Abstract
BackgroundSerum bilirubin may have potent antioxidant and cytoprotective effects. Serum bilirubin levels are inversely associated with several cardiovascular and metabolic endpoints, but their association with nonalcoholic fatty liver disease (NAFLD) has not been investigated except for a single cross-sectional study in a pediatric population. We assessed the prospective association between serum bilirubin concentrations (total, direct, and indirect) and the risk for NAFLD.Methods and FindingsWe performed a cohort study in 5,900 Korean men, 30 to 59 years of age, with no evidence of liver disease and no major risk factors for liver disease at baseline. Study participants were followed in annual or biennial health examinations between 2002 and 2009. The presence of fatty liver was determined at each visit by ultrasonography. We observed 1,938 incident cases of NAFLD during 28,101.8 person-years of follow-up. Increasing levels of serum direct bilirubin were progressively associated with a decreasing incidence of NAFLD. In age-adjusted models, the hazard ratio for NAFLD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.61 (95% CI 0.54–0.68). The association persisted after adjusting for multiple metabolic parameters (hazard ratio comparing the highest to the lowest quartile 0.86, 95% CI 0.76–0.98; P trend = 0.039). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of NAFLD.ConclusionsIn this large prospective study, higher serum direct bilirubin levels were significantly associated with a lower risk of developing NAFLD, even adjusting for a variety of metabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for NAFLD risk.
Highlights
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by steatosis with varying degrees of inflammatory activity, necrosis and fibrosis [1,2]
In this large prospective study, higher serum direct bilirubin levels were significantly associated with a lower risk of developing nonalcoholic fatty liver disease (NAFLD), even adjusting for a variety of metabolic parameters
Serum direct bilirubin levels were inversely associated with a variety of metabolic parameters, including body mass index, glucose, total cholesterol, LDLcholesterol, triglycerides, liver enzymes, High sensitivity-C reactive protein (hsCRP), insulin and HOMA-IR, and positively associated with high-density lipoprotein (HDL)-cholesterol levels (Table 1)
Summary
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by steatosis with varying degrees of inflammatory activity, necrosis and fibrosis [1,2]. A growing body of literature shows that higher bilirubin levels are inversely associated with HOMA-IR and insulin levels [13] and with the prevalence of cardiovascular disease [14,15,16,17,18] and diabetes [19]. One cross-sectional study, conducted among obese children, has evaluated the association between serum bilirubin and NAFLD [22]. The goal of our study was to evaluate the prospective association between bilirubin concentrations (total, direct, and indirect) and the risk of NAFLD. Serum bilirubin levels are inversely associated with several cardiovascular and metabolic endpoints, but their association with nonalcoholic fatty liver disease (NAFLD) has not been investigated except for a single cross-sectional study in a pediatric population. We assessed the prospective association between serum bilirubin concentrations (total, direct, and indirect) and the risk for NAFLD
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