Inability to detect an inhibitor of thyroxine-serum protein binding in sera from patients with nonthyroid illness

Abstract

Sera from 111 patients hospitalized on acute-care wards (including 32 in the intensive care unit) were examined for the possible presence of inhibitors of thyroxine (T 4)-serum protein binding in an assay employing equilibrium dialysis. In 38 of these sera, the unbound (free) T 4 fraction was 50% or more higher than the free T 4 fraction in a pool of normal sera. From the free T 4 fraction in each of the 111 serum samples and the free T 4 fraction in the pool of normal sera, the predicted free T 4 fractions in mixtures (1:1) of each of these sera with the normal pool were calculated (assuming the absence of binding inhibitors) from the appropriate mass action equations. It was reasoned that a free T 4 fraction in any mixture that exceeded this predicted value would indicate the possible presence of a binding inhibitor. (The normal pool was selected for having a low serum triglyceride concentration, to minimize in vitro generation of free fatty acids.) However, for the 111 serum samples studied, the free T 4 fraction in the mixture exceeded the upper 95% confidence limit of this predicted value in only one case, and then just barely. Thus, evidence for an inhibitor of T 4-serum protein binding in sera from patients with nonthyroid illness could not be found. Twenty-eight of the serum samples were also examined in a similar assay that employed ultrafiltration of undiluted serum instead of equilibrium dialysis. Evidence for an inhibitor of T 4-serum protein binding similarly could not be found. Because part of the reason for postulating the existence of such a binding inhibitor has been the performance of the triiodothyronine (T 3) resin uptake test in patients with nonthyroid illness, an alternative explanation for this phenomenon was sought. When thyroid hormone-binding globulin (TBG) was desialylated by treatment with neuraminidase, its avidity for T 4 was markedly decreased, but its avidity for T 3 was unchanged. Thus, if desialylated TBG circulates in patients with nonthyroid illness as previously reported, it could explain not only the low serum T 4 concentrations despite near normal immunoreactive TBG concentrations, but also the poor performance of the T 3 resin uptake test (where T 4 binding capacity is overestimated) in these patients.