In plasma, thyroid hormone is bound to three proteins, thyroxine- binding globulin (TBG), transthyretin (TTR, previously known as thyroxine- binding prealbumin (TBPA)), and albumin (Table 1). Human TBG is a 54- kDa glycoprotein produced in the liver and consists of 395 amino acids and four carbohydrate residues. The TBG gene is located on the human chromosome Xq22.2, spans about 5.5 kb, and contains five exons. Among the different thyroid hormone transport proteins, it shows by far the highest affinity for T4, with an equilibrium dissociation constant (Kd ) of approximately 0.1 nM, but also the lowest plasma concentration (c.15 mg/ L).

Table1. Characteristics of T4- binding proteins in human plasma

TTR is composed of four identical subunits, each consisting of 127 amino acids. The TTR gene is located on human chromosome 18q11.2- q12.1, covers about 7 kb, and contains four exons. TTR can bind two T4 molecules, with a Kd value of approximately 10 nM of the first T4 molecule, and the plasma concentration of TTR amounts to approximately 250 mg/ L. Plasma TTR is produced in the liver, but the protein is also expressed in the choroid plexus where it is probably involved in T4 transfer from plasma to the cerebrospinal fluid. Furthermore, TTR is expressed in trophoblasts where it may participate in the transplacental transfer of ma ternal T4 to the fetus.

Albumin has multiple low- affinity binding sites for thyroid hormone, with Kd values for T4 of 1– 10 μM, but it has by far the highest plasma concentration (c.40 g/ L).

The resultant of the concentrations and affinities of the different thyroid hormone- binding proteins is that in normal human subjects approximately 75% of plasma T4 is bound to TBG, approximately 15% is bound to albumin, and approximately 10% is bound to TTR. The total binding capacity of these proteins is so high that only approximately 0.02% of plasma T4 is free (non- protein- bound). The affinity of T3 for the different proteins is roughly 10% of that of T4. Therefore, plasma T3 shows a similar distribution to T4 over the different proteins, and the free T3 fraction in normal plasma amounts to approximately 0.2%. Thus, while the mean normal plasma total T4 (c.100 nmol/ L) and T3 (c.2 nmol/ L) levels differ about 50- fold, the difference in the mean normal free T4 (c.20 pmol/ L) and free T3 (c.5 pmol/ L) is only about fourfold. Reverse T3 binds with inter mediate affinity to the plasma proteins.

Since it is the plasma free T4 and free T3 concentrations that deter mine the tissue availability of thyroid hormone, they are more important parameters than the plasma total T4 and T3 concentrations in the assessment of thyroid status. Both concentration and thyroid hormone- binding affinity of the different plasma proteins are in fluenced by a variety of (patho)physiological factors. Beside genetic variation resulting in deficiency or excess, TBG levels are also influenced by various endogenous and exogenous factors. Notably, plasma TBG levels are increased by oestrogens. Different endogenous factors, such as free fatty acids, and drugs, such as salicylates, competitively inhibit T4 binding to TBG.

A large number of mutations have also been identified in the TTR gene, some of which are associated with a decrease in T4 binding affinity, whereas others result in an increased affinity for T4. TTR mutations often cause neuropathic or cardiomyopathic amyloidosis, resulting from the deposition of insoluble TTR fibrils in nerves or the heart. Finally, binding of thyroid hormone to albumin is subject to genetic variation. In particular, a specific increase in the binding of T4 to albumin is frequently observed in otherwise healthy subjects, which may lead to the false diagnosis of hyperthyroidism if inadequate methods for analysis of plasma free T4 are used. This phenomenon of familial dysalbuminaemic hyperthyroxinaemia has been attributed to mutations in the albumin gene (typically R218H mutation), resulting in a marked increase in T4 affinity.

Perturbation of plasma iodothyronine binding provokes an adaptation of the hypothalamus– pituitary– thyroid axis until normal free T4 and free T3 concentrations are again obtained. Therefore, measurement of plasma free T4 rather than total T4 levels is, together with analysis of plasma TSH, the cornerstone of the diagnosis of thyroid disorders.

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عادة بسيطة تدعم الصحة وتحافظ على الوزن المثالي

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الحليب قليل أم كامل الدسم.. أيهما أفضل؟

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مواضيع ذات صلة

Iodide Uptake

Biosynthesis of Thyroid Hormone

Regulation of Thyroid Function

Regulation of Thyroid Hormone Secretion : The Hypothalamic-Pituitary Thyroid Axis

Transport and Metabolism of Thyroid Hormones

−Secretion of T4 and T3 and Recycling of I

Thyroglobulin Storage, Endocytosis, and Breakdown

Thyroid Peroxidase and DUOX: Tyrosine Iodination and Coupling

Thyroglobulin

The Thyroid Epithelial Cell

Introduction to Thyroid Hormones

 Regulation of Calcemia and Calcium- Phosphorus Homeostasis