The Relationship of the Anti-Oxidant Bilirubin with Free Thyroxine Is Modified by Insulin Resistance in Euthyroid Subjects

Background: The strong anti-oxidative properties of bilirubin largely explain its cardioprotective effects. Insulin resistance is featured by low circulating bilirubin. Thyroid hormone affects both bilirubin generation and its biliary transport, but it is unknown whether circulating bilirubin is associated with thyroid function in euthyroid subjects. Aim is to determine relationships of bilirubin with TSH, free T-4 and free T-3 in euthyroid subjects without type 2 diabetes mellitus (T2DM), and to assess whether such a relationship would be modified by the degree of insulin resistance. Methods: Total bilirubin, TSH, free T-4, free T-3, glucose, insulin, lipids and transaminases were measured in 1854 fasting euthyroid subjects without T2DM, recruited from the general population (PREVEND cohort). Insulin resistance was assessed by homeostasis model assessment. Results: Bilirubin was positively related to free T-4 (beta = 0.116, P<0.001) and free T-3 (beta = 0.078, P = 0.001), but bilirubin was unrelated to TSH. The relationship of bilirubin with free T-4 was modified by insulin resistance with a larger effect in more insulin resistant individuals (adjusted for age and sex: beta = 0.043, P = 0.056 for interaction; additionally adjusted for smoking, alcohol intake, transaminases and total cholesterol (beta = 0.044, P = 0.044 for interaction). The association of bilirubin with free T-4 was also modified by high density lipoprotein cholesterol (age- and sex-adjusted: beta = 0.040, P = 0.072). Conclusions: Low bilirubin relates to low free T-4 in euthyroid non-diabetic subjects. Low normal free T-4 may particularly confer low bilirubin in more insulin resistant individuals.