Thyroid Hormone Receptor Isoform Expression in Livers of Critically Ill Patients

Abstract

Objective: The THRA gene encodes two isoforms of the thyroid hormone receptor (TR), TRα1 and TRα2. The ratio of these splice variants could have a marked influence on T₃–regulated gene expression, especially during illness. Design: We studied the expression of the isoforms TRβ1, TRα1, and TRα2 and 5′-deiodinase in postmortem liver biopsies of 58 patients who were critically ill and died in the intensive care unit (ICU). All mRNA levels were determined using real-time PCR. Main outcome: All ratios of the biopsies were higher than those found in three normal liver biopsies due to an increased TRα1 level. The TRα1/TRα2 ratio increased with age and severity of illness following the equation: TRα1/TRα2 ratio = − 1.854 + (0.0323 × age) + (0.0431 × Therapeutic Intervention Scoring System score) indicating that 28% of the changed TRα1/TRα2 ratio can be predicted by these clinical variables. There was no effect of randomization to intensive insulin therapy or glucocorticoid or thyroid hormone treatment on the TRα1/TRα2 ratio or TRβ1. Furthermore, no relation was seen between the expression levels of the 5′-deiodinase mRNA and TR isoforms or the triiodothyronine (T₃) levels. Conclusion: It appears that in critically ill patients the ratio of TRα1/TRα2 expression increases with age and severity of illness, possibly indicating a mechanism to enhance sensitivity to T₃ in the oldest and sickest patients.