Variant thyroxine-binding globulin in serum of Australian Aborigines: a comparison with familial TBG deficiency in Caucasians and American Blacks

Abstract

About 40% of clinically euthyroid Australian Aborigines have low concentrations of total thyroxine (TT₄) and triiodothyronine (TT₃) in serum. While the finding of normal concentrations of serum thyrotropin (TSH) in such individuals is compatible with their eumetabolic state, the reason for the finding of a low free T₄ index (FT₄I) has been unclear. A genetic variant of T₄-binding globulin (TBG) with reduced affinity for T₄ has been suggested but decrease in the absolute concentration of TBG has also been reported. In this study, we measured various parameters of thyroid function in 20 serum samples from euthyroid Australian Aborigines selected for their low TT₄ levels. Results were compared to those obtained in serum samples from Caucasians and American Blacks with inherited partial TBG deficiency, 15 of which were matched to the Aborigines by their TBG and 20 by their TT₄ concentrations. Results were also compared with those from another group of 20 samples from Caucasians and American Blacks with normal TBG concentration, matched to the Aborigines by their serum TT₄ concentration. TBG in serum from these Australian Aborigines was immunologically identical to that in Caucasians and American Blacks in terms of parallelism of serially diluted samples in the TBG radioimmunoassay (RIA). Comparison of measurements of TBG concentration by RIA and by T₄-binding capacity (CAP) gave identical results indicating that, in Aborigines as in non-Aborigines, TBG molecules have a single T₄-binding site. Serum TBG concentration in this group of Aborigines with lowTT₄was 1.1 ± 0.3 mg/dl (mean ± SD) and significantly lower (p< 0.001) than that in non-Aborigines of 1.6 ± 0.2 mg/dl. When the Aboriginal samples were matched to euthyroid Caucasians and American Blacks by their TBG concentration, their mean TT₄ concentration was significantly lower (4.1 ± 0.8µg/dl vs. 5.6 ± 1.1 µg/dl, p < 0.001), as was their mean TT₃ concentration (88 ± 17 ng/dl vs. 139 ± 27 ng/dl, p < 0.001). In contrast when matched by their TT₄ concentration, the mean serum TBG level was significantly higher (1.1 ± 0.3 mg/dl vs. 0.7 ± 0.3 mg/dl, p < 0.001). TSH concentration was normal and not significantly different in the Aborigines and the two non-Aboriginal groups with familial partial TBG deficiency. All serum samples from non-Aborigines with normal TBG which were matched to the Aborigines by their TT₄ concentration had high serum TSH values and thus belonged to patients with primary hypothyroidism. The mean FT₄I value was significantly (p < 0.001) lower in the Aborigines (4.9 ± 1.0) as compared to the two euthyroid non-Aboriginal groups matched by their TBG or TT₄ (7.4 ± 0.8 and 7.5 ± 1.3, respectively). In contrast, the free T₄ (FT₄) values measured by equilibrium dialysis in 5 Aboriginal samples spanned over the same normal range as that of 8 euthyroid non-Aborigines. There was an excellent correlation between the FT₄I and FT₄ in both Aborigines and non-Aborigines (r = 0.957 and 0.918 respectively). However, the slopes of the two regression lines were significantly different (p < 0.001). These results indicate that the degree of reduction of TT₄ and TT₃ concentration in euthyroid Australian Aborigines cannot be explained solely on the basis of diminished serum TBG level. They support the hypothesis that such individuals have a variant TBG with reduced affinity for T₄ and T₃.