Evidence for a Factor in the Sera of Patients with Nonthyroidal Disease which Inhibits Iodothyronine Binding by Solid Matrices, Serum Proteins, and Rat Hepatocytes*

We have measured the plasma protein binding of 125IT4 and 125IT3 in several groups of patients using assays of equilibrium dialysis and binding by dextran-coated charcoal carriedout under conditions of physiological pH. Subjects included 45 patients with nonthyroidalillnesses (NTI), 5 patients with hyperthyroidism, 5 with hypothyroidism, 1 with familial low T4-binding globulin (TBG), and 11 healthy controls. Both test results wereexpressed as the ratio of nonprotein-bound to protein-bound hormone, which was normalizedto the average ratio obtained for the control group normalized dialysis ratio (NDR); normalized charcoal binding ratio (NBR). Our data suggest that for subjects with thyroid disease or alterations in TBG, both tests reflect similar changes in plasma protein binding and did not differ significantly from each other low TBG; T4 NDR, 2.39; T4 NBR, 2.37; hyperthyroid: T4 NDR, 1.70 ± 0.29; T4 NBR, 1.53 ± 0.26; hypothyroid: T4 NDR, 1.10 ± 0.09; T4 NBR, 0.94 ± 0.11 (mean ± SD). Among NTI subjects, however, marked discrepancies in results were noted (T4 NDR, 1.86 ± 1.01; T4 NBR, 1.27 ± 0.34; P < 0.01). Similar, but smaller, discrepancies were noted with 125IT3. Tests of the assay systems indicate that these results are not artifacts of methodology. We have, therefore, inferred the existence in the serum of NTI patients of a factor which inhibits binding of the charcoal matrix. This factor was not readily dialyzable and could not be identified with any immunoglobulin fraction. The finding that the NDR in NTI patients is proportional to the inhibitory ratio (IR − NDR/ NBR) suggests that the inhibitoryfactor also plays a major role in the decreased plasma protein binding in such patients. Seventy- fourpercent of NTI patients with a high NDR also had a high IR. Of particular interest was the observation that the uptake of 125IT4 by isolatedhepatocytes incubated with normal, NTI, and low TBG sera was much lower in the presenceofNTI sera than would be expected from equilibrium dialysis. These results suggest that the postulated inhibitory factor also reduces cellular accumulation of iodothyronine by tissues and raise the possibility that the exchangeable cellular pool of hormonein NTI patients may not be proportional to the free T4 concentration as determined by equilibrium dialysis.