Thyroid Gland PDF

Chapter 19 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 hormo...

Chapter 19 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. 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. Thyroid function is controlled by the thyroid-stimulating 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. FORMATION & 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. The oxidation and reaction of iodide with the secreted thyroglobulin is mediated by thyroid peroxidase, a membrane-bound 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. 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). 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). 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. 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 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. 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 (Figure 19–8). The plasma proteins that bind thyroid hormones are albumin, a prealbumin called transthyretin (formerly called thyroxine-binding 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. 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 (Table 19–1), 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. 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. One third of the circulating T4 is normally converted to T3 in adult humans, and 45% is converted to RT3. As shown in Figure 19–7, 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 Thyroid function is regulated primarily by variations in the circulating level of pituitary TSH (Figure 19–8). 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 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. Iodide trapping is increased in a few hours; blood flow increases; and, with longterm 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 goit 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 (Table 19–5). They also increase the dissociation of oxygen from hemoglobin by increasing red cell 2,3diphosphoglycerate (DPG) 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.