Lecture 34-Thyroid Gland.pdf

THYROID GLAND Master of Arts in Biomedical Sciences Bluefield College, VCOM Campus LEARNING OBJECTIVES 1. Describe the synthesis, secretion and transport of T3 and T4. 2. Describe the feedback systems used in the regulation of thyroid hormone, including the Wolf-Chaikoff effect. 3. Describe...

THYROID GLAND Master of Arts in Biomedical Sciences Bluefield College, VCOM Campus LEARNING OBJECTIVES 1. Describe the synthesis, secretion and transport of T3 and T4. 2. Describe the feedback systems used in the regulation of thyroid hormone, including the Wolf-Chaikoff effect. 3. Describe the signs and symptoms related to hyperthyroidism and hypothyroidism. THYROID Apical Membrane Colloid Basal Membrane THYROID GLAND: HORMONES AND IODINE METABOLISM Thyroid hormones are synthesized by the follicular epithelial cells of the thyroid gland. The follicular epithelial cells are arranged in circular follicles 200– 300 µm in diameter, as shown The material in the lumen of the follicles is colloid, which is composed of newly synthesized thyroid hormones attached to thyroglobulin (TG) THYROXINE AND ITS PRECURSORS: STRUCTURE & SYNTHESIS THE STEPS IN THYROID HORMONE BIOSYNTHESIS IN FOLLICULAR EPITHELIAL CELLS High levels of I− inhibit organification and synthesis of thyroid hormones, which is known as the Wolff-Chaikoff effect the gland secretes 90% of its thyroid hormone as T4 and 10% as T3. (10x more T4 is produced) THYROXINE AND ITS PRECURSORS: STRUCTURE & SYNTHESIS THYROID PEROXIDASE (TPO) “Coupling Reaction” “Iodination Reaction” Oxidation of I− to I2 Thyroid peroxidase catalyzes this oxidation step and the next two steps (i.e., organification of I2 into TG and the coupling reactions). Clinical correlation: Thyroid peroxidase is inhibited by propylthiouracil (PTU), which blocks the synthesis of thyroid hormones by blocking all of the steps catalyzed by thyroid peroxidase. Thus administration of PTU is an effective treatment for hyperthyroidism. IODINE THYROID TESTING • TSH • Best test for screening for thyroid dysfunction • Not specific for a particular thyroid disease. • Don’t use TSH alone for diagnosis • Also useful in • Assessing T4 levels in 1° hypothyroidism • Monitoring TSH-suppressive in thyroid Ca THYROID HORMONE: TRANSPORT • T3 & T4 leave the thyroid gland by diffusion • Both are transported in blood by three transport proteins, Thyroxine binding globulin (TBG), transthyretin and albumin • A majority (70%) of T4 & T3 is bound to thyroxine binding globulin • Both enter their target cells by diffusion T4 mainly functions as a prohormone. THYROXINE AND ITS PRECURSORS: ACTIVITY T3 is the main active thyroid hormone and has the highest binding affinity for thyroid hormone receptor (TR). Thyroid hormone activity can be increased in plasma without new synthesis, by converting T4 to T3. If too much thyroid activity is present, T4 is converted to the inactive metabolite rT3 to reduce activity. CLINICAL CORRELATION • hepatic failure, blood levels of TBG decrease because there is decreased hepatic protein synthesis. The decrease in TBG levels results in a transient increase in the level of free thyroid hormones; a consequence of increased free thyroid hormone is inhibition of synthesis of thyroid hormones (by negative feedback). • In contrast, during pregnancy, the high level of estrogen inhibits hepatic breakdown of TBG and increases TBG levels. With a higher level of TBG, more thyroid hormone is bound to TBG and less thyroid hormone is free and unbound. The transiently decreased level of free hormone causes, by negative feedback, increased synthesis and secretion of thyroid hormones by the thyroid gland. In pregnancy, as a consequence of all these changes, levels of total T4 and T3 are increased (due to the increased level of TBG), but levels of free, physiologically active, thyroid hormones are normal and the person is said to be “clinically euthyroid.” THYROXINE AND ITS PRECURSORS: ACTIVITY UCP: Uncoupling protein REGULATION OF THYROID GLAND ACTIVITY • Thyroid hormone feedback regulation of gland activity via suppression of TRH and TSH secretion • Autoregulation of thyroid gland activity via the Wolf-Chaikoff Effect* • Energy intake and adipose tissue stores regulation of thyroid gland activity via leptin and CNS regulation of TRH secretion *High levels of I− inhibit organification and synthesis of thyroid hormones, which is known as the Wolff-Chaikoff effect THYROID HORMONE FEEDBACK REGULATION • Hypothalamic TRH stimulates pituitary thyrotrope cells to release thyroid stimulating hormone (TSH). • TSH stimulates thyroid epithelial cells to release T3 and T4. • T3 (mainly) stimulates a multitude of cell types resulting in the activities exhibited • T4 & T3 feedback to inhibit pituitary & hypothalamic secretion of TSH and TRH T 3 & T 4 CONTROL PATHWAYS & DISEASES FROM MALFUNCTION FACTORS AFFECTING THYROID HORMONE SECRETION ACTIONS OF THYROID HORMONES HYPOTHYROIDISM • More common than hyperthyroidism • 99% is primary (< 1% due to TSH deficiency) • Hashimoto’s • most common thyroid problem (4% of population) • most common cause in iodine-replete areas • Also known as chronic lymphocytic thyroiditis • Postpartum (silent) thyroiditis • Silent/painless • Occurs within 6 weeksà6 months postpartum • Incidence: 10-15% of all women, ≈ 25% women w/ Type 1 diabetes • 70% chance of recurrence w/ subsequent pregnancies HYPOTHYROIDISM • Symptoms • General Slowing Down • Lethargy/somnolence • Depression • Modest Weight Gain • Cold Intolerance • Dry skin • Constipation (↓ peristaltic activity) • General Aches/Pains • Arthralgias or myalgias (worsened by cold temps) • Brittle Hair • Menstrual irregularities • Excessive bleeding • Failure of ovulation • ↓ Libido HYPERTHYROIDISM • Symptoms • Jittery, shaky, nervous • Difficulty concentrating • Emotional lability • Insomnia • Rapid Heart Rate, palpitations, Dyspnea on exertion • Feeling Hot • Weight Loss (can see weight gain) • Frequent bowel movements (hyperdefecation, not diarrhea) • Fatigue • Menses w/ lighter flow, shorter duration HYPERTHYROID EYE DISEASE • Hyperthyroidism (any cause) • Eye lid retraction and stare • Due to increased adrenergic tone stimulating the levator palpebral muscles. • True Graves’ Ophthalmopathy • Proptosis • Diplopia • Inflammatory changes • Conjunctival infection • Periorbital edema • Due to thyroid autoAb’s that cross-react w/ Ag’s in fibroblasts, adipocytes, + myocytes behind the eyes. GRAVES’ DERMOPATHY Localized plaque on the outer aspect of the skin. Horny form over shin and dorsum of the foot HYPERTHYROIDISM • Thyrotoxicosis = “any condition that results in thyroid hormone excess” • Includes: Graves Disease, Toxic Goiter, Thyroiditis, and Excessive Thyroxine Ingestion • Hyperthyroidism = “Specifically hyperfunctioning of the thyroid gland” • Most Commonly caused by Graves Disease in the young • Toxic Nodular Goiter in the elderly THANK YOU THYROID GLAND SUMMARY I • The thyroid gland is the source of tetraiodothyronine T4 and triiodothyronine (T3). The basic unit of the thyroid gland is the follicle which consists of a single layer of epithelial cells surrounding a central lumen that contains colloid or stored hormone. • T4 and T3 are synthesized from tyrosine and iodide by the enzyme peroxidase. Tyrosine is incorporated in peptide linkage within the protein thyroglobulin. After iodination, two iodotyrosine molecules are coupled to yield iodothyronines. • Secretion of stored T4 & T3 requires retrieval of thyroglobulin from the follicle lumen by endocytosis. To support hormone synthesis, Iodine is actively concentrated by the gland and conserved within it by recycling the iodotyrosine molecules that escape coupling within the thyroglobulin. • Thyrotropin (TSH) acts on the thyroid gland via its plasma membrane receptor and cAMP to stimulate all steps in the production of T4 & T3. These steps include iodide uptake, iodination and coupling, and retrieval from thyroglobulin. TSH also stimulates glucose oxidation, protein synthesis, and growth of the thyroid epithelial cells. This last effect is partly mediated by insulin-like Growth factors. THYROID GLAND SUMMARY II • More than 99.5% of the T4 and T3 circulate bound to the protein thyroglobulin (TBG), transthyretin, and albumin. Only the free fraction of T4 & T3 are biologically active. Changes in TBG levels require corresponding changes in thyroid hormone secretion to maintain normal concentrations of free T4 & T3. • T4 functions largely as a prohormone. Mono-deiodination of the outer ring yields 75% of the daily production of T3, which is the principle active hormone. Alternatively, mono-deiodination of the inner ring yields reverse T3 (rT3), which is biologically inactive. Proportioning of T4 between T3 & rT3 regulates the availability of active hormone. • T3 and, to a much lesser extent, T4 bind to a thyroid hormone receptor (TR) that itself exists linked to thyroid regulatory elements (TREs) in target DNA molecules. Activation results in expression or suppression of the expression of a large number of enzymes. As well as structural and other functional proteins. • Thyroid hormone increase is a major regulator of the basal metabolic rate. Oxygen utilization is increased by a mechanism that include increases in the size and number of mitochondria, Na,K-ATPase activity, and the rates of glucose and fatty acid oxidation and synthesis THYROID GLAND SUMMARY III • Additional important actions of thyroid hormone are to increase heart rate, cardiac output, and ventilation and to decrease peripheral resistance. These actions require the increased tissue oxygen demand. The corresponding increase in heat production leads to increased sweating. Substrate mobilization and disposal of metabolic products are enhanced. • Other thyroid hormone effects on the central nervous system and skeleton are crucial for normal growth and development. With children, in the absence the hormone, brain development is retarded and cretinism results. The stature shortens and the bones fail to mature. With adults, thyroid hormone increases the rate of bone resorption and the rates of skin and hair degradation. • Hyperthyroidism and hypothyroidism are usually easily diagnosed. Both are very amenable to therapy.