Thyroglobulin mechanism

Lithium affects thyroid function (52-56), and in most patients, after 4 months of treatment, there is a transient fall in serum levels of thyroxine (T4) and a rise in thyrotropic hormone (thyroid-stimulating hormone, TSH). After 1 year of treatment, these hormones have generally returned to their baseline. The mechanisms for this are obscure, but lithium inhibits both thyroxine synthesis and its release from the gland (201). Lithium may inhibit endocytosis in the thyroid gland, which results in an accumulation of colloid and thyroglobulin within the follicles, thereby reducing hormone release (202). Thyroid volume... 

Heterocyclic thioureas such as 6-propylthiouracil, methimidazole and carbimidazole (Figure 20.47) are used as antithyroid drugs. They inhibit the formation of thyroid hormones one of the presumed mechanisms is the inhibition of the iodine incorporation into the tyrosyl residues of thyroglobulin. It was proposed that the iodine atom is... 

Thyroglobulin is stored in the follicular lumen and must re-enter the cell, where the process of proteolysis liberates thyroid hormone into the bloodstream. Thyroid follicles active in hormone synthesis are identified histologically by columnar epithelial cells lining follicular lumens, which are depleted of colloid. Inactive follicles are lined by cuboidal epithelial cells and are replete with colloid. Both iodide and lithium block the release of preformed thyroid hormone, through poorly understood mechanisms. 

MECHANISM OF ACTION Antithyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin they also inhibit the couphng of these iodotyrosyl residues to form iodothyronines. The inhibition of hormone synthesis eventually results in depletion of stores of iodinated thyroglobulin as the protein is hydrolyzed and the hormones are released into the circulation. Clinical effects only become apparent when the preformed hormone is reduced and the concentrations of circulating thyroid hormones begin to decline. 

The oxidation of intracellular iodide is catalyzed by thyroid peroxidase (located at the apical border of the thyroid acinar cell) in what may be a two-electron oxidation step forming 1 (iodinium ion), lodinium ion may react with a tyrosine residue in the protein thyroglobulin to form a tyrosine quinoid and then a 3 -monoiodotyrosine (MIT) residue. It has been suggested that a second iodide is added to the ring by similar mechanisms to form a 3,5-diiodotyrosine (DIT) residue. Because iodide is added to these organic compounds, iodination is also referred to as the organification of iodide. ... 

Thioamides Propylthiouracil (PTU) and methimazole are small sulfur-containing molecules that inhibit thyroid hormone production by several mechanisms. The most important effect is to block iodination of the tyrosine residues of thyroglobulin (Figure 38-2). In addition, these drugs may block coupling of DIT and MIT. The thioamides can be used by the oral route and are effective in most patients with uncomplicated hyperthyroidism. Since synthesis of thyroid hormone rather than release is inhibited, the onset of activity of these drugs is usually slow, of-... 

Hashimoto s disease, named after the physician who first described it. Is an autoimmune disorder in which plasma cells, lymphocytes, and fibrous tissue attack and destroy the thyroid gland. Pitt-Rivers and Tata (57) suggested that the sequence of events in Hashimoto s disease was initiated by injury to some thyroid structure, following which the normally sequestered thyroglobulin would be released and exposed to immunological mechanisms, thus setting into motion a progressive interaction between ... 

Studies on the incorporation of labeled amino acids in thyroid slices have provided a more detailed description of the mechanism of synthesis of the hormone. The radioactivity first appears in soluble polypeptides with sedimentation coefficients of 3, 8, or 12. Puromy-cin or actinomycin blocks the incorporation of the precursor into the soluble polypeptides. The half-life of the messenger RNA for thyroglobulin polypeptide was estimated to be 15-20 hours. Indeed, after inclusion of actinomycin in the incubation mixture, thyroglobulin synthesis continues for several hours. The subunits are transferred from the site of synthesis to an assembly center, in which the subunits are iodinated, carbohydrate units are included in the molecule, and subunits are condensed into a finished protein. Puromycin fails to interfere with the formation of 19 S units. 

A number of inborn errors have been described in patients with sporadic cretinism (1) a defect in the iodine-trapping mechanism (2) an inability to convert inorganic iodide to iodine (3) a lack of thyroid peroxidase [178] (4) an inability to couple iodotyrosine to form iodothyronines and thyroglobulins (5) a lack of dehalogenase (6) an interference with thyroglobulin metabolism and (7) a defect in thyrotropin secretion [179-180]. 

The mechanism by which the absence of the dehalogenase leads to low thyroxine levels and cretinism is not clear. Two different theories have been proposed. The first postulates the existence of an additional defect namely, an inability to couple iodotyrosine to form T3 and T4. The second proposes that the absence of dehalogenase leads to a glandular hyperfunction in which hormone precursors are released before they can be used for thyroglobulin biosynthesis. It has now been established that the dehalogenase defect results from the absence of a single autosomal recessive gene. 

Numerous L-tyrosine containing peptides and proteins may be utilised to synthesise thyroxine (80) by iodination and without enzymic mediation . Iodine reacts with the L-tyrosine residues in the peptide to form mono- and di-iodo-L-tyrosine residues. An oxidative coupling of two, appropriately placed, di-iodo-L-tyrosyl residues then occurs to give thyroxine (80). Considerable evidence has been accumulated to surest that thyroxine biosynthesis follows the same pathway in vivo, but other mechanisms have been suggested and examined . The exact role of the protein thyroglobulin in thyroxine biosynthesis is, however, not clear for although L-tyrosine residues of other proteins may be readily iodinated in vitro only thyroglobulin is known to make thyroxine in vivo. 

In the most simplistic physiological model, inadequate intake of iodine results in a reduction in thyroid hormone production, which stimulates increased TSH production. TSH acts directly on thyroid cells, and without the ability to increase hormone production, the gland becomes hyperplastic. In addition, iodine trapping becomes more efficient, as demonstrated by increased radioactive iodine uptake in deficient individuals. However, this simplistic model is complicated by complex adaptive mechanisms which vary depending on the age of the individual affected. In adults with mild deficiency, reduced intake causes a decrease in extrathyroidal iodine and reduced clearance, demonstrated by decreased urinary iodine excretion, but iodine concentration in the gland may remain within normal limits. With further reduction in intake, this adaptive mechanism is overwhelmed, and the iodine content of the thyroid decreases with alterations in iodination of thyroglobulin, in the ratio of DIT to MIT, and reduction in efficient thyroid hormone production. The ability to adapt appears to decrease with decreasing age, and in children the iodine pool in the thyroid is smaller, and the dynamics of iodine metabolism and peripheral use more rapid. In neonates, the effects of iodine deficiency are more directly reflected in increased TSH. Diminished thyroid iodine content and increased turnover make neonates the most vulnerable to the effects of iodine deficiency and decreased hormone production, even with mild deficiency. 

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