Normal cellular uptake of thyroxine from serum of patients with familial dysalbuminemic hyperthyroxinemia or elevated thyroxine-binding globulin

To determine whether thyroid hormone-binding proteins in serum, particularly albumin, facilitate the transfer of T₄ into human tissues, we studied cellular T₄ uptake (CT₄) by human liver (Hep G2) cells from medium containing serum from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) and acquired and familial T₄-binding globulin (TBG) excess and patients with normal T₄-binding to albumin and normal TBG concentrations. Serum from nine subjects with FDH whose mean serum total T₄ (TT₄) concentration was 203 ± 27 nmol/L were matched for TT₄ concentrations with serum from nine subjects with acquired TBG excess (TT₄, 201 ± 23 nmol/L) and nine subjects with thyrotoxicosis and normal TBG concentrations (TT₄, 205 ± 28 nmol/L). The subjects’ CT₄ results were compared to their serum free T₄ concentration, measured by equilibrium dialysis (DT₄), and their serum free T₄ index (FT₄I) value. The mean serum DT₄ value for the subjects with FDH (23 ± 5 fmol/L) and those with TBG excess (23 ± 3 fmol/L) were normal, whereas it was elevated (44 ± 9 fmol/L; P < 0.001) for the thyrotoxic patients with normal TBG concentrations. The mean CT₄ value also was normal for the subjects with FDH (37.7 ± 4.9 fmol/plate) and those with TBG excess (36.6 ± 4.6 fmol/ plate), but was elevated for the thyrotoxic patients (62.3 ± 11.2 fmol/plate; P < 0.001). In all three groups studied, the relationship between individual CT₄ and DT₄ values was similar to that previously found in subjects with no T₄-binding protein abnormalities. The mean serum FT₄I value was lower for the subjects with acquired TBG excess (111 ± 22) than for the subjects with FDH (133 ± 22; P < 0.05), and it was much higher for the subjects with thyrotoxicosis (221 ± 31; P < 0.001). In the subjects with FDH and those with thyrotoxicosis the normal relationship between CT₄ and FT₄I was maintained, while in the subjects with acquired TBG excess, FT₄I values were lower than expected. In seven of the nine subjects with TBG excess, the abnormality was associated with conditions known to increase its sialic acid content: hepatitis (one subject), pregnancy (four subjects), and estrogen therapy (two subjects). The CT₄ values were similar in nine subjects with acquired TBG excess (seven pregnant women and two subjects with chronic active hepatitis) and five subjects with familial TBG excess (34.8 ± 4.3 vs. 34.0 ± 8.6 fmol/plate, respectively). The mean serum FT₄I value was, however, slightly but not significantly lower in the subjects with acquired TBG excess (98 ±21 vs. 116 ± 25). Isoelectric focusing of TBG from pregnant women revealed the well known anodal shift attributed to alterations in the carbohydrate moiety of the molecule. No such shift was found in subjects with familial TBG excess, except in one woman with familial TBG excess who was pregnant. These slightly lower serum FT₁I values in the subjects with acquired TBG excess appear to be related to changes in the carbohydrate structure of their TBG that slightly alter the T₄ resin uptake test but not the free T₄ fraction or CT₄. These studies demonstrate that cellular uptake reflects the free T₄ concentration and is not influenced by the fraction or amount of T₄ bound to TBG or to the variant albumin of FDH.