A Cohort Study of Serum Bilirubin Levels and Incident Non-Alcoholic Fatty Liver Disease in Middle Aged Korean Workers

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.

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…Similar inverse relationship of NAFLD was discovered with conjugated and unconjugated bilirubin respectively [50,51] . In addition, serum bilirubin has been long recognised to have an inverse relationship with the development of coronary artery disease [52] .…”

Diabetes, bilirubin and amputations: is there a link?

“…Lower serum bilirubin levels were also reported in patients with the metabolic syndrome, in which bilirubin negatively correlated with circulating insulin levels and visceral adipose tissue [11]. In a large prospective study (5,900 Korean men; followed up between 2002 and 2009) higher serum direct (conjugated) bilirubin levels were significantly associated with a lower risk of developing nonalcoholic fatty liver disease (NAFLD) [12]. Less than 1% of the participants in the study had diabetes.…”

“…Less than 1% of the participants in the study had diabetes. One of the limitations of this study [12] is that the diagnosis of NAFLD was based on ultrasound findings instead of the 'gold standard' liver biopsy. However, it is difficult to see how such a large study could cope with the logistics of liver biopsies let alone the ethical restrictions associated with such a procedure.…”

Liver enzymes in patients diagnosed with non-alcoholic fatty liver disease (NAFLD) in Veracruz: a comparative analysis with the literature

“…So far the literature had excluded bilirubin as a guiding test for NAFLD. However, a study by Chang et al [35] revealed that serum conjugated bilirubin levels were significantly associated with a lower incidence of NAFLD. Nevertheless, some authors found that total bilirubin levels are associated in a negative way [36], and still others observed that unconjugated bilirubin levels are rigorously related to NAFLD [37,38], therefore, it is not clear which bilirubin influences NAFLD presence.…”