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Biosynthesis of thyroid hormones Production, storage , and release of thyroid hormones Metabolic effect of thyroid hormones Clinical significance of thyroid H. disorders
Thyroglobulin:
large glycoprotein molecule -the major component of colloid- (the precursor for all
thyroid hormones).
Transport proteins
Thyroglobulin
1. Thyroglobulin is the precursor of t4 and T3. It is a large iodinated, glycosylated protein of 660 kDa (5000 aa), Carbohydrate accounts for 810% of the weight of thyroglobulin and iodide for about 0.21%, depending upon the iodine content in the diet. Thyroglobulin is composed of two large subunits. It contains 115 tyrosine residues, each of which is a potential site of iodination. About 70% of the iodide in thyroglobulin exists in the inactive precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT), while 30% is in the iodothyronyl residues, T4 and T3. (the coupling of two iodinated tyrosine molecules to form either T3 or T4). Tg is synthesized in the basal portion of the cell and moves to the lumen, where it is a storage form of T3 and T4 in the colloid; several weeks supply of these hormones exist in the normal thyroid. Within minutes after stimulation of the thyroid by TSH, colloid reenters the cell and there is a marked increase of phagolysosome activity. Various acid proteases and peptidases hydrolyze the thyroglobulin into its constituent amino acids, including T4 and T3, which are discharged from the basal portion of the cell Thyroglobulin is thus a very large pro-hormone.
2. 3.
4.
5.
Iodide metabolism
Iodine is an essential dietary component because of its role in thyroid
hormone synthesis.
Iodide is actively transported (Na-K ATPase) into the thyroid gland against
gradients by a sodium/iodide cotransport system located in the basal membrane of the thyroid follicular cells called an iodide trap The thyroid is the only tissue that can oxidize iodide I to a higher valence state iodine I+, an obligatory step in I organification and thyroid hormone biosynthesis. This step involves T.peroxidase (and occurs at the luminal surface of the follicular cell). (A number of compounds inhibit I oxidation and therefore its subsequent incorporation into MIT and DIT. The most important of these are the thiourea drugs. They are used as antithyroid drugs because of their ability to inhibit thyroid hormone biosynthesis.
Iodide
MIT / DIT
Iodine organification: incorporation of iodine into organic molecule (phenol ring of tyrosine residue) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) within the thyroglobulin. About 70% of the iodide in thyroglobulin exists in the inactive precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT). About 30% is in the iodothyronyl residues, T4 and T3. Once iodination occurs, the iodine does not readily leave the thyroid.
I2
I
I I
I I
Thyroid peroxidase
Thyroperoxidase, a tetrameric protein with a molecular mass of
60 kDa, requires hydrogen peroxide as an oxidizing agent. The H2O2 is produced by an NADPH-dependent enzyme resembling cytochrome c reductase.
Thyroid peroxidase is a heme-containing peroxidase enzyme that
Factors Affecting Binding Changes in BP Concentration Abnormal BP affinity Binding Inhibitors Pathological BPs Total T4 conc. 55-145 nmol/l Total T3 conc. 1.4-2.8 nmol/l
A peripheral deiodinase in target tissues such as pituitary, kidney, and liver selectively removes I from the 5 position of T4 to make T3 In this sense, T4 can be thought of as a pro-hormone, though it does have some intrinsic activity. The de-Iodinization of T4 to yield T3 that occurs in target tissues yields equal amounts of two isomers of T3, the active T3) and the inactive (reverse T3). So, the ratio of T3 to rT3 falls in febrile illness. During starvation, T4 may be converted to reverse T3 (rT3), which is biologically not active. Both T3 and rT3 are deiodinated to inactive T2 (bisIodothyronine).
Regulation of TH
Negative feedback regulation of TH release
Rising TH levels provide negative feedback
inhibition on release of TSH Hypothalamic thyrotropin-releasing hormone (TRH) can overcome the negative feedback during pregnancy or exposure to cold
Hypothalamus
TRH
Anterior pituitary
TSH
Thyroid gland
Thyroid hormones
Target cells
Stimulates
Inhibits
Figure 16.7
TSH Tests
TSH test is the best way to initially test thyroid function. A high TSH level indicates a thyroid gland failure (a problem that is directly affecting the thyroid (primary hypothyroidism). A low TSH level indicates an overactive thyroid that is producing too much thyroid hormone (hyperthyroidism). Occasionally, a low TSH may result from an abnormality in the pituitary gland, which prevents synthesis of enough TSH to stimulate the thyroid (secondary hypothyroidism).
In most healthy individuals, a normal TSH value means that the thyroid is functioning normally.
T4 Tests
T4 circulates in the blood in two forms: T4 bound to proteins that prevent the T4 from entering the various tissues that need thyroid hormone and free T4, which enter the various target tissues to exert its effects. The free T4 is important test to determine how the thyroid is functioning, and tests to measure this are called the Free T4 (FT4) and the Free T4 Index (FT4I or FTI). Individuals who have hyperthyroidism will have an elevated FT4 or FTI, whereas patients with hypothyroidism will have a low level of FT4 or FTI. Combining the TSH test with the FT4 or FTI accurately determines how the thyroid gland is functioning. The finding of an elevated TSH and low FT4 or FTI indicates primary hypothyroidism due to disease in the thyroid gland. A low TSH and low FT4 or FTI indicates hypothyroidism due to a problem involving the pituitary gland. A low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism.
T3 Tests
T3 tests are often useful to diagnosis hyperthyroidism or to determine the severity of the hyperthyroidism. Patients who are hyperthyroid will have an elevated T3 level. In some individuals with a low TSH, only the T3 is elevated and the FT4 or FTI is normal. T3 testing rarely is helpful in the hypothyroid patient, since it is the last test to become abnormal. Patients can be severely hypothyroid with a high TSH and low FT4 or FTI, but have a normal T3. In some situations, such as during pregnancy or while taking birth control pills, high levels of total T4 and T3 can exist. This is because the estrogens increase the level of the binding proteins. In these situations, it is better to ask both for TSH and free T4 for thyroid evaluation.