HYPERTHYROXINAEMIA: ABNORMAL BINDING OF T4 BY AN INHERITED ALBUMIN VARIANT

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Abstract
Two euthyroid subjects with high total concentrations of T4 [thyroxine] in their sera were studied (subject 1: T4, 170; T3 [triiodothyronine], 1.90; rT3 [reverse triiodothyronine], 0.54 nmol/l. Subject 2: T4, 185; T3, 1.63; rT3, 0.37 nmol/l). Concentrations of all 3 T4-binding proteins were within normal limits in both cases. On reverse-flow electrophoresis an abnormally large amount of T4 was found to travel with albumin. The 3 T4-binding proteins in the sera of both patients were separated from each other by a novel affinity chromatographic method using dye-Sepharose conjugates. Affinity constants for T4 binding to TBG [thyroid hormone-binding globulin] and to prealbumin from both patients were normal. The albumin preparations were further purified and shown by physical and immunochemical techniques to be uncontaminated by other proteins. Scatchard plots of the binding of T4 to each of these pure albumins revealed 2 components, 1 having a normal affinity constant (subject 1), 1.8 .times. 105 1 mol-1 and subject 2, 2.3 .times. 105 1 mol-1), the other having a raised affinity constant (subject 1, 5.4 .times. 106 1 mol-1 and subject 2, 5.8 .times. 106 1 mol-1). Extrapolation of the plots showed that the high affinity components comprised 66% (subject 1) and 54% (subject 2) of the total purified albumin. The raised affinity and high concentrations of the variants account for the raised total T4 concentrations in the patients. The presumed amino acid substitution in the albumins may be different in the 2 patients since the affinities for rT3 differ. Some methods for the estimation of free T4 levels give misleading results in the presence of these albumin variants. In the course of 2 episodes of illness, subject 1 manifested large falls in serum T4 levels which could only be accounted for by reduced carriage of T4 by the abnormal and conventional binding proteins. Many cases reported in the literature as partial peripheral resistance to thyroid hormone may be examples of similar albumin variants.

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