Non-linear associations of circulating total bilirubin concentration with the risk of nonalcoholic fatty liver disease and all-cause mortality

: Accumulating evidence has supported that mild elevated total bilirubin exerts antioxidant and anti-inflammatory properties in multiple metabolic diseases. We aimed to explore the association of circulating total bilirubin concentration with non-alcoholic fatty liver disease (NAFLD) risk and all-cause mortality and examined the potential nonlinear relationship between them. : We used nationally representative data from the National Health and Nutrition Examination Survey (NHANES). NAFLD was assessed using the fatty liver index (FLI) and United States fatty liver index (USFLI), respectively. : A total of 35 912 and 17 329 participants were included in FLI-NAFLD (case with NAFLD was diagnosed by FLI) and USFLI-NAFLD (case with NAFLD was diagnosed by USFLI) groups, respectively. The mean age of total population was 46.25 years, and 48.51% were male. Compared to participants with lowest quintile of total bilirubin concentration, those with highest quintile had lower risk of NAFLD in both of FLI-NAFLD (OR: 0.48, 95% CI: 0.40, 0.59) and USFLI- NAFLD (OR: 0.55, 95% CI: 0.43, 0.70) groups. Compared to participants with lowest quintile of total bilirubin concentration, the association between total bilirubin concentration and all-cause mortality was not significant among those with highest quintile of total bilirubin concentration (HR: 0.89, 95% CI: 0.66, 1.20). The restricted spline curves showed the nonlinear U-shaped association of total bilirubin concentration with NAFLD risk and all-cause mortality. The segmented linear regression analysis showed negative associations between total bilirubin concentration and risk of NAFLD in both of FLI-NAFLD (OR: 0.94, 95% CI: 0.93, 0.95) and USFLI- NAFLD (OR: 0.95, 95% CI: 0.93, 0.96) groups when total bilirubin concentration was below the turning point (FLI-NAFLD: 18.81 μmol/L; USFLI-NAFLD: 15.39 μmol/L) and these associations were not significant when total bilirubin concentration was higher than the turning point. Furthermore, all-cause mortality decreased (OR: 0.97, 95%CI: 0.95, 1.00) with increased total bilirubin concentration up to the turning point (11.97 μmol/L), and then all-cause mortality increased with increasing total bilirubin concentration (OR: 1.03, 95%CI: 1.02, 1.04). : We found that higher circulating total bilirubin concentration within the physiological range was associated with decreased risk of NAFLD and all-cause mortality among NAFLD patients.