Week 1 Thyroid Hormone PDF

Thyroid Gland & Thyroid Hormones Physiology of the Endocrine System Guyton and Hall, Chapter 76 Objectives: After completion of this material, the student should be able to  Describe the functional anatomy of the thyroid gland.  Describe the synthesis and regulation of secretion of thyroid hormone...

Thyroid Gland & Thyroid Hormones Physiology of the Endocrine System Guyton and Hall, Chapter 76 Objectives: After completion of this material, the student should be able to  Describe the functional anatomy of the thyroid gland.  Describe the synthesis and regulation of secretion of thyroid hormones.  List the physiologic functions of thyroid hormones.  Explain the role the liver plays in thyroid function.  Describe the role of thyroid hormones in wellness.  Compare Hypothyroidism vs. Hyperthyroidism Thyroid & Thyroid Hormones  Thyroid Hormone (T3, T4) ◦ Thyroid hormones are synthesized and secreted by epithelial cells of the thyroid gland.  T3 – Triiodothyronine  T4 - Thyroxine  Effect: Maintain Metabolism ◦ Thyroid hormone effects virtually every organ system in the body including those involved in normal growth and development. Histology of the Thyroid Gland  The thyroid gland is composed of a large number of follicles. Colloid  Each follicle is surrounded by a single layer of epithelial cells (thyrocytes) and filled with a proteinaceous material called colloid. The primary constituent of colloid is the large glycoprotein thyroglobulin The thyroid gland also contains C cells that secrete calcitonin, a hormone that contributes to regulation of plasma calcium ion concentration. This will be covered next lecture. Thyroglobulin  Thyroglobulin (TG), a glycoprotein containing large quantities of tyrosine  TG is synthesized on the rough endoplasmic reticulum and the Golgi apparatus of the thyroid follicular cells.  Thyroglobulin is stored in the follicular lumen ◦ TG is incorporated into secretory vesicles and extruded across the apical membrane into the follicular lumen.  Iodination of Thyroglobulin ◦ Eventually, tyrosine residues of thyroglobulin will be iodinated to form the precursors of thyroid hormones. Thyroid Hormones  There are two forms thyroid hormone: ◦ Triiodothyronine (T3) ◦ Tetraiodothyronine, or thyroxine (T4) – 93%  Almost all of the thyroid hormone produced is T4.  The biologically active form of thyroid hormone is T3 ◦ T3 is four times as potent as T4  The target tissues convert T4 to T3 via the enzyme deiodinase ◦ Triiodothyronine is about four times as potent as thyroxine deiodinase Unusual Features of the Synthetic Process  Thyroid hormones contain large amounts of iodine, which must be adequately supplied in the diet.  Synthesis of thyroid hormones is partially intracellular and partially extracellular. The completed hormones are stored extracellularly in the follicular lumen until the thyroid gland is stimulated to secrete the active forms of thyroid hormone. T4 is the most abundant secretory product of the thyroid gland (9:1)  T3 is the most active form of the hormone.  Physiological Effects of Thyroid Hormone  Increased Basal Metabolic Rate Increase Cellular Metabolic Activity  Increased Heart Rate, Contractility, CO & Blood Flow  Stimulation of energy metabolism  ◦ (Carbs, Fats)      Excitatory Effects on the Central Nervous System Skeletal muscle – “react with vigor” Growth (prior to adulthood) Sleep Sexual function Thyroid Hormone - Regulation  The principal regulatory mechanism is the hypothalamic-pituitary negative feedback control system Thyroid regulating hormone (TRH)  Thyroid Stimulating Hormone (TSH)  Thyroid Hormone:  ◦ thyroxine (T4) and triiodothyronine (T3) Regulation of Thyroid Hormone Secretion  Thyroid hormone secretion is primarily regulated by thyroid-stimulating hormone (TSH) from the pituitary gland  TSH secretion from the pituitary gland is increased by the hypophysiotropic hormone thyrotropin-releasing hormone(TRH)  TSH is inhibited in a negative feedback fashion by circulating T4 and T3 Effects of TSH on the Thyroid Gland  Increased formation of the thyroglobulin  Increased activity of the iodide pump  Increased iodination of tyrosine  Increased size & increased secretory activity of the thyroid cells TSH increases all the known secretory activities of the thyroid glandular cells Physiological Functions of Thyroid Hormones  By structure thyroid hormones are peptide hormones  However the actions of thyroid hormones are more characteristic of steroid hormones.  Thyroid hormones: ◦ are transported in the blood bound to carrier proteins ◦ have a long half –life in plasma ◦ are poorly soluble in water and move easily through phospholipid membranes ◦ act at the level of a target cell’s DNA and ◦ increase transcription of large numbers of genes (Protein Synthesis) Mode of Action of Thyroid Hormones  Thyroid Hormones Increase Transcription of Large Numbers of Genes in Target Cells ◦ ◦ ◦ ◦  Increasing cellular function of target cells Increase protein synthesis in target cells Increase the number and activity of mitochondria Increase in metabolic activity in target cells Net result is a generalized increase in functional activity throughout the body  Increased Metabolism Synthesis of Thyroid Hormones  Iodide (I2) / Iodine (I-) ◦ To form normal quantities of thyroxine, about 50 milligrams of ingested iodine (in the form of iodides – KI or NaI) are required each year, or about 1 mg/week.  Dietary iodide is derived primarily from fish, seafood and seaweed.  In goiter endemic regions, iodinated salt or iodinated vegetable oil are employed in prophylaxis. Iodide vs. Iodine : Iodide is essentially the only form found in nature. Iodide is the ionic state of iodine. (I2) Iodide forms a salt with another element, such as sodium or potassium. Iodine Trapping : Na+-I− cotransport  I− is actively transported from blood into the follicular epithelial cells against both chemical and electrical gradients When there is a dietary deficiency of I−, the Na+-I− cotransport increases its activity, attempting to compensate for the deficiency. If the dietary deficiency is severe, even the Na+- I− cotransport pump cannot compensate. Synthesis of thyroid hormones will be decreased. Iodide Trapping  In a normal gland, the iodide pump concentrates the iodide to about 30 times its concentration in the blood.  When the thyroid gland becomes maximally active, this concentration ratio can rise to as high as 250 times.  The most important factor influencing the rate of iodide trapping by the thyroid is the concentration of TSH Synthesis of Thyroglobulin & T3 / T4 Tyrosine Propylthiouracil (PTU) X Propylthiouracil (PTU) Deiodinase  Deiodinase is selenium-containing enzymes that is used for the synthesis of the active form of thyroid hormone, T3. (T4 → T3)  Deiodinase is inhibited by propylthiouracil (PTU), a drug used to inhibit thyroid hormone production. Deiodinase Enzymes - Embellishnemt Type 1 and type 2 deiodinase (D1 and D2) convert T4 into T3  D3 degrades T4 and T3 into inactive metabolites and is thus the major physiological TH inactivator.  Propylthiouracil does not inhibit the type II or III enzymes  D3 degrades T4 and T3 into inactive metabolites and is thus the major physiological TH inactivator.  Propylthiouracil (PTU) does not inhibit the type II or III enzymes Effects of Dietary Factors and Drugs  Cassava ◦ Contains thiocyanate that blocks iodine uptake  Cruciferous vegetables ◦ (kale, broccoli, cabbage, brussel sprouts) Iodine deficiency  Propylthiouracil (PTU)  ◦ Inhibits thyroid peroxidase  enzyme that iodinates tyrosine residues on thyroglobulin ◦ Blocks 5’ deiodinase needed for peripheral conversion of T4 to T3 Binding of Thyroid Hormones in the Circulation Binding of Thyroid Hormones in the Circulation  Thyroid hormones are lipid soluble, but not very soluble in water. Thus to circulate in blood, thyroid hormones must be associated with binding proteins. Thyroxine-binding globulin (TBG) ~ 70% “Resevoir”  Prealbumin (transthyretin) ~ 15%  Albumin~ 15%   Less than 1% of thyroid hormone is found free in circulation Slow Release of T3 and T4  Because of high affinity of the plasma-binding proteins for the T4 (Thyroxine) and T3 (Triiodothyronine) , these substances are slowly released to the tissue cells. ◦ Half the T4 in the blood is released to the tissue cells about every 6 days, whereas half the T3 is released to the cells in about 1 day. Slow Onset and Long Duration of Action  Long latent period  After injection of a large quantity of thyroxine into a human being, essentially no effect on the metabolic rate can be discerned for 2 to 3 days  Maximum effect  activity increases progressively  reaches a maximum in 10 to12 days  Long Half Life  half-life of about 15 days.  Some activity persists for as long as 6 weeks to 2 months. Physiological Effects of Thyroid Hormones Thyroid Hormone Effects on Cellular Metabolic Activity  Thyroid hormones increase the metabolic activities of almost all the tissues of the body  Increased basal metabolic rate (BMR) Rate of utilization of foods for energy is greatly accelerated Rate of protein synthesis / protein catabolism is increased Increase the number and activity of mitochondria Increase active transport of ions through cell membranes Increases activity in response to Na-K-ATPase. Increases in rate of transport of both sodium and potassium ions through the cell membranes of some tissues.       Effects of Thyroid Hormones  Increase basal metabolic rate (BMR)  Heat production – Increased body temperature  Increased Oxygen consumption ◦ Thyroid hormone alters the cardiovascular and respiratory systems to increase blood flow and oxygen delivery to the tissues  Bone Formation  Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation; BMR → Metabolism of Nutrients  Increased BMR creates a demand for nutrients  Stimulation of Carbohydrate Metabolism ◦ rapid glucose uptake by cells, enhanced glycolysis, ◦ enhanced gluconeogenesis, increased rate of absorption  Stimulation of Fat Metabolism ◦ mobilization of lipids from adipose ◦ increases the free fatty acid concentration in the plasma ◦ accelerated oxidation of free fatty acids by cells. Effect on Plasma and Liver Fats  Increased thyroid hormone decreases the concentrations of cholesterol, phospholipids, and triglycerides in plasma  Initially increases the release of free fatty acids from adipose  Decreased thyroid secretion greatly increases the plasma concentrations of cholesterol, phospholipids, and TRGs → excessive deposition of fat in the liver  The large increase in circulating plasma cholesterol in prolonged hypothyroidism is often associated with severe atherosclerosis Cardiovascular and Respiratory  Because thyroid hormones increase O2 consumption, they create a higher demand for O2 in the tissues.  Increase in Cardiac Output ◦ Thyroid hormone induces the up- regulation of cardiac β1adrenergic receptors which mediate the effects of the sympathetic nervous system to increase heart rate and contractility. ◦ Myocardium is more sensitive to stimulation by the sympathetic nervous system Growth  In humans, the effect of thyroid hormone on growth is manifest mainly in growing children. Thyroid hormone is required for growth to adult stature.  Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation.  Thyroid hormones promote ossification and fusion of bone plates and bone maturation.  In hypothyroidism, bone age is less than chronologic age. Growth - Skeletal  In children with hypothyroidism, the rate of growth is greatly limited →Short stature  In children with hyperthyroidism, excessive skeletal growth often occurs, causing the child to become considerably taller at an earlier age.  In Hyperthyroidism, bones mature more rapidly and the epiphyses close at an early age. The eventual height of the adult actually may be shortened. Central Nervous System (CNS)  In the perinatal period, thyroid hormone is essential for normal maturation of the CNS. Hypothyroidism in the perinatal period causes irreversible mental retardation. ◦ Screening of newborns for hypothyroidism is mandated  In adults, hypothyroidism causes listlessness, slowed movement, somnolence, impaired memory, decreased mental capacity and clinical signs of depression.  Hyperthyroidism causes hyperexcitability, hyperreflexia, and irritability. Psychologically, hyperthyroid can present as a hypermanic state. Autonomic Nervous System  Thyroid hormones interact with the sympathetic nervous system ◦ Basal metabolic rate (BMR), heat production, heart rate, and stroke volume changes are similar to those produced by catecholamines via β-receptors. (Sympathomimetic) ◦ The effects of thyroid hormones and catecholamines (NE/EPI) on heat production, cardiac output, lipolysis, and gluconeogenesis appear to be synergistic. Physiological Effects of Thyroid Hormones Increased thermogenesis and sweating  Increased rate and depth of respiration  Increased cardiac output  Increased pulse pressure (but not mean arterial pressure)  Increased utilization of substrates for energy  Stimulation of Carbohydrate & Fat Metabolism  Effect on Plasma and Liver Fats  Increased Basal Metabolic Rate  Decreased Body Weight  Hyperthyroidism Manifestations          Elevated BMR Heat intolerance Nervousness / irritability Hyperactivity Tachycardia, palpitations, atrial fibrillation Fine tremor Weight loss w increased appetite Insomnia Mania         Increased body temperature Proximal muscle weakness, Scant menses, decreased fertility Fine hair /hair loss /grey hair Increased perspiration Skin moist and warm to touch Soft nails Increased frequency of bowel movements Grave’s Disease  Three distinct parts of Graves' disease:  Overactivity of the thyroid gland (hyperthyroidism)  Inflammation of the tissues around the eyes causing swelling, (exophthalmos )  Thickening of the skin over the lower legs. (Late manifestation) RX: Propylthiouracil (PTU) / Surgery Radiation rx/ Beta Blocker Exophthalmos PTU inhibits iodine and peroxidase from their normal interactions with thyroglobulin to form T4 and T3 Hypothyroidism  A condition in which the body lacks sufficient thyroid hormone.  The major function of thyroid hormone is to "run the body's metabolism”  Therefore, people with this condition will have symptoms associated with a slow metabolism. Hypothyroidism Manifestations          Lethargy and fatigue Intolerance to cold Weight gain - Increased BMI Decreased appetite Slowing of mental and physical performance Depression, Arthralgias Myalgias, muscle cramps, Constipation       Thin, brittle nails Thinning of hair Pallor Delayed relaxation of deep tendon reflexes Bradycardia (slow HR) Goiter – Enlarged Thyroid Actions of TSH on the Thyroid Gland  TSH increases the synthesis and secretion of thyroid hormones by stimulating each step in the biosynthetic pathway  TSH has a trophic effect on the thyroid gland. ◦ When TSH levels are elevated for a sustained period of time and leads to hypertrophy and hyperplasia of thyroid follicular cells and increased thyroidal blood flow.