Rapid Communication| Volume 269, P306-311, February 2018

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Mild hyperbilirubinaemia as an endogenous mitigator of overweight and obesity: Implications for improved metabolic health


      • Mildly elevated unconjugated bilirubin (UCB) might mitigate cardiovascular disease risk factors including overweight/obesity.
      • Gilbert's syndrome(GS) subjects with mildly elevated UCB were metabolically healthier than age- and gender matched controls.
      • The condition of mild hyperbilirubinaemia (GS) seems to protect from age-related weight gain and dyslipidaemia.


      Background and aims

      Mild endogenous elevation of unconjugated bilirubin (UCB) as seen in Gilbert's syndrome (GS), might mitigate cardiovascular disease (CVD) risk factors including overweight/obesity. This study aimed to determine whether hyperbilirubinaemia is linked to improved anthropometric data and lipid profile.


      Our study considered GS and age-/gender-matched healthy controls (n = 248). Additionally, obese female type 2 diabetic patients (DM2) (n = 26) were included as a “disease control group”.


      BMI, hip circumference (HC), and lipid profile were significantly lower in GS. UCB was inversely correlated with BMI (p <0 .001), HC as well as with fat mass (FM) and lipid variables (p < 0.05). Moreover, DM2 patients had significantly lower UCB compared to GS and healthy controls. Older GS subjects (≥35 years) had significantly reduced anthropometric data and improved lipid profile.


      Our results propose that the health promoting potential of mild hyperbilirubinaemia may extend to protection from age-related weight gain and dyslipidaemia.


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        • Dhana K.
        • Berghout M.A.
        • Peeters A.
        • Ikram M.A.
        • Tiemeier H.
        • Hofman A.
        • Nusselder W.
        • Kavousi M.
        • Franco O.H.
        Obesity in older adults and life expectancy with and without cardiovascular disease.
        Int. J. Obes. 2005; 40: 1535-1540
        • Joshy G.
        • Korda R.J.
        • Attia J.
        • Liu B.
        • Bauman A.E.
        • Banks E.
        Body mass index and incident hospitalisation for cardiovascular disease in 158 546 participants from the 45 and up study.
        Int. J. Obes. 2005; 38: 848-856
        • Kee C.C.
        • Sumarni M.G.
        • Lim K.H.
        • Selvarajah S.
        • Haniff J.
        • Tee G.H.
        • Gurpreet K.
        • Faudzi Y.A.
        • Amal N.M.
        Association of BMI with risk of CVD mortality and all-cause mortality.
        Publ. Health Nutr. 2017; : 1-9
        • Wagner K.H.
        • Wallner M.
        • Molzer C.
        • Gazzin S.
        • Bulmer A.C.
        • Tiribelli C.
        • Vitek L.
        Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases.
        Clin. Sci. 2015; 1979 (London, England): 1-25
        • Bhuiyan A.R.
        • Srinivasan S.R.
        • Chen W.
        • Sultana A.
        • Berenson G.S.
        Association of serum bilirubin with pulsatile arterial function in asymptomatic young adults: the Bogalusa heart study.
        Metabol.: Clin. Exp. 2008; 57: 612-616
        • Temme E.H.
        • Zhang J.
        • Schouten E.G.
        • Kesteloot H.
        Serum bilirubin and 10-year mortality risk in a Belgian population.
        Canc. Causes Contr.: CCC. 2001; 12: 887-894
        • Bulmer A.C.
        • Verkade H.J.
        • Wagner K.H.
        Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection.
        Prog. Lipid Res. 2013; 52: 193-205
        • Andersson C.
        • Weeke P.
        • Fosbol E.L.
        • Brendorp B.
        • Kober L.
        • Coutinho W.
        • Sharma A.M.
        • Van Gaal L.
        • Finer N.
        • James W.P.
        • Caterson I.D.
        • Rode R.A.
        • Torp-Pedersen C.
        Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial.
        Metabol.: Clin. Exp. 2009; 58: 1109-1115
        • Lin J.P.
        • O'Donnell C.J.
        • Schwaiger J.P.
        • Cupples L.A.
        • Lingenhel A.
        • Hunt S.C.
        • Yang S.
        • Kronenberg F.
        Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham heart study.
        Circulation. 2006; 114: 1476-1481
        • Novotny L.
        • Vitek L.
        Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies.
        Exp. Biol. Med. 2003; 228 (Maywood, N.J.): 568-571
        • Molzer C.
        • Wallner M.
        • Kern C.
        • Tosevska A.
        • Schwarz U.
        • Zadnikar R.
        • Doberer D.
        • Marculescu R.
        • Wagner K.H.
        Features of an altered AMPK metabolic pathway in Gilbert's syndrome, and its role in metabolic health.
        Sci. Rep. 2016; 6: 30051
        • Wallner M.
        • Bulmer A.C.
        • Molzer C.
        • Mullner E.
        • Marculescu R.
        • Doberer D.
        • Wolzt M.
        • Wagner O.F.
        • Wagner K.H.
        Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome.
        Eur. J. Clin. Invest. 2013; 43: 912-919
        • Wallner M.
        • Blassnigg S.M.
        • Marisch K.
        • Pappenheim M.T.
        • Mullner E.
        • Molzer C.
        • Nersesyan A.
        • Marculescu R.
        • Doberer D.
        • Knasmuller S.
        • Bulmer A.C.
        • Wagner K.H.
        Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilbert's syndrome measured with the micronucleus cytome assay.
        Mutagenesis. 2012; 27: 731-735
        • Grindel A.
        • Guggenberger B.
        • Eichberger L.
        • Poppelmeyer C.
        • Gschaider M.
        • Tosevska A.
        • Mare G.
        • Briskey D.
        • Brath H.
        • Wagner K.H.
        Oxidative stress, DNA damage and DNA repair in female patients with diabetes mellitus type 2.
        PLoS One. 2016; 11e0162082
        • Bi X.
        • Tey S.L.
        • Leong C.
        • Quek R.
        • Loo Y.T.
        • Henry C.J.
        Correlation of adiposity indices with cardiovascular disease risk factors in healthy adults of Singapore: a cross-sectional study.
        BMC obes. 2016; 3
        • Bulmer A.C.
        • Blanchfield J.T.
        • Toth I.
        • Fassett R.G.
        • Coombes J.S.
        Improved resistance to serum oxidation in Gilbert's syndrome: a mechanism for cardiovascular protection.
        Atherosclerosis. 2008; 199: 390-396
        • Hwang H.J.
        • Kim S.H.
        Inverse relationship between fasting direct bilirubin and metabolic syndrome in Korean adults.
        Clin. Chim. Acta; Int. Fed. Clin. Chem. 2010; 411: 1496-1501
        • Lippi G.
        • Targher G.
        • Montagnana M.
        • Salvagno G.L.
        • Guidi G.C.
        Bilirubin concentration and cardiovascular risk profile.
        Liver Int.: Offic. J. Int. Assoc. Stud. Liver. 2009; 29: 315-316
        • Kunutsor S.K.
        • Zaccardi F.
        • Karppi J.
        • Kurl S.
        • Laukkanen J.A.
        Is high serum LDL/HDL cholesterol ratio an emerging risk factor for sudden cardiac death? findings from the KIHD study.
        J. Atherosclerosis Thromb. 2017; 24: 600-608
        • Abbasi A.
        Mendelian randomization studies of biomarkers and type 2 diabetes.
        Endocr. Connections. 2015; 4: 249-260
        • Kwon Y.J.
        • Lee Y.J.
        • Park B.J.
        • Hong K.W.
        • Jung D.H.
        Total serum bilirubin and 8-year incident type 2 diabetes mellitus: the Korean genome and epidemiology study.
        Diabetes Metabol. 2017; (pii: S1262-3636(17)30477-9)
        • Inoguchi T.
        • Sasaki S.
        • Kobayashi K.
        • Takayanagi R.
        • Yamada T.
        Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes.
        Jama. 2007; 298: 1398-1400
        • Nano J.
        • Muka T.
        • Cepeda M.
        • Voortman T.
        • Dhana K.
        • Brahimaj A.
        • Dehghan A.
        • Franco O.H.
        Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: a systematic review and meta-analysis of observational evidence.
        Diabetes Metabol. 2016; 42: 389-397
        • 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
        • Stec D.E.
        • John K.
        • Trabbic C.J.
        • Luniwal A.
        • Hankins M.W.
        • Baum J.
        • Hinds Jr., T.D.
        Bilirubin binding to PPARalpha inhibits lipid accumulation.
        PLoS One. 2016; 11e0153427