Top

Published in:

Open Access 01-02-2020 | Fatty Liver | HEPATIC DISEASE

Circulating total bilirubin and risk of non-alcoholic fatty liver disease in the PREVEND study: observational findings and a Mendelian randomization study

Authors: Setor K. Kunutsor, Monika Frysz, Niek Verweij, Lyanne M. Kieneker, Stephan J. L. Bakker, Robin P. F. Dullaart

Published in: European Journal of Epidemiology | Issue 2/2020

Abstract

The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28–75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73–0.92; p = 0.001) per 1 standard deviation (SD) change in log_e total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78–0.97; p = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69–1.38; p = 0.900) for FLI and 1.14 (0.81–1.59; p = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.

Available only for authorised users

Kunutsor SK, Bakker SJ, Gansevoort RT, Chowdhury R, Dullaart RP. Circulating total bilirubin and risk of incident cardiovascular disease in the general population. Arterioscler Thromb Vasc Biol. 2015;35(3):716–24. https://doi.org/10.1161/ATVBAHA.114.304929.CrossRefPubMed

Kunutsor SK, Kieneker LM, Burgess S, Bakker SJL, Dullaart RPF. Circulating total bilirubin and future risk of hypertension in the general population: the prevention of renal and vascular end-stage disease (PREVEND) prospective study and a mendelian randomization approach. J Am Heart Assoc. 2017. https://doi.org/10.1161/jaha.117.006503.CrossRefPubMedPubMedCentral

Nano J, Muka T, Cepeda M, et al. Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: a systematic review and meta-analysis of observational evidence. Diabetes Metab. 2016;42(6):389–97. https://doi.org/10.1016/j.diabet.2016.06.002.CrossRefPubMed

Abbasi A, Deetman PE, Corpeleijn E, et al. Bilirubin as a potential causal factor in type 2 diabetes risk: a Mendelian randomization study. Diabetes. 2015;64(4):1459–69. https://doi.org/10.2337/db14-0228.CrossRefPubMed

Kunutsor SK. Serum total bilirubin levels and coronary heart disease–causal association or epiphenomenon? Exp Gerontol. 2015;72:63–6. https://doi.org/10.1016/j.exger.2015.09.014.CrossRefPubMed

Stender S, Frikke-Schmidt R, Nordestgaard BG, 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(1):59–68. https://doi.org/10.1111/j.1365-2796.2012.02576.x.CrossRefPubMed

Lidofsky SD. Nonalcoholic fatty liver disease: diagnosis and relation to metabolic syndrome and approach to treatment. Curr Diab Rep. 2008;8(1):25–30.CrossRef

Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21. https://doi.org/10.1002/hep.20701.CrossRefPubMed

Adams LA, Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol. 2007;17(11):863–9. https://doi.org/10.1016/j.annepidem.2007.05.013.CrossRefPubMed

10.

Bedogni G, Bellentani S, Miglioli L, et al. The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33. https://doi.org/10.1186/1471-230X-6-33.CrossRefPubMedPubMedCentral

11.

Lee JH, Kim D, Kim HJ, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42(7):503–8. https://doi.org/10.1016/j.dld.2009.08.002.CrossRefPubMed

12.

Jager S, Jacobs S, Kroger J, et al. Association between the fatty liver index and risk of type 2 diabetes in the EPIC-potsdam study. PLoS ONE. 2015;10(4):e0124749. https://doi.org/10.1371/journal.pone.0124749.CrossRefPubMedPubMedCentral

13.

Vitek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol. 2012;3:55. https://doi.org/10.3389/fphar.2012.00055.CrossRefPubMedPubMedCentral

14.

Schwertner HA, Vitek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis. 2008;198(1):1–11. https://doi.org/10.1016/j.atherosclerosis.2008.01.001.CrossRefPubMed

15.

Vitek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1–57.CrossRef

16.

Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA. Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004. Am J Med. 2008;121(9):781–8. https://doi.org/10.1016/j.amjmed.2008.03.045.CrossRefPubMedPubMedCentral

17.

Chang Y, Ryu S, Zhang Y, et al. A cohort study of serum bilirubin levels and incident non-alcoholic fatty liver disease in middle aged Korean workers. PLoS ONE. 2012;7(5):e37241. https://doi.org/10.1371/journal.pone.0037241.CrossRefPubMedPubMedCentral

18.

Lin YC, Chang PF, Hu FC, Chang MH, Ni YH. Variants in the UGT1A1 gene and the risk of pediatric nonalcoholic fatty liver disease. Pediatrics. 2009;124(6):e1221–7. https://doi.org/10.1542/peds.2008-3087.CrossRefPubMed

19.

Kwak MS, Kim D, Chung GE, et al. Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease. Clin Mol Hepatol. 2012;18(4):383–90. https://doi.org/10.3350/cmh.2012.18.4.383.CrossRefPubMedPubMedCentral

20.

Tian J, Zhong R, Liu C, et al. Association between bilirubin and risk of non-alcoholic fatty liver disease based on a prospective cohort study. Sci Rep. 2016;6:31006. https://doi.org/10.1038/srep31006.CrossRefPubMedPubMedCentral

21.

Hjelkrem M, Morales A, Williams CD, Harrison SA. Unconjugated hyperbilirubinemia is inversely associated with non-alcoholic steatohepatitis (NASH). Aliment Pharmacol Ther. 2012;35(12):1416–23. https://doi.org/10.1111/j.1365-2036.2012.05114.x.CrossRefPubMed

22.

Chisholm J, Seki Y, Toouli J, Stahl J, Collins J, Kow L. Serologic predictors of nonalcoholic steatohepatitis in a population undergoing bariatric surgery. Surg Obes Relat Dis. 2012;8(4):416–22. https://doi.org/10.1016/j.soard.2011.06.010.CrossRefPubMed

23.

Horsfall LJ, Nazareth I, Petersen I. Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort. Circulation. 2012;126(22):2556–64. https://doi.org/10.1161/CIRCULATIONAHA.112.114066.CrossRefPubMed

24.

Seppen J, Bosma P. Bilirubin, the gold within. Circulation. 2012;126(22):2547–9. https://doi.org/10.1161/CIRCULATIONAHA.112.147082.CrossRefPubMed

25.

Wang L, Bautista LE. Serum bilirubin and the risk of hypertension. Int J Epidemiol. 2015;44(1):142–52. https://doi.org/10.1093/ije/dyu242.CrossRefPubMed

26.

Keavney B. Genetic epidemiological studies of coronary heart disease. Int J Epidemiol. 2002;31(4):730–6.CrossRef

27.

Petitti DB, Freedman DA. Invited commentary: how far can epidemiologists get with statistical adjustment? Am J Epidemiol. 2005;162(5):415–8. https://doi.org/10.1093/aje/kwi224(discussion 9–20).CrossRefPubMed

28.

Clarke R, Shipley M, Lewington S, et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999;150(4):341–53.CrossRef

29.

Fibrinogen Studies C, Wood AM, White I, Thompson SG, Lewington S, Danesh J. Regression dilution methods for meta-analysis: assessing long-term variability in plasma fibrinogen among 27,247 adults in 15 prospective studies. Int J Epidemiol. 2006;35(6):1570–8. https://doi.org/10.1093/ije/dyl233.CrossRef

30.

Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Extreme bilirubin levels as a causal risk factor for symptomatic gallstone disease. JAMA Intern Med. 2013;173(13):1222–8. https://doi.org/10.1001/jamainternmed.2013.6465.CrossRefPubMed

31.

von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9. https://doi.org/10.1016/j.jclinepi.2007.11.008.CrossRef

32.

Kunutsor SK, Bakker SJ, Kootstra-Ros JE, Gansevoort RT, Dullaart RP. Circulating gamma glutamyltransferase and prediction of cardiovascular disease. Atherosclerosis. 2014;238(2):356–64. https://doi.org/10.1016/j.atherosclerosis.2014.12.045.CrossRefPubMed

33.

Borggreve SE, Hillege HL, Dallinga-Thie GM, et al. High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. Eur Heart J. 2007;28(8):1012–8. https://doi.org/10.1093/eurheartj/ehm062.CrossRefPubMed

34.

Dullaart RP, Perton F, van der Klauw MM, Hillege HL, Sluiter WJ, Group PS. High plasma lecithin:cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: possible attenuation of cardioprotection associated with high HDL cholesterol. Atherosclerosis. 2010;208(2):537–42. https://doi.org/10.1016/j.atherosclerosis.2009.07.042.CrossRefPubMed

35.

Corsetti JP, Bakker SJ, Sparks CE, Dullaart RP. Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein. PLoS ONE. 2012;7(6):e39110. https://doi.org/10.1371/journal.pone.0039110.CrossRefPubMedPubMedCentral

36.

Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20–9. https://doi.org/10.1056/NEJMoa1114248.CrossRefPubMedPubMedCentral

37.

McArdle PF, Whitcomb BW, Tanner K, Mitchell BD, Shuldiner AR, Parsa A. Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference. BMC Cardiovasc Disord. 2012;12:16. https://doi.org/10.1186/1471-2261-12-16.CrossRefPubMedPubMedCentral

38.

Groenwold RH, Klungel OH, Grobbee DE, Hoes AW. Selection of confounding variables should not be based on observed associations with exposure. Eur J Epidemiol. 2011;26(8):589–93. https://doi.org/10.1007/s10654-011-9606-1.CrossRefPubMedPubMedCentral

39.

Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40(3):740–52. https://doi.org/10.1093/ije/dyq151.CrossRefPubMed

40.

Gallagher CJ, Balliet RM, Sun D, Chen G, Lazarus P. Sex differences in UDP-glucuronosyltransferase 2B17 expression and activity. Drug Metab Dispos. 2010;38(12):2204–9. https://doi.org/10.1124/dmd.110.035345.CrossRefPubMedPubMedCentral

41.

Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet. 1996;347(9001):578–81.CrossRef

42.

Borlak J, Thum T, Landt O, Erb K, Hermann R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert’s syndrome) in healthy subjects. Hepatology. 2000;32(4 Pt 1):792–5. https://doi.org/10.1053/jhep.2000.18193.CrossRefPubMed

43.

Biondi ML, Turri O, Dilillo D, Stival G, Guagnellini E. Contribution of the TATA-box genotype (Gilbert syndrome) to serum bilirubin concentrations in the Italian population. Clin Chem. 1999;45(6 Pt 1):897–8.CrossRef

44.

Abraham NG, Junge JM, Drummond GS. Translational significance of heme oxygenase in obesity and metabolic syndrome. Trends Pharmacol Sci. 2016;37(1):17–36. https://doi.org/10.1016/j.tips.2015.09.003.CrossRefPubMed

45.

Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci USA. 2002;99(25):16093–8. https://doi.org/10.1073/pnas.252626999.CrossRefPubMed

46.

Nakagami T, Toyomura K, Kinoshita T, Morisawa S. A beneficial role of bile pigments as an endogenous tissue protector: anti-complement effects of biliverdin and conjugated bilirubin. Biochim Biophys Acta. 1993;1158(2):189–93.CrossRef

47.

Videla LA, Rodrigo R, Araya J, Poniachik J. Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med. 2006;12(12):555–8. https://doi.org/10.1016/j.molmed.2006.10.001.CrossRefPubMed

48.

du Plessis J, van Pelt J, Korf H, et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology. 2015;149(3):635–48. https://doi.org/10.1053/j.gastro.2015.05.044.CrossRefPubMed

49.

Lin JP, O’Donnell CJ, Schwaiger JP, et al. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation. 2006;114(14):1476–81. https://doi.org/10.1161/CIRCULATIONAHA.106.633206.CrossRefPubMed

50.

Maruhashi T, Soga J, Fujimura N, et al. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation. 2012;126(5):598–603. https://doi.org/10.1161/CIRCULATIONAHA.112.105775.CrossRefPubMed

51.

Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779. https://doi.org/10.1371/journal.pmed.1001779.CrossRefPubMedPubMedCentral

Title: Circulating total bilirubin and risk of non-alcoholic fatty liver disease in the PREVEND study: observational findings and a Mendelian randomization study
Authors: Setor K. Kunutsor
Monika Frysz
Niek Verweij
Lyanne M. Kieneker
Stephan J. L. Bakker
Robin P. F. Dullaart
Publication date: 01-02-2020
Publisher: Springer Netherlands
Keyword: Fatty Liver
Published in: European Journal of Epidemiology / Issue 2/2020
Print ISSN: 0393-2990
Electronic ISSN: 1573-7284
DOI: https://doi.org/10.1007/s10654-019-00589-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Circulating total bilirubin and risk of non-alcoholic fatty liver disease in the PREVEND study: observational findings and a Mendelian randomization study

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2020

Observational and genetic studies of short telomeres and Alzheimer’s disease in 67,000 and 152,000 individuals: a Mendelian randomization study

Using Mendelian randomization to evaluate the causal relationship between serum C-reactive protein levels and age-related macular degeneration

Rationale and Design of the Hamburg City Health Study

Mendel’s laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues

Lifelines NEXT: a prospective birth cohort adding the next generation to the three-generation Lifelines cohort study

On the relationship of machine learning with causal inference