Thyroid Hormone Transport

Thyroid Factor

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Transport in the Blood

More than 99% of the circulating thyroid hormone is bound to plasma proteins but can be liberated with great rapidity for entry into cells. The thyroid hormone-binding proteins are comprised of thyroxine-binding globulin (TBG), transthyretin (TTR or thyroxine-binding prealbumin), human serum albumin (HSA) and lipoproteins. Their functions are most probably to ensure a constant supply of TH to the cells and tissues by preventing urinary loss [3], protect the organism against abrupt changes in thyroid hormone production and degradation, protect against iodine deficiency [2] and target the amount of TH delivery by ensuring a site-specific, enzymatic alteration of TBG [4]. TBG has by far the highest affinity for T4, the result of which being that TBG binds 75% of serum T4, whereas TTR binds 20% and HSA 5% [2]. Some of the properties of the binding proteins are displayed in table 1.

Table 1. Some properties and metabolic parameters of the prinicpal thyroid hormone-binding proteins in serum

TBG TTR HSA

Molecular weight, kDa Structure

Carbohydrate content, % Number of binding sites for T4 and T3 Association constant, K (M-1) For T4 For T3

Concentration in serum

(mean normal, mg/l) Relative distribution of T4 and T3 in serum, % T4 T3

In vivo survival Half-life, days Degradation rate, mg/day

monomer tetramer monomer

1 2 several

16 250 40,000

75 20 5

15 650 17,000

HSA = human serum albumin; TBG = Thyroxine-binding globulin; TTR = transthyretin. * Apparent molecular weight on acrylamide gel electrophoresis 60 kDa. ** Value given is for the high affinity binding site only. *** Longer under the influence of estrogen.

Reproduced with permission from Hayashi and Refetoff: Molecular Endocrinology: Basic Concepts and Clinical Correlations. New York, Raven Press, 1995.

Thyroxine-Binding Globulin

TBG carries the major part of both circulating T4 and T3 (as well as reverse T3), and therefore quantitative or qualitative changes in TBG concentration have a high impact on total serum T4 and T3. The protein is encoded by a single gene on the X-chromosome and is produced and cleared by the liver. It has a single iodothyronine-binding site with a slightly higher affinity for T4 compared to T3 [5]. When it is fully saturated it carries approximately 200 |xg T4/l. The TBG concentration in serum is between 11 and 21 mg/l (180-350 nmol/l), present from 12th week of fetal life and 1.5 times higher in newborns and children until 2-3 years of age [6]. Estrogen has a marked effect on TBG by prolonging the biological half-life from the normal 5 days, thus resulting in increased plasma concentrations of TBG and total TH [7] while testosterone has the opposite effect [8]. In children and adolescents this may have an implication in diseases with a severe sex hormone overproduction related to the age, as well as oral contraceptives and pregnancy in adolescent girls.

Inherited TBG excess was first described in 1959 [9], and several familial X-chromosome-linked TBG abnormalities have been described [10, 11]. A rare TBG abnormality is seen in carbohydrate-deficient glycoprotein syndrome, which is associated with severe mental and motor retardation [12]. Acquired TBG abnormalities are mostly resulting in altered synthesis and/or degradation and caused by, e.g., severe terminal illness, hypo- and hyperthyroidism, severe liver disease and a variety of critical non-thyroidal illnesses [2, 13]. The latter may be mediated by interleukin-6 or other cytokines suppressing acute-phase reactants [14].

Transthyretin

TTR, previously called thyroxine-binding prealbumin binds only about 15-20% of the circulating TH and has a lower affinity for the hormones thus dissociating from them more rapidly and thus responsible for much of the immediate delivery of T4 and T3. Transthyretin is the major thyroid hormone-binding protein in cerebrospinal fluid. It is synthesized in the liver and the choroids plexus and secreted into the blood and cerebrospinal fluid, respectively. Only 0.5% of the circulating TTR is occupied by T4 and it has a rapid turnover of 2 days in plasma. Hence, acute reduction of the rate of synthesis results in a rapid decrease of its serum concentration [2]. Acquired abnormalities in TTR include major illness, nephrotic syndrome, liver disease, cystic fibrosis, protein fasting and hyperthyroidism. However, changes in TTR concentrations have little effect on the serum concentrations of TH [15].

Albumin

HSA binds about 5% of the circulating T4 and T3. Its affinity for the hormones is even lower, and since HSA associates with a wide variety of substances, including a number of different hormones and drugs, the association between TH and HSA can hardly be regarded specific. Even marked fluctuations in serum HSA concentrations have no effect on TH levels [16].

Lipoproteins

Lipoproteins transport a minor fraction of circulating T4 and to some extent T3 [17]. The binding site for TH on apolipoprotein A1 is distinct from that which binds to cellular protein receptors.

Consequences of Abnormal Binding Protein Concentrations

Abnormalities of the TH-binding proteins do not cause alterations in the metabolic state of the individual nor do they result in thyroid disease. Thus, abnormal concentrations of these binding proteins, due to changed synthesis, degradation or stability, result in maintaining normal free TH concentrations.

Fig. 1. Thyroid hormone transport and metabolism in a 3,3',5-triiodothyronine (T3) target cell. Reproduced with kind permission from Jansen et al. [21].

However, they do give rise to misinterpretation of most of the measurements of serum levels of TH by available techniques. Depending on the severity of the abnormality only total TH concentrations are affected, but also the measured free TH levels by automated currently used methods give rise to incorrect results [18]. In such cases, it may be necessary to provide a free TH estimate by quantifying total hormone concentration with a subsequent estimate of the available binding places by use of a TH uptake test or direct measurement of TBG [2]. Even better is measurement of free TH concentrations by equilibrium dialysis or ultrafiltration, but not many laboratories in the world perform these measurements anymore.

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