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

The Chinese University of Hong Kong, Hong Kong
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e37241. DOI: 10.1371/journal.pone.0037241
Source: PubMed


Serum 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 Findings
We 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.

In 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.

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    ABSTRACT: Bilirubin is an endogenous metabolite of heme that possesses potent natural antioxidant effects [1]. Of interest, elevated serum bilirubin concentration is strongly associated with protection against many immune and inflammatory diseases including cancer [2], rheumatoid arthritis [3], non-alcoholic fatty liver disease [4] and diabetes mellitus [5], as well as ischaemic heart disease (IHD) and myocardial infarction (MI) [6, 7]. However, it remains unclear whether bilirubin directly mediates disease protection or is simply a biomarker for other risk factors or causal mechanisms. The distinction is important: if bilirubin is merely a correlated biomarker, it might only serve a limited prognostic or diagnostic role for IHD; whereas if it is mechanistically involved in IHD causation, it could serve as a target for new therapies. © 2012 The Association for the Publication of the Journal of Internal Medicine.
    Full-text · Article · Aug 2012 · Journal of Internal Medicine
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    Full-text · Article · Dec 2012 · Clinical and molecular hepatology
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    ABSTRACT: Serum bilirubin exerts antioxidant and cytoprotective effects. In addition, elevated serum bilirubin levels are associated with a decreased risk of metabolic and cardiovascular diseases. However, few studies have evaluated whether serum bilirubin is associated with non-alcoholic fatty liver disease (NAFLD), which is closely associated with other metabolic diseases. The aim of this study was thus to elucidate the association between serum total bilirubin levels and NAFLD. A cross-sectional study of 17,348 subjects undergoing a routine health check-up was conducted. Subjects positive for hepatitis B or hepatitis C virus, or with other hepatitis history were excluded. NAFLD was diagnosed on the basis of typical ultrasonographic findings and an alcohol consumption of less than 20 g/day. The mean age of the subjects was 49 years and 9,076 (52.3%) were men. The prevalence of NAFLD decreased steadily as the serum bilirubin level increased in both men and women (P<0.001 for both). Multivariate regression analysis adjusted for other metabolic risk factors showed that serum bilirubin level was inversely associated with the prevalence of NAFLD [odds ratio (OR)=0.88, 95% confidence interval (CI)=0.80-0.97]. Furthermore, there was an inverse, dose-dependent association between NAFLD and serum total bilirubin levels (OR=0.83, 95% CI=0.75-0.93 in the third quartile; OR=0.80, 95% CI=0.71-0.90 in the fourth quartile vs. lowest quartile, P for trend <0.001). Serum bilirubin levels were found to be inversely associated with the prevalence of NAFLD independent of known metabolic risk factors. Serum bilirubin might be a protective marker for NAFLD.
    Full-text · Article · Dec 2012 · Clinical and molecular hepatology
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