Thyroid hormones - Metabolism
Iodine is essential for the synthesis of thyroid hormones. It is supplied in the diet in the form of iodide I- or of iodate IO3- which are absorbed by the digestive tract .In plasma the concentration of mineral iodine is between 2 to 4 micrograms per liter but total iodine represented essentially by iodine of thyroid hormones, especially thyroxine, is comprised between 40 and 80 micrograms per liter
An iodine intake in sufficient amount in the diet is necessary to avoid hypothyroidism in adults and especially in children. For an adult, a daily intake of 100 to 150 micrograms of iodine is recommended. When the urinary elimination of iodine is lower than 50 micrograms per gram of creatinine, there is risk of deficiency and when it is lower than 25 the deficiency can be regarded as certain.
Synthesis of thyroid hormones
The synthesis of thyroid hormones involves several steps:- iodation of tyrosyl residues of thyroglobulin which is a glycosylated protein of 670 Kda,- coupling of these residues to form hormones -and release of the hormones by hydrolysis of thyroglobulin:
- Uptake of iodine
Iodine in iodide form is preferentially taken up by the thyroid. Its uptake by the thyroid cell or thyrocyte is dependant on the sodium-iodide cotransport for crossing of the basement membrane and on two types of anion channels for the transfer into the colloid. Uptake of iodide which induces a plasma clearance of approximately 15 ml/mn is stimulated by TSH and is inhibited by anions like thiocyanate, SCN- and perchlorate, ClO4-. Iodide is concomitantly eliminated by the kidney. Its total plasma clearance resulting from its thyroid uptake and its renal elimination is approximately 45 to 60 ml/mn, which corresponds to a half-life of approximately 5 hours. These results were obtained with physiological iodide intake.
- Binding of iodine to tyrosyl groups of thyroglobulin
Iodide, arriving into the colloid of the thyroid follicle is activated by thyroid peroxidase also called thyroperoxydase, a selenium enzyme, in I° or I+ which binds to tyrosine of thyroglobulin to form residues of monoiodotyrosine (MIT) and of diiodotyrosine (DIT).
- Coupling reactions
A residu of monoiodotyrosine and a residu of diiodotyrosine combine to form the triiodothyronine, T3, and two residus of diiodotyrosine to form the tétraiodothyronine or thyroxine T4. T3 and T4 are bound to thyroglobulin. In case of iodine deficiency there is a relative increase in the synthesis of T3 compared to T4.
- Storage
Thyroglobulin with its bound molecules T3, T4, MIT and DIT, is stored in the colloid.
- Release
After its transfer by microendocytosis from the colloid into the epithelial cell, thyroglobulin is hydrolyzed by proteolytic enzymes releasing thyroid hormones T3 and T4 which are then secreted into plasma. DIT and MIT molecules, also released by hydrolysis of thyroglobulin are mainly deiodinated in the epithelial cell and iodide recovered for a new hormonal synthesis. Part of the T3 released by thyrocytes comes from the transformation of T4 into T3 by 5'-deiodinase.
These steps, in particular the release, are activated by TSH whose secretion is reduced by thyroid hormones
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Distribution
- Circulating hormones
In plasma, thyroid hormones T4 and T3 are bound to proteins, particularly TBG (thyroxine binding globulin) and TBPA (thyroxine binding prealbumin). Plasma concentration of TBG is increased by estrogens and is decreased by androgens. The measurements in plasma of T4 and T3 or more interestingly of free T4 and free T3 are the basis for the diagnosis of thyroid diseases. Plasma half-life of T4 is about seven days and that of T3 about one day.
- Tissue uptake and transformation of T4 into T3
T4 and T3 in free form are taken up by tissues by poorly known mechanisms. In tissues, in particular the liver, T4 can be transformed into T3 which is the true active molecule, or transformed into rT3, reverse triiodothyronine inactive. The conversion of T4 into T3 is achieved by 5' iodothyronine-deiodinase, which exists under two types: type I present in thyroid, liver, kidneys and type II present particularly in the brain. The 5'-deiodinase of type I is a selenium enzyme, selenium being incorporated in selenocysteine. This enzyme is inhibited by propylthiouracil and propranolol
In theory, thyroid hormones do not cross the placental barrier
Catabolism
T3 is transformed by deiodination into inactive diiodo-thyronine.
T3 andT4 are moreover inactivated by glucuronic and sulphuric acid conjugaisons.
The T3 andT4 are also metabolized to TRIAC, triodoacetic acid, and TETRAC, tetraiodoacetic-acid, which have some hormonal activity.
Regulation
In physiological conditions, secretion of thyroid hormones is controlled by TRH and TSH. In patients with Graves' disease the secretion of TRH and TSH is reduced by the high levels of T3 and T4 whose production is stimulated by abnormal antibodies.
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