Total Bilirubin Levels in Nonalcoholic Fatty Liver Disease and All-cause and Cause-specific Mortality in US Adults

Background & 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 multivariable model [hazard ratio (HR): 0.83, 95% confidence interval (CI): 0.71-0.97 for quartile 4 (highest bilirubin levels) vs. quartile 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 quartile 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 national 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.