The Thyroid Gland PDF

The Thyroid gland Ani sergeenko costanzo The thyroid gland The thyroid gland, located immediately below the larynx on each side of and anterior to the trachea. The thyroid secretes two major metabolic hormones, thyroxine and triiodothyronine, commonly called T4 and T3, Thyro...

The Thyroid gland Ani sergeenko costanzo The thyroid gland The thyroid gland, located immediately below the larynx on each side of and anterior to the trachea. The thyroid secretes two major metabolic hormones, thyroxine and triiodothyronine, commonly called T4 and T3, Thyroid secretion is controlled primarily by thyroid- stimulating hormone (TSH) secreted by the anterior pituitary gland. The thyroid gland also contains C cells that secrete calcitonin. SYNTHESIS AND SECRETION OF THE THYROID METABOLIC HORMONES About 93% of the metabolically active hormones secreted by the thyroid gland is thyroxine and 7% is triiodothyronine. almost all the thyroxine is eventually converted to triiodothyronine in the tissues, so both are functionally important. Triiodothyronine T3 is about four times as potent as thyroxine but persists for a much shorter time compared with thyroxine T4.. Thyroid hormones are synthesis Thyroid hormones are synthesized by the follicular epithelial cells of the thyroid gland The cells have a basal membrane facing the blood and an apical membrane facing the follicular lumen. The material in the lumen of the follicles is colloid, which is composed of newly synthesized thyroid hormones attached to thyroglobulin (TG). When the thyroid gland is stimulated, this colloidal thyroid hormone is absorbed into the follicular cells by endocytosis.  1. Thyroglobulin is synthesized from tyrosine in the thyroid follicular cells, packaged in secretory vesicles, and extruded into the follicular lumen (step 1).. 2. The iodide (I–) pump, or Na+–I– cotransport is present in the thyroid follicular epithelial cells.(step 2). is inhibited by thiocyanate and perchlorate anions. 3.Oxidation of I– to I2 is catalyzed by a peroxidase enzyme in the follicular cell membrane (step3). I2 is the reactive form, which will be “organified” by combination with tyrosine on thyroglobulin. The peroxidase enzyme is inhibited by propylthiouracil, which is used therapeutically to reduce thyroid hormone synthesis for the treatment of hyperthyroidism. The same peroxidase enzyme catalyzes the remaining organification and coupling reactions involved in the synthesis of thyroid hormones. 4. Organification of I2--tyrosine residues of thyroglobulin react with I2 to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) (step 4). High levels of I– inhibit organification and, therefore, inhibit synthesis of thyroid hormone (Wolff–Chaikoff effect). 5. Coupling of MIT and DIT (step 5). a. When two molecules of DIT combine, thyroxine (T4) is formed. b. When one molecule of DIT combines with one molecule of MIT, triiodothyronine (T3) is formed.. c. Iodinated thyroglobulin is stored in the follicular lumen until the thyroid gland is stimulated to secrete thyroid hormones. 6. Stimulation of thyroid cells by TSH When the thyroid cells are stimulated, iodinated thyroglobulin is taken back into the follicular cells by endocytosis (step 6). Lysosomal enzymes then digest thyroglobulin, releasing T4 and T3 into the circulation (step 7). Leftover MIT and DIT are deiodinated by thyroid deiodinase (step 8). The I2 that is released is reutilized to synthesize more thyroid hormones. Therefore, deficiency of thyroid deiodinase mimics I2 deficiency. Binding of Thyroid Hormones in the Circulation circulate bound to T4-binding prealbumin and albumin. Still smaller amounts circulate in the free unbound form. only free thyroid hormones are physiologically active a. In hepatic failure, TBG levels decrease, leading to a decrease in total thyroid hormone levels, but normal levels of free hormone. b. In pregnancy, the high level of estrogen inhibits hepatic breakdown of TBG and increases TBG levels. by negative feedback, increased synthesis and secretion of thyroid hormones by the thyroid gland. TBG levels increase, leading to an increase in total thyroid hormone levels, but normal levels of free hormone (i.e., clinically, euthyroid). Activation of T4 in Target Tissues the enzyme 5′-iodinase, which converts T4 to T3 by removing one atom of I2 from the outer ring of the Molecule In starvation (fasting), target tissue 5′-iodinase plays an interesting role. Starvation inhibits 5′-iodinase in tissues such as skeletal muscle, thus lowering O2 consumption and basal metabolic rate (BMR) during periods of caloric deprivation. However, brain 5′-iodinase differs from the 5′-iodinase in other tissues and is therefore not inhibited in starvation; in this way, brain levels of T3 are protected even during caloric deprivation REGULATION OF THYROID HORMONE SECRETION (TRH), which is synthesized by neurons in the paraventricular nucleus (PVN) of the hypothalamus TRH causes TSH-secreting cells of the anterior pituitary to produce TSH TSH (FROM THE ANTERIOR PITUITARY GLAND) INCREASES THYROID SECRETION TSH increases all the known secretory activities of the thyroid glandular cells. other effects require hours or even days and weeks to develop fully cAMP Mediates the Stimulatory Effect of TSH. (1) It increases the synthesis and secretion of thyroid hormones by stimulating every step in the biosynthetic pathway: I− uptake and oxidation, organification of I2 into MIT and DIT, coupling of MIT and DIT (2) TSH has a trophic effect on the thyroid gland. This trophic effect is exhibited when TSH levels are elevated for a sustained period of time and leads to hypertrophy and hyperplasia of thyroid follicular cells GRAVES DISEASE ♦ The TSH receptor on the thyroid cells also is activated by thyroid-stimulating immunoglobulins, which are antibodies to the TSH receptor. When these immunoglobulins bind to the TSH receptor, they produce the same response in thyroid cells as TSH: (i.e., hyperthyroidism). Graves disease, a common form of hyperthyroidism, is caused by increased circulating levels of thyroid-stimulating immunoglobulins. In this disorder, the thyroid gland is intensely stimulated by the antibodies, causing circulating levels of thyroid hormones to be increased. In Graves disease, TSH levels are actually lower than normal because the high- circulating levels of thyroid hormones inhibit TSH secretion by negative feedback  Actions of Thyroid Hormones Fig. 9.20 Mechanism of action of thyroid hormones T3 is produced inside the target cells, it enters the nucleus and binds to a nuclear receptor, it stimulates DNA transcription. The newly transcribed mRNAs are translated, and new proteins are synthesized. BMR In most tissues, Na+-K+ ATPase synthesis is induced, which leads to increased oxygen consumption, BMR, and heat production. In myocardial cells, myosin, β1-adrenergic receptors, and Ca2+ ATPase are induced, accounting for thyroid hormone–induced increases in heart rate and contractility. The increase in cardiac output is the result of a combination of increased heart rate and increased stroke volume (increased contractility). These cardiac effects are explained by the fact that thyroid hormones induce the synthesis of (i.e., upregulate) cardiac β1-adrenergic receptors. thyroid hormones also induce the synthesis of cardiac myosin and sarcoplasmic reticulum Ca2+ ATPase.)  Metabolism. In liver and adipose tissue, key metabolic enzymes are induced, leading to alterations in carbohydrate, fat, and protein metabolism. Thyroid hormones increase glucose absorption from the gastrointestinal tract and potentiate the effects of other hormones on gluconeogenesis, lipolysis, and proteolysis. Thyroid hormones increase both protein synthesis and degradation, but overall their effect is catabolic (i.e., net degradation), which results in decreased muscle mass. thyroid hormones induce the synthesis of key metabolic enzymes including cytochrome oxidase, NADPH cytochrome C reductase, α-glycerophosphate dehydrogenase, malic enzyme, and several proteolytic enzyme G.Lipolysis is increased. decreases the concentrations of cholesterol, phospholipids, and triglycerides in the plasma, even though it increases the free fatty acids because thyroid hormone induces increased numbers of Low density lipoprotein receptors on the liver cells, leading to rapid removal of LDL. EFFECT OF THYROID HORMONE ON GROWTH and CNS the effect of thyroid hormone on growth is manifest mainly in growing children. In children with hypothyroidism, the rate of growth is greatly retarded thyroid hormone is to promote growth and development of the brain during fetal life and for the first few years of postnatal life In adults, hypothyroidism causes listlessness, slowed movement, somnolence, impaired memory, and decreased mental capacity. Hyperthyroidism causes hyperexcitability, hyperreflexia, and irritability ♦ Autonomic nervous system. Thyroid hormones interact with the sympathetic nervous system in ways that are not fully understood. Many of the effects of thyroid hormones on BMR, heat production, heart rate, and stroke volume are similar to those produced by catecholamines via β-adrenergic receptors. The effects of thyroid hormones and catecholamines on heat production, cardiac output, lipolysis, and gluconeogenesis appear to be synergistic. The significance of this synergism is illustrated by the effectiveness of β-adrenergic blocking agents (e.g., propranolol) in treating many of the symptoms of hyperthyroidism  + Increased Respiration Increased Gastrointestinal Motility. Excitatory Effects on the Central Nervous System person with hyperthyroidism is likely to be extremely nervous and have many psychoneurotic tendencies, such as anxiety complexes, extreme worry, and paranoia. Effect on the function of muscles  Slight increase in thyroid hormone usually makes the muscles react with vigor(strength)  excessive hormone quantities, the muscles become weakened because of excess protein catabolism  lack of thyroid hormone causes the muscles to become sluggish(slow movement), and they relax slowly after a contraction Effect on sleep  the hyperthyroid subject often: 1. has a feeling of constant tiredness. 2. difficult to sleep  hypothyroidism : 1. extreme somnolence(sleepiness). 2. with sleep sometimes lasting 12 to 14 hours a day. Effect on other endocrine glands Increased thyroid hormone increases the rates of secretion Effect on sexual function In men lack of thyroid hormone is likely to cause loss of libido great excesses of the hormone, however, sometimes cause impotence Effects of Thyroid Hormone on Specific Bodily Mechanisms In women Lack of thyroid hormone often causes menorrhagia (excessive) & polymenorrhea(frequent) menstrual bleeding may cause irregular periods and occasionally even amenorrhea  the hyperthyroid woman, Oligomenorrhea (greatly reduced bleeding) amenorrhea.  Hyperthyroidism Causes of Hyperthyroidism (Toxic Goiter, Thyrotoxicosis, Graves’ Disease). The most common form of hyperthyroidism is Graves disease, an autoimmune disorder characterized by increased circulating levels of thyroid- stimulating Immunoglobulins. antibodies intensely stimulate the thyroid gland, resulting in increased secretion of thyroid hormones and hypertrophy of the gland The diagnosis of hyperthyroidism TSH levels may be decreased or increased, depending on the cause of the hyperthyroidism. If the cause of hyperthyroidism is Graves disease, thyroid -TSH levels will be decreased by negative feedback if the cause of hyperthyroidism is increased secretion of TRH or TSH i.e., the disorder is in the hypothalamus or anterior pituitary), then TSH levels will be increased Treatment of hyperthyroidism includes administration of drugs such as propylthiouracil, which inhibit the synthesis of thyroid hormones; surgical removal of the gland; or radioactive ablation of the thyroid gland with I−.  Symptoms of Hyperthyroidism 1. a high state of excitability 10.exophthalmos  2. intolerance to heat. protrusion of the eyeballs  3. increased sweating. in 1/3 of hyperthyroid patients 4. mild to extreme weight loss Eyeball protrusion may (sometimes as much as 100 pounds), damage vision  5. varying degrees of diarrhea. eyelids do not close completely 6. muscle weakness. when person blinks or sleeps 7. nervousness or other psychic which results in dryness and disorders. infection, resulting in ulceration 8. Extreme fatigue but inability to of the cornea.  sleep. Caused by: Edematous swelling 9. tremor of the hands. of the retro-orbital tissues and degenerative changes in the extraocular muscles. Hypothyroidism The most common cause of hypothyroidism is autoimmune destruction of the thyroid gland (thyroiditis) in which antibodies may either frankly destroy the gland or block thyroid hormone synthesis. Other causes of hypothyroidism are surgical removal of the thyroid or I− deficiency. Rarely, hypothyroidism is the result of target tissue resistance caused by down-regulation of the receptors. The diagnosis If the defect is in the thyroid gland (e.g., thyroiditis), TSH levels will be increased by negative feedback; the low circulating levels of T3 stimulate TSH secretion. If the defect is in the hypothalamus or pituitary, then TSH levels will be decreased Treatment of hypothyroidism involves thyroid hormone replacement therapy, usually T4 Standard treatment for hypothyroidism involves daily use of the synthetic thyroid hormone levothyroxine Hypothyroidism symptoms In general, the symptoms are opposite to those of hyperthyroidism: (1) decreased metabolic rate; (2) cold intolerance and decreased sweating; (3) weight gain without increased caloric intake; (4) bradycardia; (5) slowness of movement, speech, and thought; and (6) lethargy and sleepiness. physiologic Characteristics of Hypothyroidism.  constipation ,mental sluggishness, depressed growth of hair and scaliness of the skin, froglike husky voice, Myxedema  in severe cases, development of an edematous appearance throughout the body called myxedema Total lack of thyroid hormone function Bagginess under the eyes Swelling of the face Nonpitting type edema If severe hypothyroidism occurs in utero or during infancy, irreversible mental retardation results, and growth is impaired; this condition is referred to as cretinism  Goiter Goiter (i.e., enlarged thyroid) can be associated with certain causes of hyperthyroidism and also, of hypothyroidism and euthyroidism.. high levels of TSH and substances that act like TSH (e.g., thyroid-stimulating immunoglobulins) have a trophic (growth) effect on the thyroid and cause it to enlarge. ♦ Graves disease. In Graves disease, the most common cause of hyperthyroidism, the high levels of thyroidstimulating immunoglobulins drive excess secretion of T4 and T3 and also have a trophic effect on the thyroid gland to produce goiter. Although TSH levels are decreased (by negative feedback) in Graves. ♦ TSH-secreting tumor. TSH-secreting tumors are an uncommon cause of hyperthyroidism. Increased levels of TSH drive the thyroid to secrete excess T4 and T3 and have a trophic effect on the thyroid gland to produce goiter. ♦ I− deficiency. Deficiency of I− leads to decreased synthesis of T4 and T3, which increases TSH secretion by negative feedback. Increased TSH levels then have a trophic effect on the gland, causing goiter. The enlarged gland can often maintain normal blood levels of thyroid hormone (due to the high TSH levels); in that case, the person will be clinically euthyroid and asymptomatic. If the gland cannot maintain normal blood levels of thyroid hormone, then the person will be clinically hypothyroid. Autoimmune thyroiditis. ♦ thyroid hormone synthesis is impaired by antibodies to peroxidase, leading to decreased T4 and T3 secretion.hypothyroidism TSH levels are increased (by negative feedback), and the resulting high levels of TSH have a trophic effect on the thyroid gland to produce goiter.. Hashimoto disease is the most common form of hypothyroidism characterized by an autoimmune response that targets the thyroid gland. Inflammation and destruction of the gland decreases triiodothyronine and thyroxine production and release. A goiter may also form but is the result of the lymph and T-cell infi ltrates rather than glandular hypertrophy. Patients lack energy, and are easily fatigued. They gain weight due to metabolic rate decline. If low levels of thyroid hormone occur during growth, growth can be stunted and development slowed. ♦ Ingestion of T4. Ingestion of exogenous thyroid hormones, or factitious hyperthyroidism, will cause decreased levels of TSH (by negative feedback). Because TSH levels are low there is no goiter; in fact, with time, the thyroid gland shrinks, or involutes ♦ TSH deficiency (anterior pituitary failure). TSH deficiency is an uncommon cause of hypothyroidism, where the decreased levels of TSH cause decreased thyroid hormone secretion and no goiter