Physiological serum bilirubin concentrations are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes

Abstract

Although severe hyperbilirubinaemia causes kernicterus in neonates, normal to modestly elevated bilirubin concentrations have been reported to be neuroprotective. However, the relationship between serum bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes is currently unknown. This study assessed the relationships between physiological serum total bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes. A total of 2991 patients with Type 2 diabetes were investigated in this cross-sectional study. Cardiovascular autonomic neuropathy was diagnosed by a cardiovascular reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded into normal, early, definite and severe. Cardiovascular autonomic neuropathy was either definite or severe in the present study. An analysis of covariance after adjustment for other covariates was performed. A logistic regression model was used to assess an association of cardiovascular autonomic neuropathy with serum total bilirubin tertiles. Serum total bilirubin concentrations were significantly lower in subjects with cardiovascular autonomic neuropathy. The mean total bilirubin values differed significantly according to the severity of cardiovascular autonomic dysfunction (normal 13.0 μmol/l; early 12.3 μmol/l; definite 11.8 μmol/l; severe 10.1 μmol/l; P for trend < 0.001) after adjustment for other covariates. In multivariate analysis, serum total bilirubin levels were significantly associated with cardiovascular autonomic neuropathy (odds ratio 0.36; 95% CI 0.21-0.63 for the highest vs. the lowest bilirubin tertile, P < 0.001). Serum total bilirubin concentrations within the physiologic range are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes.