SOLUBLE CYTOKINE RECEPTORS AND THE LOW 3,5,3'-TRIIODOTHYRONINE SYNDROME IN PATIENTS WITH NONTHYROIDAL DISEASE

Cytokines have been implicated in the pathogenesis of the low T-3 syndrome during illness. This is supported by our recent observation of a strong negative relationship between serum T-3 and serum interleukin-6 (IL-6) in nonthyroidal illness (NTI). In the last few years, soluble cytokine receptors and cytokine receptor antagonists have been discovered in human serum. These proteins have the potential to further regulate cytokine activity. Therefore, we now studied the association between serum T-3 and serum levels of soluble tumor necrosis factor-cu receptors (sTNF alpha R p55 and sTNF alpha R p75), soluble interleukin-2 receptor (sIL-2R), and the interleukin-1 receptor antagonist (IL-1RA) in 100 consecutive hospital admissions with a wide variety of nonthyroidal diseases. Patients were divided into group A (T-3, greater than or equal to 1.30 nmol/L; T-4 greater than or equal to 75 nmol/L; n = 41), group B (T-3 <1.30 nmol/L; T-4, greater than or equal to 75 nmol/L; n = 46), and group C (T-3 <1.30 nmol/L; T-4, <75 nmol/L; n = 13). Serum sTNF alpha R p55, sTNF alpha R p75, sIL-2R, and IL-1RA were lower in group A than in groups B and C [median values: sTNF alpha R p55, 1.26, 2.25, and 3.55 ng/mL (P < 0.001); sTNF alpha R p75, 2.02, 4.56, and 7.00 ng/mL (P < 0.001); sIL-2R, 184, 259, and 272 U/mL (P = 0.0004), respectively]. Serum IL-1RA levels were not different in the three groups (median values, 122, 193, and 258 pg/mL, respectively). Taking all patients together, a significant negative relation was found among serum T-3 and sTNF alpha p55 (r = -0.59; P < 0.0001), sTNF alpha R p75 (r = -0.55; P < 0.0001), sIL-2R (r = -0.54; P < 0.0001), IL-1RA (r = -0.38; P = 0.001), and IL-6 (r = -0.56; P < 0.0001). A remarkable high correlation (r = -0.70; P < 0.0001) was found between serum T-3 and a newly designed total score based on the summation of serum levels of IL-6 and the four soluble cytokine receptor proteins. IL-6 and the four cytokine receptor proteins were all significantly related to each other. Stepwise multiple regression indicated IL-6 and sTNF alpha R p75 as independent determinants of T-3 [serum T-3 = 2.09 - 0.32ln (sTNF alpha R p75) - 0.15ln (IL-6); r = 0.70]. The variability in serum T-3 was accounted for 35% by changes in In (sTNF alpha R p75) and 14% by changes in ln (IL-6). In conclusion, 1) serum T-3 is negatively related to serum sTNF alpha R p55, sTNF alpha R p75, sIL-2R, IL-1RA, and IL-6 in patients; and 2) sTNF alpha R p75 and IL-6 are independent determinants of serum T-3 in NTI, accounting for 35% and 14%, respectively, of the variability in T-3. The results suggest that the sick euthyroid syndrome is part of the acute phase response during illness generated by activation of the cytokine network.