Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications

Claudio Tana, Stefano Ballestri, Fabrizio Ricci, Angelo Di Vincenzo, Andrea Ticinesi, Sabina Gallina, Maria Adele Giamberardino, Francesco Cipollone, Richard Sutton, Roberto Vettor, Artur Fedorowski, Tiziana Meschi, Claudio Tana, Stefano Ballestri, Fabrizio Ricci, Angelo Di Vincenzo, Andrea Ticinesi, Sabina Gallina, Maria Adele Giamberardino, Francesco Cipollone, Richard Sutton, Roberto Vettor, Artur Fedorowski, Tiziana Meschi

Abstract

New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD-in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome-and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.

Keywords: cardiovascular disease; cardiovascular risk factors; metabolic syndrome; non-alcoholic fatty liver disease.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A Spotlight on the Pathogenesis of Cardiovascular Risk Associated with Non-Alcoholic Fatty Liver Disease.

References

    1. Charlton M.R., Burns J.M., Pedersen R.A., Watt K.D., Heimbach J.K., Dierkhising R.A. Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States. Gastroenterology. 2011;141:1249–1253. doi: 10.1053/j.gastro.2011.06.061.
    1. Targher G., Day C.P., Bonora E. Risk of Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease. N. Engl. J. Med. 2010;363:1341–1350. doi: 10.1056/NEJMra0912063.
    1. Ma J., Hwang S.J., Pedley A., Massaro J.M., Hoffmann U., Chung R.T., Benjamin E.J., Levy D., Fox C.S., Long M.T. Bidirectional analysis between fatty liver and cardiovascular disease risk factors. J. Hepatol. 2017;66:390–397. doi: 10.1016/j.jhep.2016.09.022.
    1. Lonardo A., Ballestri S., Marchesini G., Angulo P., Loria P. Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome. Dig. Liver Dis. 2015;47:181–190. doi: 10.1016/j.dld.2014.09.020.
    1. Ballestri S., Lonardo A., Bonapace S., Byrne C.D., Loria P., Targher G. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J. Gastroenterol. 2014;20:1724–1745. doi: 10.3748/wjg.v20.i7.1724.
    1. Younossi Z., Anstee Q.M., Marietti M., Hardy T., Henry L., Eslam M., George J., Bugianesi E. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 2018;15:11–20. doi: 10.1038/nrgastro.2017.109.
    1. Bedogni G., Miglioli L., Masutti F., Castiglione A., Croce’ L.S., Tiribelli C., Bellentani S. Incidence and natural course of fatty liver in the general population: The Dionysos study. Hepatology. 2007;46:1387–1391. doi: 10.1002/hep.21827.
    1. Ballestri S., Zona S., Targher G., Romagnoli D., Baldelli E., Nascimbeni F., Roverato A., Guaraldi G., Lonardo A. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 2016;31:936–944. doi: 10.1111/jgh.13264.
    1. Bellentani S., Scaglioni F., Marino M., Bedogni G. Epidemiology of Non-Alcoholic Fatty Liver Disease. Dig. Dis. 2010;28:155–161. doi: 10.1159/000282080.
    1. Lazo M., Clark J. The Epidemiology of Nonalcoholic Fatty Liver Disease: A Global Perspective. Semin. Liver Dis. 2008;28:339–350. doi: 10.1055/s-0028-1091978.
    1. Kim C.H., Kallman J.B., Bai C., Pawloski L., Gewa C., Arsalla A., Sabatella M.E., Younossi Z.M. Nutritional assessments of patients with non-alcoholic fatty liver disease. Obes Surg. 2010;20:154–160. doi: 10.1007/s11695-008-9549-0.
    1. Nseir W., Hellou E., Assy N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World J. Gastroenterol. 2014;20:9338–9344.
    1. Asgari-Taee F., Zerafati-Shoae N., Dehghani M., Sadeghi M., Baradaran H.R., Jazayeri S. Association of sugar sweetened beverages consumption with non-alcoholic fatty liver disease: A systematic review and meta-analysis. Eur. J. Nutr. 2019;58:1759–1769. doi: 10.1007/s00394-018-1711-4.
    1. Pan A., Sun Q., Bernstein A.M., Manson J.E., Willett W.C., Hu F.B. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: Three cohorts of US men and women. JAMA Intern Med. 2013;173:1328–1335. doi: 10.1001/jamainternmed.2013.6633.
    1. Heidemann C., Schulze M.B., Franco O.H., Van Dam R.M., Mantzoros C.S., Hu F.B. Dietary Patterns and Risk of Mortality from Cardiovascular Disease, Cancer, and All-Causes in a Prospective Cohort of Women. Circulation. 2008;118:230–237. doi: 10.1161/CIRCULATIONAHA.108.771881.
    1. Seidelmann S.B., Claggett B., Cheng S., Henglin M., Shah A., Steffen L.M., Folsom A.R., Rimm E.B., Willett W.C., Solomon S.D. Dietary carbohydrate intake and mortality: A prospective cohort study and meta-analysis. Lancet Public Health. 2018;3:e419–e428. doi: 10.1016/S2468-2667(18)30135-X.
    1. Thoma C., Day C.P., Trenell M.I. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: A systematic review. J. Hepatol. 2012;56:255–266. doi: 10.1016/j.jhep.2011.06.010.
    1. Chan R., Wong V.W.-S., Chu W.C.-W., Wong G.L.-H., Li L.S., Leung J., Chim A.M.-L., Yeung D.K.-W., Sea M.M.-M., Woo J., et al. Diet-Quality Scores and Prevalence of Nonalcoholic Fatty Liver Disease: A Population Study Using Proton-Magnetic Resonance Spectroscopy. PLoS ONE. 2015;10:e0139310. doi: 10.1371/journal.pone.0139310.
    1. Musso G., Cassader M., Rosina F., Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55:885–904. doi: 10.1007/s00125-011-2446-4.
    1. Wong V.W., Wong G.L., Chan R.S., Shu S.S., Cheung B.H., Li L.S., Mei-Ling Chim A., Chan C.K., Leung J.K., Chu W.C., et al. Beneficial Effects of Lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J. Hepatol. 2018;69:1349–1356. doi: 10.1016/j.jhep.2018.08.011.
    1. Younossi Z.M., Koenig A.B., Abdelatif D., Fazel Y., Henry L., Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. doi: 10.1002/hep.28431.
    1. Targher G., Byrne C.D., Lonardo A., Zoppini G., Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J. Hepatol. 2016;65:589–600. doi: 10.1016/j.jhep.2016.05.013.
    1. Ekstedt M., Hagström H., Nasr P., Fredrikson M., Stål P., Kechagias S., Hultcrantz R. 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. doi: 10.1002/hep.27368.
    1. Mahfood Haddad T., Hamdeh S., Kanmanthareddy A., Alla V.M. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: A systematic review and meta-analysis. Diabetes MetabSyndr. 2017;11(Suppl. 1):209–216. doi: 10.1016/j.dsx.2016.12.033.
    1. Mellinger J.L., Pencina K.M., Massaro J.M., Hoffmann U., Seshadri S., Fox C.S., O’Donnell C.J., Speliotes E.K. Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study. J. Hepatol. 2015;63:470–476. doi: 10.1016/j.jhep.2015.02.045.
    1. Wong V.W.-S., Wong G.L.-H., Yip G.W.-K., Lo A.O.-S., Limquiaco J., Chu W.C.-W., Chim A.M.-L., Yu C.-M., Yu J., Chan F.K., et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut. 2011;60:1721–1727. doi: 10.1136/gut.2011.242016.
    1. Wong V.W., Wong G.L., Yeung J.C., Fung C.Y., Chan J.K., Chang Z.H., Kwan C.T., Lam H.W., Limquiaco J., Chim A.M., et al. Long-term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: A prospective cohort study. Hepatology. 2016;63:754–763. doi: 10.1002/hep.28253.
    1. Targher G., Bertolini L., Rodella S., Tessari R., Zenari L., Lippi G., Arcaro G. Nonalcoholic Fatty Liver Disease Is Independently Associated With an Increased Incidence of Cardiovascular Events in Type 2 Diabetic Patients. Diabetes Care. 2007;30:2119–2121. doi: 10.2337/dc07-0349.
    1. Lazo M., Hernaez R., Bonekamp S., Kamel I.R., Brancati F.L., Guallar E., Clark J.M. Non-alcoholic fatty liver disease and mortality among US adults: Prospective cohort study. BMJ. 2011;343:d6891. doi: 10.1136/bmj.d6891.
    1. Mantovani A., Zoppini G., Targher G., Golia G., Bonora E. Non-alcoholic fatty liver disease is independently associated with left ventricular hypertrophy in hypertensive Type 2 diabetic individuals. J. Endocrinol. Investig. 2012;35:215–218. doi: 10.1007/BF03345421.
    1. Mantovani A., Pernigo M., Bergamini C., Bonapace S., Lipari P., Pichiri I., Bertolini L., Valbusa F., Barbieri E., Zoppini G., et al. Nonalcoholic Fatty Liver Disease Is Independently Associated with Early Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes. PLoS ONE. 2015;10:e0135329. doi: 10.1371/journal.pone.0135329.
    1. VanWagner L.B., Wilcox J.E., Colangelo L.A., Lloyd-Jones D.M., Carr J.J., Lima J.A., Lewis C.E., Rinella M.E., Shah S.J. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. Hepatology. 2015;62:773–783. doi: 10.1002/hep.27869.
    1. Markus M.R., Baumeister S.E., Stritzke J., Dörr M., Wallaschofski H., Völzke H., Lieb W. Hepatic steatosis is associated with aortic valve sclerosis in the general population: The Study of Health in Pomerania (SHIP) Arterioscler. Thromb. Vasc. Biol. 2013;33:1690–1695. doi: 10.1161/ATVBAHA.112.300556.
    1. Bonapace S., Valbusa F., Bertolini L., Pichiri I., Mantovani A., Rossi A., Zenari L., Barbieri E., Targher G. Nonalcoholic Fatty Liver Disease Is Associated with Aortic Valve Sclerosis in Patients with Type 2 Diabetes Mellitus. PLoS ONE. 2014;9:e88371. doi: 10.1371/journal.pone.0088371.
    1. Valbusa F., Agnoletti D., Scala L., Grillo C., Arduini P., Bonapace S., Calabria S., Scaturro G., Mantovani A., Zoppini G., et al. Non-alcoholic fatty liver disease and increased risk of all-cause mortality in elderly patients admitted for acute heart failure. Int. J. Cardiol. 2018;265:162–168. doi: 10.1016/j.ijcard.2018.04.129.
    1. Yoshihisa A., Sato Y., Yokokawa T., Sato T., Suzuki S., Oikawa M., Kobayashi A., Yamaki T., Kunii H., Nakazato K., et al. Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction. ESC Heart Fail. 2018;5:262–270. doi: 10.1002/ehf2.12222.
    1. Wijarnpreecha K., Boonpheng B., Thongprayoon C., Jaruvongvanich V., Ungprasert P. The association between non-alcoholic fatty liver disease and atrial fibrillation: A meta-analysis. Clin. Res. Hepatol. Gastroenterol. 2017;41:525–532. doi: 10.1016/j.clinre.2017.08.001.
    1. Markus M.R., Meffert P.J., Baumeister S.E., Lieb W., Siewert U., Schipf S., Koch M., Kors J.A., Felix S.B., Dörr M., et al. Association between hepatic steatosis and serum liver enzyme levels with atrial fibrillation in the general population: The Study of Health in Pomerania (SHIP) Atherosclerosis. 2016;245:123–131. doi: 10.1016/j.atherosclerosis.2015.12.023.
    1. Käräjämäki A.J., Pätsi O.-P., Savolainen M., Kesäniemi Y.A., Huikuri H., Ukkola O. Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle-Aged Population (OPERA Study) PLoS ONE. 2015;10:e0142937. doi: 10.1371/journal.pone.0142937.
    1. Targher G., Valbusa F., Bonapace S., Bertolini L., Zenari L., Rodella S., Zoppini G., Mantovani W., Barbieri E., Byrne C.D. Non-Alcoholic Fatty Liver Disease Is Associated with an Increased Incidence of Atrial Fibrillation in Patients with Type 2 Diabetes. PLoS ONE. 2013;8:e57183. doi: 10.1371/journal.pone.0057183.
    1. Mantovani A., Rigamonti A., Bonapace S., Bolzan B., Pernigo M., Morani G., Franceschini L., Bergamini C., Bertolini L., Valbusa F., et al. Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring. Diabetes Care. 2016;39:1416–1423. doi: 10.2337/dc16-0091.
    1. Mantovani A., Rigolon R., Pichiri I., Bonapace S., Morani G., Zoppini G., Bonora E., Targher G. Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus. PLoS ONE. 2017;12:e0185459. doi: 10.1371/journal.pone.0185459.
    1. Hu J., Xu Y., He Z., Zhang H., Lian X., Zhu T., Liang C., Li J. Increased risk of cerebrovascular accident related to non-alcoholic fatty liver disease: A meta-analysis. Oncotarget. 2017;9:2752–2760. doi: 10.18632/oncotarget.22755.
    1. Kim S.U., Song D., Heo J.H., Yoo J., Kim B.K., Park J.Y., Kim D.Y., Ahn S.H., Kim K.J., Han K.-H., et al. Liver fibrosis assessed with transient elastography is an independent risk factor for ischemic stroke. Atherosclerosis. 2017;260:156–162. doi: 10.1016/j.atherosclerosis.2017.02.005.
    1. Abdeldyem S.M., Goda T., Khodeir S.A., Saif S.A., Abd-Elsalam S. Nonalcoholic fatty liver disease in patients with acute ischemic stroke is associated with more severe stroke and worse outcome. J. Clin. Lipidol. 2017;11:915–919. doi: 10.1016/j.jacl.2017.04.115.
    1. Tziomalos K., Giampatzis V., Bouziana S.D., Spanou M., Papadopoulou M., Pavlidis A., Kostaki S., Bozikas A., Savopoulos C., Hatzitolios A.I. Association between nonalcoholic fatty liver disease and acute ischemic stroke severity and outcome. World J. Hepatol. 2013;5:621–626. doi: 10.4254/wjh.v5.i11.621.
    1. Tripodi A., Fracanzani A.L., Primignani M., Chantarangkul V., Clerici M., Mannucci P.M., Peyvandi F., Bertelli C., Valenti L., Fargion S. Procoagulant imbalance in patients with non-alcoholic fatty liver disease. J. Hepatol. 2014;61:148–154. doi: 10.1016/j.jhep.2014.03.013.
    1. Stine J.G., Niccum B.A., Zimmet A.N., Intagliata N., Caldwell S.H., Argo C.K., Northup P.G. Increased risk of venous thromboembolism in hospitalized patients with cirrhosis due to non-alcoholic steatohepatitis. Clin. Transl. Gastroenterol. 2018;9:140. doi: 10.1038/s41424-018-0002-y.
    1. EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 2016;64:1388–1402. doi: 10.1016/j.jhep.2015.11.004.
    1. Simon T.G., Bamira D.G., Chung R.T., Weiner R.B., Corey K.E. Nonalcoholic steatohepatitis (NASH) is associated with cardiac remodeling and dysfunction. Obesity. 2017;25:1313–1316. doi: 10.1002/oby.21879.
    1. Cuenza L.R., Razon T.L.J., Dayrit J.C. Correlation between severity of ultrasonographic nonalcoholic fatty liver disease and cardiometabolic risk among Filipino wellness patients. J. Cardiovasc. Thorac. Res. 2017;9:85–89. doi: 10.15171/jcvtr.2017.14.
    1. Ballestri S., Romagnoli D., Nascimbeni F., Francica G., Lonardo A. Role of ultrasound in the diagnosis and treatment of nonalcoholic fatty liver disease and its complications. Expert Rev. Gastroenterol. Hepatol. 2015;9:603–627. doi: 10.1586/17474124.2015.1007955.
    1. Speliotes E.K., Yerges-Armstrong L.M., Wu J., Hernaez R., Kim L.J., Palmer C.D., Gudnason V., Eiriksdottir G., Garcia M.E., Launer L.J. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7:e1001324. doi: 10.1371/journal.pgen.1001324.
    1. Wagenknecht L.E., Scherzinger A.L., Stamm E.R., Hanley A.J.G., Norris J.M., Chen Y.-D.I., Bryer-Ash M., Haffner S.M., Rotter J.I. Correlates and Heritability of Nonalcoholic Fatty Liver Disease in a Minority Cohort. Obesity. 2009;17:1240–1246. doi: 10.1038/oby.2009.4.
    1. Palmer N.D., Musani S.K., Yerges-Armstrong L.M., Feitosa M.F., Bielak L.F., Hernaez R., Kahali B., Carr J.J., Harris T.B., Jhun M.A., et al. Characterization of European-ancestry NAFLD-Associated Variants in Individuals of African and Hispanic Descent. Hepatology. 2013;58:966–975. doi: 10.1002/hep.26440.
    1. Romeo S., Kozlitina J., Xing C., Pertsemlidis A., Cox D., Pennacchio L.A., Boerwinkle E., Cohen J.C., Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008;40:1461–1465. doi: 10.1038/ng.257.
    1. Sookoian S., Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53:1883–1894. doi: 10.1002/hep.24283.
    1. Petta S., Valenti L., Marchesini G., Di Marco V., Licata A., Camma’ C., Barcellona M.R., Cabibi D., Donati B., Fracanzani A.L., et al. PNPLA3 GG Genotype and Carotid Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease. PLoS ONE. 2013;8:e74089. doi: 10.1371/journal.pone.0074089.
    1. Pare G., Ridker P.M., Rose L., Barbalić M., Dupuis J., Dehghan A., Bis J.C., Benjamin E.J., Shiffman D., Parker A.N., et al. Genome-Wide Association Analysis of Soluble ICAM-1 Concentration Reveals Novel Associations at the NFKBIK, PNPLA3, RELA, and SH2B3 Loci. PLoS Genet. 2011;7:e1001374. doi: 10.1371/journal.pgen.1001374.
    1. Kozlitina J., Smagris E., Stender S., Nordestgaard B.G., Zhou H.H., Tybjærg-Hansen A., Vogt T.F., Hobbs H.H., Cohen J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014;46:352–356. doi: 10.1038/ng.2901.
    1. Dongiovanni P., Petta S., Maglio C., Fracanzani A.L., Pipitone R.M., Mozzi E., Motta B.M., Kaminska D., Rametta R., Grimaudo S., et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61:506–514. doi: 10.1002/hep.27490.
    1. Holmen O.L., Zhang H., Fan Y., Hovelson D.H., Schmidt E.M., Zhou W., Guo Y., Zhang J., Langhammer A., Løchen M.-L., et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat. Genet. 2014;46:345–351. doi: 10.1038/ng.2926.
    1. Tokushige K., Hashimoto E., Noto H., Yatsuji S., Taniai M., Torii N., Shiratori K. Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease. J. Gastroenterol. 2009;44:976–982. doi: 10.1007/s00535-009-0085-z.
    1. Lu H., Sun J., Sun L., Shu X., Xu Y., Xie D. Polymorphism of human leptin receptor gene is associated with type 2 diabetic patients complicated with non-alcoholic fatty liver disease in China. J. Gastroenterol. Hepatol. 2009;24:228–232. doi: 10.1111/j.1440-1746.2008.05544.x.
    1. Swellam M., Hamdy N. Association of nonalcoholic fatty liver disease with a single nucleotide polymorphism on the gene encoding leptin receptor. IUBMB Life. 2012;64:180–186. doi: 10.1002/iub.597.
    1. Zain S.M., Mohamed Z., Mahadeva S., Cheah P.-L., Rampal S., Chin K.-F., Mahfudz A.S., Basu R.C., Tan H.-L., Mohamed R. Impact of leptin receptor gene variants on risk of non-alcoholic fatty liver disease and its interaction with adiponutrin gene. J. Gastroenterol. Hepatol. 2013;28:873–879. doi: 10.1111/jgh.12104.
    1. Loria P., Marchesini G., Nascimbeni F., Ballestri S., Maurantonio M., Carubbi F., Ratziu V., Lonardo A. Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. Atherosclerosis. 2014;232:99–109. doi: 10.1016/j.atherosclerosis.2013.10.030.
    1. Alkhouri N., Tamimi T.A.-R., Yerian L., Lopez R., Zein N.N., Feldstein A.E. The inflamed liver and atherosclerosis: A link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk. Dig. Dis. Sci. 2010;55:2644–2650. doi: 10.1007/s10620-009-1075-y.
    1. Pereira E.N.G.D.S., Silvares R.R., Flores E.E.I., Rodrigues K.L., Ramos I.P., da Silva I.J., Machado M.P., Miranda R.A., Pazos-Moura C.C., Gonçalves-de-Albuquerque C.F., et al. Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease. PLoS ONE. 2017;12:e0179654. doi: 10.1371/journal.pone.0179654.
    1. Jaruvongvanich V., Wijarnpreecha K., Sanguankeo A., Chenbhanich J., Rattanawong P., Upala S. Increased Arterial Stiffness in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Eur. J. Gastroenterol. Hepatol. 2017;152:S1203. doi: 10.1097/MEG.0000000000000909.
    1. Steffen H., Demir M., Lang S., Schulte S., Töx U. High rate of undetected arterial hypertension in patients with non-alcoholic steatohepatitis (Nash): PP.34.356. J. Hypertens. 2010;28:e557. doi: 10.1097/01.hjh.0000379894.33597.07.
    1. Tana C., Tana M., Rossi S., Silingardi M., Schiavone C. Hepatic artery resistive index (HARI) and non-alcoholic fatty liver disease (NAFLD) fibrosis score in NAFLD patients: Cut-off suggestive of non-alcoholic steatohepatitis (NASH) evolution. J. Ultrasound. 2016;19:183–189. doi: 10.1007/s40477-016-0203-8.
    1. Tana C., Schiavone C., Ticinesi A., Lauretani F., Nouvenne A., Dietrich C.F., Meschi T. Hepatic artery resistive index as surrogate marker for fibrosis progression in NAFLD patients: A clinical perspective. Int. J. Immunopathol. Pharmacol. 2018;32 doi: 10.1177/2058738418781373.
    1. Latea L., Negrea S., Bolboaca S. Primary non alcoholic fatty liver disease in hypertensive patients. Australas. Med. J. 2013;6:325–330. doi: 10.4066/AMJ.2013.1648.
    1. Ryoo J.-H., Suh Y.J., Shin H.C., Cho Y.K., Choi J.-M., Park S.K. Clinical association between non-alcoholic fatty liver disease and the development of hypertension. J. Gastroenterol. Hepatol. 2014;29:1926–1931. doi: 10.1111/jgh.12643.
    1. Francque S., Laleman W., Verbeke L., Van Steenkiste C., Casteleyn C., Kwanten W., Van Dyck C., D’Hondt M., Ramon A., Vermeulen W., et al. Increased intrahepatic resistance in severe steatosis: Endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Lab. Investig. 2012;92:1428–1439. doi: 10.1038/labinvest.2012.103.
    1. Vonghia L., Magrone T., Verrijken A., Michielsen P., Van Gaal L., Jirillo E., Francque S. Peripheral and Hepatic Vein Cytokine Levels in Correlation with Non-Alcoholic Fatty Liver Disease (NAFLD)-Related Metabolic, Histological, and Haemodynamic Features. PLoS ONE. 2015;10:e0143380. doi: 10.1371/journal.pone.0143380.
    1. Coulon S., Francque S., Colle I., Verrijken A., Blomme B., Heindryckx F., De Munter S., Prawitt J., Caron S., Staels B., et al. Evaluation of inflammatory and angiogenic factors in patients with non-alcoholic fatty liver disease. Cytokine. 2012;59:442–449. doi: 10.1016/j.cyto.2012.05.001.
    1. Kotronen A., Joutsi-Korhonen L., Sevastianova K., Bergholm R., Hakkarainen A., Pietiläinen K.H., Lundbom N., Rissanen A., Lassila R., Yki-Järvinen H. Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease. Liver Int. 2011;31:176–183. doi: 10.1111/j.1478-3231.2010.02375.x.
    1. Verrijken A., Francque S., Mertens I., Prawitt J., Caron S., Hubens G., Van Marck E., Staels B., Michielsen P., Van Gaal L. Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2014;59:121–129. doi: 10.1002/hep.26510.
    1. Chow W.S., Xu A., Woo Y.C., Tso A.W.K., Cheung S.C.W., Fong C.H.Y., Tse H.F., Chau M.T., Cheung B.M.Y., Lam K.S.L. Serum Fibroblast Growth Factor-21 Levels Are Associated With Carotid Atherosclerosis Independent of Established Cardiovascular Risk Factors. Arter. Thromb. Vasc. Boil. 2013;33:2454–2459. doi: 10.1161/ATVBAHA.113.301599.
    1. Shen Y., Ma X., Zhou J., Pan X., Hao Y., Zhou M., Lu Z., Gao M., Bao Y., Jia W. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc. Diabetol. 2013;12:124. doi: 10.1186/1475-2840-12-124.
    1. Jensen M.K., Bartz T.M., Mukamal K.J., Djoussé L., Kizer J.R., Tracy R.P., Zieman S.J., Rimm E.B., Siscovick D.S., Shlipak M., et al. Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: The cardiovascular health study. Diabetes Care. 2013;36:1222–1228. doi: 10.2337/dc12-1591.
    1. Aron-Wisnewsky J., Clément K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat. Rev. Nephrol. 2016;12:169–181. doi: 10.1038/nrneph.2015.191.
    1. Brown J.M., Hazen S.L. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. Annu. Rev. Med. 2015;66:343–359. doi: 10.1146/annurev-med-060513-093205.
    1. Ticinesi A., Tana C., Nouvenne A. The intestinal microbiome and its relevance for functionality in older persons. Curr. Opin. Clin. Nutr. Metab. Care. 2019;22:4–12. doi: 10.1097/MCO.0000000000000521.
    1. Ticinesi A., Nouvenne A., Tana C., Prati B., Cerundolo N., Miraglia C., De’ Angelis G.L., Di Mario F., Meschi T. The impact of intestinal microbiota on bio-medical research: Definitions, techniques and physiology of a “new frontier”. Acta Biomed. 2018;89:52–59.
    1. Tang W.H., Wang Z., Levison B.S., Koeth R.A., Britt E.B., Fu X., Wu Y., Hazen S.L. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 2013;368:1575–1584. doi: 10.1056/NEJMoa1109400.
    1. Nouvenne A., Ticinesi A., Tana C., Prati B., Catania P., Miraglia C., De’ Angelis G.L., Di Mario F., Meschi T. Digestive disorders and Intestinal microbiota. Acta Biomed. 2018;89:47–51.
    1. Koren O., Spor A., Felin J., Fåk F., Stombaugh J., Tremaroli V., Behre C.J., Knight R., Fagerberg B., Ley R.E., et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. Natl. Acad. Sci. USA. 2011;108:S4592–S4598. doi: 10.1073/pnas.1011383107.
    1. Mantovani A., Byrne C.D., Bonora E., Targher G. Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis. Diabetes Care. 2018;41:372–382. doi: 10.2337/dc17-1902.
    1. Motamed N., Rabiee B., Poustchi H., Dehestani B., Hemasi G.R., Khonsari M.R., Maadi M., Saeedian F.S., Zamani F. Non-alcoholic fatty liver disease (NAFLD) and 10-year risk of cardiovascular diseases. Clin. Res. Hepatol. Gastroenterol. 2017;41:31–38. doi: 10.1016/j.clinre.2016.07.005.
    1. Treeprasertsuk S., Leverage S., Adams L.A., Lindor K.D., Sauver J.S., Angulo P. The framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int. 2012;32:945–950. doi: 10.1111/j.1478-3231.2011.02753.x.
    1. Nascimbeni F., Pais R., Bellentani S., Day C.P., Ratziu V., Loria P., Lonardo A. From NAFLD in clinical practice to answers from guidelines. J. Hepatol. 2013;59:859–871. doi: 10.1016/j.jhep.2013.05.044.
    1. Vilar-Gomez E., Martinez-Perez Y., Calzadilla-Bertot L., Torres-Gonzalez A., Gra-Oramas B., Gonzalez-Fabian L., Friedman S.L., Diago M., Romero-Gomez M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149:367–378. doi: 10.1053/j.gastro.2015.04.005.
    1. Katsagoni C.N., Georgoulis M., Papatheodoridis G.V., Panagiotakos D.B., Kontogianni M.D. Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: A meta-analysis. Metabolism. 2017;68:119–132. doi: 10.1016/j.metabol.2016.12.006.
    1. Chalasani N., Younossi Z., Lavine J.E., Charlton M., Cusi K., Rinella M., Harrison S.A., Brunt E.M., Sanyal A.J. 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. doi: 10.1002/hep.29367.
    1. Italian Association for the Study of the Liver (AISF) AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig. Liver Dis. 2017;49:471–483. doi: 10.1016/j.dld.2017.01.147.
    1. Estruch R., Ros E., Salas-Salvadó J., Covas M.I., Corella D., Arós F., Gómez-Gracia E., Ruiz-Gutiérrez V., Fiol M., Lapetra J., et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N. Engl. J. Med. 2018;378:e34. doi: 10.1056/NEJMoa1800389.
    1. Ryan M.C., Itsiopoulos C., Thodis T., Ward G., Trost N., Hofferberth S., O’Dea K., Desmond P.V., Johnson N.A., Wilson A.M. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J. Hepatol. 2013;59:138–143. doi: 10.1016/j.jhep.2013.02.012.
    1. Anania C., Perla F.M., Olivero F., Pacifico L., Chiesa C. Mediterranean diet and nonalcoholic fatty liver disease. World J. Gastroenterol. 2018;24:2083–2094. doi: 10.3748/wjg.v24.i19.2083.
    1. Ajmera V.H., Terrault N.A., Harrison S.A. Is Moderate Alcohol Use in Non-Alcoholic Fatty Liver Disease Good or Bad? A Critical Review. Hepatology. 2017;65:2090–2099. doi: 10.1002/hep.29055.
    1. Jung H.S., Chang Y., Kwon M.J., Sung E., Yun K.E., Cho Y.K., Shin H., Ryu S. Smoking and the Risk of Non-Alcoholic Fatty Liver Disease: A Cohort Study. Am. J. Gastroenterol. 2019 doi: 10.1038/s41395-018-0283-5.
    1. Ma S., Zheng Y., Xiao Y., Zhou P., Tan H. Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients. Medicine. 2017;96:e6888. doi: 10.1097/MD.0000000000006888.
    1. Musso G., Cassader M., Paschetta E., Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis. JAMA Intern. Med. 2017;177:633–640. doi: 10.1001/jamainternmed.2016.9607.
    1. Lincoff A.M., Wolski K., Nicholls S.J., Nissen S.E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis of randomized trials. JAMA. 2007;298:1180–1188. doi: 10.1001/jama.298.10.1180.
    1. Tang H., Shi W., Fu S., Wang T., Zhai S., Song Y., Han J. Pioglitazone and bladder cancer risk: A systematic review and meta-analysis. Cancer Med. 2018;7:1070–1080. doi: 10.1002/cam4.1354.
    1. Low Wang C.C., Hess C.N., Hiatt W.R., Goldfine A.B. Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus—Mechanisms, Management, and Clinical Considerations. Circulation. 2016;133:2459–2502. doi: 10.1161/CIRCULATIONAHA.116.022194.
    1. Tacelli M., Celsa C., Magro B., Giannetti A., Pennisi G., Spatola F., Petta S. Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once? Pharmaceuticals. 2018;11:121. doi: 10.3390/ph11040121.
    1. Armstrong M.J., Gaunt P., Aithal G.P., Barton D., Hull D., Parker R., Hazlehurst J.M., Guo K., LEAN Trial Team. Abouda G., et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–690. doi: 10.1016/S0140-6736(15)00803-X.
    1. Cui J., Philo L., Nguyen P., Hofflich H., Hernandez C., Bettencourt R., Richards L., Salotti J., Bhatt A., Hooker J., et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J. Hepatol. 2016;65:369–376. doi: 10.1016/j.jhep.2016.04.021.
    1. Shimizu M., Suzuki K., Kato K., Jojima T., Iijima T., Murohisa T., Iijima M., Takekawa H., Usui I., Hiraishi H., et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes. Metab. 2019;21:285–292. doi: 10.1111/dom.13520.
    1. Eriksson J.W., Lundkvist P., Jansson P.A., Johansson L., Kvarnström M., Moris L., Miliotis T., Forsberg G.B., Risérus U., Lind L., et al. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: A double-blind randomised placebo-controlled study. Diabetologia. 2018;61:1923–1934. doi: 10.1007/s00125-018-4675-2.
    1. Nauck M.A., Meier J.J., Cavender M.A., El Aziz M.A., Drucker D.J. Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors. Circulation. 2017;136:849–870. doi: 10.1161/CIRCULATIONAHA.117.028136.
    1. Zinman B., Wanner C., Hantel S., Mattheus M., Devins T., Broedl U.C., Inzucchi S.E., Lachin J.M., Fitchett D., Bluhmki E., et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.
    1. Taylor F., Macedo A.F., Moore T.H.M., Burke M., Smith G.D., Ward K., Ebrahim S., Huffman M.D. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2013;2013:CD004816. doi: 10.1002/14651858.CD004816.pub5.
    1. Athyros V.G., Boutari C., Stavropoulos K., Anagnostis P., Imprialos K.P., Doumas M., Karagiannis A. Statins: An Under-Appreciated Asset for the Prevention and the Treatment of NAFLD or NASH and the Related Cardiovascular Risk. Curr. Vasc. Pharmacol. 2018;16:246–253. doi: 10.2174/1570161115666170621082910.
    1. Eslami L., Merat S., Malekzadeh R., Aramin H., Nasseri-Moghaddam S. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst. Rev. 2013;12:CD008623. doi: 10.1002/14651858.CD008623.pub2.
    1. Rattanachaisit P., Susantitaphong P., Thanapirom K., Chaiteerakij R., Komolmit P., Tangkijvanich P., Treeprasertsuk S. Statin use and histopathological change in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. Asian Biomed. 2018;12:3–13. doi: 10.1515/abm-2018-0026.
    1. Zhou Y.Y., Zhu G.Q., Wang Y., Zheng J.N., Ruan L.Y., Cheng Z., Hu B., Fu S.W., Zheng M.H. Systematic review with network meta-analysis: Statins and risk of hepatocellular carcinoma. Oncotarget. 2016;7:21753–21762. doi: 10.18632/oncotarget.7832.
    1. Ishii N., Ohashi T., Nakade Y., Murotani K., Inoue T., Kobayashi Y., Yamamoto T., Ito K., Fukuzawa Y., Yoneda M. Ezetimibe for the treatment of non-alcoholic fatty liver disease: A meta-analysis. Hepatol. Res. 2017;47:1417–1428.
    1. Catapano A.L., Graham I., De Backer G., Wiklund O., Chapman M.J., Drexel H., Hoes A.W., Jennings C.S., Landmesser U., Pedersen T.R., et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur. Heart J. 2016;37:2999–3058. doi: 10.1093/eurheartj/ehw272.
    1. Athyros V.G., Tziomalos K., Gossios T.D., Griva T., Anagnostis P., Kargiotis K., Pagourelias E.D., Theocharidou E., Karagiannis A., Mikhailidis D.P. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: A post-hoc analysis. Lancet. 2010;376:1916–1922. doi: 10.1016/S0140-6736(10)61272-X.
    1. Tikkanen M.J., Fayyad R., Faergeman O., Olsson A.G., Wun C.-C., Laskey R., Kastelein J.J., Holme I., Pedersen T.R. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int. J. Cardiol. 2013;168:3846–3852. doi: 10.1016/j.ijcard.2013.06.024.
    1. Simon T.G., Corey K.E., Cannon C.P., Blazing M., Park J.-G., O’Donoghue M.L., Chung R.T., Giugliano R.P. The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe. Int. J. Cardiol. 2018;270:245–252. doi: 10.1016/j.ijcard.2018.05.087.
    1. Abdelhamid A.S., Brown T.J., Brainard J.S., Biswas P., Thorpe G.C., Moore H.J., Deane K.H., AlAbdulghafoor F.K., Summerbell C.D., Worthington H.V., et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2018;11:CD003177.
    1. Zhu Q., Li N., Li F., Zhou Z., Han Q., Lv Y., Sang J., Liu Z. Therapeutic effect of renin angiotensin system inhibitors on liver fibrosis. J. Renin Angiotensin Aldosterone Syst. 2016;17 doi: 10.1177/1470320316628717.
    1. Li Y., Xu H., Wu W., Ye J., Fang D., Shi D., Li L. Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. Oncotarget. 2018;9:24155–24167. doi: 10.18632/oncotarget.23816.
    1. Al-Mallah M., Khawaja O., Sinno M., Alzohaili O., Samra A.B.A. Do angiotensin converting enzyme inhibitors or angiotensin receptor blockers prevent diabetes mellitus? A meta-analysis. Cardiol. J. 2010;17:448–456.
    1. Singh S., Khera R., Allen A.M., Murad M.H., Loomba R. Comparative effectiveness of pharmacological interventions for non-alcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015;62:1417–1432. doi: 10.1002/hep.27999.
    1. Bjelaković G., Nikolova D., Gluud C. Antioxidant Supplements to Prevent Mortality. JAMA. 2013;310:1178. doi: 10.1001/jama.2013.277028.
    1. Vardi M., Levy N.S., Levy A.P. Vitamin E in the prevention of cardiovascular disease: The importance of proper patient selection. J. Lipid Res. 2013;54:2307–2314. doi: 10.1194/jlr.R026641.
    1. Lee Y., Doumouras A.G., Yu J., Brar K., Banfield L., Gmora S., Anvari M., Hong D. Complete Resolution of Nonalcoholic Fatty Liver Disease After Bariatric Surgery: A Systematic Review and Meta-Analysis. Clin. Gastroenterol. Hepatol. 2018 doi: 10.1016/j.cgh.2018.10.017.
    1. Carlsson L.M., Peltonen M., Ahlin S., Anveden Å., Bouchard C., Carlsson B., Jacobson P., Lönroth H., Maglio C., Näslund I., et al. Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N. Engl. J. Med. 2012;367:695–704. doi: 10.1056/NEJMoa1112082.
    1. Sjöström L., Peltonen M., Jacobson P., Sjöström C.D., Karason K., Wedel H., Ahlin S., Anveden Å., Bengtsson C., Bergmark G., et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307:56–65. doi: 10.1001/jama.2011.1914.

Source: PubMed

3
Prenumerera