Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.

Abstract

A B S T R A C T It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility.Human TBG was purified by affinity chromatography, labeled under sterile conditions with 'I or 'I, and mixed with ['I]thyroxine (T4) or ['I] T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +SD for TBG and T4 respectively, were as follows: Half time (ti) 5.3±0.4 and 7.0±0.6 days; distribution space (DS) 7.2± 1.0 and 10.8± 1.2 liters; and total daily degradation (D) 0.211±0.053 and 0.088±0.011 /smol/day. In all subjects, ti of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the ti and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool This work was published in part in abstract form (1973. Clin. Res. 21: 201) and was presented in part at the 49th Annual Meeting of the American Thyroid Association, Seattle, Wash., 12-15 September 1973. Received for publication 27 January 1975 and in revised form 18 October 1975. associated with the changes in serum TBG concentration. A striking decrease in the ti of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction.TBG ti was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG ti was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG.These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.

The effects of sex-steroid administration on the pituitary–thyroid axis in transsexuals

“…non-steady state conditions, the availability of free T 4 and T 3 for deiodination could fluctuate, resulting in different T 3 /T 4 ratios independent of 5 0 -deiodinase activity. However, it seems safe to assume that steady state was achieved, since we studied the subjects after 8 weeks of sex-steroid administration, which is more than five times the half-life of T 4 and TBG (10).…”

Two new inherited defects of the thyroxine-binding globulin (TBG) molecule presenting as partial TBG deficiency.

“…On this basis, it has been postulated that these X-chromosome-linked TBG abnormalities represent either mutations of a gene regulating TBG synthesis (6) or subtle structural gene mutations that indirectly affect the rate of TBG synthesis (1). In 1981, Dick and Watson (8) reported that 40% of Australian Aborigines have low serum T4 concentration due to a variant TBG (TBG-A) with low affinity for T4.…”

Increase in Serum Concentrations of Thyroxine-Binding Globulin and of Cortisol-Binding Globulin After the Induction of Normal Thyroid Function in Previously Hyperthyroid Patients

“…We observed a simultaneous rise in the serum concentrations of CBG and TBG, two other hepatic carrier proteins. The production of TBG is decreased by excess triiodothyronine (T3) (12) and its half-life is decreased in hyperthyroidism (13). Thyroid hormones may (6) or may not (14) influence the production of their own main carrier protein by a modulatory effect of T3 on TBG mRNA synthesis (6).…”