Association between nonalcoholic fatty liver disease with advanced fibrosis and stroke

  • Author Footnotes
    1 Permanent address: Department of Neurology, Weill Cornell Medicine, New York, NY.
    Neal S. Parikh
    Correspondence
    Corresponding author at: 420 E 70th St, LH Suite 408, New York, NY 10021, United States of America.
    Footnotes
    1 Permanent address: Department of Neurology, Weill Cornell Medicine, New York, NY.
    Affiliations
    Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, United States of America
    Search for articles by this author
  • Lisa B. VanWagner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
    Search for articles by this author
  • Mitchell S.V. Elkind
    Affiliations
    Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, United States of America

    Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY, United States of America
    Search for articles by this author
  • Jose Gutierrez
    Affiliations
    Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, United States of America
    Search for articles by this author
  • Author Footnotes
    1 Permanent address: Department of Neurology, Weill Cornell Medicine, New York, NY.
Published:October 13, 2019DOI:https://doi.org/10.1016/j.jns.2019.116524

      Highlights

      • Advanced liver fibrosis in nonalcoholic fatty liver disease leads to worse outcomes.
      • Associations with heart disease had previously been identified.
      • We analyzed nationally-representative health survey data to study stroke.
      • An association with stroke was also identified.

      Abstract

      Background

      There is an increasing appreciation of the cardiovascular implications of nonalcoholic fatty liver disease with advanced fibrosis (NAFLD-fibrosis). However, data regarding stroke risk are limited. We sought to investigate whether NAFLD-fibrosis is associated with stroke in addition to heart disease.

      Methods

      We performed a cross-sectional study using data from the United States National Health and Nutrition Examination Survey (2005–2014). After excluding participants with competing causes of liver disease, the Fibrosis-4 score (FIB-4) and NAFLD Fibrosis Score (NFS) were calculated. First, we used a composite measure to classify participants: NAFLD-fibrosis was defined as having at least one score above its validated cut-off. Second, we also used the FIB-4 and NFS scores individually. The key outcome was prevalent stroke, and we also evaluated heart disease; both were self-reported. Multivariable logistic regression assessed the association between NAFLD-fibrosis and these outcomes while adjusting for demographic variables and cardiovascular risk factors.

      Results

      We identified 1653 participants with NAFLD-fibrosis from a sample of 27,040 participants. In total, 753 had prior stroke. An association between NAFLD-fibrosis and stroke was seen when using the FIB-4 score (OR 1.87, 95% CI 1.00–3.50) but not the NFS (OR 1.31, 95% CI 0.92–1.87). NAFLD-fibrosis was associated with heart disease (OR 1.46, 95% CI 1.06–2.01) using the composite measure and both scores individually.

      Conclusions

      NAFLD-fibrosis may be associated with stroke in addition to heart disease, with differences depending on the measure used to define NAFLD-fibrosis.

      Keywords

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

      Purchase one-time access:

      Academic and Personal

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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
        • 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
        • 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
        • Stepanova M.
        • Younossi Z.M.
        Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.
        Clin. Gastroenterol. Hepatol. 2012; 10: 646-650
        • Wu S.
        • Wu F.
        • Ding Y.
        • et al.
        Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and meta-analysis.
        Sci. Rep. 2016; 6: 33386
        • Ekstedt M.
        • Hagström 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
        • 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
        • Di Costanzo A.
        • D’Erasmo L.
        • Polimeni L.
        • et al.
        Non-alcoholic fatty liver disease and subclinical atherosclerosis: a comparison of metabolically- versus genetically-driven excess fat hepatic storage.
        Atherosclerosis. 2017; 257: 232-239
        • Pisto P.
        • Santaniemi M.
        • Bloigu R.
        • et al.
        Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study.
        BMJ Open. 2014; 4e004973
        • Lauridsen B.K.
        • Stender S.
        • Kristensen T.S.
        • et al.
        Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals.
        Eur. Heart J. 2018; 39: 385-393
        • Le M.H.
        • Devaki P.
        • Ha N.B.
        • et al.
        Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States.
        PLoS One. 2017; 12e0173499
        • 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 (e310): 389-397
        • 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
        • 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
        • Moshayedi H.
        • Ahrabi R.
        • Mardani A.
        • et al.
        Association between non-alcoholic fatty liver disease and ischemic stroke.
        Iran J. Neurol. 2014; 13: 144-148
        • Ying I.
        • Saposnik G.
        • Vermeulen M.J.
        • et al.
        Nonalcoholic fatty liver disease and acute ischemic stroke.
        Epidemiology. 2011; 22: 129-130
        • Hamaguchi M.
        • Kojima T.
        • Takeda N.
        • et al.
        Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease.
        World J. Gastroenterol. 2007; 13: 1579-1584
        • Alexander K.S.
        • Zakai N.A.
        • Lidofsky S.D.
        • et al.
        Non-alcoholic fatty liver disease, liver biomarkers and stroke risk: the reasons for geographic and racial differences in stroke cohort.
        PLoS One. 2018; 13e0194153
        • Kim S.U.
        • Song D.
        • Heo J.H.
        • et al.
        Liver fibrosis assessed with transient elastography is an independent risk factor for ischemic stroke.
        Atherosclerosis. 2017; 260: 156-162
        • Kim Y.D.
        • Song D.
        • Heo J.H.
        • et al.
        Relationship between cerebral microbleeds and liver stiffness determined by transient elastography.
        PLoS One. 2015; 10e0139227
        • Parikh N.S.
        • Navi B.B.
        • Schneider Y.
        • et al.
        Association between cirrhosis and stroke in a nationally representative cohort.
        JAMA Neurol. 2017; 74: 927-932
        • Wu H.Y.
        • Lin C.S.
        • Yeh C.C.
        • et al.
        Cirrhosis patients’ stroke risks and adverse outcomes: two nationwide studies.
        Atherosclerosis. 2017; 263: 29-35
        • National Center for Health Statistics
        National Health and Nutrition Examination Survey. (NHANES): Questionnaires, Datasets, and Related Documentation.
        • Kabbany M.N.
        • Conjeevaram Selvakumar P.K.
        • et al.
        Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the United States: an analysis of National Health and nutrition examination survey data.
        Am. J. Gastroenterol. 2017; 112: 581-587
        • Xiao G.
        • Zhu S.
        • Xiao X.
        • et al.
        Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis.
        Hepatology. 2017; 66: 1486-1501
        • Shah A.G.
        • Lydecker A.
        • Murray K.
        • et al.
        Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease.
        Clin. Gastroenterol. Hepatol. 2009; 7: 1104-1112
        • Angulo P.
        • Hui J.M.
        • Marchesini G.
        • et al.
        The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.
        Hepatology. 2007; 45: 846-854
        • McPherson S.
        • Stewart S.F.
        • Henderson E.
        • et al.
        Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease.
        Gut. 2010; 59: 1265-1269
        • Okura Y.
        • Urban L.H.
        • Mahoney D.W.
        • et al.
        Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure.
        J. Clin. Epidemiol. 2004; 57: 1096-1103
        • Lin M.P.
        • Ovbiagele B.
        • Markovic D.
        • et al.
        “Life’s simple 7” and long-term mortality after stroke.
        J. Am. Heart Assoc. 2015; 4https://doi.org/10.1161/JAHA.114.001470
        • Shah N.S.
        • Huffman M.D.
        • Ning H.
        • et al.
        Trends in myocardial infarction secondary prevention: the National Health and nutrition examination surveys (NHANES), 1999-2012.
        J. Am. Heart Assoc. 2015; 4https://doi.org/10.1161/JAHA.114.001709
        • Targher G.
        • Bertolini L.
        • Padovani R.
        • et al.
        Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients.
        Diabetes Care. 2007; 30: 1212-1218
        • 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
        • Targher G.
        • Bertolini L.
        • Scala L.
        • et al.
        Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue.
        Diabet. Med. 2005; 22: 1354-1358
        • Lee H.J.
        • Lee C.H.
        • Kim S.
        • et al.
        Association between vascular inflammation and non-alcoholic fatty liver disease: analysis by 18f-fluorodeoxyglucose positron emission tomography.
        Metabolism. 2017; 67: 72-79
        • VanWagner L.B.
        • Ning H.
        • Lewis C.E.
        • et al.
        Associations between nonalcoholic fatty liver disease and subclinical atherosclerosis in middle-aged adults: the coronary artery risk development in young adults study.
        Atherosclerosis. 2014; 235: 599-605
        • 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
        • Wong V.W.
        • Wong G.L.
        • Yeung J.C.
        • et al.
        Long-term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: a prospective cohort study.
        Hepatology. 2016; 63: 754-763
        • Kim J.
        • Lee D.Y.
        • Park S.E.
        • et al.
        Increased risk for development of coronary artery calcification in subjects with non-alcoholic fatty liver disease and systemic inflammation.
        PLoS One. 2017; 12e0180118
        • Madan S.A.
        • John F.
        • Pyrsopoulos N.
        • et al.
        Nonalcoholic fatty liver disease and carotid artery atherosclerosis in children and adults: a meta-analysis.
        Eur. J. Gastroenterol. Hepatol. 2015; 27: 1237-1248
        • Tripodi A.
        • Primignani M.
        • Chantarangkul V.
        • et al.
        An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.
        Gastroenterology. 2009; 137: 2105-2111
        • Lonardo A.
        • Ballestri S.
        • Targher G.
        “Not all forms of nafld were created equal”. Do metabolic syndrome-related nafld and pnpla3-related nafld exert a variable impact on the risk of early carotid atherosclerosis?.
        Atherosclerosis. 2017; 257: 253-255