Thyroid hormones thyroglobulin

The secretion of thyroid hormones starts with endocy-tosis of the modified thyroglobulin, followed by fusion of the endocytotic vesicles with lysosomes. The lysosomal enzymes then degrade the thyroglobulin, liberating triiodothyronine and thyroxine into the circulation. Only about five molecules of T3 and T4 are generated from each molecule of thyroglobulin. Thyroid hormone secretion is stimulated by thyrotropin (TSH), a pituitary hormone that activates adenylate cyclase in its target cells. 

Thyroid Hormones. Iodine, absorbed as P, is oxidized in the thyroid and bound to a thyroglobulin. The resultant glycoprotein, mol wt 670,000, contains 120 tyrosine residues of which ca two-thirds are available for binding iodine in several ways. Proteolysis introduces the active hormones 3,5,3 -triiodothyronine (T ) and 3,5,3, 5 -tetraiodothyronine (T, (thyroxine) in the ratio Ty.T of 4 1 (121,122). 

Figure 42-11. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (at bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (Tgb, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyro-sine Tj, triiodothyronine T4, tetraiodothyronine.) Asterisks indicate steps or processes that are inherited enzyme deficiencies which cause congenital goiter and often result in hypothyroidism.

Thyroglobulin A thyroid hormone-containing protein, usually stored in the colloid within the thyroid follicles. 

Amine hormones include the thyroid hormones and the catecholamines. The thyroid hormones tend to be biologically similar to the steroid hormones. They are mainly insoluble in the blood and are transported predominantly (>99%) bound to proteins. As such, these hormones have longer half-lives (triiodothyronine, t3, = 24 h thyroxine, T4, = 7 days). Furthermore, thyroid hormones cross cell membranes to bind with intracellular receptors and may be administered orally (e.g., synthryoid). In contrast to steroid hormones, however, thyroid hormones have the unique property of being stored extra-cellularly in the thyroid gland as part of the thyroglobulin molecule. 

Thyroid hormones. Internally, the thyroid consists of follicles, which are spherical structures with walls formed by a single layer of epithelial cells called follicular cells. The center of each follicle contains a homogenous gel referred to as colloid. Thyroid hormones are stored here as a component of the larger molecule, thyroglobulin. The amount of thyroid hormones stored within the colloid is enough to supply the body for 2 to 3 months. 

Derived from the amino acid tyrosine, thyroid hormones are unique because they contain iodine. At this time, its incorporation into thyroid hormones is the only known use for iodine in the body. There are two thyroid hormones, named for the number of iodides added to the tyrosine residues of the thyroglobulin triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine). Although significantly more T4 is synthesized by the thyroid gland, T3 is the active hormone. At the target tissue, T4 is deiodoninated to form the more potent T3. 

The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are formed on thyroglobulin, a large glycoprotein synthesized within the thyroid cell. Inorganic iodide enters the thyroid follicular cell and is oxidized by thyroid peroxidase and covalently bound (organified) to tyrosine residues of thyroglobulin. 

Amiodarone may induce thyrotoxicosis (2% to 3% of patients) or hypothyroidism. It interferes with type I 5 -deiodinase, leading to reduced conversion of T4 to T3, and iodide release from the drug may contribute to iodine excess. Amiodarone also causes a destructive thyroiditis with loss of thyroglobulin and thyroid hormones. 

Thyrotoxicosis factitia should be suspected in a thyrotoxic patient without evidence of increased hormone production, thyroidal inflammation, or ectopic thyroid tissue. The RAIU is low because thyroid gland function is suppressed by the exogenous thyroid hormone. Measurement of plasma thyroglobulin reveals the presence of very low levels. 

Sodium iodide 131 is an oral liquid that concentrates in the thyroid and initially disrupts hormone synthesis by incorporating into thyroid hormones and thyroglobulin. Over a period of weeks, follicles that have taken up RAI and surrounding follicles develop evidence of cellular necrosis and fibrosis of the interstitial tissue. 

Excessive doses of thyroid hormone may lead to heart failure, angina pectoris, and myocardial infarction. Allergic or idiosyncratic reactions can occur with the natural animal-derived products such as desiccated thyroid and thyroglobulin, but they are extremely rare with the synthetic products used today. Excess exogenous thyroid hormone may reduce bone density and increase the risk of fracture. 

Fig. 1 Thyroid hormone synthesis in a thyroid follicular cell. NIS and TPO (organification and coupling reaction) have been marked in red dashed line as the two main targets for direct thyroid gland function disrupters. DEHALl iodotyrosine dehalogenase 1, DIT diiodotyrosine, DUOX2 dual oxidase 2, MIT monoiodotyrosine, Na/K-ATPase sodium-potassium ATPase, NIS sodium-iodide symporter, PSD pendrin, TG thyroglobulin, TPO thyroperoxidase. Reprinted from [7] with permission from Elsevier...

Thyroid Hormones The thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) are synthesized from the precursor protein thyroglobulin (Mr 660,000). Up to 20 Tyr residues in thyroglobulin are enzymatically iodinated... 

Thyroxine (T4) and the more potent triiodothyronine (T3) are cleaved from a large precursor protein called thyroglob-ulin. Thyroglobulin exists as a dimer of two identical polypeptides (Mr 330,000). It is a storage protein for iodine and can be considered a prohormone of the circulating thyroid hormones. Thyroglobulin is secreted into the lumen of the thyroid gland, where specific residues are iodinated in... 

Radioactive isotopes of iodine are handled by the thyroid in the same way as stable iodine and are therefore actively concentrated, incorporated into thyroglobulin, stored, metabolized, and secreted as thyroid hormones. Small amounts of radioactive iodine are therefore ideal probes to analyse the uptake of iodine, the distribution of iodine in the gland, and possibly even its turnover and incorporation into thyroid hormones. Larger amounts of radioactive iodine selectively radiate the thyroid gland and therefore selectively impair the function of the follicular thyroid cells and eventually destroy them. 

FIGURE 31-2 Thyroid hormone biosynthesis. Iodide is taken into the follicle cell, where it is converted by thyroid peroxidase to an oxidized form of iodine (Ip). h is transported to the follicle lumen, where it is bonded to tyrosine residues of the thyroglobulin [TGB] molecule. Iodinated TGB is incorporated back into the cell, where it undergoes lysis to yield the thyroid hormones T3 and T4. See text for further discussion. 

Thyrotropin alpha has the biologic properties of pituitary TSH. It binds to TSH receptors on both normal thyroid and differentiated thyroid cancer cells. The TSH-activated receptor stimulates intracellular adenylyl cyclase activity. Increased cAMP production causes increased iodine uptake and increased production of thyroid hormones and thyroglobulin. 

Thiocyanate ion, SCN-, inhibits formation of thyroid hormones by inhibiting the iodination of tyrosine residues in thyroglobulin by thyroid peroxidase. This ion is also responsible for the goitrogenic effect of cassava (manioc, tapioca). Cyanide, CN-, is liberated by hydrolysis from the cyanogenic glucoside linamarin it contains, which in turn is biodetoxified to SCN. 

The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with colloid (thyroglobulin), the storage form of thyroid hormone. A diagram of the steps in thyroid hormone synthesis and secretion is shown in Figure 25.6. 

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