Effect of Low Serum Total Bilirubin Levels (≤0.32 mg/dl) on Risk of Coronary Artery Disease in Patients With Metabolic Syndrome

Published:September 14, 2014DOI:
      The objective of this study was to investigate the effects of low serum bilirubin levels on the risk for future coronary artery disease (CAD) in a prospective cohort. CAD events were examined according to baseline serum bilirubin levels in a prospective large-scale, community-based Korean cohort in 2 subsequent prospective biennial surveys. A total of 8,593 subjects were included, 0.9% of whom reported newly developed CAD events during the 4 years of follow-up. Cox regression analyses showed that the lowest serum total bilirubin level category (bilirubin ≤0.32 mg/dl) was an independent risk factor for future CAD events (adjusted hazard ratio [HR] 1.890, 95% confidence interval [CI] 1.088 to 3.284; p = 0.024). Subjects with metabolic syndrome had a higher risk for future CAD events than those without metabolic syndrome (HR 3.366, 95% CI 2.079 to 5.448, p <0.001). Low bilirubin levels increased the CAD risk in subjects with metabolic syndrome further (HR 2.016, 95% CI 1.069 to 3.800; p = 0.030), with these subjects showing a >6 times higher risk for CAD than subjects with bilirubin levels >0.32 mg/dl and no metabolic syndrome (HR 6.228, 95% CI 3.118 to 12.437; p <0.001). In conclusion, the addition of low serum bilirubin levels to the traditional risk factors for CAD, such as metabolic syndrome, may yield an improvement of risk prediction.
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        • Stocker R.
        • Yamamoto Y.
        • McDonagh A.F.
        • Glazer A.N.
        • Ames B.N.
        Bilirubin is an antioxidant of possible physiological importance.
        Science. 1987; 235: 1043-1046
        • Stocker R.
        • Glazer A.N.
        • Ames B.N.
        Antioxidant activity of albumin-bound bilirubin.
        Proc Natl Acad Sci U S A. 1987; 84: 5918-5922
        • Neuzil J.
        • Stocker R.
        Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation.
        J Biol Chem. 1994; 269: 16712-16719
        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N Engl J Med. 2005; 352: 1685-1695
        • Breimer L.H.
        • Wannamethee G.
        • Ebrahim S.
        • Shaper A.G.
        Serum bilirubin and risk of ischemic heart disease in middle-aged British men.
        Clin Chem. 1995; 41: 1504-1508
        • Djousse L.
        • Rothman K.J.
        • Cupples L.A.
        • Levy D.
        • Ellison R.C.
        Effect of serum albumin and bilirubin on the risk of myocardial infarction (the Framingham Offspring Study).
        Am J Cardiol. 2003; 91: 485-488
        • Horsfall L.J.
        • Nazareth I.
        • Petersen I.
        Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort.
        Circulation. 2012; 126: 2556-2564
        • Koo B.K.
        • Kim Y.G.
        • Park K.S.
        • Moon M.K.
        Asymptomatic subjects with diabetes have a comparable risk of coronary artery disease to non-diabetic subjects presenting chest pain: a 4-year community-based prospective study.
        BMC Cardiovasc Disord. 2013; 13: 87
        • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
        Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
        JAMA. 2001; 285: 2486-2497
        • WHO/IASO/IOTF
        The Asia-Pacific Perspective: Redefining Obesity and Its Treatment.
        (Australia)2000: 20
        • Wilson P.W.
        • D’Agostino R.B.
        • Levy D.
        • Belanger A.M.
        • Silbershatz H.
        • Kannel W.B.
        Prediction of coronary heart disease using risk factor categories.
        Circulation. 1998; 97: 1837-1847
        • National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
        Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
        Circulation. 2002; 106: 3143-3421
        • Malik S.
        • Wong N.D.
        • Franklin S.S.
        • Kamath T.V.
        • L’Italien G.J.
        • Pio J.R.
        • Williams G.R.
        Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults.
        Circulation. 2004; 110: 1245-1250
        • Jung C.H.
        • Lee M.J.
        • Kang Y.M.
        • Hwang J.Y.
        • Jang J.E.
        • Leem J.
        • Park J.Y.
        • Kim H.K.
        • Lee W.J.
        Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: A 4year retrospective longitudinal study.
        Metabolism. 2014; 63: 87-93
        • Kwak M.S.
        • Kim D.
        • Chung G.E.
        • Kang S.J.
        • Park M.J.
        • Kim Y.J.
        • Yoon J.H.
        • Lee H.S.
        Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease.
        Clin Mol Hepatol. 2012; 18: 383-390
        • Haffner S.M.
        Abdominal obesity, insulin resistance, and cardiovascular risk in pre-diabetes and type 2 diabetes.
        Eur Heart J Suppl. 2006; 8: B20-B25
        • Mahabadi A.A.
        • Lehmann N.
        • Mohlenkamp S.
        • Kalsch H.
        • Bauer M.
        • Schulz R.
        • Moebus S.
        • Jockel K.H.
        • Erbel R.
        • Heusch G.
        Association of bilirubin with coronary artery calcification and cardiovascular events in the general population without known liver disease: the Heinz Nixdorf Recall study.
        Clin Res Cardiol. 2014; 103: 647-653
        • Stender S.
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Grande P.
        • Tybjaerg-Hansen A.
        Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis.
        J Intern Med. 2013; 273: 59-68
        • Hwang H.J.
        • Lee S.W.
        • Kim S.H.
        Relationship between bilirubin and C-reactive protein.
        Clin Chem Lab Med. 2011; 49: 1823-1828
        • Braunstein S.
        • Deramaudt T.
        • Rosenblum D.
        • Dunn M.
        • Abraham N.G.
        Heme oxygenase-1 gene expression as a stress index to ocular irritation.
        Curr Eye Res. 1999; 19: 115-122
        • Stocker R.
        • Perrella M.A.
        Heme oxygenase-1-A novel drug target for atherosclerotic diseases?.
        Circulation. 2006; 114: 2178-2189
        • Wilson P.W.
        • Garrison R.J.
        • Castelli W.P.
        • Feinleib M.
        • McNamara P.M.
        • Kannel W.B.
        Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols.
        Am J Cardiol. 1980; 46: 649-654