Background and Aims: Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic progressive illness with a spectrum of disease severity from steatosis to end-stage liver disease. Emerging evidence suggests total serum bilirubin levels are inversely related to the prevalence of metabolic syndrome including NAFLD. We investigated the effects of bilirubin on all-cause and cause-specific mortality stratified by NAFLD status.

Methods: We used the third National Health and Nutrition Examination Survey Cohort (1988-1994) and linked mortality dataset through 2019. Cox-regression models were constructed to assess the association between bilirubin levels categorized by quartile with all-cause and cause-specific mortality.

Results: During the median follow-up of 324 months (n=11,078), higher bilirubin levels were associated with a reduction in risk of all-cause mortality in the multivariate model (hazard ratio [HR]: 0.83, 95% confidence interval [CI]: 0.71-0.97 for quarter 4 [highest bilirubin levels] vs. quarter 1 [lowest bilirubin levels], p for trend=0.033). Higher bilirubin levels were associated with a lower risk for all-cause mortality in individuals with NAFLD (HR; 0.68, 95% CI: 0.55-0.86 for quarter 4, p for trend=0.010); however, this protective association with higher bilirubin levels was not noted in those without NAFLD. Higher bilirubin levels were associated with a lower risk for cardiovascular and cancer-related mortality in individuals with NAFLD.

Conclusions: In this large nationally representative sample of American adults, higher bilirubin levels in NAFLD were associated with a lower risk of all-cause mortality, which may be derived from a lower risk of cardiovascular/cancer-related mortality.


bilirubin, NAFLD, hepatic steatosis, death, NHANES