Endocrine Sys. , Thyroid gland.pdf

Physiology Endocrine System Chapter 19 | Thyroid Gland Endocrine System | Thyroid Gland Contents : Introduction 3 Formation and secretion of Thyroid Hormone 7 Transport & Metabolism Of Thyroid Hormones 17 Metabolism Of Thyroid Hormones 24 Regulation Of Thyroid Secretion 26 Hypothyroidism 32 Hyperthy...

Physiology Endocrine System Chapter 19 | Thyroid Gland Endocrine System | Thyroid Gland Contents : Introduction 3 Formation and secretion of Thyroid Hormone 7 Transport & Metabolism Of Thyroid Hormones 17 Metabolism Of Thyroid Hormones 24 Regulation Of Thyroid Secretion 26 Hypothyroidism 32 Hyperthyroidism 43 Chapter Summary 56 Endocrine System | Thyroid Gland Introduction : The thyroid gland is one of the larger endocrine glands of the body. The gland has two primary functions. The first is to secrete the thyroid hormones, which maintain the level of metabolism in the tissues that is optimal for their normal function. Thyroid hormones stimulate O2 consumption by most of the cells in the body, help regulate lipid and carbohydrate metabolism, and thereby influence body mass and mentation. Endocrine System | Thyroid Gland Consequences of thyroid gland dysfunction depend on the life stage at which they occur. The thyroid is not essential for life, but its absence or hypofunction during fetal and neonatal life results in severe mental retardation and dwarfism. In adults, hypothyroidism is accompanied by mental and physical slowing and poor resistance to cold. Conversely, excess thyroid secretion leads to body wasting, nervousness, tachycardia, tremor, and excess heat production. Endocrine System | Thyroid Gland Thyroid function is controlled by the thyroidstimulating hormone (TSH, thyrotropin) of the anterior pituitary. The secretion of this hormone is in turn increased by thyrotropin releasing hormone (TRH) from the hypothalamus and is also subject to negative feedback control by high circulating levels of thyroid hormones acting on the anterior pituitary and the hypothalamus. The second function of the thyroid gland is to secrete calcitonin, a hormone that regulates circulating levels of calcium. Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland Formation and secretion of Thyroid Hormone: Thyroglobulin is a glycoprotein made up of two subunits and has a molecular weight of 660 kDa. It contains 10% carbohydrate by weight. It also contains 123 tyrosine residues, but only 4–8 of these are normally incorporated into thyroid hormones. Thyroglobulin is synthesized in the thyroid cells and secreted into the colloid by exocytosis of granules. Endocrine System | Thyroid Gland The oxidation and reaction of iodide with the secreted thyroglobulin is mediated by thyroid peroxidase, a membranebound enzyme found in the thyrocyte apical membrane. The thyroid hormones so produced remain part of the thyroglobulin molecule until needed. As such, colloid represents a reservoir of thyroid hormones, and humans can ingest a diet completely devoid of iodide for up to 2 months before a decline in circulating thyroid hormone levels is seen. Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland When there is a need for thyroid hormone secretion, colloid is internalized by the thyrocytes by endocytosis, and directed toward lysosomal degradation. Thyroid hormone synthesis is a multistep process. Thyroid peroxidase generates reactive iodine species that can attack thyroglobulin. The first product is monoiodotyrosine (MIT). MIT is next iodinated on the carbon 5 position to form diiodotyrosine (DIT). Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland Two DIT molecules then undergo an oxidative condensation to form T4 with the elimination of the alanine side chain from the molecule that forms the outer ring. There are two theories of how this coupling reaction occurs. One holds that the coupling occurs with both DIT molecules attached to thyroglobulin (intramolecular coupling). Endocrine System | Thyroid Gland The other holds that the DIT that forms the outer ring is first detached from thyroglobulin (intermolecular coupling). In either case, thyroid peroxidase is involved in coupling as well as iodination. T3 is formed by condensation of MIT with DIT. A small amount of RT3 is also formed, probably by condensation of DIT with MIT. Endocrine System | Thyroid Gland In the normal human thyroid, the average distribution of iodinated compounds is 3% MIT, 33% DIT, 35% T4, and 7% T3. Only traces of RT3 and other components are present. The human thyroid secretes about 80 μg (103 nmol) of T4, 4 μg (7 nmol) of T3, and 2 μg (3.5 nmol) of RT3 per day. Endocrine System | Thyroid Gland Secretion and interconversion of thyroid hormones in normal adult humans Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland Transport & Metabolism Of Thyroid Hormones : Protein Binding The normal total plasma T4 level in adults is approximately 8 μg/dL (103 nmol/L), and the plasma T3 level is approximately 0.15 μg/dL (2.3 nmol/L). T4 and T3 are relatively lipophilic; thus, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma and in tissues. Endocrine System | Thyroid Gland Free thyroid hormones are added to the circulating pool by the thyroid. It is the free thyroid hormones in plasma that are physiologically active and that feed back to inhibit pituitary secretion of TSH. Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland The plasma proteins that bind thyroid hormones are albumin, a prealbumin called transthyretin (formerly called thyroxinebinding prealbumin), and a globulin known as thyroxine-binding globulin (TBG). Of the three proteins, albumin has the largest capacity to bind T4 (ie, it can bind the most T4 before becoming saturated) and TBG has the smallest capacity. Endocrine System | Thyroid Gland TABLE: Binding of thyroid hormones to plasma proteins in normal adult humans. Protein Thyroxine-binding globulin (TBG) Transthyretin (thyroxinebinding prealbumin, TBPA) Albumin Plasma Concentration (mg/dL) Amount of Circulating Hormone Bound (%) T4 T3 2 67 46 15 20 1 3500 13 53 Endocrine System | Thyroid Gland However, the affinities of the proteins for T4 (ie, the avidity with which they bind T4 under physiologic conditions) are such that most of the circulating T4 is bound to TBG , with over a third of the binding sites on the protein occupied. Smaller amounts of T4 are bound to transthyretin and albumin. The half-life of transthyretin is 2 days, that of TBG is 5 days, and that of albumin is 13 days. Endocrine System | Thyroid Gland Metabolism Of Thyroid Hormones T4 and T3 are deiodinated in the liver, the kidneys, and many other tissues. These deiodination reactions serve not only to catabolize the hormones, but also to provide a local supply specifically of T3, which is believed to be the primary mediator of the physiologic effects of thyroid secretion. Endocrine System | Thyroid Gland One third of the circulating T4 is normally converted to T3 in adult humans, and 45% is converted to RT3. Only about 13% of the circulating T3 is secreted by the thyroid while 87% is formed by deiodination of T4; similarly, only 5% of the circulating RT3 is secreted by the thyroid and 95% is formed by deiodination of T4. Regulation Of Thyroid Secretion Endocrine System | Thyroid Gland Regulation Of Thyroid Secretion : Thyroid function is regulated primarily by variations in the circulating level of pituitary TSH. TSH secretion is increased by the hypothalamic hormone TRH and inhibited in a negative feedback manner by circulating free T4 and T3. The effect of T4 is enhanced by production of T3. Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland Effects Of TSH On The Thyroid : When the pituitary is removed, thyroid function is depressed and the gland atrophies; when TSH is administered, thyroid function is stimulated. Within a few minutes after the injection of TSH, there are increases in iodide binding, synthesis of T3, T4, and iodotyrosines, secretion of thyroglobulin into the colloid, and endocytosis of colloid. Endocrine System | Thyroid Gland Iodide trapping is increased in a few hours; blood flow increases; and, with long-term TSH treatment, the cells hypertrophy and the weight of the gland increases. Whenever TSH stimulation is prolonged, the thyroid becomes detectably enlarged. Enlargement of the thyroid is called a goiter. Hypothyroidism Endocrine System | Thyroid Gland Reduced Thyroid Function (Hypothyroidism) The syndrome of adult hypothyroidism is generally called myxedema, although this term is also used to refer specifically to the skin changes in the syndrome. Hypothyroidism may be the end result of a number of diseases of the thyroid gland, or it may be secondary to pituitary or hypothalamic failure. In the latter two conditions, the thyroid remains able to respond to TSH. Thyroid function may be reduced by a number of conditions. Endocrine System | Thyroid Gland TABLE: Causes of congenital hypothyroidism Causes of Congenital hypothyroidism Maternal iodine deficiency Fetal thyroid dysgenesis Inborn errors of thyroid hormone synthesis Maternal antithyroid antibodies that cross the placenta Fetal hypopituitary hypothyroidism Endocrine System | Thyroid Gland For example, when the dietary iodine intake falls below 50 μg/day, thyroid hormone synthesis is inadequate and secretion declines. As a result of increased TSH secretion, the thyroid hypertrophies, producing an iodine deficiency goiter that may become very large. Such “endemic goiters” have been substantially reduced by the practice of adding iodide to table salt. Endocrine System | Thyroid Gland Drugs may also inhibit thyroid function. Most do so either by interfering with the iodide-trapping mechanism or by blocking the organic binding of iodine. In either case, TSH secretion is stimulated by the decline in circulating thyroid hormones, and a goiter is produced. Paradoxically, another substance that inhibits thyroid function under certain conditions is iodide itself. Endocrine System | Thyroid Gland In normal individuals, large doses of iodide act directly on the thyroid to produce a mild and transient inhibition of organic binding of iodide and hence of hormone synthesis. This inhibition is known as the Wolff-Chaikoff effect. Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland In completely athyreotic adults, the BMR falls to about 40%. The hair is coarse and sparse, the skin is dry and yellowish (carotenemia), and cold is poorly tolerated. Mentation is slow, memory is poor, and in some patients there are severe mental symptoms (“myxedema madness”). Plasma cholesterol is elevated. Children who are hypothyroid from birth or before are called cretins. They are dwarfed and mentally retarded. Worldwide, congenital hypothyroidism is one of the most common causes of preventable mental retardation. Endocrine System | Thyroid Gland They include not only maternal iodine deficiency and various congenital abnormalities of the fetal hypothalamo–pituitary– thyroid axis, but also maternal antithyroid antibodies that cross the placenta and damage the fetal thyroid. T4 crosses the placenta, and unless the mother is hypothyroid, growth and development are normal until birth. If treatment is started at birth, the prognosis for normal growth and development is good, and mental retardation can generally be avoided; for this reason, screening tests for congenital hypothyroidism are becoming routine. Endocrine System | Thyroid Gland When the mother is hypothyroid as well, as in the case of iodine deficiency, the mental deficiency is more severe and less responsive to treatment after birth. It has been estimated that 20 million people in the world now have various degrees of brain damage caused by iodine deficiency in utero. Uptake of tracer doses of radioactive iodine can be used to assess thyroid function contrast this with the use of large doses to ablate thyroid tissue in cases of hyperthyroidism. Endocrine System | Thyroid Gland Therapeutic Highlights The treatment of hypothyroidism depends on the underlying mechanisms. Iodide deficiency can be addressed by adding it to the diet, as is done routinely in developed countries with the use of iodized salt. In congenital hypothyroidism, levothyroxine—a synthetic form of the thyroid hormone T4—can be given. It is important that this take place as soon as possible after birth, with levels regularly monitored, to minimize long-term adverse effects. Hyperthyroidism Endocrine System | Thyroid Gland Hyperthyroidism The symptoms of an overactive thyroid gland follow logically from the actions of thyroid hormone. Thus, hyperthyroidism is characterized by nervousness; weight loss; hyperphagia; heat intolerance; increased pulse pressure; a fine tremor of the outstretched fingers; warm, soft skin; sweating; and a BMR from +10 to as high as +100. It has various causes (Table next slide); however,the most common cause is Graves disease (Graves hyperthyroidism), which accounts for 60–80% of the cases. Endocrine System | Thyroid Gland TABLE: The main causes are Graves disease Administration of T3 or T4 (factitious or iatrogenic hyperthyroidism) Solitary toxic adenoma Ectopic thyroid tissue Toxic multinodular goiter Early stages of Hashimoto thyroiditis TSH-secreting pituitary tumor Mutations causing constitutive activation of TSH receptor Other rare causes Extrathyroidal Thyroid overactivity Causes of hyperthyroidism Endocrine System | Thyroid Gland Endocrine System | Thyroid Gland This is an autoimmune disease, more common in women, in which antibodies to the TSH receptor stimulate the receptor. This produces marked T4 and T3 secretion and enlargement of the thyroid gland (goiter). However, due to the feedback effects of T4 and T3, plasma TSH is low, not high. Another hallmark of Graves disease is the occurrence of swelling of tissues in the orbits, producing protrusion of the eyeballs (exophthalmos). Endocrine System | Thyroid Gland This occurs in 50% of patients and often precedes the development of obvious hyperthyroidism. Other antithyroid antibodies are present in Graves disease, including antibodies to thyroglobulin and thyroid peroxidase. In Hashimoto thyroiditis, autoimmune antibodies and infiltrating cytotoxic T cells ultimately destroy the thyroid, but during the early stage the inflammation of the gland causes excess thyroid hormone secretion and thyrotoxicosis similar to that seen in Graves disease. Endocrine System | Thyroid Gland Therapeutic Highlights Some of the symptoms of hyperthyroidism can be controlled by the thioureylenes. These are a group of compounds related to thiourea, which inhibit the iodination of monoiodotyrosine and block the coupling reaction. The two used clinically are propylthiouracil and methimazole. Iodination of tyrosine is inhibited because propylthiouracil and methimazole compete with tyrosine residues for iodine and become iodinated. Endocrine System | Thyroid Gland In addition, propylthiouracil but not methimazole inhibits D2 deiodinase, reducing the conversion of T4 to T3 in many extrathyroidal tissues. In severe cases, hyperthyroidism can also be treated by the infusion of radioactive iodine, which accumulates in the gland and then partially destroys it. Surgery is also considered if the thyroid becomes so large that it affects swallowing and/or breathing. Effects Of Thyroid Hormones Endocrine System | Thyroid Gland Effects Of Thyroid Hormones : Some of the widespread effects of thyroid hormones in the body are secondary to stimulation of O2 consumption (calorigenic action), although the hormones also affect growth and development in mammals, help regulate lipid metabolism, and increase the absorption of carbohydrates from the intestine. They also increase the dissociation of oxygen from hemoglobin by increasing red cell 2,3-diphosphoglycerate (DPG). Endocrine System | Thyroid Gland Mechanism Of Action : Thyroid hormones enter cells and T3 binds to TR in the nuclei. T4 can also bind, but not as avidly. The hormone–receptor complex then binds to DNA via zinc fingers and increases (or in some cases, decreases) the expression of a variety of different genes that code for proteins that regulate cell function. Thus, the nuclear receptors for thyroid hormones are members of the superfamily of hormone-sensitive nuclear transcription factors. Endocrine System | Thyroid Gland TABLE: Physiologic effects of thyroid hormones. Target Tissue Effect Mechanism Heart Chronotropic and inotropic Increased number of β-adrenergic receptors Enhanced responses to circulating catecholamines Increased proportion of α-myosin heavy chain (with higher ATPase activity) Adipose tissue Catabolic Stimulated lipolysis Muscle Catabolic Increased protein breakdown Bone Developmental Promote normal growth and skeletal development Endocrine System | Thyroid Gland Target Tissue Effect Nervous system Developmental Mechanism Promote normal brain development Gut Metabolic Increased rate of carbohydrate absorption Lipoprotein Metabolic Formation of LDL receptors Calorigenic Stimulated oxygen consumption by metabolically active tissues (exceptions: testes, uterus, lymph nodes, spleen, anterior pituitary) Increased metabolic rate Other Chapter Summary Endocrine System | Thyroid Gland Chapter Summary : The thyroid gland transports and fixes iodide to amino acids present in thyroglobulin to generate the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Synthesis and secretion of thyroid hormones is stimulated by thyroid-stimulating hormone (TSH) from the pituitary, which in turn is released in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. These releasing factors are controlled by changes in whole body status (eg, exposure to cold or stress). Endocrine System | Thyroid Gland Thyroid hormones circulate in the plasma predominantly in protein-bound forms. Only the free hormones are biologically active, and both feed back to reduce secretion of TSH. Thyroid hormones exert their effects by entering cells and binding to thyroid receptors. The liganded forms of thyroid receptors are nuclear transcription factors that alter gene expression. Thyroid hormones stimulate metabolic rate, calorigenesis, cardiac function, and normal mentation, and interact synergistically with catecholamines. Endocrine System | Thyroid Gland Thyroid hormones also play critical roles in development, particularly of the nervous system, and growth. Disease results with both underactivity and overactivity of the thyroid gland. Hypothyroidism is accompanied by mental and physical slowing in adults, and by mental retardation and dwarfism if it occurs in neonatal life. Overactivity of the thyroid gland, which most commonly is caused by autoantibodies that trigger secretion (Graves disease) results in body wasting, nervousness, and tachycardia.