Advertisement

Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes

  • Fabio Nascimbeni
    Correspondence
    Corresponding author.
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Elisa Pellegrini
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Simonetta Lugari
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Alberto Mondelli
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Serena Bursi
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Giovanna Onfiani
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Francesca Carubbi
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author
  • Amedeo Lonardo
    Affiliations
    Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
    Search for articles by this author

      Abstract

      Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of alcohol-like hepatic histological changes, which occur in the absence of any competing causes of chronic liver disease, notably including significant alcohol consumption. A close and bi-directional relationship links NAFLD with the metabolic syndrome (MetS), and concurrent MetS will hasten the progression to more severe forms of NAFLD, including cirrhosis and hepatocellular carcinoma (HCC). Patients with NAFLD will typically exhibit atherogenic dyslipidemia and increased cardiovascular risk (CVR).
      Statins are among the most widely prescribed lipid-lowering drugs. Their use has historically been hampered, in individuals with liver disease, owing to the fear of hepatotoxicity. However, studies suggest that statins are not only effective in reducing cardiovascular events, but may also exert multiple beneficial effects on the liver.
      CVR in those with NAFLD has extensively been covered by our group and others. This updated clinical narrative review will critically examine the effects of statins on the pathogenesis of NAFLD, including the key elementary pathological lesions of NAFLD, i.e. steatosis, inflammation and fibrosis, and its liver-related complications, i.e. cirrhosis, portal hypertension and HCC.

      Keywords

      Abbreviations:

      AMPK (adenosine monophosphate-activated protein kinase), ChREBP (carbohydrate response element binding protein), CVD (cardiovascular disease), CVR (cardiovascular risk), DILI (drug-induced liver injury), ER (endoplasmic reticulum), FC (free cholesterol), HDL (high-density lipoprotein), HSCs (hepatic stellate cells), HVPG (hepatic venous pressure gradient), ICAM-1 (intercellular adhesion molecule-1), IR (insulin resistance), KLF2 (Krüppel-like Factor 2), LDL (low-density lipoprotein), LFA-1 (lymphocyte function-associated antigen 1), MAPK (mitogen-activated protein kinase), MetS (metabolic syndrome), NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), NF-kB (nuclear factor-kB), NO (nitric oxide), NgBR (Nogo-B receptor), PKA (protein kinase-A), Plin5 (perilipin 5), PNPLA8 (patatin-like phospholipase domain-containing enzyme 8), PPAR (peroxisome proliferator-activated receptor), SREBPs (sterol regulatory element-binding proteins), TGF-β1 (transforming growth factor-β1), TNFα (tumour necrosis factor α)
      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:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lonardo A.
        • Nascimbeni F.
        • Maurantonio M.
        • Marrazzo A.
        • Rinaldi L.
        • Adinolfi L.E.
        Nonalcoholic fatty liver disease: evolving paradigms.
        World J. Gastroenterol. WJG. 2017; 23: 6571-6592
        • Nascimbeni F.
        • Loria P.
        • Ratziu V.
        Non-alcoholic Fatty liver disease: diagnosis and investigation.
        Dig. Dis. 2014; 32: 586-596
        • Arrese M.
        Burning hepatic fat: therapeutic potential for liver-specific thyromimetics in the treatment of nonalcoholic fatty liver disease.
        Hepatology. 2009; 49: 348-351
        • Vilar-Gomez E.
        • Calzadilla-Bertot L.
        • Wai-Sun Wong V.
        • Castellanos M.
        • Aller-de la Fuente R.
        • Metwally M.
        • Eslam M.
        • Gonzalez-Fabian L.
        • Alvarez-Quinones Sanz M.
        • Conde-Martin A.F.
        • De Boer B.
        • McLeod D.
        • Hung Chan A.W.
        • Chalasani N.
        • George J.
        • Adams L.A.
        • Romero-Gomez M.
        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 (e417): 443-457
        • 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
        • Lonardo A.
        • Ballestri S.
        • Targher G.
        • Loria P.
        Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease.
        Expert Rev. Gastroenterol. Hepatol. 2015; 9: 629-650
        • 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
      1. L. European association for the study of the, D. European association for the study of, O. European association for the study of, EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
        J. Hepatol. 2016; 64: 1388-1402
        • Athyros V.G.
        • Alexandrides T.K.
        • Bilianou H.
        • Cholongitas E.
        • Doumas M.
        • Ganotakis E.S.
        • Goudevenos J.
        • Elisaf M.S.
        • Germanidis G.
        • Giouleme O.
        • Karagiannis A.
        • Karvounis C.
        • Katsiki N.
        • Kotsis V.
        • Kountouras J.
        • Liberopoulos E.
        • Pitsavos C.
        • Polyzos S.
        • Rallidis L.S.
        • Richter D.
        • Tsapas A.G.
        • Tselepis A.D.
        • Tsioufis K.
        • Tziomalos K.
        • Tzotzas T.
        • Vasiliadis T.G.
        • Vlachopoulos C.
        • Mikhailidis D.P.
        • Mantzoros C.
        The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk.
        An Expert Panel Statement, Metabolism: Clin. Exp. 2017; 71: 17-32
        • Lonardo A.
        • Loria P.
        Potential for statins in the chemoprevention and management of hepatocellular carcinoma.
        J. Gastroenterol. Hepatol. 2012; 27: 1654-1664
        • Heller D.J.
        • Coxson P.G.
        • Penko J.
        • Pletcher M.J.
        • Goldman L.
        • Odden M.C.
        • Kazi D.S.
        • Bibbins-Domingo K.
        Evaluating the impact and cost-effectiveness of statin use guidelines for primary prevention of coronary heart disease and stroke.
        Circulation. 2017; 136: 1087-1098
        • Argo C.K.
        • Loria P.
        • Caldwell S.H.
        • Lonardo A.
        Statins in liver disease: a molehill, an iceberg, or neither?.
        Hepatology. 2008; 48: 662-669
        • Bishnu S.
        • Ahammed S.M.
        • Sarkar A.
        • Hembram J.
        • Chatterjee S.
        • Das K.
        • Dhali G.K.
        • Chowdhury A.
        • Das K.
        Effects of atorvastatin on portal hemodynamics and clinical outcomes in patients with cirrhosis with portal hypertension: a proof-of-concept study.
        Eur. J. Gastroenterol. Hepatol. 2018; 30: 54-59
        • Moctezuma-Velazquez C.
        • Abraldes J.G.
        • Montano-Loza A.J.
        The use of statins in patients with chronic liver disease and cirrhosis.
        Curr. Treat. Options Gastroenterol. 2018; 16: 226-240
        • Wong J.C.
        • Chan H.L.
        • Tse Y.K.
        • Yip T.C.
        • Wong V.W.
        • Wong G.L.
        Statins reduce the risk of liver decompensation and death in chronic viral hepatitis: a propensity score weighted landmark analysis.
        Aliment. Pharmacol. Ther. 2017; 46: 1001-1010
        • Chang F.M.
        • Wang Y.P.
        • Lang H.C.
        • Tsai C.F.
        • Hou M.C.
        • Lee F.Y.
        • Lu C.L.
        Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study.
        Hepatology. 2017; 66: 896-907
        • Horsmans Y.
        • Desager J.P.
        • Harvengt C.
        Biochemical changes and morphological alterations of the liver in Guinea-pigs after administration of simvastatin (HMG CoA reductase-inhibitor).
        Pharmacol. Toxicol. 1990; 67: 336-339
        • Chalasani N.
        Statins and hepatotoxicity: focus on patients with fatty liver.
        Hepatology. 2005; 41: 690-695
        • de Denus S.
        • Spinler S.A.
        • Miller K.
        • Peterson A.M.
        Statins and liver toxicity: a meta-analysis.
        Pharmacotherapy. 2004; 24: 584-591
        • Dale K.M.
        • White C.M.
        • Henyan N.N.
        • Kluger J.
        • Coleman C.I.
        Impact of statin dosing intensity on transaminase and creatine kinase.
        Am. J. Med. 2007; 120: 706-712
        • Pastori D.
        • Polimeni L.
        • Baratta F.
        • Pani A.
        • Del Ben M.
        • Angelico F.
        The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease, Digestive and liver disease.
        Off. J. Italian Soc. Gastroenterol. Ital. Assoc. Study. Liver. 2015; 47: 4-11
        • Schachter M.
        Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.
        Fundam. Clin. Pharmacol. 2005; 19: 117-125
        • Bjornsson E.
        • Jacobsen E.I.
        • Kalaitzakis E.
        Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing.
        J. Hepatol. 2012; 56: 374-380
        • Bjornsson E.
        • Olsson R.
        Outcome and prognostic markers in severe drug-induced liver disease.
        Hepatology. 2005; 42: 481-489
        • Andrade R.J.
        • Lucena M.I.
        • Fernandez M.C.
        • Pelaez G.
        • Pachkoria K.
        • Garcia-Ruiz E.
        • Garcia-Munoz B.
        • Gonzalez-Grande R.
        • Pizarro A.
        • Duran J.A.
        • Jimenez M.
        • Rodrigo L.
        • Romero-Gomez M.
        • Navarro J.M.
        • Planas R.
        • Costa J.
        • Borras A.
        • Soler A.
        • Salmeron J.
        • Martin-Vivaldi R.
        • Spanish D.
        Group for the Study of Drug-Induced Liver, Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.
        Gastroenterology. 2005; 129: 512-521
        • Chalasani N.
        • Fontana R.J.
        • Bonkovsky H.L.
        • Watkins P.B.
        • Davern T.
        • Serrano J.
        • Yang H.
        • Rochon J.
        N. drug Induced Liver Injury, Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.
        Gastroenterology. 2008; 135 (1934 e1921-1924): 1924-1934
        • Russo M.W.
        • Hoofnagle J.H.
        • Gu J.
        • Fontana R.J.
        • Barnhart H.
        • Kleiner D.E.
        • Chalasani N.
        • Bonkovsky H.L.
        Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.
        Hepatology. 2014; 60: 679-686
        • Bjornsson E.S.
        Hepatotoxicity of statins and other lipid-lowering agents.
        Liver Int. : Off. J. Int. Assoc. Study Liver. 2017; 37: 173-178
        • Rzouq F.S.
        • Volk M.L.
        • Hatoum H.H.
        • Talluri S.K.
        • Mummadi R.R.
        • Sood G.K.
        Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians.
        Am. J. Med. Sci. 2010; 340: 89-93
        • Nascimbeni F.
        • Aron-Wisnewsky J.
        • Pais R.
        • Tordjman J.
        • Poitou C.
        • Charlotte F.
        • Bedossa P.
        • Poynard T.
        • Clement K.
        • Ratziu V.
        • Group L.s.
        Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease.
        BMJ Open Gastroenterology. 2016; 3 (e000075)
        • Del Ben M.
        • Baratta F.
        • Polimeni L.
        • Pastori D.
        • Loffredo L.
        • Averna M.
        • Violi F.
        • Angelico F.
        Under-prescription of statins in patients with non-alcoholic fatty liver disease, Nutrition, metabolism, and cardiovascular diseases.
        Nutr. Metabol. Cardiovasc. Dis. 2017; 27: 161-167
        • Blais P.
        • Lin M.
        • Kramer J.R.
        • El-Serag H.B.
        • Kanwal F.
        Statins are underutilized in patients with nonalcoholic fatty liver disease and dyslipidemia.
        Dig. Dis. Sci. 2016; 61: 1714-1720
        • Labenz C.
        • Huber Y.
        • Kalliga E.
        • Nagel M.
        • Ruckes C.
        • Straub B.K.
        • Galle P.R.
        • Worns M.A.
        • Anstee Q.M.
        • Schuppan D.
        • Schattenberg J.M.
        Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany.
        Aliment. Pharmacol. Ther. 2018; 48: 1109-1116
        • Chalasani N.
        • Aljadhey H.
        • Kesterson J.
        • Murray M.D.
        • Hall S.D.
        Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity.
        Gastroenterology. 2004; 126: 1287-1292
        • Athyros V.G.
        • Tziomalos K.
        • Gossios T.D.
        • Griva T.
        • Anagnostis P.
        • Kargiotis K.
        • Pagourelias E.D.
        • Theocharidou E.
        • Karagiannis A.
        • Mikhailidis D.P.
        • Group G.S.C.
        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
        • Browning J.D.
        Statins and hepatic steatosis: perspectives from the Dallas heart study.
        Hepatology. 2006; 44: 466-471
        • de Keyser C.E.
        • Koehler E.M.
        • Schouten J.N.
        • Visser L.E.
        • Hofman A.
        • Janssen H.L.
        • Stricker B.H.
        Statin therapy is associated with a reduced risk of non-alcoholic fatty liver in overweight individuals, Digestive and liver disease.
        Off. J. Italian Soc. Gastroenterol. Ital. Assoc. Study. Liver. 2014; 46: 720-725
        • Bril F.
        • Portillo Sanchez P.
        • Lomonaco R.
        • Orsak B.
        • Hecht J.
        • Tio F.
        • Cusi K.
        Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial.
        J. Clin. Endocrinol. Metab. 2017; 102: 2950-2961
        • Bays H.
        • Cohen D.E.
        • Chalasani N.
        • Harrison S.A.
        F. The national lipid association's statin safety task, an assessment by the statin liver safety task force: 2014 update.
        J. Clinic. Lipidol. 2014; 8: S47-S57
        • Newman C.B.
        • Preiss D.
        • Tobert J.A.
        • Jacobson T.A.
        • Page R.L.
        • 2nd
        • Goldstein L.B.
        • Chin C.
        • Tannock L.R.
        • Miller M.
        • Raghuveer G.
        • Duell P.B.
        • Brinton E.A.
        • Pollak A.
        • Braun L.T.
        • Welty F.K.
        • American Heart Association Clinical Lipidology L.M.
        • Thrombosis Committee a.J.C.o.t.C.o.A.T.
        • Vascular B.
        • Council on L.
        • Cardiometabolic H.
        Y. Council on cardiovascular disease in the, C. Council on clinical, C. Stroke, statin safety and associated adverse events: a scientific statement from the American heart association.
        Arterioscler. Thromb. Vasc. Biol. 2019; 39: e38-e81
        • Casula M.
        • Mozzanica F.
        • Scotti L.
        • Tragni E.
        • Pirillo A.
        • Corrao G.
        • Catapano A.L.
        Statin use and risk of new-onset diabetes: a meta-analysis of observational studies, Nutrition, metabolism, and cardiovascular diseases.
        Nutr. Metabol. Cardiovasc. Dis. 2017; 27: 396-406
        • Thakker D.
        • Nair S.
        • Pagada A.
        • Jamdade V.
        • Malik A.
        Statin use and the risk of developing diabetes: a network meta-analysis.
        Pharmacoepidemiol. Drug Saf. 2016; 25: 1131-1149
        • Swerdlow D.I.
        • Preiss D.
        • Kuchenbaecker K.B.
        • Holmes M.V.
        • Engmann J.E.
        • Shah T.
        • Sofat R.
        • Stender S.
        • Johnson P.C.
        • Scott R.A.
        • Leusink M.
        • Verweij N.
        • Sharp S.J.
        • Guo Y.
        • Giambartolomei C.
        • Chung C.
        • Peasey A.
        • Amuzu A.
        • Li K.
        • Palmen J.
        • Howard P.
        • Cooper J.A.
        • Drenos F.
        • Li Y.R.
        • Lowe G.
        • Gallacher J.
        • Stewart M.C.
        • Tzoulaki I.
        • Buxbaum S.G.
        • van der A.D.
        • Forouhi N.G.
        • Onland-Moret N.C.
        • van der Schouw Y.T.
        • Schnabel R.B.
        • Hubacek J.A.
        • Kubinova R.
        • Baceviciene M.
        • Tamosiunas A.
        • Pajak A.
        • Topor-Madry R.
        • Stepaniak U.
        • Malyutina S.
        • Baldassarre D.
        • Sennblad B.
        • Tremoli E.
        • de Faire U.
        • Veglia F.
        • Ford I.
        • Jukema J.W.
        • Westendorp R.G.
        • de Borst G.J.
        • de Jong P.A.
        • Algra A.
        • Spiering W.
        • Maitland-van der Zee A.H.
        • Klungel O.H.
        • de Boer A.
        • Doevendans P.A.
        • Eaton C.B.
        • Robinson J.G.
        • Duggan D.
        • Consortium D.
        • Consortium M.
        • InterAct C.
        • Kjekshus J.
        • Downs J.R.
        • Gotto A.M.
        • Keech A.C.
        • Marchioli R.
        • Tognoni G.
        • Sever P.S.
        • Poulter N.R.
        • Waters D.D.
        • Pedersen T.R.
        • Amarenco P.
        • Nakamura H.
        • McMurray J.J.
        • Lewsey J.D.
        • Chasman D.I.
        • Ridker P.M.
        • Maggioni A.P.
        • Tavazzi L.
        • Ray K.K.
        • Seshasai S.R.
        • Manson J.E.
        • Price J.F.
        • Whincup P.H.
        • Morris R.W.
        • Lawlor D.A.
        • Smith G.D.
        • Ben-Shlomo Y.
        • Schreiner P.J.
        • Fornage M.
        • Siscovick D.S.
        • Cushman M.
        • Kumari M.
        • Wareham N.J.
        • Verschuren W.M.
        • Redline S.
        • Patel S.R.
        • Whittaker J.C.
        • Hamsten A.
        • Delaney J.A.
        • Dale C.
        • Gaunt T.R.
        • Wong A.
        • Kuh D.
        • Hardy R.
        • Kathiresan S.
        • Castillo B.A.
        • van der Harst P.
        • Brunner E.J.
        • Tybjaerg-Hansen A.
        • Marmot M.G.
        • Krauss R.M.
        • Tsai M.
        • Coresh J.
        • Hoogeveen R.C.
        • Psaty B.M.
        • Lange L.A.
        • Hakonarson H.
        • Dudbridge F.
        • Humphries S.E.
        • Talmud P.J.
        • Kivimaki M.
        • Timpson N.J.
        • Langenberg C.
        • Asselbergs F.W.
        • Voevoda M.
        • Bobak M.
        • Pikhart H.
        • Wilson J.G.
        • Reiner A.P.
        • Keating B.J.
        • Hingorani A.D.
        • Sattar N.
        HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
        Lancet. 2015; 385: 351-361
        • Navarese E.P.
        • Buffon A.
        • Andreotti F.
        • Kozinski M.
        • Welton N.
        • Fabiszak T.
        • Caputo S.
        • Grzesk G.
        • Kubica A.
        • Swiatkiewicz I.
        • Sukiennik A.
        • Kelm M.
        • De Servi S.
        • Kubica J.
        Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus.
        Am. J. Cardiol. 2013; 111: 1123-1130
        • Preiss D.
        • Seshasai S.R.
        • Welsh P.
        • Murphy S.A.
        • Ho J.E.
        • Waters D.D.
        • DeMicco D.A.
        • Barter P.
        • Cannon C.P.
        • Sabatine M.S.
        • Braunwald E.
        • Kastelein J.J.
        • de Lemos J.A.
        • Blazing M.A.
        • Pedersen T.R.
        • Tikkanen M.J.
        • Sattar N.
        • Ray K.K.
        Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
        Jama. 2011; 305: 2556-2564
        • Kamran H.
        • Kupferstein E.
        • Sharma N.
        • Karam J.G.
        • Myers A.K.
        • Youssef I.
        • Sowers J.R.
        • Gustafson D.R.
        • Salifu M.O.
        • McFarlane S.I.
        Statins and new-onset diabetes in cardiovascular and kidney disease cohorts: a meta-analysis.
        Cardiorenal medicine. 2018; 8: 105-112
        • Antonopoulos S.
        • Mikros S.
        • Mylonopoulou M.
        • Kokkoris S.
        • Giannoulis G.
        Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients.
        Atherosclerosis. 2006; 184: 233-234
        • Hyogo H.
        • Tazuma S.
        • Arihiro K.
        • Iwamoto K.
        • Nabeshima Y.
        • Inoue M.
        • Ishitobi T.
        • Nonaka M.
        • Chayama K.
        Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia.
        Metab. Clin. Exp. 2008; 57: 1711-1718
        • Chatrath H.
        • Vuppalanchi R.
        • Chalasani N.
        Dyslipidemia in patients with nonalcoholic fatty liver disease.
        Semin. Liver Dis. 2012; 32: 22-29
        • Kargiotis K.
        • Athyros V.G.
        • Giouleme O.
        • Katsiki N.
        • Katsiki E.
        • Anagnostis P.
        • Boutari C.
        • Doumas M.
        • Karagiannis A.
        • Mikhailidis D.P.
        Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.
        World J. Gastroenterol. WJG. 2015; 21: 7860-7868
        • Schierwagen R.
        • Uschner F.E.
        • Magdaleno F.
        • Klein S.
        • Trebicka J.
        Rationale for the use of statins in liver disease.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2017; 312: G407-G412
        • Pose E.
        • Trebicka J.
        • Mookerjee R.P.
        • Angeli P.
        • Gines P.
        Statins: old drugs as new therapy for liver diseases?.
        J. Hepatol. 2019 Jan; 70: 194-202
        • Ballestri S.
        • Nascimbeni F.
        • Romagnoli D.
        • Baldelli E.
        • Lonardo A.
        The role of nuclear receptors in the pathophysiology, natural course, and drug treatment of NAFLD in humans.
        Adv. Ther. 2016; 33: 291-319
        • Nascimbeni F.
        • Ballestri S.
        • Machado M.V.
        • Mantovani A.
        • Cortez-Pinto H.
        • Targher G.
        • Lonardo A.
        Clinical relevance of liver histopathology and different histological classifications of NASH in adults.
        Expert Rev. Gastroenterol. Hepatol. 2018; 12: 351-367
        • Imprialos K.P.
        • Stavropoulos K.
        • Doumas M.
        • Skalkou A.
        • Zografou I.
        • Athyros V.G.
        The potential role of statins in treating liver disease.
        Expert Rev. Gastroenterol. Hepatol. 2018; 12: 331-339
        • Rallidis L.S.
        • Drakoulis C.K.
        • Parasi A.S.
        Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study.
        Atherosclerosis. 2004; 174: 193-196
        • Ekstedt M.
        • Franzen L.E.
        • Mathiesen U.L.
        • Holmqvist M.
        • Bodemar G.
        • Kechagias S.
        Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
        J. Hepatol. 2007; 47: 135-141
        • Nelson A.
        • Torres D.M.
        • Morgan A.E.
        • Fincke C.
        • Harrison S.A.
        A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
        J. Clin. Gastroenterol. 2009; 43: 990-994
        • Hyogo H.
        • Ikegami T.
        • Tokushige K.
        • Hashimoto E.
        • Inui K.
        • Matsuzaki Y.
        • Tokumo H.
        • Hino F.
        • Tazuma S.
        Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study.
        Hepatol. Res. Off. J. Japan Soc. Hepatol. 2011; 41: 1057-1065
        • Nakahara T.
        • Hyogo H.
        • Kimura Y.
        • Ishitobi T.
        • Arihiro K.
        • Aikata H.
        • Takahashi S.
        • Chayama K.
        Efficacy of rosuvastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study.
        Hepatol. Res. Off. J. Japan Soc. Hepatol. 2012; 42: 1065-1072
        • Dongiovanni P.
        • Petta S.
        • Mannisto V.
        • Mancina R.M.
        • Pipitone R.
        • Karja V.
        • Maggioni M.
        • Kakela P.
        • Wiklund O.
        • Mozzi E.
        • Grimaudo S.
        • Kaminska D.
        • Rametta R.
        • Craxi A.
        • Fargion S.
        • Nobili V.
        • Romeo S.
        • Pihlajamaki J.
        • Valenti L.
        Statin use and non-alcoholic steatohepatitis in at risk individuals.
        J. Hepatol. 2015; 63: 705-712
        • Eslami L.
        • Merat S.
        • Malekzadeh R.
        • Nasseri-Moghaddam S.
        • Aramin H.
        Statins for Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis.
        The Cochrane database of systematic reviews, 2013: CD008623
        • Angulo P.
        • Kleiner D.E.
        • Dam-Larsen S.
        • Adams L.A.
        • Bjornsson E.S.
        • Charatcharoenwitthaya P.
        • Mills P.R.
        • Keach J.C.
        • Lafferty H.D.
        • Stahler A.
        • Haflidadottir S.
        • Bendtsen F.
        Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2015; 149: 389-397 e310
        • Goldstein J.L.
        • Brown M.S.
        A century of cholesterol and coronaries: from plaques to genes to statins.
        Cell. 2015; 161: 161-172
        • Rodriguez-Calvo R.
        • Barroso E.
        • Serrano L.
        • Coll T.
        • Sanchez R.M.
        • Merlos M.
        • Palomer X.
        • Laguna J.C.
        • Vazquez-Carrera M.
        Atorvastatin prevents carbohydrate response element binding protein activation in the fructose-fed rat by activating protein kinase A.
        Hepatology. 2009; 49: 106-115
        • Zhang W.
        • Yang X.
        • Chen Y.
        • Hu W.
        • Liu L.
        • Zhang X.
        • Liu M.
        • Sun L.
        • Liu Y.
        • Yu M.
        • Li X.
        • Li L.
        • Zhu Y.
        • Miao Q.R.
        • Han J.
        • Duan Y.
        Activation of hepatic Nogo-B receptor expression-A new anti-liver steatosis mechanism of statins, Biochimica et biophysica acta.
        Molecular and cell biology of lipids. 2018; 1863: 177-190
        • Gao X.
        • Nan Y.
        • Zhao Y.
        • Yuan Y.
        • Ren B.
        • Sun C.
        • Cao K.
        • Yu M.
        • Feng X.
        • Ye J.
        Atorvastatin reduces lipid accumulation in the liver by activating protein kinase A-mediated phosphorylation of perilipin 5, Biochimica et biophysica acta.
        Mol. Cell Biol. Lipids. 2017; 1862: 1512-1519
        • Kim K.Y.
        • Jang H.J.
        • Yang Y.R.
        • Park K.I.
        • Seo J.
        • Shin I.W.
        • Jeon T.I.
        • Ahn S.C.
        • Suh P.G.
        • Osborne T.F.
        • Seo Y.K.
        SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy.
        Sci. Rep. 2016; 6: 35732
        • Lahera V.
        • Goicoechea M.
        • de Vinuesa S.G.
        • Miana M.
        • de las Heras N.
        • Cachofeiro V.
        • Luno J.
        Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins.
        Curr. Med. Chem. 2007; 14: 243-248
        • Costa S.
        • Reina-Couto M.
        • Albino-Teixeira A.
        • Sousa T.
        Statins and oxidative stress in chronic heart failure, Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese.
        J. Cardiol.: an official journal of the Portuguese Society of Cardiology. 2016; 35: 41-57
        • Malizia G.
        • D'Amico G.
        Statins in cirrhosis: the magic pill?.
        Hepatology. 2016; 63: 2047-2049
        • Nishibori M.
        • Takahashi H.K.
        • Mori S.
        The regulation of ICAM-1 and LFA-1 interaction by autacoids and statins: a novel strategy for controlling inflammation and immune responses.
        J. Pharmacol. Sci. 2003; 92: 7-12
        • Hothersall E.
        • McSharry C.
        • Thomson N.C.
        Potential therapeutic role for statins in respiratory disease.
        Thorax. 2006; 61: 729-734
        • Hyogo H.
        • Yamagishi S.
        • Maeda S.
        • Kimura Y.
        • Ishitobi T.
        • Chayama K.
        Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-alpha-lowering property, Digestive and liver disease.
        Off. J. Italian Soc. Gastroenterol. Ital. Assoc. Study. Liver. 2012; 44: 492-496
        • Schierwagen R.
        • Maybuchen L.
        • Hittatiya K.
        • Klein S.
        • Uschner F.E.
        • Braga T.T.
        • Franklin B.S.
        • Nickenig G.
        • Strassburg C.P.
        • Plat J.
        • Sauerbruch T.
        • Latz E.
        • Lutjohann D.
        • Zimmer S.
        • Trebicka J.
        Statins improve NASH via inhibition of RhoA and ras.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2016; 311: G724-G733
        • Wagner A.H.
        • Schwabe O.
        • Hecker M.
        Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ.
        Br. J. Pharmacol. 2002; 136: 143-149
        • Huang K.C.
        • Chen C.W.
        • Chen J.C.
        • Lin W.W.
        HMG-CoA reductase inhibitors inhibit inducible nitric oxide synthase gene expression in macrophages.
        J. Biomed. Sci. 2003; 10: 396-405
        • Moreno M.
        • Ramalho L.N.
        • Sancho-Bru P.
        • Ruiz-Ortega M.
        • Ramalho F.
        • Abraldes J.G.
        • Colmenero J.
        • Dominguez M.
        • Egido J.
        • Arroyo V.
        • Gines P.
        • Bataller R.
        Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 296: G147-G156
        • Dold S.
        • Laschke M.W.
        • Lavasani S.
        • Menger M.D.
        • Jeppsson B.
        • Thorlacius H.
        Simvastatin protects against cholestasis-induced liver injury.
        Br. J. Pharmacol. 2009; 156: 466-474
        • Klein S.
        • Klosel J.
        • Schierwagen R.
        • Korner C.
        • Granzow M.
        • Huss S.
        • Mazar I.G.
        • Weber S.
        • van den Ven P.F.
        • Pieper-Furst U.
        • Furst D.O.
        • Nattermann J.
        • Lammert F.
        • Sauerbruch T.
        • Trebicka J.
        Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats, Laboratory investigation.
        a journal of technical methods and pathology. 2012; 92: 1440-1450
        • Marrone G.
        • Russo L.
        • Rosado E.
        • Hide D.
        • Garcia-Cardena G.
        • Garcia-Pagan J.C.
        • Bosch J.
        • Gracia-Sancho J.
        The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins.
        J. Hepatol. 2013; 58: 98-103
        • Chong L.W.
        • Hsu Y.C.
        • Lee T.F.
        • Lin Y.
        • Chiu Y.T.
        • Yang K.C.
        • Wu J.C.
        • Huang Y.T.
        Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells.
        BMC Gastroenterol. 2015; 15: 22
        • Cheng Y.
        • Zheng H.
        • Wang B.
        • Xu W.
        • Xu J.
        • Zhu Y.
        Sorafenib and fluvastatin synergistically alleviate hepatic fibrosis via inhibiting the TGFbeta1/Smad3 pathway, Digestive and liver disease.
        Off. J. Italian Soc. Gastroenterol. Ital. Assoc. Study. Liver. 2018; 50: 381-388
        • Janicko M.
        • Drazilova S.
        • Pella D.
        • Fedacko J.
        • Jarcuska P.
        Pleiotropic effects of statins in the diseases of the liver.
        World J. Gastroenterol. : WJG. 2016; 22: 6201-6213
        • Abraldes J.G.
        • Albillos A.
        • Banares R.
        • Turnes J.
        • Gonzalez R.
        • Garcia-Pagan J.C.
        • Bosch J.
        Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.
        Gastroenterology. 2009; 136: 1651-1658
        • Pollo-Flores P.
        • Soldan M.
        • Santos U.C.
        • Kunz D.G.
        • Mattos D.E.
        • da Silva A.C.
        • Marchiori R.C.
        • Rezende G.F.
        Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: a randomized controlled trial, Digestive and liver disease.
        Off. J. Italian Soc. Gastroenterol. Ital. Assoc. Study. Liver. 2015; 47: 957-963
        • Abraldes J.G.
        • Villanueva C.
        • Aracil C.
        • Turnes J.
        • Hernandez-Guerra M.
        • Genesca J.
        • Rodriguez M.
        • Castellote J.
        • Garcia-Pagan J.C.
        • Torres F.
        • Calleja J.L.
        • Albillos A.
        • Bosch J.
        • Group B.S.
        Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis.
        Gastroenterology. 2016; 150 (e1163): 1160-1170
        • Kamal S.
        • Khan M.A.
        • Seth A.
        • Cholankeril G.
        • Gupta D.
        • Singh U.
        • Kamal F.
        • Howden C.W.
        • Stave C.
        • Nair S.
        • Satapathy S.K.
        • Ahmed A.
        Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis.
        Am. J. Gastroenterol. 2017; 112: 1495-1505
        • Kim R.G.
        • Loomba R.
        • Prokop L.J.
        • Singh S.
        Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis.
        Clin. Gastroenterol. Hepatol. : the official clinical practice journal of the American Gastroenterological Association. 2017; 15 (e1528): 1521-1530
        • Singh S.
        • Singh P.P.
        • Singh A.G.
        • Murad M.H.
        • Sanchez W.
        Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.
        Gastroenterology. 2013; 144: 323-332
        • Shi M.
        • Zheng H.
        • Nie B.
        • Gong W.
        • Cui X.
        Statin use and risk of liver cancer: an update meta-analysis.
        BMJ open. 2014; 4 (e005399)
        • 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
        • Kim G.
        • Jang S.Y.
        • Nam C.M.
        • Kang E.S.
        Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study.
        J. Hepatol. 2018; 68: 476-484
        • Wu L.L.
        • Hsieh M.C.
        • Chow J.M.
        • Liu S.H.
        • Chang C.L.
        • Wu S.Y.
        Statins improve outcomes of nonsurgical curative treatments in hepatocellular carcinoma patients.
        Medicine. 2016; 95: e4639
        • Nishio T.
        • Taura K.
        • Nakamura N.
        • Seo S.
        • Yasuchika K.
        • Kaido T.
        • Okajima H.
        • Hatano E.
        • Uemoto S.
        Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection: a subgroup analysis of patients without chronic hepatitis viral infection.
        Surgery. 2018; 163: 264-269
        • Patel S.S.
        • Guzman L.A.
        • Lin F.P.
        • Pence T.
        • Reichman T.
        • John B.
        • Celi F.S.
        • Liptrap E.
        • Bhati C.
        • Siddiqui M.S.
        Utilization of aspirin and statin in management of coronary artery disease in patients with cirrhosis undergoing liver transplant evaluation, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the.
        Int. Liver Transplant. Soc. 2018; 24: 872-880
        • Nemes K.
        • Aberg F.
        • Gylling H.
        • Isoniemi H.
        Cholesterol metabolism in cholestatic liver disease and liver transplantation: from molecular mechanisms to clinical implications.
        World J. Hepatol. 2016; 8: 924-932
        • Zachoval R.
        • Gerbes A.L.
        • Schwandt P.
        • Parhofer K.G.
        Short-term effects of statin therapy in patients with hyperlipoproteinemia after liver transplantation: results of a randomized cross-over trial.
        J. Hepatol. 2001; 35: 86-91
        • Martin J.E.
        • Cavanaugh T.M.
        • Trumbull L.
        • Bass M.
        • Weber Jr., F.
        • Aranda-Michel J.
        • Hanaway M.
        • Rudich S.
        Incidence of adverse events with HMG-CoA reductase inhibitors in liver transplant patients.
        Clin. Transplant. 2008; 22: 113-119
        • Zafra C.
        • Abraldes J.G.
        • Turnes J.
        • Berzigotti A.
        • Fernandez M.
        • Garca-Pagan J.C.
        • Rodes J.
        • Bosch J.
        Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis.
        Gastroenterology. 2004; 126: 749-755
        • Abraldes J.G.
        • Rodriguez-Vilarrupla A.
        • Graupera M.
        • Zafra C.
        • Garcia-Caldero H.
        • Garcia-Pagan J.C.
        • Bosch J.
        Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats.
        J. Hepatol. 2007; 46: 1040-1046
        • Trebicka J.
        • Hennenberg M.
        • Laleman W.
        • Shelest N.
        • Biecker E.
        • Schepke M.
        • Nevens F.
        • Sauerbruch T.
        • Heller J.
        Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase.
        Hepatology. 2007; 46: 242-253
        • Trebicka J.
        • Schierwagen R.
        Statins, Rho GTPases and KLF2: new mechanistic insight into liver fibrosis and portal hypertension.
        Gut. 2015; 64: 1349-1350
        • Piscaglia F.
        • Svegliati-Baroni G.
        • Barchetti A.
        • Pecorelli A.
        • Marinelli S.
        • Tiribelli C.
        • Bellentani S.
        • Group H.-N.I.S.
        Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
        Hepatology. 2016; 63: 827-838
        • Fujiwara N.
        • Friedman S.L.
        • Goossens N.
        • Hoshida Y.
        Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine.
        J. Hepatol. 2018; 68: 526-549
        • Relja B.
        • Meder F.
        • Wang M.
        • Blaheta R.
        • Henrich D.
        • Marzi I.
        • Lehnert M.
        Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK.
        Int. J. Oncol. 2011; 38: 879-885
        • Uschner F.E.
        • Ranabhat G.
        • Choi S.S.
        • Granzow M.
        • Klein S.
        • Schierwagen R.
        • Raskopf E.
        • Gautsch S.
        • van der Ven P.F.
        • Furst D.O.
        • Strassburg C.P.
        • Sauerbruch T.
        • Diehl A.M.
        • Trebicka J.
        Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension.
        Sci. Rep. 2015; 5: 14573
        • Ridruejo E.
        • Romero-Caimi G.
        • Obregon M.J.
        • Kleiman de Pisarev D.
        • Alvarez L.
        Potential molecular targets of statins in the prevention of hepatocarcinogenesis.
        Ann. Hepatol. 2018; 17: 490-500
        • Sigler M.A.
        • Congdon L.
        • Edwards K.L.
        An evidence-based review of statin use in patients with nonalcoholic fatty liver disease, clinical medicine insights.
        Gastroenterology. 2018; 11 (1179552218787502)
        • Hoeke G.
        • Wang Y.
        • van Dam A.D.
        • Mol I.M.
        • Gart E.
        • Klop H.G.
        • van den Berg S.M.
        • Pieterman E.H.
        • Princen H.M.G.
        • Groen A.K.
        • Rensen P.C.N.
        • Berbee J.F.P.
        • Boon M.R.
        Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis.
        Atherosclerosis. 2017; 267: 116-126