Liver, Pancreas and Biliary Tract| Volume 53, ISSUE 1, P79-85, January 2021

Download started.


Liver fibrosis marker is an independent predictor of cardiovascular morbidity and mortality in the general population

  • Yochai Schonmann
    Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    Department of Quality Measurements and Research, Clalit Health Services, Tel Aviv, Israel
    Search for articles by this author
  • Author Footnotes
    † Equal first contribution
    Hanny Yeshua
    † Equal first contribution
    Clalit Health Services, Tel-Aviv District, Israel

    Department of Family Medicine, Rabin Medical Center, Petah Tikva, Israel

    Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    Search for articles by this author
  • Itay Bentov
    Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
    Search for articles by this author
  • Shira Zelber-Sagi
    Corresponding author.
    School of Public Health, University of Haifa, Haifa 3498838, Israel

    Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv 6423906, Israel
    Search for articles by this author
  • Author Footnotes
    † Equal first contribution
Published:November 01, 2020DOI:



      A growing body of evidence suggests that Non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are associated with cardiovascular disease (CVD). However, the independent role of liver fibrosis markers in the prediction of CVD in the general population is seldom tested.


      To assess whether a marker of liver fibrosis predicts the first occurrence of a CVD event in a large sample of community-based general population.


      Historical cohort using data from a large health provider that operates a centralized computerized medical record. The level of liver fibrosis was measured by the fibrosis-4 (FIB-4) score, and the association with CVD was adjusted for the European Systematic Coronary Risk Evaluation calculator (SCORE).


      The study included 8,511 individuals, 3,292 with inconclusive fibrosis and 195 with advanced fibrosis (FIB-4 ≥ 2.67). People with advanced fibrosis had higher risk for CVD, after adjustment for sociodemographic characteristics, the SCORE, use of statins and aspirin (HR [95%CI], 1.63 [1.29–2.06]). The association persisted in both women and men. Using age-specific cut-offs, there was a dose-response association between inconclusive and advanced fibrosis and CVD (HR [95%CI], 1.15 [1.01–1.31]) and HR [95%CI], 1.60 [1.27–2.01], respectively, P for trend<0.001).


      A simple fibrosis score is independently associated with CVD, suggesting that fibrosis markers should be considered in primary-care risk assessment.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Digestive and Liver Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
        EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
        J Hepatol. 2016; 64: 1388-1402
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • et al.
        The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases.
        Hepatology. 2018; 67: 328-357
        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • et al.
        Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Collaborators GBDCoD
        Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the global burden of disease study 2017.
        Lancet. 2018; 392: 1736-1788
        • Kunutsor S.K.
        • Apekey T.A.
        • Khan H
        Liver enzymes and risk of cardiovascular disease in the general population: a meta-analysis of prospective cohort studies.
        Atherosclerosis. 2014; 236: 7-17
        • Chang Y.
        • Ryu S.
        • Sung K.C.
        • et al.
        Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung health Study.
        Gut. 2019; 68: 1667-1675
        • Al Rifai M.
        • Silverman M.G.
        • Nasir K.
        • et al.
        The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the multi-ethnic study of atherosclerosis (MESA).
        Atherosclerosis. 2015; 239: 629-633
        • Oni E.T.
        • Agatston A.S.
        • Blaha M.J.
        • et al.
        A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?.
        Atherosclerosis. 2013; 230: 258-267
        • Mellinger J.L.
        • Pencina K.M.
        • Massaro J.M.
        • et al.
        Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham heart study.
        J Hepatol. 2015; 63: 470-476
        • Ekstedt M.
        • Hagstrom H.
        • Nasr P.
        • et al.
        Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
        Hepatology. 2015; 61: 1547-1554
        • Angulo P.
        • Kleiner D.E.
        • Dam-Larsen S.
        • et al.
        Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2015; 149 (e10): 389-397
        • Dulai P.S.
        • Singh S.
        • Patel J.
        • et al.
        Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.
        Hepatology. 2017; 65: 1557-1565
        • Vilar-Gomez E.
        • Calzadilla-Bertot L.
        • Wong V.W.-.S.
        • et al.
        Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
        Gastroenterology. 2018; 155 (e17): 443-457
        • Hagström H.
        • Nasr P.
        • Ekstedt M.
        • et al.
        Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD.
        J Hepatol. 2017; 67: 1265-1273
        • Ostovaneh M.R.
        • Ambale-Venkatesh B.
        • Fuji T.
        • et al.
        Association of liver fibrosis with cardiovascular diseases in the general population: the multi-ethnic study of atherosclerosis (MESA).
        Circ Cardiovasc Imaging. 2018; 11e007241
        • Song D.S.
        • Chang U.I.
        • Kang S.G.
        • et al.
        Noninvasive serum fibrosis markers are associated with coronary artery calcification in patients with nonalcoholic fatty liver disease.
        Gut Liver. 2019;
        • Kim D.
        • Kim W.R.
        • Kim H.J.
        • et al.
        Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States.
        Hepatology. 2013; 57: 1357-1365
        • Sinn D.H.
        • Cho S.J.
        • Gu S.
        • et al.
        Persistent nonalcoholic fatty liver disease increases risk for carotid atherosclerosis.
        Gastroenterology. 2016; 151 (e1): 481-488
        • Unalp-Arida A.
        • Ruhl C.E.
        Liver fibrosis scores predict liver disease mortality in the United States population.
        Hepatology. 2017; 66: 84-95
        • Anstee Q.M.
        • Lawitz E.J.
        • Alkhouri N.
        • et al.
        Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials.
        Hepatology. 2019; 70: 1521-1530
        • Schonmann Y.
        • Bleich O.
        • Matalon A.
        • et al.
        Validation of the 2016 USPSTF recommendations for primary cardiovascular prevention in a large contemporary cohort.
        Eur J Prev Cardiol. 2018; 25: 870-880
        • Grundy S.M.
        • Stone N.J.
        • Bailey A.L.
        • et al.
        2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
        Circulation. 2019; 139: e1082-ee143
      1. Goldberger N., Aburbeh M., Haklai Z., Ministry of health, health information division. Leading causes of death in Israel 2000-2014 [Internet]. 2017. Available from:

        • Castera L.
        • Friedrich-Rust M.
        • Loomba R
        Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2019; 156 (e4): 1264-1281
        • McPherson S.
        • Hardy T.
        • Dufour J.F.
        • et al.
        Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis.
        Am J Gastroenterol. 2017; 112: 740-751
        • Conroy R.M.
        • Pyorala K.
        • Fitzgerald A.P.
        • et al.
        Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
        Eur Heart J. 2003; 24: 987-1003
        • Israel Society in Internal Medicine
        Israel association of family medicine, Israel heart society.
        Updated Guidel Treat Hypercholesterolemia. 2014; ([Hebrew])
      2. The Israel Drug Registry. 13 April 2016.

        • Younossi Z.
        • Anstee Q.M.
        • Marietti M.
        • et al.
        Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20
        • Adams L.A.
        • Anstee Q.M.
        • Tilg H.
        • et al.
        Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.
        Gut. 2017; 66: 1138-1153
        • Sinn D.H.
        • Kang D.
        • Chang Y.
        • et al.
        Non-alcoholic fatty liver disease and progression of coronary artery calcium score: a retrospective cohort study.
        Gut. 2017; 66: 323-329
        • Pais R.
        • Redheuil A.
        • Cluzel P.
        • et al.
        Relationship among fatty liver, specific and multiple-site atherosclerosis, and 10-year Framingham score.
        Hepatology. 2019; 69: 1453-1463
        • Alexander M.
        • Loomis A.K.
        • van der Lei J.
        • et al.
        Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults.
        BMJ. 2019; 367: l5367
        • Targher G.
        • Byrne C.D.
        • Lonardo A.
        • et al.
        Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
        J Hepatol. 2016; 65: 589-600
        • Francque S.M.
        • van der Graaff D.
        • Kwanten W.J
        Non-alcoholic fatty liver disease and cardiovascular risk: pathophysiological mechanisms and implications.
        J Hepatol. 2016; 65: 425-443
        • Siddiqui M.S.
        • Fuchs M.
        • Idowu M.O.
        • et al.
        Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile.
        Clin Gastroenterol Hepatol. 2015; 13 (e3): 1000-1008
        • Nitzan Kaluski D.
        • Goldsmith R.
        • Chinitz A.
        • et al.
        First national health and nutrition survey, part I 1999-2001.
        Jerusalem, Israel: Israel Cent Dis Control. 2003;
        • Weil C.
        • Nwankwo C.
        • Friedman M.
        • et al.
        Epidemiology of hepatitis C virus infection in a large Israeli health maintenance organization.
        J Med Virol. 2016; 88: 1044-1050
        • Leibowitz M.
        • Karpati T.
        • Cohen-Stavi C.J.
        • et al.
        Association between achieved low-density lipoprotein levels and major adverse cardiac events in patients with stable ischemic heart disease taking statin treatment.
        JAMA Intern Med. 2016; 176: 1105-1113
        • Augustin S.
        • Ahmed A.
        • Alkhouri N.
        • et al.
        Identification of patients with advanced fibrosis due to nonalcoholic fatty liver disease: considerations for best practice.
        J Gastrointestin Liver Dis. 2020; 29: 235-245
        • Newsome P.N.
        • Cramb R.
        • Davison S.M.
        • et al.
        Guidelines on the management of abnormal liver blood tests.
        Gut. 2018; 67: 6-19

      Linked Article

      • Assessment of hepatic fibrosis in MAFLD: A new player in the evaluation of residual cardiovascular risk?
        Digestive and Liver DiseaseVol. 53Issue 3
        • Preview
          We read with great interest the recently published paper by Shonmann et al. [1] reporting on an independent positive association between liver fibrosis and ten-year incidence of cardiovascular events (CVEs) in a large sample of community-based general population in Israel. Fibrosis was non-invasively assessed by the FIB-4 score, a simple and well validated score used to rule out (cut-off value ≤1.3) or rule in (cut-off ≥2.67) significant liver fibrosis (F2-F3) [2,3]. These results are of considerable interest since they suggest that hepatic fibrosis could therefore be interpreted as an additional non-lipid marker of residual cardiovascular risk, defined as the risk that remains after the optimal multifactorial treatment of all the coexisting risk factors in the individual.
        • Full-Text
        • PDF