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Thyroid Function Tests and Hyperthyroidism

Objectives. General review of thyroid physiology and functionDescribe tests which determine the level of thyroid function (4)Describe the clinical features, causes, investigation and pathophysiology of hyperthyroidism (8). Outline. CaseSome tips for examination of the thyroidGeneral review of t

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Thyroid Function Tests and Hyperthyroidism

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    1. Thyroid Function Tests and Hyperthyroidism

    2. Objectives General review of thyroid physiology and function Describe tests which determine the level of thyroid function (4) Describe the clinical features, causes, investigation and pathophysiology of hyperthyroidism (8)

    3. Outline Case Some tips for examination of the thyroid General review of thyroid physiology and function Assays of thyroid hormones, TSH and antibodies Causes of hyperthyroidism Management of hyperthyroidism Pregnancy and the thyroid and assay interference

    4. Joan Peters Mrs. JP is a 53y old female who presented with a 3 months history of weight loss, palpitations, diarrhea, rash on the shins, and lacrimation. On physical examination she has a tremor of the outstretched hand, lid lag and a diffuse goitre. Her BP is 170/80 with a PR 102 regular

    5. Joan Peters – Eye findings

    6. Joan Peters - Legs

    7. Questions What is your diagnosis? What blood tests would you request to confirm your diagnosis? What further tests, if any, would you request?

    8. What is your diagnosis Viral Thyroiditis Hashimoto’s disease Myxoedema Graves Disease

    9. What blood tests would you order? T4 Thyroglobulin T3 TSH autoantibodies

    10. The Thyroid Gland and Thyroid Hormones

    11. Anatomy of the Thyroid Gland Anatomy of the Thyroid gland. The thyroid gland is located anterior and caudal to the cartilages of the larynx1 and is the largest endocrine gland in adults.2 It is a small, butterfly-shaped bilateral organ with 2 lobes joined by an isthmus.1,3 Each lobe is about 4 cm long.3 The normal weight of a nongoitrous adult thyroid is about 20 g,2 depending on body size and iodine supply.3 The thyroid is highly vascularized and receives blood from the superior thyroid arteries and branches of the external carotid artery.3 It is drained by corresponding veins into the internal jugular vein.3 Thyroid glandular tissue is comprised of spherical follicles that vary in size.3 Each follicle is lined with cuboidal epithelial cells1 (follicular epithelium) that encircle the inner colloid space (colloid lumen).4 References Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill;1998:2012. 2. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:20. 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. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105. Anatomy of the Thyroid gland. The thyroid gland is located anterior and caudal to the cartilages of the larynx1 and is the largest endocrine gland in adults.2 It is a small, butterfly-shaped bilateral organ with 2 lobes joined by an isthmus.1,3 Each lobe is about 4 cm long.3 The normal weight of a nongoitrous adult thyroid is about 20 g,2 depending on body size and iodine supply.3 The thyroid is highly vascularized and receives blood from the superior thyroid arteries and branches of the external carotid artery.3 It is drained by corresponding veins into the internal jugular vein.3 Thyroid glandular tissue is comprised of spherical follicles that vary in size.3 Each follicle is lined with cuboidal epithelial cells1 (follicular epithelium) that encircle the inner colloid space (colloid lumen).4 References Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill;1998:2012. 2. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:20. 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. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105.

    12. Follicles: the Functional Units of the Thyroid Gland 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.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.

    13. The Thyroid Produces and Secretes 2 Metabolic Hormones Two principal hormones Thyroxine (T4 ) and triiodothyronine (T3) Required for homeostasis of all cells Influence cell differentiation, growth, and metabolism Considered the major metabolic hormones because they target virtually every tissue The Thyroid Produces and Secretes 2 Metabolic Hormones. Triiodothyronine (T3) and tetraiodothyronine1 (or thyroxine, T4) are the 2 principal hormones of the thyroid gland.2 Chemically, they are iodothyronine hormones ? iodine-containing amino acid derivatives of thyronine.2 They are the only known iodine-containing compounds with biological activity.1,2 Often referred to as the major metabolic hormones,3 the 2 thyroid hormones have profound effects on essential physiologic processes.1,3 References 1. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1383. 3. Kirsten D. Neonatal Netw. 2000;19:11-26 The Thyroid Produces and Secretes 2 Metabolic Hormones. Triiodothyronine (T3) and tetraiodothyronine1 (or thyroxine, T4) are the 2 principal hormones of the thyroid gland.2 Chemically, they are iodothyronine hormones ? iodine-containing amino acid derivatives of thyronine.2 They are the only known iodine-containing compounds with biological activity.1,2 Often referred to as the major metabolic hormones,3 the 2 thyroid hormones have profound effects on essential physiologic processes.1,3 References 1. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1383. 3. Kirsten D. Neonatal Netw. 2000;19:11-26

    14. Thyroid-Stimulating Hormone (TSH) Regulates thyroid hormone production, secretion, and growth Is regulated by the negative feedback action of T4 and T3 Thyroid-Stimulating Hormone (TSH). Thyroid stimulating hormone (TSH; also called thyrotropin), a glycoprotein hormone with ? and ? subunits, is secreted by the anterior pituitary gland.1,2 Thyroid stimulating hormone is inhibited by thyroid hormone in a classic endocrine negative feedback loop.2 Its synthesis and release is stimulated by thyrotropin-releasing hormone (TRH), which is the major positive regulator of TSH secretion.3 TSH is the major regulator of the thyroid gland.4 Physiological roles of TSH include stimulation of various thyroid functions, eg, iodine uptake and organification, production and release of thyroid hormone from the gland, and promotion of thyroid growth.2,5 TSH-cyclic adenosine monophosphate (cAMP) is the prime regulator of iodide uptake and concentration and T3/T4 formation.6 TSH-cAMP induces the expression and activation of the 3 necessary genes encoding proteins involved in iodide uptake and thyroid hormone formation: the sodium-iodide symporter (NIS), thyroglobulin (Tg), and thyroperoxidase (TPO).6 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1390. 2. Grossman M, et al. Endocr Rev. 1997;18:476-501. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:208. 4. Nillni EA, et al. Endocr Rev. 1999;20:599-648. 5. Grossman M, et al. Mol Endocrinol. 1995;9:948-958. 6. Kohn LD, et al. Trends Endocrinol Metab. 2001;12:10-16. Thyroid-Stimulating Hormone (TSH). Thyroid stimulating hormone (TSH; also called thyrotropin), a glycoprotein hormone with ? and ? subunits, is secreted by the anterior pituitary gland.1,2 Thyroid stimulating hormone is inhibited by thyroid hormone in a classic endocrine negative feedback loop.2 Its synthesis and release is stimulated by thyrotropin-releasing hormone (TRH), which is the major positive regulator of TSH secretion.3 TSH is the major regulator of the thyroid gland.4 Physiological roles of TSH include stimulation of various thyroid functions, eg, iodine uptake and organification, production and release of thyroid hormone from the gland, and promotion of thyroid growth.2,5 TSH-cyclic adenosine monophosphate (cAMP) is the prime regulator of iodide uptake and concentration and T3/T4 formation.6 TSH-cAMP induces the expression and activation of the 3 necessary genes encoding proteins involved in iodide uptake and thyroid hormone formation: the sodium-iodide symporter (NIS), thyroglobulin (Tg), and thyroperoxidase (TPO).6 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1390. 2. Grossman M, et al. Endocr Rev. 1997;18:476-501. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:208. 4. Nillni EA, et al. Endocr Rev. 1999;20:599-648. 5. Grossman M, et al. Mol Endocrinol. 1995;9:948-958. 6. Kohn LD, et al. Trends Endocrinol Metab. 2001;12:10-16.

    15. Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism 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. 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.

    16. Biosynthesis of T4 and T3 The process includes Dietary iodine (I) ingestion Active transport and uptake of iodide (I-) by thyroid gland 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 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.

    17. Iodine Sources Available through certain foods (eg, seafood, bread, dairy products), iodized salt, or dietary supplements, as a trace mineral The recommended minimum intake is 150 ?g/day 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.

    18. 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 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. 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.

    19. 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 that enables I- to enter the thyroid for hormone biosynthesis NIS confers basal cell membranes of thyroid follicular cells with the ability to effect “iodide trapping” by an active transport mechanism Specialized system assures that adequate dietary I- accumulates in the follicles and becomes available for T4 and T3 biosynthesis Iodide Active Transport is Mediated by the Sodium-Iodide Symporter (NIS). The NIS is a membrane protein located within the basolateral membrane of the follicle cells of the thyroid.1 It mediates the accumulation of iodide (I-) by the epithelium of the thyroid ("iodide trap") and active transport of I- into the thyroid ("iodide pump"), which is critical for thyroid hormone biosynthesis.2 The NIS functions by cotransporting iodide with sodium ions.3 Iodide is transported across the basolateral plasma membrane into the cytoplasm of the follicle cells against an electrochemical concentration gradient, which couples the inward ‘downhill’ translocation of Na+ to the inward ‘uphill’ translocation of I-.2 Iodide is then passively carried across the apical membrane into the colloid located in the follicular lumen.2 References 1. Eskandari S, et al. J Biol Chem. 1997;272:27230-27238. 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. 3. Morris JC. J Clin Endocrin. 1997;82:3964-3965. Iodide Active Transport is Mediated by the Sodium-Iodide Symporter (NIS). The NIS is a membrane protein located within the basolateral membrane of the follicle cells of the thyroid.1 It mediates the accumulation of iodide (I-) by the epithelium of the thyroid ("iodide trap") and active transport of I- into the thyroid ("iodide pump"), which is critical for thyroid hormone biosynthesis.2 The NIS functions by cotransporting iodide with sodium ions.3 Iodide is transported across the basolateral plasma membrane into the cytoplasm of the follicle cells against an electrochemical concentration gradient, which couples the inward ‘downhill’ translocation of Na+ to the inward ‘uphill’ translocation of I-.2 Iodide is then passively carried across the apical membrane into the colloid located in the follicular lumen.2 References 1. Eskandari S, et al. J Biol Chem. 1997;272:27230-27238. 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. 3. Morris JC. J Clin Endocrin. 1997;82:3964-3965.

    20. Oxidation of I- and Iodination of Thyroglobulin (Tg) Tyrosyl Residues 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 Oxidation of I- and Iodination of Thyroglobulin (Tg) Tyrosyl Residues. In order to effect iodination of tyrosine residues, I-, the iodinating species, must first be activated to a higher state of oxidation than the anion. The oxidation of I- to its active form is catalyzed by TPO. Once activated, I+ reacts with the tyrosine in Tg to form iodinated tyrosine residues: diiodotyrosine (DIT), which becomes T4 when coupled with a second DIT; or monoiodotyrosine (MIT) with 1 iodine, which forms T3 when coupled with 1 DIT. Both the activation and coupling steps are catalyzed by TPO.1 Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1386.Oxidation of I- and Iodination of Thyroglobulin (Tg) Tyrosyl Residues. In order to effect iodination of tyrosine residues, I-, the iodinating species, must first be activated to a higher state of oxidation than the anion. The oxidation of I- to its active form is catalyzed by TPO. Once activated, I+ reacts with the tyrosine in Tg to form iodinated tyrosine residues: diiodotyrosine (DIT), which becomes T4 when coupled with a second DIT; or monoiodotyrosine (MIT) with 1 iodine, which forms T3 when coupled with 1 DIT. Both the activation and coupling steps are catalyzed by TPO.1 Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1386.

    21. 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 to activate I- to hypoiodate (OI-), the iodinating species Thyroperoxidase (TPO). Thyroperoxidase is a membrane-bound, glycosylated, heme-containing enzyme that catalyzes both the activation of iodine and iodination of tyrosyl residues in Tg, as well as the coupling of iodotyrosyl residues in Tg to form the iodothyronine hormones, T4 and T3.1,2 The enzyme uses H2O2 as the oxidant for these reactions.2 The nature of the iodinating species was identified as hypoiodate, either as a hypoiodous acid (HOI) or as an enzyme-linked species (E-OI).2 The thyroid hormones are synthesized by the coupling of iodotyrosine residues.3 In the coupling reaction, 2 molecules of diiodotyrosine (DIT) combine with Tg to form T4. One molecule of monoiodotyrosine (MIT) and one molecule of DIT combine to form T3.3 References 1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:63, 65. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1386. 3. De Vijlder JJM et al. Eur J Endocrinol. 1998;138:227-231.Thyroperoxidase (TPO). Thyroperoxidase is a membrane-bound, glycosylated, heme-containing enzyme that catalyzes both the activation of iodine and iodination of tyrosyl residues in Tg, as well as the coupling of iodotyrosyl residues in Tg to form the iodothyronine hormones, T4 and T3.1,2 The enzyme uses H2O2 as the oxidant for these reactions.2 The nature of the iodinating species was identified as hypoiodate, either as a hypoiodous acid (HOI) or as an enzyme-linked species (E-OI).2 The thyroid hormones are synthesized by the coupling of iodotyrosine residues.3 In the coupling reaction, 2 molecules of diiodotyrosine (DIT) combine with Tg to form T4. One molecule of monoiodotyrosine (MIT) and one molecule of DIT combine to form T3.3 References 1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:63, 65. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1386. 3. De Vijlder JJM et al. Eur J Endocrinol. 1998;138:227-231.

    22. 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 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. 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.

    23. Conversion of T4 to T3 in Peripheral Tissues

    24. 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 ?g of T4 per day T3 is derived from 2 processes The total daily production rate of T3 is about 15-30 ?g About 80% of circulating T3 comes from deiodination of T4 in peripheral tissues About 20% comes from direct thyroid secretion 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.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.

    25. T4: A Prohormone for T3 T4 is biologically inactive in target tissues until converted to T3 Activation occurs with 5' iodination of the outer ring of T4 T3 then becomes the biologically active hormone responsible for the majority of thyroid hormone effects T4 : A Prohormone for T3. T4 can be considered to be a prohormone, whose hormonal action is related to its conversion to T3 in peripheral tissues.1,2 Until T4 is deiodinated, it has no physiological effect because it does not enter the target nucleus at high enough concentrations to bind to the required thyroid receptors.3 Loss of a single iodine from the outer ring of T4 produces the active hormone T3.3 Removal of the 5' (or 3') iodine atom from the phenolic ring of iodothyronines is called 5'-deiodination.2 At least 2 iodothyronine 5'- monodeiodinases remove the 5' ring of T4 to convert it to T3.2 Three 5'-deiodinase isoenzymes have been identified: type I (D1), type II (D2), type III (D3).3-6 The deiodinases modulate the thyroid status of various tissues in response to iodine or thyroid hormone deficiency, or hormone excess.3 D1 and D2 are responsible for the greater portion of the activation of T4 to T3 in target tissues.3 D3 and also D15,6 inactivate T4 and T3 in the brain, skin, and placenta.2,6 Hormone inactivation occurs by removal of a single iodine on position 5- (or 3-) of the inner tyrosyl ring.2,5,6 This reaction, called 5-deiodination, produces metabolically inactive reverse T3 (rT3).2,6 References 1. Bogazzi F, et al. Mol Cell Endocrin. 1997;134:23-31. 2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:124-125,129, 139. 3. Bianco AC, et al. Endocr Rev. 2002:23:38-89. 4. Köhrle J. Exp Clin Endocrinol. 1994;102:63-89. 5. Köhrle J. Mol Cell Endocrinol. 1999;151:103-119 6. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1388.T4 : A Prohormone for T3. T4 can be considered to be a prohormone, whose hormonal action is related to its conversion to T3 in peripheral tissues.1,2 Until T4 is deiodinated, it has no physiological effect because it does not enter the target nucleus at high enough concentrations to bind to the required thyroid receptors.3 Loss of a single iodine from the outer ring of T4 produces the active hormone T3.3 Removal of the 5' (or 3') iodine atom from the phenolic ring of iodothyronines is called 5'-deiodination.2 At least 2 iodothyronine 5'- monodeiodinases remove the 5' ring of T4 to convert it to T3.2 Three 5'-deiodinase isoenzymes have been identified: type I (D1), type II (D2), type III (D3).3-6 The deiodinases modulate the thyroid status of various tissues in response to iodine or thyroid hormone deficiency, or hormone excess.3 D1 and D2 are responsible for the greater portion of the activation of T4 to T3 in target tissues.3 D3 and also D15,6 inactivate T4 and T3 in the brain, skin, and placenta.2,6 Hormone inactivation occurs by removal of a single iodine on position 5- (or 3-) of the inner tyrosyl ring.2,5,6 This reaction, called 5-deiodination, produces metabolically inactive reverse T3 (rT3).2,6 References 1. Bogazzi F, et al. Mol Cell Endocrin. 1997;134:23-31. 2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:124-125,129, 139. 3. Bianco AC, et al. Endocr Rev. 2002:23:38-89. 4. Köhrle J. Exp Clin Endocrinol. 1994;102:63-89. 5. Köhrle J. Mol Cell Endocrinol. 1999;151:103-119 6. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1388.

    26. Sites of T4 Conversion The liver is the major extrathyroidal T4 conversion site for production of T3 Some T4 to T3 conversion also occurs in the kidney and other tissues 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. 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.

    27. 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 ?g/dL T3 60-180 ng/dL (~100-fold less than T4) 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. 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.

    28. Hormonal Transport

    29. 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 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. 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.

    30. 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 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.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.

    31. 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 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. 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.

    32. 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 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 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.

    33. 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 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. 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.

    34. Thyroid Hormone Action

    35. Thyroid Hormone Plays a Major Role in Growth and Development Thyroid hormone initiates or sustains differentiation and growth Stimulates formation of proteins, which exert trophic effects on tissues Is essential for normal brain development Essential for childhood growth Untreated congenital hypothyroidism or chronic hypothyroidism during childhood can result in incomplete development and mental retardation Thyroid Hormone Plays a Major Role in Growth and Development. Thyroid hormone receptors (TRs) are critical regulators of growth, differentiation, and homeostasis.1 Through TRs, thyroid hormone initiates or sustains differentiation and growth mostly by modulating gene transcription, thereby stimulating protein formation, which has a trophic effect on tissues.2 Thyroid hormone plays a critical role in brain development.2 In addition, thyroid hormone is essential for childhood growth.2 Incomplete development and severe mental retardation can result from congenital absence of thyroid hormone or chronic iodine deficiency during childhood.2 References Lin HM, et al. J Biol Chem. 2002;277:28733-28741. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1392.Thyroid Hormone Plays a Major Role in Growth and Development. Thyroid hormone receptors (TRs) are critical regulators of growth, differentiation, and homeostasis.1 Through TRs, thyroid hormone initiates or sustains differentiation and growth mostly by modulating gene transcription, thereby stimulating protein formation, which has a trophic effect on tissues.2 Thyroid hormone plays a critical role in brain development.2 In addition, thyroid hormone is essential for childhood growth.2 Incomplete development and severe mental retardation can result from congenital absence of thyroid hormone or chronic iodine deficiency during childhood.2 References Lin HM, et al. J Biol Chem. 2002;277:28733-28741. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1392.

    36. Thyroid Hormones and the Central Nervous System (CNS) Thyroid hormones are essential for neural development and maturation and function of the CNS Decreased thyroid hormone concentrations may lead to alterations in cognitive function Patients with hypothyroidism may develop impairment of attention, slowed motor function, and poor memory Thyroid-replacement therapy may improve cognitive function when hypothyroidism is present Thyroid Hormones and the Central Nervous System (CNS) Thyroid hormones regulate neural development and the central nervous system is dependent on thyroid hormones for normal maturation and function.1 Research has found a relationship between thyroid hormones and acetylcholine, nerve growth factor, and hippocampal function.1 Changes in thyroid function may affect mood, behavior, and cognitive function.2 Cognitive disturbance is commonly associated with disorders of the thyroid, particularly hypothyroidism.2 Patients with hypothyroidism showed significant impairment in attention and ability to concentrate, slowed motor function, poor memory, and slowing of thought and speech.2 Treatment with thyroid hormone-replacement therapy may result in normalization of cognitive functions.2 References Smith JW, et al. Neurosci Behav Rev. 2002;26:45-60. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:837-838. Thyroid Hormones and the Central Nervous System (CNS) Thyroid hormones regulate neural development and the central nervous system is dependent on thyroid hormones for normal maturation and function.1 Research has found a relationship between thyroid hormones and acetylcholine, nerve growth factor, and hippocampal function.1 Changes in thyroid function may affect mood, behavior, and cognitive function.2 Cognitive disturbance is commonly associated with disorders of the thyroid, particularly hypothyroidism.2 Patients with hypothyroidism showed significant impairment in attention and ability to concentrate, slowed motor function, poor memory, and slowing of thought and speech.2 Treatment with thyroid hormone-replacement therapy may result in normalization of cognitive functions.2 References Smith JW, et al. Neurosci Behav Rev. 2002;26:45-60. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:837-838.

    37. Thyroid Hormone Influences Cardiovascular Hemodynamics Thyroid Hormone Influences Cardiovascular Hemodynamics. The administration of thyroid hormone causes a decrease in peripheral vascular resistance, which some investigators propose is caused by the release of local vasodilators that results from increased metabolic activity and oxygen consumption prompted by the thyroid hormone.1 A low systemic vascular resistance then decreases diastolic blood pressure, which then increases cardiac output.1 T3 administration also increases total blood volume, which produces the elevation of right atrial pressure, an increased preload, and a resulting elevated cardiac output.1 Changes in the cardiovascular system are prominent clinical consequences in thyroid dysfunction.2 Hyperthyroidism is associated with the hemodynamic changes listed above, as well as with tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, and increased pulse. In hypothyroidism, there is bradycardia, decreased cardiac index, pericardial effusion, increased peripheral vascular resistance, decreased pulse pressure, and elevations of mean arterial pressure.2 References Gomberg-Maitland M, et al. Am Heart J. 1998;135:187-196. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1393. Thyroid Hormone Influences Cardiovascular Hemodynamics. The administration of thyroid hormone causes a decrease in peripheral vascular resistance, which some investigators propose is caused by the release of local vasodilators that results from increased metabolic activity and oxygen consumption prompted by the thyroid hormone.1 A low systemic vascular resistance then decreases diastolic blood pressure, which then increases cardiac output.1 T3 administration also increases total blood volume, which produces the elevation of right atrial pressure, an increased preload, and a resulting elevated cardiac output.1 Changes in the cardiovascular system are prominent clinical consequences in thyroid dysfunction.2 Hyperthyroidism is associated with the hemodynamic changes listed above, as well as with tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, and increased pulse. In hypothyroidism, there is bradycardia, decreased cardiac index, pericardial effusion, increased peripheral vascular resistance, decreased pulse pressure, and elevations of mean arterial pressure.2 References Gomberg-Maitland M, et al. Am Heart J. 1998;135:187-196. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1393.

    38. Thyroid Hormone Influences the Female Reproductive System Normal thyroid hormone function is important for reproductive function Hypothyroidism may be associated with menstrual disorders, infertility, risk of miscarriage, and other complications of pregnancy Thyroid Hormone Regulates the Female Reproductive System. Thyroid hormones influence the beginning of puberty and the reproductive system in females. Research has suggested that the HPT axis and the hypothalamic-pituitary–ovarian (HPO) axis are physiologically related and act together in a number of pathological conditions, including reproductive conditions.1 In addition, research has found that there are specific thyroid hormone receptors at the ovarian level that might regulate reproductive function.1 These receptors, along with the estrogen effect at the higher levels of the HPT axis, integrate the reciprocal relationship between the HPT and HPO axes.1 Abnormal thyroid levels result in delayed puberty and oligomenorrhea.1 There is a known association between hypothyroidism and infertility.2,3 Hypothyroid women who become pregnant have an increased risk of miscarriage and other obstetrical risks, eg, intrauterine fetal demise, gestational hypertension, placental abruption and poorer perinatal outcome.2,3 References Doufas AG, et al. Ann N Y Acad Sci. 2000;900:65-76. Glinoer D. Trends Endocrinol Metab. 1998;9:403-411. Glinoer D. Endocr Rev. 1997;18:404-433. Thyroid Hormone Regulates the Female Reproductive System. Thyroid hormones influence the beginning of puberty and the reproductive system in females. Research has suggested that the HPT axis and the hypothalamic-pituitary–ovarian (HPO) axis are physiologically related and act together in a number of pathological conditions, including reproductive conditions.1 In addition, research has found that there are specific thyroid hormone receptors at the ovarian level that might regulate reproductive function.1 These receptors, along with the estrogen effect at the higher levels of the HPT axis, integrate the reciprocal relationship between the HPT and HPO axes.1 Abnormal thyroid levels result in delayed puberty and oligomenorrhea.1 There is a known association between hypothyroidism and infertility.2,3 Hypothyroid women who become pregnant have an increased risk of miscarriage and other obstetrical risks, eg, intrauterine fetal demise, gestational hypertension, placental abruption and poorer perinatal outcome.2,3 References Doufas AG, et al. Ann N Y Acad Sci. 2000;900:65-76. Glinoer D. Trends Endocrinol Metab. 1998;9:403-411. Glinoer D. Endocr Rev. 1997;18:404-433.

    39. Thyroid Hormone is Critical for Normal Bone Growth and Development T3 is an important regulator of skeletal maturation at the growth plate T3 regulates the expression of factors and other contributors to linear growth directly in the growth plate T3 also may participate in osteoblast differentiation and proliferation, and chondrocyte maturation leading to bone ossification Thyroid Hormone is Critical for Normal Bone Growth and Development. Thyroid hormone is an important regulator of endochondral bone formation in epiphyseal growth plates.1,2 Linear growth takes place during childhood as a result of endochondral ossification in the growth plate.3 Prepubertal growth is primarily regulated by growth hormone (GH), insulin-like growth factor (IGF)-I and by glucocorticoids (GC), and thyroid hormone.3 Locally acting IGF-I is a key determinant of endochondral ossification.3 Thyroid hormone may act on bone by stimulating GH and IGF-I or by direct effects on target genes, or by direct stimulation of IGF-I production in osteoblasts.4 The direct stimulation of IGF-I by thyroid hormone suggests that thyroid hormone may participate in osteoblast differentiation and proliferation by regulation of growth factor synthesis.4 Thyroid hormone also induces terminal differentiation of growth plate chondrocytes.2 References 1. Robson H, et al. Endocrinology. 2000;141:3887-3897. 2. Ballock RT, et al. J Orthop Res. 2001;19:43-49 3. Siebler T et al. Horm Res. 2001;56(Suppl 1):7-12. 4. Yen PM. Physiol Rev. 2001;81:1097-1142. Thyroid Hormone is Critical for Normal Bone Growth and Development. Thyroid hormone is an important regulator of endochondral bone formation in epiphyseal growth plates.1,2 Linear growth takes place during childhood as a result of endochondral ossification in the growth plate.3 Prepubertal growth is primarily regulated by growth hormone (GH), insulin-like growth factor (IGF)-I and by glucocorticoids (GC), and thyroid hormone.3 Locally acting IGF-I is a key determinant of endochondral ossification.3 Thyroid hormone may act on bone by stimulating GH and IGF-I or by direct effects on target genes, or by direct stimulation of IGF-I production in osteoblasts.4 The direct stimulation of IGF-I by thyroid hormone suggests that thyroid hormone may participate in osteoblast differentiation and proliferation by regulation of growth factor synthesis.4 Thyroid hormone also induces terminal differentiation of growth plate chondrocytes.2 References 1. Robson H, et al. Endocrinology. 2000;141:3887-3897. 2. Ballock RT, et al. J Orthop Res. 2001;19:43-49 3. Siebler T et al. Horm Res. 2001;56(Suppl 1):7-12. 4. Yen PM. Physiol Rev. 2001;81:1097-1142.

    40. Thyroid Hormone Regulates Mitochondrial Activity T3 is considered the major regulator of mitochondrial activity A potent T3-dependent transcription factor of the mitochondrial genome induces early stimulation of transcription and increases transcription factor (TFA) expression T3 stimulates oxygen consumption by the mitochondria Thyroid Hormone Regulates Mitochondrial Activity. Thyroid hormone (T3) is a major regulator of mitochondrial activity that stimulates oxygen consumption by mitochondria, mitochondrial protein synthesis, and mitochondriogenesis.1 Both a nuclear and a direct extranuclear pathway are thought to be present. Data indicate that T3 exerts a short-term, early influence on protein synthesis outside the nucleus. A protein located on the mitochondrial matrix and acting as a potent T3-dependent transcription factor of the mitochondrial genome induces early stimulation of organelle gene transcription. This protein can bind to thyroid hormone response elements (TREs) and mitochondrial DNA sequences.2 T3 also increases mitochondrial expression of a mitochondrial transcription factor (TFA) encoded by a nuclear gene, and these may also function as specific mitochondrial receptors for T3.2 Both pathways stimulate mitochondriogenesis.1 The direct pathway is involved in the regulation of fuel metabolism and cell differentiation.1 References Wrutniak-Cabello C, et al. J Mol Endocrinol. 2001;26:67-77 2. Yen PM. Physiol Rev. 2001;81:1097-1142.Thyroid Hormone Regulates Mitochondrial Activity. Thyroid hormone (T3) is a major regulator of mitochondrial activity that stimulates oxygen consumption by mitochondria, mitochondrial protein synthesis, and mitochondriogenesis.1 Both a nuclear and a direct extranuclear pathway are thought to be present. Data indicate that T3 exerts a short-term, early influence on protein synthesis outside the nucleus. A protein located on the mitochondrial matrix and acting as a potent T3-dependent transcription factor of the mitochondrial genome induces early stimulation of organelle gene transcription. This protein can bind to thyroid hormone response elements (TREs) and mitochondrial DNA sequences.2 T3 also increases mitochondrial expression of a mitochondrial transcription factor (TFA) encoded by a nuclear gene, and these may also function as specific mitochondrial receptors for T3.2 Both pathways stimulate mitochondriogenesis.1 The direct pathway is involved in the regulation of fuel metabolism and cell differentiation.1 References Wrutniak-Cabello C, et al. J Mol Endocrinol. 2001;26:67-77 2. Yen PM. Physiol Rev. 2001;81:1097-1142.

    41. Thyroid Hormones Stimulate Metabolic Activities in Most Tissues Thyroid hormones (specifically T3) regulate rate of overall body metabolism T3 increases basal metabolic rate Calorigenic effects T3 increases oxygen consumption by most peripheral tissues Increases body heat production Thyroid Hormones Stimulate Metabolic Activities in Most Tissues. When the existence of specific nuclear binding sites in different T3-sensitive tissues was first demonstrated, T3 binding was also observed in almost all tissues.1 Thyroid hormone receptors are expressed in virtually all tissues.1 Heart, skeletal muscle, liver, and kidney are markedly stimulated by thyroid hormone. Brain, gonads, and spleen are heat sensitive and unresponsive to the calorigenic effect of thyroid hormone.1,2 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;1996:1393. Thyroid Hormones Stimulate Metabolic Activities in Most Tissues. When the existence of specific nuclear binding sites in different T3-sensitive tissues was first demonstrated, T3 binding was also observed in almost all tissues.1 Thyroid hormone receptors are expressed in virtually all tissues.1 Heart, skeletal muscle, liver, and kidney are markedly stimulated by thyroid hormone. Brain, gonads, and spleen are heat sensitive and unresponsive to the calorigenic effect of thyroid hormone.1,2 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;1996:1393.

    42. Metabolic Effects of T3 Stimulates lipolysis and release of free fatty acids and glycerol Induces expression of lipogenic enzymes Effects cholesterol metabolism Stimulates metabolism of cholesterol to bile acids Facilitates rapid removal of LDL from plasma Generally stimulates all aspects of carbohydrate metabolism and the pathway for protein degradation Metabolic Effects of T3. Thyroid hormone (T3) plays important roles in regulating basal oxygen consumption, fat stores, and lipogenesis,1 and it stimulates lipolysis.2 Thyroid hormones stimulate metabolism of cholesterol to bile acids, and increase the specific binding of low density lipoprotein (LDL) by liver cells. Hypercholesterolemia is a characteristic feature of hypothyroid states.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; 1996:1393. Metabolic Effects of T3. Thyroid hormone (T3) plays important roles in regulating basal oxygen consumption, fat stores, and lipogenesis,1 and it stimulates lipolysis.2 Thyroid hormones stimulate metabolism of cholesterol to bile acids, and increase the specific binding of low density lipoprotein (LDL) by liver cells. Hypercholesterolemia is a characteristic feature of hypothyroid states.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; 1996:1393.

    43. Thyroid Disease Spectrum Thyroid Disease Spectrum. Hyperthyroidism is characterized by sustained increases in thyroid hormone biosynthesis and secretion.1 Hypothyroidism is associated with decreases in thyroid hormone production.1 Overt hypothyroidism is defined as the triad of classical signs and symptoms of hypothyroidism, elevated serum TSH, and abnormally low free T4.1 Mild thyroid failure is less often associated with the classical signs and symptoms of hypothyroidism.1 Serum TSH levels are elevated, but to a lesser extent than in overt hypothyroidism.1 Unlike overt disease, the serum free T4 concentration is typically in the normal range. Mild thyroid failure is associated with health consequences (eg, unhealthy changes in lipid profiles).2 If untreated, it has been estimated that 3% to 18% of patients with mild thyroid failure will progress to overt hypothyroidism.3 References 1. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. 2. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. 3. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.Thyroid Disease Spectrum. Hyperthyroidism is characterized by sustained increases in thyroid hormone biosynthesis and secretion.1 Hypothyroidism is associated with decreases in thyroid hormone production.1 Overt hypothyroidism is defined as the triad of classical signs and symptoms of hypothyroidism, elevated serum TSH, and abnormally low free T4.1 Mild thyroid failure is less often associated with the classical signs and symptoms of hypothyroidism.1 Serum TSH levels are elevated, but to a lesser extent than in overt hypothyroidism.1 Unlike overt disease, the serum free T4 concentration is typically in the normal range. Mild thyroid failure is associated with health consequences (eg, unhealthy changes in lipid profiles).2 If untreated, it has been estimated that 3% to 18% of patients with mild thyroid failure will progress to overt hypothyroidism.3 References 1. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. 2. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. 3. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.

    44. Typical Thyroid Hormone Levels in Thyroid Disease TSH T4 T3 Hypothyroidism High Low Low Hyperthyroidism Low High High Typical Thyroid Hormone Levels in Thyroid Disease. Measurement of the total plasma hormone concentration may not provide an accurate assessment of thyroid gland activity because total hormone concentration is affected by changes in either the amount of thyroxine-binding globulin (TBG) or the affinity of hormones to TBG in plasma.1 For more than 25 years, TSH methods have been able to detect the elevations in TSH that typify hypothyroidism.2 In the past 10 years, the sensitivity of TSH assays has increased to the extent that TSH measurement is now recognized as a more sensitive test than FT4 for detecting both hypo- and hyperthyroidism.2 However, some patients may be incorrectly or incompletely diagnosed if only TSH is measured.3 If serum TSH is high, serum FT4 should be measured to distinguish between mild thyroid failure and overt hypothyroidism.3 If serum TSH is low, both serum FT4 and FT3 should be assayed to identify overt thyrotoxicosis and T3 thyrotoxicosis.3 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1394. 2. Thyroid. 2003;13:33-44. 3. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:379. Typical Thyroid Hormone Levels in Thyroid Disease. Measurement of the total plasma hormone concentration may not provide an accurate assessment of thyroid gland activity because total hormone concentration is affected by changes in either the amount of thyroxine-binding globulin (TBG) or the affinity of hormones to TBG in plasma.1 For more than 25 years, TSH methods have been able to detect the elevations in TSH that typify hypothyroidism.2 In the past 10 years, the sensitivity of TSH assays has increased to the extent that TSH measurement is now recognized as a more sensitive test than FT4 for detecting both hypo- and hyperthyroidism.2 However, some patients may be incorrectly or incompletely diagnosed if only TSH is measured.3 If serum TSH is high, serum FT4 should be measured to distinguish between mild thyroid failure and overt hypothyroidism.3 If serum TSH is low, both serum FT4 and FT3 should be assayed to identify overt thyrotoxicosis and T3 thyrotoxicosis.3 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1394. 2. Thyroid. 2003;13:33-44. 3. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:379.

    45. Thyroid-Stimulating Hormone (TSH) Assays Key test for diagnosis of hypothyroidism and hyperthyroidism TSH assay sensitivity has improved with subsequent test generations First generation: RIA Sensitivity: 1.0 ?IU/mL Second generation: IRMA Sensitivity: 0.1 ?IU/mL Third generation: ELISA Sensitivity: 0.03 ?IU/mL Thyroid-Stimulating Hormone (TSH) Assays. TSH measurement is the most reliable test to diagnose common forms of hypothyroidism and hyperthyroidism.1 In both overt and mild hypothyroidism, serum TSH is elevated and its measurement can identify a patient with primary hypothyroidism.1 In secondary hypothyroidism, TSH concentrations may be low, normal, or mildly elevated. Therefore, TSH measurement cannot reliably identify patients with central (secondary) hypothyroidism.1 Typically, hyperthyroidism is accompanied by suppressed TSH concentrations >0.1 ?IU/mL.1 In order to diagnose hyperthyroidism, the lowest reliably measured TSH concentration (assay sensitivity) must be 0.02 ?IU/mL or less.1 The first generation assay used for measuring TSH was the radioimmunoassay (RIA).2 It has a functional sensitivity of 1.0 ?IU/mL.2 The sensitivity of tests has improved with subsequent generations. The second generation immunoradiometric assay (IRMA) has a sensitivity of 0.1 ?IU/mL, and the third generation enzyme-linked immunosorbent assay (ELISA) has a sensitivity of 0.03 ?IU/mL.2,3 References Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Zophel K, et al. Nuklearmedizin. 1999;38:150-155.Thyroid-Stimulating Hormone (TSH) Assays. TSH measurement is the most reliable test to diagnose common forms of hypothyroidism and hyperthyroidism.1 In both overt and mild hypothyroidism, serum TSH is elevated and its measurement can identify a patient with primary hypothyroidism.1 In secondary hypothyroidism, TSH concentrations may be low, normal, or mildly elevated. Therefore, TSH measurement cannot reliably identify patients with central (secondary) hypothyroidism.1 Typically, hyperthyroidism is accompanied by suppressed TSH concentrations >0.1 ?IU/mL.1 In order to diagnose hyperthyroidism, the lowest reliably measured TSH concentration (assay sensitivity) must be 0.02 ?IU/mL or less.1 The first generation assay used for measuring TSH was the radioimmunoassay (RIA).2 It has a functional sensitivity of 1.0 ?IU/mL.2 The sensitivity of tests has improved with subsequent generations. The second generation immunoradiometric assay (IRMA) has a sensitivity of 0.1 ?IU/mL, and the third generation enzyme-linked immunosorbent assay (ELISA) has a sensitivity of 0.03 ?IU/mL.2,3 References Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Zophel K, et al. Nuklearmedizin. 1999;38:150-155.

    46. Additional Laboratory Tests for Thyroid Function Test Normal Levels When to Use Serum total T4 5-11 µg/dL Bound and free T4; use with TSH for diagnosis Free T4 0.7-1.8 ng/dL Use with TSH to assess degree of hypothyroidism TPOAb, TgAb Negative In combination with TSH, predictor of disease progression Additional Laboratory Tests for Thyroid Function. Sensitive immunometric assays have become the mainstay of thyroid testing.1 Thyroid disease is a graded phenomenon and changes in serum T4 and especially TSH concentrations can be detected before any clinical evidence of hypothyroidism appears.1,2 These laboratory findings are particularly valuable in diagnosing the spectrum of thyroid dysfunction as well as for monitoring thyroid hormone replacement therapy.2 However, patients with subclinical and milder forms of the disorder have shifts in other measures of thyroid disease. For this reason, TSH assays combined with other measurements, such as free and bound T3 and T4, are useful indicators of disease state.2 Serum total T3 or T4 tests measure the total serum concentration of T3 or T4 using RIA techniques.1,3 Free T4 and T3 measures the quantity of free or unbound serum T4 and T3.3 Free hormones are measured by immunometric assay or by equilibrium dialysis.3 TPOAb and TgAb detection measures antimicrosomal antibodies that are predictors of disease progression. Normal ranges for these tests may vary from laboratory to laboratory, depending on test methodologies and laboratory differences.2 References 1. Endocr Pract. 2002;8:457-469. 2. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. 3. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.Additional Laboratory Tests for Thyroid Function. Sensitive immunometric assays have become the mainstay of thyroid testing.1 Thyroid disease is a graded phenomenon and changes in serum T4 and especially TSH concentrations can be detected before any clinical evidence of hypothyroidism appears.1,2 These laboratory findings are particularly valuable in diagnosing the spectrum of thyroid dysfunction as well as for monitoring thyroid hormone replacement therapy.2 However, patients with subclinical and milder forms of the disorder have shifts in other measures of thyroid disease. For this reason, TSH assays combined with other measurements, such as free and bound T3 and T4, are useful indicators of disease state.2 Serum total T3 or T4 tests measure the total serum concentration of T3 or T4 using RIA techniques.1,3 Free T4 and T3 measures the quantity of free or unbound serum T4 and T3.3 Free hormones are measured by immunometric assay or by equilibrium dialysis.3 TPOAb and TgAb detection measures antimicrosomal antibodies that are predictors of disease progression. Normal ranges for these tests may vary from laboratory to laboratory, depending on test methodologies and laboratory differences.2 References 1. Endocr Pract. 2002;8:457-469. 2. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. 3. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

    47. Overview of Thyroid Disease States Hypothyroidism Hyperthyroidism Overview of Thyroid Disease States. Disorders of the thyroid are common and consist of 2 general presentations: changes in the size or shape of the gland or changes in secretion of hormones from the gland.1 Hypothyroidism refers to the inadequate production of thyroid hormone or diminished stimulation of the thyroid by TSH; hyperthyroidism refers to those conditions in which thyroid hormones are excessively released due to gland hyperfunction. Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1383,1394.Overview of Thyroid Disease States. Disorders of the thyroid are common and consist of 2 general presentations: changes in the size or shape of the gland or changes in secretion of hormones from the gland.1 Hypothyroidism refers to the inadequate production of thyroid hormone or diminished stimulation of the thyroid by TSH; hyperthyroidism refers to those conditions in which thyroid hormones are excessively released due to gland hyperfunction. Reference 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1383,1394.

    48. Hyperthyroidism Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues Hyperthyroidism. The term hyperthyroidism is restricted to those conditions in which thyroid hormones are excessively released as a result of gland overactivity.1,2 Iodine uptake by the gland is increased1 and there can be excessive production of body heat, increased motor activity, and increased activity of the sympathetic nervous system.2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1393-1394. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:515-516. Hyperthyroidism. The term hyperthyroidism is restricted to those conditions in which thyroid hormones are excessively released as a result of gland overactivity.1,2 Iodine uptake by the gland is increased1 and there can be excessive production of body heat, increased motor activity, and increased activity of the sympathetic nervous system.2 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1393-1394. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:515-516.

    49. Signs and Symptoms of Hyperthyroidism Signs and Symptoms of Hyperthyroidism. This slide shows systems of the body that are affected by hyperthyroidism. The throat region is strained with hoarseness, dryness, goiter, and difficulty swallowing.1 Rapid heartbeat occurs. There are gynecological problems: infertility, menstrual irregularities and first-trimester miscarriage, as well as excessive vomiting in pregnancy. There is sweating, heat intolerance, and frequent bowel movements. The patient may also be nervous, cranky, and sleepless. The eyes appear bulging and staring. In addition, patients with hyperthyroidism may have tremors, weight loss or gain, and alterations in appetite, changes in vision, fatigue and muscle weakness, and exertional intolerance and dyspnea. Reference 1. Endocr Pract. 2002; 8:458-467. Signs and Symptoms of Hyperthyroidism. This slide shows systems of the body that are affected by hyperthyroidism. The throat region is strained with hoarseness, dryness, goiter, and difficulty swallowing.1 Rapid heartbeat occurs. There are gynecological problems: infertility, menstrual irregularities and first-trimester miscarriage, as well as excessive vomiting in pregnancy. There is sweating, heat intolerance, and frequent bowel movements. The patient may also be nervous, cranky, and sleepless. The eyes appear bulging and staring. In addition, patients with hyperthyroidism may have tremors, weight loss or gain, and alterations in appetite, changes in vision, fatigue and muscle weakness, and exertional intolerance and dyspnea. Reference 1. Endocr Pract. 2002; 8:458-467.

    51. Hyperthyroidism Underlying Causes Signs and symptoms can be caused by any disorder that results in an increase in circulation of thyroid hormone Toxic diffuse goiter (Graves disease) Toxic uninodular or multinodular goiter Painful subacute thyroiditis Silent thyroiditis Toxic adenoma Iodine and iodine-containing drugs and radiographic contrast agents Trophoblastic disease, including hydatidiform mole Exogenous thyroid hormone ingestion Hyperthyroidism. Underlying Causes. The signs and symptoms of hyperthyroidism are caused by excessive thyroid hormone in the circulation.1 A number of disorders cause the increase in circulating thyroid hormone including toxic diffuse goiter (Graves disease), which is the most common cause;2,3 toxic uninodular and multinodular goiter;2,3 painful subacute thyroiditis, silent thyroiditis;2 toxic adenomas;3 iodine and iodine-containing drugs and radiographic contrast agents,3 trophoblastic disease including hydatidiform mole;3,4,5 and exogenous thyroid hormone ingestion.3 References 1. Endocr Pract. 2002;8:458-467. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394. 3. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:515-516,688-689. 4. Yoshimura M, et al. J Endocrinol Metab. 1994;78:862-866. 5. Mestman JH. Endocrinol Metab Clin North Am. 1998; 27:127-149. Hyperthyroidism. Underlying Causes. The signs and symptoms of hyperthyroidism are caused by excessive thyroid hormone in the circulation.1 A number of disorders cause the increase in circulating thyroid hormone including toxic diffuse goiter (Graves disease), which is the most common cause;2,3 toxic uninodular and multinodular goiter;2,3 painful subacute thyroiditis, silent thyroiditis;2 toxic adenomas;3 iodine and iodine-containing drugs and radiographic contrast agents,3 trophoblastic disease including hydatidiform mole;3,4,5 and exogenous thyroid hormone ingestion.3 References 1. Endocr Pract. 2002;8:458-467. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394. 3. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:515-516,688-689. 4. Yoshimura M, et al. J Endocrinol Metab. 1994;78:862-866. 5. Mestman JH. Endocrinol Metab Clin North Am. 1998; 27:127-149.

    52. Graves Disease (Toxic Diffuse Goiter) The most common cause of hyperthyroidism Accounts for 60% to 90% of cases Incidence in North America estimated at 0.02% to 0.4% of the population Affects more females than males, especially in the reproductive age range Graves disease is an autoimmune disorder possibly related to a defect in immune tolerance Graves Disease (Toxic Diffuse Goiter). Graves disease (also called toxic diffuse goiter) is the most common cause of high radioactive iodine uptake (RAIU) thyrotoxicosis.1 Its prevalence ranges from 60% to 90% of the RAIU cases, depending upon age and geographic region. Women are affected by Graves disease to a greater extent than men, and though the disease can occur at any age, it is more common between the ages of 20 and 50.1 Graves disease is an autoimmune disorder characterized by hyperthyroidism1 (elevated levels of thyroid hormone, suppressed levels of TSH, and increased RAIU),2 diffuse (uniformly enlarged) goiter, and IgG antibodies that bind and activate the TSH receptor (TSH-R).1 By binding to the TSH-R, these antibodies stimulate thyroid function, thus elevating concentrations of circulating free thyroid hormones.3 The eyes show characteristic exophthalmos, which is considered to be an autoimmune-mediated inflammation of the periorbital connective tissue and extraocular muscle.1,3 The production of excessive heat, increased motor activity, and increased activity of the sympathetic nervous system causes the skin to become warm, moist, and flushed, the muscles weak and trembling, and the heart rate rapid with a forceful beat.1 Although appetite increases, there may be weight loss, insomnia, anxiety, and apprehension, heat intolerance, and increased bowel movement frequency. Older patients may experience angina, heart failure, and arrhythmias.1 Thyroid nodules are frequently seen in patients with Graves disease.4 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394. Sklar C, et al. J Clin Endocrinol Metab. 2000;85:3227-3232. Weetman AP, et al. Endocr Rev. 1994;15:788-830. Mishra A, et al. J Postgrad Med. 2001;47:244-247.Graves Disease (Toxic Diffuse Goiter). Graves disease (also called toxic diffuse goiter) is the most common cause of high radioactive iodine uptake (RAIU) thyrotoxicosis.1 Its prevalence ranges from 60% to 90% of the RAIU cases, depending upon age and geographic region. Women are affected by Graves disease to a greater extent than men, and though the disease can occur at any age, it is more common between the ages of 20 and 50.1 Graves disease is an autoimmune disorder characterized by hyperthyroidism1 (elevated levels of thyroid hormone, suppressed levels of TSH, and increased RAIU),2 diffuse (uniformly enlarged) goiter, and IgG antibodies that bind and activate the TSH receptor (TSH-R).1 By binding to the TSH-R, these antibodies stimulate thyroid function, thus elevating concentrations of circulating free thyroid hormones.3 The eyes show characteristic exophthalmos, which is considered to be an autoimmune-mediated inflammation of the periorbital connective tissue and extraocular muscle.1,3 The production of excessive heat, increased motor activity, and increased activity of the sympathetic nervous system causes the skin to become warm, moist, and flushed, the muscles weak and trembling, and the heart rate rapid with a forceful beat.1 Although appetite increases, there may be weight loss, insomnia, anxiety, and apprehension, heat intolerance, and increased bowel movement frequency. Older patients may experience angina, heart failure, and arrhythmias.1 Thyroid nodules are frequently seen in patients with Graves disease.4 References Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394. Sklar C, et al. J Clin Endocrinol Metab. 2000;85:3227-3232. Weetman AP, et al. Endocr Rev. 1994;15:788-830. Mishra A, et al. J Postgrad Med. 2001;47:244-247.

    53. Graves Disease Autoimmune disorder Production of TSH receptor autoantibodies Stimulate thyroid hormone overproduction Characterized by the presence of B- and T-lymphocytes in thyroid tissue TSH receptor activation Thyroglobulin and thyroid peroxidase antibodies Sodium/iodide cotransporter (NIS) activity enhanced (increased RAI) Autoantigens Graves Disease. Graves disease is an autoimmune disorder that results in the production of autoantibodies to the TSH receptor located on the surface of thyroid cells.1 These antibodies bind to the TSH receptor and stimulate it to overproduce thyroid hormones, resulting in a hyperthyroid state.1 Graves disease is characterized by the presence of B-lymphocytes and T-lymphocytes that are sensitized to at least 4 autoantigens: 1) TSH receptor; 2) thyroglobulin and thyroid peroxidase; 3) sodium/iodide cotransporter (NIS); and 4) secondary involvement of additional autoantigens.2 Symptoms of Graves disease include nervousness, irritability, unexplained weight loss, increased appetite, heat intolerance, excessive sweating, rapid pulse, thyroid enlargement, diarrhea, finger tremors, and warm, moist skin.2 References 1. Abbott Laboratories Diagnostics Division Web site. Available at: http://www.abbottdiagnostics.com/medical_conditions/thyroid/disorders/graves.htm. Accessed July 1, 2003. 2. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Graves Disease. Graves disease is an autoimmune disorder that results in the production of autoantibodies to the TSH receptor located on the surface of thyroid cells.1 These antibodies bind to the TSH receptor and stimulate it to overproduce thyroid hormones, resulting in a hyperthyroid state.1 Graves disease is characterized by the presence of B-lymphocytes and T-lymphocytes that are sensitized to at least 4 autoantigens: 1) TSH receptor; 2) thyroglobulin and thyroid peroxidase; 3) sodium/iodide cotransporter (NIS); and 4) secondary involvement of additional autoantigens.2 Symptoms of Graves disease include nervousness, irritability, unexplained weight loss, increased appetite, heat intolerance, excessive sweating, rapid pulse, thyroid enlargement, diarrhea, finger tremors, and warm, moist skin.2 References 1. Abbott Laboratories Diagnostics Division Web site. Available at: http://www.abbottdiagnostics.com/medical_conditions/thyroid/disorders/graves.htm. Accessed July 1, 2003. 2. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

    55. Chronic Autoimmune Thyroiditis (Hashimoto Thyroiditis) Occurs when there is a severe defect in thyroid hormone synthesis Is a chronic inflammatory autoimmune disease characterized by destruction of the thyroid gland by autoantibodies against thyroglobulin, thyroperoxidase, and other thyroid tissue components Patients present with hyperthyroidism, hypothyroidism, painless goiter, and other overt signs Persons with autoimmune thyroid disease may have other concomitant autoimmune disorders Most commonly associated with type 1 diabetes mellitus Chronic Autoimmune Thyroiditis (Hashimoto Thyroiditis). Hashimoto thyroiditis (HT), also called chronic autoimmune thyroiditis or chronic goitrous thyroiditis,1 is characterized by hypothyroidism with autoantibodies directed against thyroglobulin and thyroperoxidase, as well as other components of thyroid tissue.1 When severe, HT is associated with multiple symptoms that affect the appearance and mental activity of the patient.2 The face is pale, puffy, and without expression.2 The skin is cold and dry, and the patient may complain of cold intolerance. The scalp is scaly, hair and fingernails brittle, and subcutaneous tissue appears thickened and edematous.2 The patient is lethargic, with a husky voice and slow speech, and depression may be present, along with poor appetite and diminished gastrointestinal activity.2 The coexistence of 2 or more autoimmune endocrine diseases is common1 and autoimmune thyroiditis is commonly associated with insulin-dependent (IDDM) (Type 1) diabetes mellitus,3 another autoimmune endocrine disease.4 References Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:721. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1394. 3. McCanlies E, et al. J Clin Endocrinol Metab. 1998;83:1548-1551. 4. Matejkova-Behanova M. Endocr Reg. 2001;35:167-172.Chronic Autoimmune Thyroiditis (Hashimoto Thyroiditis). Hashimoto thyroiditis (HT), also called chronic autoimmune thyroiditis or chronic goitrous thyroiditis,1 is characterized by hypothyroidism with autoantibodies directed against thyroglobulin and thyroperoxidase, as well as other components of thyroid tissue.1 When severe, HT is associated with multiple symptoms that affect the appearance and mental activity of the patient.2 The face is pale, puffy, and without expression.2 The skin is cold and dry, and the patient may complain of cold intolerance. The scalp is scaly, hair and fingernails brittle, and subcutaneous tissue appears thickened and edematous.2 The patient is lethargic, with a husky voice and slow speech, and depression may be present, along with poor appetite and diminished gastrointestinal activity.2 The coexistence of 2 or more autoimmune endocrine diseases is common1 and autoimmune thyroiditis is commonly associated with insulin-dependent (IDDM) (Type 1) diabetes mellitus,3 another autoimmune endocrine disease.4 References Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:721. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1394. 3. McCanlies E, et al. J Clin Endocrinol Metab. 1998;83:1548-1551. 4. Matejkova-Behanova M. Endocr Reg. 2001;35:167-172.

    57. Time Course of Thyroiditis - TFTs

    58. Toxic Multinodular Goiter More common in places with lower iodine intake Accounts for less than 5% of thyrotoxicosis cases in iodine-sufficient areas Evolution from sporadic diffuse goiter to toxic multinodular goiter is gradual Thyrotropin receptor mutations and TSH mutations have been found in some patients with toxic multinodular goiters Surgery or 131I is recommended treatment Toxic Multinodular Goiter. Toxic multinodular goiters are a more common occurrence and cause of thyrotoxicosis in areas where there is a lower iodine intake.1 These goiters account for less than 5% of thyrotoxicosis cases in iodine-sufficient areas compared with a 50% occurrence in iodine-deficient areas. The evolution of a sporadic diffuse goiter to a nontoxic multinodular goiter to a toxic multinodular goiter is gradual. Thyrotropin receptor mutations have been detected in the hyperfunctioning nodules of patients with multinodular goiters, along with TSH receptor mutations. Surgery is the recommended treatment for patients with goiters and for patients in whom there is concern about the possibility of a carcinoma within the goiter. Reference 1. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Toxic Multinodular Goiter. Toxic multinodular goiters are a more common occurrence and cause of thyrotoxicosis in areas where there is a lower iodine intake.1 These goiters account for less than 5% of thyrotoxicosis cases in iodine-sufficient areas compared with a 50% occurrence in iodine-deficient areas. The evolution of a sporadic diffuse goiter to a nontoxic multinodular goiter to a toxic multinodular goiter is gradual. Thyrotropin receptor mutations have been detected in the hyperfunctioning nodules of patients with multinodular goiters, along with TSH receptor mutations. Surgery is the recommended treatment for patients with goiters and for patients in whom there is concern about the possibility of a carcinoma within the goiter. Reference 1. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

    59. Multinodular Goiter (MNG) MNG is an enlarged thyroid gland containing multiple nodules The thyroid gland becomes more nodular with increasing age In MNG, nodules typically vary in size Most MNGs are asymptomatic MNG may be toxic or nontoxic Toxic MNG occurs when multiple sites of autonomous nodule hyperfunction develop, resulting in thyrotoxicosis Toxic MNG is more common in the elderly Multinodular Goiter (MNG). The thyroid gland becomes more nodular with age.1 MNG develops in an enlarged thyroid gland and is especially prevalent in populations in iodine-deficient areas.2 Thyroid enlargement may have progressed from a simple nontoxic goiter or have been associated with Hashimoto disease.3 MNG usually results from a low-grade, probably intermittent stimulus to the thyroid gland from iodine deficiency, goitrogens (foods that induce hypothyroidism and goiter in the diet such as cabbage, broccoli, cauliflower, and brussels sprouts),4 decreased thyroid hormone production, or an autoimmune disease, which causes multiplication and growth of small groups of thyroid cells.3 After Graves disease, toxic multinodular goiter (TMG) is the most common cause of hyperthyroidism5 and thyrotoxicosis in the elderly.6 TMG occurs most often in patients aged 50 or older and mainly in women, when the nodules in a nontoxic MNG become autonomous5 and function independent of TSH stimulation.7 It is very prevalent in geographic regions with iodine deficiency and rarely occurs in places where iodine intake is sufficient. Thyroid autonomy is most frequently found in TMGs.7 Patients are often asymptomatic or very mildly toxic, and have a goiter, and lab findings that indicate suppressed TSH with normal FT4 and T3 levels.5 References 1. Hurley DL, et al. Geriatrics. 1995;50:24-26,29-31. 2. Tonacchera M, et al. J Clin Endocrinol Metab. 2002;87:352-367. 3. Bayliss RIS, Tunbridge WMG. Thyroid Disease: the Facts. 3rd ed. Oxford, UK: Oxford University Press; 1998:121. 4. Stoewsand GS. Food Chem Toxicol. 1995;33:537-543. 5. Fisher JN. South Med J. 2002;95:493-505. 6. Vitti P, et al. J Endocrinol Invest. 2002;25(10 Suppl):16-18. 7. Krohn K, et al. J Clin Endocrinol Metab. 2001;86:3336-3345.Multinodular Goiter (MNG). The thyroid gland becomes more nodular with age.1 MNG develops in an enlarged thyroid gland and is especially prevalent in populations in iodine-deficient areas.2 Thyroid enlargement may have progressed from a simple nontoxic goiter or have been associated with Hashimoto disease.3 MNG usually results from a low-grade, probably intermittent stimulus to the thyroid gland from iodine deficiency, goitrogens (foods that induce hypothyroidism and goiter in the diet such as cabbage, broccoli, cauliflower, and brussels sprouts),4 decreased thyroid hormone production, or an autoimmune disease, which causes multiplication and growth of small groups of thyroid cells.3 After Graves disease, toxic multinodular goiter (TMG) is the most common cause of hyperthyroidism5 and thyrotoxicosis in the elderly.6 TMG occurs most often in patients aged 50 or older and mainly in women, when the nodules in a nontoxic MNG become autonomous5 and function independent of TSH stimulation.7 It is very prevalent in geographic regions with iodine deficiency and rarely occurs in places where iodine intake is sufficient. Thyroid autonomy is most frequently found in TMGs.7 Patients are often asymptomatic or very mildly toxic, and have a goiter, and lab findings that indicate suppressed TSH with normal FT4 and T3 levels.5 References 1. Hurley DL, et al. Geriatrics. 1995;50:24-26,29-31. 2. Tonacchera M, et al. J Clin Endocrinol Metab. 2002;87:352-367. 3. Bayliss RIS, Tunbridge WMG. Thyroid Disease: the Facts. 3rd ed. Oxford, UK: Oxford University Press; 1998:121. 4. Stoewsand GS. Food Chem Toxicol. 1995;33:537-543. 5. Fisher JN. South Med J. 2002;95:493-505. 6. Vitti P, et al. J Endocrinol Invest. 2002;25(10 Suppl):16-18. 7. Krohn K, et al. J Clin Endocrinol Metab. 2001;86:3336-3345.

    60. Joan Peters Mrs. Peters is a 53y old female who presented with a 3 months history of weight loss, palpitations, diarrhea, rash on the shins, and lacrimation. She has a goite, wide pulse pressure and tachcardia Her TFTs are as follows: TSH = <0.01 mU/L (0.35-5.5) fT4 = 53.7 pmol/L (11.5-23.2) fT3 = 7.4 pmol/L (3.4-5.2)

    61. Joan Peters – Eye findings

    62. Joan Peters - Legs

    63. What is your diagnosis What is your diagnosis? What blood tests would you request to confirm your diagnosis? What further radiological tests, if any, would you request?

    64. Commonly used thyroid autoantibodies

    65. Anti TSHr autoantibodies Although Anti TSHr antibody is the most prevalent antibody in patients with Graves’ disease, up to 10% patients with GD may be antibody negative and the test is not routinely available.

    66. The Value of Uptake Scan Increased Uptake – Graves Disease Decreased Uptake - Thyroiditis

    67. Diffuse uptake

    68. Spurious uptake scan results False positive Iodine deficiency Recovery phase of acute thyroiditis ESRD Lithium therapy Hydatidiform mole Rare congenital thyroid anomalies False Negative Iodine containing drugs Renal failure with iodine retention Central hypothyroidism Subacute thyroiditis Anti-thyroid drugs High dose steroids Factitious thyrotoxicosis

    69. Hyperthyroidism: Treatment Beta-blockers (hyperadrenergic symptoms) Hyperthyroidism: Anti-thyroid Drugs (*used in pregnancy) *Propylthiouracil (PTU), Methimazole Radioiodine Ablation Surgical Thyroidectomy Thyroiditis: ASA, NSAIDS, +/- corticosteroids Iodine (high doses ?Wolff Chaikoff effect)

    70. Thyrotoxic Storm Biochemically indistinguishable from severe thyrotoxicosis Clinical diagnosis based on the following criteria: a) Fever b) Tachycardia out of proportion to the fever c) CNS dysfunction d) GI dysfunction + jaundice and elevated liver enzymes ? Features of Graves’ disease or Goiter.

    71. Thyrotoxic Storm Management Reduce thyroid hormone production with (tapazole 20-30 mg bid or PTU 200mg tid) Reduce thyroid hormone secretion with Lugol’s iodine, ipodate or Lithium Glucocorticoids and beta blockers Tylenol for fever (not aspirin) Management of volume depletion Supportive therapy

    72. Stephanie Peters Stephanie is a 27 y old female who is 6 wk pregnant. She has been referred to you because her TSH is 0.04 mU/L. She is otherwise asymptomatic and feels a bit nauseous in the morning. Her thyroid is mildly enlarged on palpation.

    74. Stephanie Peters What is your diagnosis? What blood tests would you request to confirm your diagnosis? What radiological tests, if any, would you request?

    75. Stephanie Peters – Possible diagnoses Graves’ disease Gestational transient thyrotoxicosis Molar pregnancy Thyroiditis Other usual causes such as toxic nodules etc.

    76. Thyroid physiology in pregnancy TBG concentration rises leading to elevated tT4 and tT3 levels. Placenta secretes de-iodinase which metabolizes Thyroxine and controls fetal thyroid levels. T4 production is enhanced during pregnancy. One fifth of pregnant women have transiently low TSH during first trimester.

    77. TSH and hCG during pregnancy

    78. Stephanie Peters – Clues from the history Graves’ disease No vomiting Thyroid is enlarged May have eye findings Typical symptoms of thyrotoxicosis Positive antibodies GTT & Molar pregnancy Associated with vomiting Thyroid not typically enlarged No eye findings Thyrotoxicosis symptoms either minimal or none Negative antibodies

    79. Stephanie Peters What is your diagnosis? What other tests would you request to confirm your diagnosis? What radiological tests, if any, would you request?

    80. Stephanie Peters - additional tests fT4 and fT3 Autoantibody screen With severe vomiting – consider molar pregnancy

    81. Stephanie Peters What is your diagnosis? What other tests would you request to confirm your diagnosis? What radiological tests, if any, would you request?

    82. Stephanie Peters Most women with mild TSH suppression, normal T4 and T3, negative antibodies and otherwise no symptoms can be simply observed. Only those who have positive antibodies or have elevated ft4 or fT3 need treatment.

    83. Thyrotoxicosis during pregnancy Most common cause is Graves’ disease Others include: Molar pregnancy Gestational transient thyrotoxicosis (HCG) Thyroiditis Toxic nodules

    84. GTT vs. GD GTT Vomiting No goiter No thyroid eye disease Minor symptoms Mild elevation of T4 No history of thyroid disease No antibodies GD No vomiting Thyroid enlarged May be TAO Severe symptoms Both T4 and T3 elevated History of thyroid disease Positive antibodies

    85. Interfering antibodies fT4 test methods are quite variable. fT4 can either be measured ‘directly’ or by ‘calculation method’ None of these methods accurately measures the free portion. Abnormal antibodies in patients’ serum can give falsely high results.

    86. Interfering antibodies If in doubt, repeat test in a different lab or ask for an assay using equilibrium dialysis

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