetate, thiocyanate Iodination of thyroglobulin Thionamides: Propylthiouracil, methimazole, carbimazole. Thiocyanate, Aniline derivatives, Sulphonamides, Iodide. Coupling reaction Thionamides, Sulphonamides, Hormone release Lithium salts, Iodide Iodotyrosine deiodination Nitrotyrosines Peripheral iodothyronine deiodination Oral cholecystographic agents Thiouracil derivatives, Amiodarone Hormone excretion/ inactivation Inducers of Hepatic drug metabolizing enzymes: Phenobarbital, rifampin, carbamazepine, phenytoin Hormone Action Thyroxine analogs, Amiodarone, Phenytoin, Binding in gut: Cholestyramine.
Editor's Notes
- Follicles: the Functional Units of the Thyroid Gland. The follicles are the functional, secretory units of the thyroid gland.1 Follicular cells produce thick, proteinaceous colloid1,2 that fills the lumen.2,3 Colloid is composed primarily of thyroglobulin (Tg).4 Thyroglobulin is a high-molecular weight glycoprotein that facilitates the assembly of thyroid hormones within the thyroid follicular lumen.1 The amino acid tyrosine, which is incorporated within the molecular structure of Tg,1 becomes iodinated.2 Iodine is bound to tyrosyl residues in Tg at the apical surface of the follicle cells to form, in turn, monoiodotyrosine (MIT) and diiodotyrosine (DIT).1 MIT and DIT combine to form the 2 biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3).1 In addition to providing the matrix for thyroid hormone synthesis,5 the Tg molecule also stores a large supply of iodine and thyroid hormone for secretion at a steady rate or on demand.5 References Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:488. Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:2012. 3. DeGroot LJ, Larson PR, Hennemann G: The Thyroid and Its Diseases. Chapter 1: Phylogeny, ontogeny, anatomy, and metabolic regulation of the thyroid, revised 01 August 2002 by Dumont JE, Corvilain B, and Maenhaut C. (Presented online at http://www.thyroidmanager.org). Accessed June 6, 2003. 4. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. McGraw Hill, New York; 1996:1385 5. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.
- Iodine Sources. Because of the scarcity and uneven distribution of iodine in the environment, the structure of the thyroid gland is adapted to collect and store this element in order to provide a continuous supply of thyroid hormone throughout life.1 The iodine ingested with the diet is the only source for this critical component of the thyroid hormones, but thyroid function largely depends on an adequate supply of iodine to the thyroid gland.2 Iodine is a trace element present in the human body in very small amounts (15 to 20 mg).2 The only role iodine has in the body is in the synthesis of thyroid hormones. If severe enough, iodine deficiency will impair thyroid hormonogenesis.2 The recommended daily dietary allowance (intake) of iodine for children and adults (except pregnant or lactating women) is 150 g.3 References 1. Nilsson M. Biofactors. 1999;10(2-3):277-85. 2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:52, 295. 3. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1549.
- Iodine Sources. Because of the scarcity and uneven distribution of iodine in the environment, the structure of the thyroid gland is adapted to collect and store this element in order to provide a continuous supply of thyroid hormone throughout life.1 The iodine ingested with the diet is the only source for this critical component of the thyroid hormones, but thyroid function largely depends on an adequate supply of iodine to the thyroid gland.2 Iodine is a trace element present in the human body in very small amounts (15 to 20 mg).2 The only role iodine has in the body is in the synthesis of thyroid hormones. If severe enough, iodine deficiency will impair thyroid hormonogenesis.2 The recommended daily dietary allowance (intake) of iodine for children and adults (except pregnant or lactating women) is 150 g.3 References 1. Nilsson M. Biofactors. 1999;10(2-3):277-85. 2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:52, 295. 3. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1549.
- Biosynthesis of T4 and T3. The major steps in the synthesis, storage, and release of thyroid hormones are: ingestion of iodine with the diet; active transport and uptake of iodide ion (I-) by the thyroid gland; the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin (Tg); coupling of iodotyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) to generate iodothyronines; storage of iodinated Tg containing MIT, DIT, T4 and T3; and the proteolysis of Tg and the release of T4 and T 3 into the blood.1,2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.
- Biosynthesis of T4 and T3. The major steps in the synthesis, storage, and release of thyroid hormones are: ingestion of iodine with the diet; active transport and uptake of iodide ion (I-) by the thyroid gland; the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin (Tg); coupling of iodotyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) to generate iodothyronines; storage of iodinated Tg containing MIT, DIT, T4 and T3; and the proteolysis of Tg and the release of T4 and T 3 into the blood.1,2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.
- Biosynthesis of T4 and T3. The major steps in the synthesis, storage, and release of thyroid hormones are: ingestion of iodine with the diet; active transport and uptake of iodide ion (I-) by the thyroid gland; the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin (Tg); coupling of iodotyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) to generate iodothyronines; storage of iodinated Tg containing MIT, DIT, T4 and T3; and the proteolysis of Tg and the release of T4 and T 3 into the blood.1,2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.
- Biosynthesis of T4 and T3. The major steps in the synthesis, storage, and release of thyroid hormones are: ingestion of iodine with the diet; active transport and uptake of iodide ion (I-) by the thyroid gland; the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin (Tg); coupling of iodotyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) to generate iodothyronines; storage of iodinated Tg containing MIT, DIT, T4 and T3; and the proteolysis of Tg and the release of T4 and T 3 into the blood.1,2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.
- Biosynthesis of T4 and T3. The major steps in the synthesis, storage, and release of thyroid hormones are: ingestion of iodine with the diet; active transport and uptake of iodide ion (I-) by the thyroid gland; the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin (Tg); coupling of iodotyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) to generate iodothyronines; storage of iodinated Tg containing MIT, DIT, T4 and T3; and the proteolysis of Tg and the release of T4 and T 3 into the blood.1,2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.
- Active Transport and I- Uptake by the Thyroid. Iodine ingested in the diet reaches the circulation in the form of the iodide anion (I-).1 Under normal circumstances, the concentration of iodine in the blood is very low (0.2 to 0.4 g/dL).1 Despite low concentrations of iodine in the blood following ingestion in the diet, the thyroid efficiently transports the iodide ion to the sites of hormone synthesis.1 The thyroid gland concentrates I- by a factor of 20 to 40 with respect to the concentration of the anion in the plasma under physiological conditions.2,3 Thus, I- accumulation in the thyroid is an active transport process that takes place against the I- electrochemical gradient, and is stimulated by TSH.1,2 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Dohan O, et al. Trends Endocrinol. Metab. 2000;11:99-105. 3. De La Vieja, et al. Physiol Rev. 2000;80:1083-105.
- Proteolysis of Tg With Release of T4 and T 3. The iodinated Tg, which contains MIT, DIT, T4, and T3, is stored in the colloid within the lumen of thyroid follicle cells.1 Proteolysis is necessary2 to release the synthesized thyroid hormones from peptide linkage within Tg.3 Proteolysis is initiated by endocytosis of colloid, which contains a high concentration of Tg3 from the follicular lumen at the cell apical surface.2 It is believed that in order for the thyroid hormones to be released, Tg must be broken down into its constituent amino acids.2 Tg forms intracellular colloid droplets that fuse with lysosomes containing proteolytic enzymes, including endopeptidases that split Tg to yield hormone-containing intermediates, and exopeptidases that act on the intermediates to release the thyroid hormones.2 The newly released hormones rapidly exit the cell at the basal membrane2 and enter the circulation.3 MIT and DIT are also released by hydrolysis of Tg, but they usually do not leave the thyroid, and instead are selectively metabolized.3 Iodothyronine-specific deiodinases can remove I- from MIT and DIT3 for reincorporation into protein2 for hormone synthesis.3 The remainder reenters the circulation.2 References 1. Yen PM. Physiol Rev. 2001;81:1097-1142. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1387. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:97-98.
- Production of T4 and T3. The thyroid gland is the sole source of endogenous T4, while only about 20% of T3 is produced in the thyroid.1 T4 is the most abundant iodothyronine in Tg and is about 10-20 times more abundant than T3.2 The thyroid secretes T4 and T3 in a proportion determined by the T4/T3 ratio in thyroglobulin (Tg), which is 15:1 in humans with minimal thyroidal conversion of T4 to T3.3 Normally, the ratio of secreted T4 to T3 is about 11:1.3 The serum concentrations and daily production rates of T4 are higher than those of any other iodothyronine.2 The estimated range of normal daily production of T4 is 70-90 g; for T3 the estimated range is about 15-30 g.4 Normal circulating concentrations of T4 in plasma range from 4.5-11.0 g/dL, while those for T3 are 100-fold less (60-180 ng/dL).4 One third to one half of the T4 that is secreted is converted to T3.2 The production of T4 and its extrathyroidal conversion to T3 provide a more constant source of T3 than were T3 to be solely produced by the thyroid.2 T3 is produced by 2 different and relatively independent processes about 20% via direct thyroid secretion and about 80% by extrathyroidal 5' deiodination of T4.4,5 References 1. Fauci AS et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:2013. 2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:122. 3. Bianco AC, et al. Endocr Rev. 2002;23:38-89. 4. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1387-1388. 5. Hennemann G, et al. Endocr Rev. 2001;22:451-476.
- Sites of T4 Conversion. The major site of extrathyroidal conversion of T4 to T3 is the liver.1 In humans, D1, which is found in the liver, kidney, thyroid,1,2 and pituitary,2 generates circulating T3 for use by most peripheral target tissues.1 D2 was thought to be limited to the brain and pituitary,1 but has been found to be present in the human thyroid, heart, brain, spinal cord, skeletal muscle, and placenta.2 The distribution of D3 is mainly in the central nervous system, skin, and placenta.1,3 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1387-1388. 2. Bianco AC, et al. Endocr Rev. 2002;23:38-89. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:125.
- T4 Disposition. In healthy individuals, about 41% of T4 is converted to T3, about 38% is converted to reverse T3 (rT3), and about 21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile. Reverse T3, which is metabolically inactive, results from removal of the iodine on position 5 of the inner ring. The normal circulating concentration of T4 is 4.5-11 g/dL. The normal circulation concentration of T3 is about 100-fold less (60-180 ng/dL).1 Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1388.
- Carriers for Circulating Thyroid Hormones. Thyroid hormones are transported in the blood by carrier plasma proteins,1 which bind more than 99% of serum T4 and T3.2 Together, the carrier proteins keep the concentration of thyroid hormone constant over a wide range and provide a means for equal distribution of hormone among the tissues.2 Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones in the circulation because of its extremely high binding affinity, even though it represents only a small fraction of the total serum proteins.2 TBG binds 75% of T4,2 and has 10-20 times greater affinity for T4 than T3.2-4 Transthyretin (TTR) binds T4, but does not significantly bind T3.4 In spite of its low binding affinity, albumin carries about 7% of T4 because of its high serum concentration.2 The thyroid hormones also bind to plasma lipoproteins, with high-density lipoproteins (HDL) being the major binders.3 HDL transports about 3% of T4 and about 6% of T3 in serum.3 The transport proteins are affected by physiological changes, pharmacologic agents, and disease.3 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1388-1389. 2. Janssen OE, et al. J Clin Endocrinol Metab. 2002;87:1217-1222. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:108-110,115. 4. Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:2014.
- Free Hormone Concept. An early version of the free hormone concept (or hypothesis) stated that the free or diffusible thyroid hormone concentration in blood and extracellular tissues would determine the rate at which thyroid hormone was distributed to its point of action and the rates at which it was degraded and excreted.1 This concept, however, was shown to be only partly correct.1 The hypothesis was later modified to state that unbound serum concentrations of T4 and T3 are directly related to the amount of hormone entering the cells and to the cells’ ultimate physiologic response.2 In an equilibrium mixture containing hormone and several carrier proteins, the amount of hormone bound to a minor transport protein, such as LDL, will be proportional to the free hormone concentration.2 Only thyroid hormones in the free, unbound state are biologically active (0.03% and 0.3% of the total serum T4 and T3, respectively)3,4 and available to tissues.5 The metabolic state correlates more closely with the concentration of free hormone than total hormone in the circulation. Therefore, homeostatic regulation of thyroid function (the role of the HPT axis)6 is designed to maintain a normal concentration of free hormone.5 References Henneman G, et al. Endocr Rev. 2001;22:451-476 2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:115. 3. Janssen OE, et al. J Clin Endocrinol Metab. 2002;87:1217-1222. 4. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1389. 5. Fauci AS et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:2013. 6. Schussler GC. Thyroid. 2000;10:141-149.
- Changes in TBG Concentration Determine Binding and Influence T4 and T3 Levels. Because of the high degree of binding of thyroid hormones to serum carrier proteins, such as TBG, quantitative or qualitative changes in either the concentrations of the proteins or molecular changes in the binding affinity of the hormones for the protein have significant effects on the total serum hormone levels.1 Increased concentrations of TBG cause T4 and T3 levels to increase, while FT4 and FT3 remain unchanged. When TBG levels are decreased, T4 and T3 decrease and FT4 and FT3 concentrations remain unchanged. For example, the alterations in total thyroid hormone levels in pregnancy are the direct result of the marked increase in serum TBG.2 Total T4 and T3 levels increase significantly during the first half of gestation, while there is a transient drop in FT4.2,3 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1389. 2. Glinoer, D. Endocr Rev. 1997;18:404-433. 3. Muller AF, et al. J Clin Endocrinol Metab. 2000;85:545-548.
- Drugs and Conditions That Increase Serum T4 and T3 Levels by Increasing TBG. Only the unbound thyroid hormone has metabolic activity. Because of the high degree of binding of thyroid hormones to plasma proteins, changes in the protein concentrations or the binding affinity of the hormones for the proteins can greatly affect total serum hormone levels. Certain drugs and physiologic conditions increase the binding of thyroid hormones to TBG. These drugs include estrogens, methadone, clofibrate, 5-fluorouracil, heroin, and tamoxifen. Conditions that increase the binding of thyroid hormones to TBG include liver disease, porphyria, HIV infection, and predisposed genetic determinants.1 Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1389.
- Drugs and Conditions That Decrease Serum T4 and T3 by Decreasing TBG Levels or Binding of Hormone to TBG. Glucocorticoids, androgens, L-asparaginase, salicylates, mefenamic acid, antiepileptic drugs, and furosemide decrease the binding of thyroid hormones to TBG. Acute and chronic illness and predisposed genetic determinants also decrease binding. Because the pituitary responds to and regulates circulating free hormone levels, minimal changes in free hormone concentrations are seen. Therefore, laboratory tests that measure only total hormone levels may be subject to misinterpretation.1 Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1389.
- Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism. In this negative-feedback system, increasing levels of circulating thyroid hormone inhibit the synthesis of TSH directly at the pituitary level and indirectly at the level of the hypothalamus by reducing the secretion of TRH.1,2 TRH is the major regulator of the synthesis and secretion of TSH, and therefore it plays a central role in regulating the hypothalamic-pituitary-thyroid (HPT) axis.3 Thyroid hormone can negatively regulate TSH transcription by direct and indirect mechanisms, and can negatively regulate TRH at the transcriptional level,1,4 decreasing transcription of TSH mRNA.4 References Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:206-207. 2. Dahl GE, et al. Endocrinology. 1994;135:2392-2397. 3. Nillni EA, et al. Endocr Rev. 1999;20:599-648. 4. Yen PM. Physiol Rev. 2001;81:1097-1142.