In Search of an Inhibitor of Thyroid Hormone Binding to Serum Proteins in Nonthyroid Illnesses*

To explore why sera of some patients with nonthyroidal illnesses (NTI) show a very high dialyzable fraction (DF) of thyroid hormones, aliquots of sera of five normal subjects and seven severely ill NTI patients with high DF of T4 (DFT4) were added to a pooled normal serum and DFT4 and DF of T3 (DFT3) were determined by equilibrium dialysis after adjustment of the final volume of the test specimens to 5 ml with 0.15 M phosphate buffer (pH 7.4). The control DFT4 of 1.2% with 100 pi pooled normal serum decreased to values of 0.48–0.57% with the addition of 200 /il and to 0.31–0.36% with the addition of 400 nl normal sera to the pooled normal serum. There was a much smaller decrease or an actual increase in DFT4 when NTI sera were added to the pooled normal serum. DFT4 ranged between 0.71–4.8% with the addition of 200 µ1 and between 0.56–4.4% with the addition of 400 /xl NTI sera to the pooled normal serum. Similar differences between sera of patients and normal subjects were observed in studies of DFT3. These data indicated the presence of a substance or substances in NTI sera that is (are) capable of inhibiting thyroid hormone binding by normal serum proteins. Further studies indicated that the inhibitory activity is nondialyzable and is precipitated by ammonium sulfate in a final concentration of 1.6 M. It can tolerate temperature of 56 C for 30 min and 70 C for 5 min but is destroyed by heating to 90 C for 30 rain. It does not migrate with the immunoglobulin G (IgG) fraction of sera prepared by DEAE–Sephadex chromatography. The inhibitor is abundant, however, in euglobulin fractions of NTI sera prepared by precipitation in 2% boric acid (pH 4.5); no inhibitor activity is demonstrable in normal euglobulins. The inhibitor activity precipitated during incubation of NTI sera or euglobulins with goat antihuman IgM antibody. The inhibitor activity was clearly demonstrable in boric acid precipitates of 20% of 30 unselected patients with NTI. The various data suggest that 1) there is an inhibitor of thyroid hormone binding to serum proteins in the serum of some NTI patients and 2) the inhibitor is either an IgM antibody, an immune complex with IgM, or a substance that shares with IgM several physicochemical andantigenic characteristics. (JClin Endocrinol Metab49: 63,1979)