Thyroid Hormones PDF

Thyroid Hormones Dr. Sovan Bagchi Professor of Physiology * www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives Describe how triiodothyronine and thyroxine are synthesized, metabolize...

Thyroid Hormones Dr. Sovan Bagchi Professor of Physiology * www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives Describe how triiodothyronine and thyroxine are synthesized, metabolized, and transported in the blood Explain the effects of thyroid hormones Explain the regulation of thyroid hormone synthesis by thyrotropin-releasing hormone and thyroid-stimulating hormone Case CR is a 64-year-old female with a long history of hypothyroidism who has been taking a stable dose of levothyroxine for 30 years. From routine lab work last week, her TSH was normal. CR has been reading about thyroid hormones and wonders why she isn’t getting both T4 and T3 supplementation. During an appointment, she tells you, “I’ve read that I might have more energy if I take T3, too. What do you think?” What will you tell CR about T3 supplementation? Clinical correlation: During thyroid surgery it is crucial to protect the recurrent laryngeal nerve, which passes posterior to the lobe of the thyroid gland. Injury to this nerve can result in paralysis of the vocal cords because it innervates all of the intrinsic muscles of the larynx, except for the cricothyroid. Another possible complication of thyroid surgery is damage to the parathyroid glands, leading to hypoparathyroidism. The thyroid gland, often described as butterfly shaped, is located deep within the infrahyoid muscles, four pairs of strap-like muscles in the anterior (frontal) part of the lower neck. The thyroid gland is anterior and lateral to the trachea and the esophagus. How Are the Thyroid Hormones Made? Together, T3 and T4 The thyroid gland commonly are produces two main referred to simply hormones as thyroid hormone triiodothyronine thyroxine (T4). (T3) Properties of T3 and T4 T4 T3 T4 is made only in the thyroid and is T3 is more biologically active than T4 the main hormone Greater affinity for thyroid hormone Considered a prohormone receptors It converts to T3 to exert their action Shorter half-life Reverse T3 (rT3) less than 1% of circulating thyroid hormone. It’s mostly made outside the thyroid gland by removal of an iodine atom from T4. Calcitonin The thyroid gland also produces calcitonin from the parafollicular C cells Responsible for Ca homeostasis Synthesis of Thyroid hormones 1. Iodide uptake 2. Oxidation: thyroid peroxidase, or TPO, oxidizes iodide to its active form, iodine. 3. Organification. In the follicular cell lumen, iodine encounters thyroglobulin (Tg). TPO can add either one or two iodine molecules to each tyrosine residue, to produce either monoiodotyrosine (MIT) or diiodotyrosine (DIT). 4. Generation of T3 and T4. Thyroid peroxidase combines MIT and DIT to form T3, or two DIT molecules join to form T4. 5. Release of T3 and T4 from thyroglobulin into circulation. When it’s time to release thyroid hormones, Tg is endocytosed from the lumen into the follicular cell. The Tg is recycled for additional iodination. Extrathyroid Metabolism Thyroid hormones are further metabolized in extra-thyroid locations Deiodination About 10% of T4 each day is deiodinated in the peripheral tissues by the enzyme 5′-deiodinase. The resulting products are a mix of T3, reverse T3 (rT3), and inactive degradation products. T3 is potent but reverse T3 is NOT But it modulates the action of the active T3 form by competing for the same receptors within cells. It prevents the body from responding too strongly to T3. Wolff-Chaikoff effect Dietary iodine is transported in the form of iodide. Too much iodide can inhibit thyroid peroxidase and reduces the thyroid’s ability to produce T3 and T4. To minimize this effect, the body regulates its iodide levels and excretes excess iodide in the urine How can too much iodide inhibit thyroid hormone production? Transport and Receptor Binding 99% of T3 and T4 are bound to thyroid-binding globulin (TBG) The small percentage are left unbound and called free T3 and free T4., they are biologically active Effects of Changes in TBG Levels TBG levels increased TBG levels decreased Pregnancy and with oral contraceptive use Hepatic failure and in patients taking (estrogen promotes TBG synthesis in the liver) corticosteroid drugs Findings: Bound and total thyroid Findings: decreased levels of bound and hormones are elevated, whereas free total thyroid hormones, whereas free T3 and T3 and free T4 remain normal free T4 remain normal Receptors Thyroid hormones cannot passively diffuse through the cell membrane like steroid hormones though T3 and T4 are lipophilic They are internalized via specific transmembrane thyroid hormone transporters Binds to nuclear receptors to modulate gene expression Metabolic Effects T3 and T4 upregulate the Na+/K+-ATPase, which increases cellular oxygen consumption, heat production, and basal metabolic rate. Think! Symptoms of hyperthyroidism T3 and T4 promotes cellular uptake of glucose Fatigue, weakness, weight loss and and increasing both the formation and “hyper” anxiety catabolism of proteins Cardiovascular Effects Think! Patients with hyperthyroidism can be recognized by increases in metabolic rate (fever, weight loss) and in sympathetic Thyroid hormones upregulate β1-adrenergic activation (rapid pulse, pounding heart). receptors in the heart, which increases the heart’s response to sympathetic activation. This leads to an elevation in pulse rate and cardiac output Effects on Growth and Fetal Development Clinical correlation Thyroid hormone stimulates growth hormone synthesis, leading to bone formation. Because thyroid hormone is critical for development, a deficiency in this hormone can have devastating effects on T3 directly enhances formation and growth of bone cells (osteoblasts) and acts fetuses and neonates. Congenital directly on growth plate chondrocytes to promote cartilage formation. hypothyroidism is characterized by congenital malformations including In the fetus and neonate, thyroid hormone plays a crucial role in both brain coarse facial features, short stature, and and bone development. cognitive delay. T3 binding to its receptors in the brain stimulates synapse formation, myelin formation, and the growth of dendrites and axons on neurons. It also helps regulate neural crest cell migration and differentiation. How Are Thyroid Hormones Regulated How do TRH and TSH work? Negative Feedback Clinical Correlation In Graves disease, a cause of hyperthyroidism, abnormal thyroid-stimulating antibodies (TSI) are made as part of a pathologic autoimmune process and bind to the TSH receptor on the thyroid follicular cells. These bound TSI chronically activate the receptor, causing persistent thyroid hormone synthesis, overriding the usual negative feedback mechanisms Hyperthyroidism Graves' Disease High excitability Intolerance to heat Increased sweating Weight loss & Muscle weakness Diarrhea Nervousness or other psychic disorders Extreme fatigue but inability to sleep Tremor of the hands Exophthalmos: edematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles Myxedema Almost total lack of thyroid function in adult Swelling of face and bagginess under eyes. In this cases due to increase in hyaluronic acid and chondroitin sulfate leads to increase in interstitial fluid accumulation and nonpitting type of edema develops The voice is husky and slow In hypothyroidism patients blood cholesterol increases and develops atherosclerosis - leads to coronary artery diseases Hypothyroidism In some areas iodine are less Endemic Goiter Iodine deficiency develops. in soil. No inhibition at TSH level leads to more TSH secretion Thyroglobulin are formed and hyperplasia and growth but no thyroid hormones. of thyroid gland and development of goiter. Thyroiditis or Hasimoto disease Development of antibody against thyroglobulin. Immunity that destroys the gland Continuous damage of thyroid cells and hypothyroidism develops. Cretinism Due to extreme hypothyroidism during prenatal or neonatal or childhood - lack of thyroid hormone or can be due to iodine deficient diet. Sluggish movement, physical and mental growth retarded. This is results from retardation of the growth, branching, and myelination of the neuronal cells of the CNS. Child with cretinism an obese, stocky, and short appearance. Duo to disproportionate rate of growth The tongue becomes large in relation to the skeletal growth that it obstructs swallowing and breathing, inducing a characteristic guttural breathing that sometimes chokes the child. Test your knowledge! Which of the following is most characteristic of triiodothyronine? A. Acts as a prohormone B. Binds Gq receptors C. Binds Gs receptors D. Predominantly produced within the thyroid E. Shorter half-life than thyroxine Which of the following most common findings in pregnancy A. Decreased free triiodothyronine B. Decreased total thyroid hormone C. Elevated free reverse triiodothyronine D. Elevated free thyroxine E. Increased thyroid-binding globulin Learning Resources Textbook: John E. Hall and Michael E. Hall. Textbook of Medical Physiology. 14th ed. Elsevier. 2021. ISBN: 978-0-323-59712-8. Chapter 77: Page no. 941-953 Power-point presentation in the moodle