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Semin Liver Dis
DOI: 10.1055/a-2319-0694
Review Article

Statins in Chronic Liver Disease: Review of the Literature and Future Role

Nguyen Pham
1   Department of Medicine, University of California, Los Angeles, Los Angeles, California
,
Jihane N. Benhammou
1   Department of Medicine, University of California, Los Angeles, Los Angeles, California
2   Veterans Affairs Greater Los Angeles, Los Angeles, California
3   Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, California
› Author Affiliations Funding J.N.B. is supported by the Veterans Affairs Career Development Award IK2CX002593–01A1 and the University of California, Los Angeles Comprehensive Liver Research Center.
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Abstract

Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.

Keywords

statin - prevention - liver disease - hepatocellular carcinoma - personalized medicine

Supplementary Material



Publication History

Accepted Manuscript online:
03 May 2024

Article published online:
29 May 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol 2023; 79 (02) 516-537
    CrossrefPubMedGoogle Scholar
  • 2 Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: a systematic review. Health Policy 2011; 100 (01) 4-17
    CrossrefPubMedGoogle Scholar
  • 3 Lai AG, Chang WH, Parisinos CA. et al. An informatics consult approach for generating clinical evidence for treatment decisions. BMC Med Inform Decis Mak 2021; 21 (01) 281
    CrossrefPubMedGoogle Scholar
  • 4 Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 2007; 40 (9-10): 575-584
    CrossrefPubMedGoogle Scholar
  • 5 Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 1976; 72 (02) 323-326
    CrossrefPubMedGoogle Scholar
  • 6 DeBose-Boyd RA. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 2008; 18 (06) 609-621
    CrossrefPubMedGoogle Scholar
  • 7 Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci U S A 1983; 80 (13) 4124-4128
    CrossrefPubMedGoogle Scholar
  • 8 Jones PH, Davidson MH, Stein EA. et al; STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003; 92 (02) 152-160
    CrossrefPubMedGoogle Scholar
  • 9 Thompson PD, Panza G, Zaleski A, Taylor B. Statin-Associated Side Effects. J Am Coll Cardiol 2016; 67 (20) 2395-2410
    CrossrefPubMedGoogle Scholar
  • 10 Nguyen KA, Li L, Lu D. et al. A comprehensive review and meta-analysis of risk factors for statin-induced myopathy. Eur J Clin Pharmacol 2018; 74 (09) 1099-1109
    CrossrefPubMedGoogle Scholar
  • 11 Pierno S, Didonna MP, Cippone V. et al. Effects of chronic treatment with statins and fenofibrate on rat skeletal muscle: a biochemical, histological and electrophysiological study. Br J Pharmacol 2006; 149 (07) 909-919
    CrossrefPubMedGoogle Scholar
  • 12 Hanai J, Cao P, Tanksale P. et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest 2007; 117 (12) 3940-3951
    PubMedGoogle Scholar
  • 13 Atsukawa M, Tsubota A, Shimada N. et al. Effect of fluvastatin on 24-week telaprevir-based combination therapy for hepatitis C virus genotype 1b-infected chronic hepatitis C. Eur J Gastroenterol Hepatol 2014; 26 (07) 781-787
    CrossrefPubMedGoogle Scholar
  • 14 Bader T, Hughes LD, Fazili J. et al. A randomized controlled trial adding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients. J Viral Hepat 2013; 20 (09) 622-627
    CrossrefPubMedGoogle Scholar
  • 15 Gharehbeglou M, Yazdani S, White K, Haeri MR, Masoumzadeh N. Atorvastatin rapidly reduces hepatitis B viral load in combination with tenofovir: a prospective clinical trial. Can J Infect Dis Med Microbiol 2022; 2022: 3443813
    CrossrefPubMedGoogle Scholar
  • 16 Mangione CM, Barry MJ, Nicholson WK. et al; US Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force Recommendation Statement. JAMA 2022; 328 (08) 746-753
    CrossrefPubMedGoogle Scholar
  • 17 Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia 2015; 58 (05) 1109-1117
    CrossrefPubMedGoogle Scholar
  • 18 Arnett DK, Blumenthal RS, Albert MA. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 140 (11) e596-e646
    PubMedGoogle Scholar
  • 19 Chou R, Cantor A, Dana T. et al. Statin use for the primary prevention of cardiovascular disease in adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2022; 328 (08) 754-771
    CrossrefPubMedGoogle Scholar
  • 20 Rinella ME, Neuschwander-Tetri BA, Siddiqui MS. et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023; 77 (05) 1797-1835
    CrossrefPubMedGoogle Scholar
  • 21 Newman CB, Preiss D, Tobert JA. et al; American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol 2019; 39 (02) e38-e81
    CrossrefPubMedGoogle Scholar
  • 22 Bays H. Statin safety: an overview and assessment of the data–2005. Am J Cardiol 2006; 97 (8A): 6C-26C
    CrossrefPubMedGoogle Scholar
  • 23 Janičko M, Veselíny E, Leško D, Jarčuška P. Serum cholesterol is a significant and independent mortality predictor in liver cirrhosis patients. Ann Hepatol 2013; 12 (04) 581-587
    CrossrefPubMedGoogle Scholar
  • 24 Zoli M, Cordiani MR, Marchesini G. et al. Prognostic indicators in compensated cirrhosis. Am J Gastroenterol 1991; 86 (10) 1508-1513
    PubMedGoogle Scholar
  • 25 Kaplan DE, Serper MA, Mehta R. et al; VOCAL Study Group. Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis. Gastroenterology 2019; 156 (06) 1693-1706.e12
    CrossrefPubMedGoogle Scholar
  • 26 Averbukh LD, Turshudzhyan A, Wu DC, Wu GY. Statin-induced liver injury patterns: a clinical review. J Clin Transl Hepatol 2022; 10 (03) 543-552
    CrossrefPubMedGoogle Scholar
  • 27 Golomb BA, Evans MA. Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008; 8 (06) 373-418
    CrossrefPubMedGoogle Scholar
  • 28 Sung S, Al-Karaghouli M, Kalainy S, Cabrera Garcia L, Abraldes JG. A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis. BMC Gastroenterol 2021; 21 (01) 120
    CrossrefPubMedGoogle Scholar
  • 29 Hui CK, Cheung BMY, Lau GKK. Pharmacokinetics of pitavastatin in subjects with Child-Pugh A and B cirrhosis. Br J Clin Pharmacol 2005; 59 (03) 291-297
    CrossrefPubMedGoogle Scholar
  • 30 Smith HT, Jokubaitis LA, Troendle AJ, Hwang DS, Robinson WT. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens 1993; 6 (11, Pt 2): 375S-382S
    CrossrefPubMedGoogle Scholar
  • 31 Simonson SG, Martin PD, Mitchell P, Schneck DW, Lasseter KC, Warwick MJ. Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment. Eur J Clin Pharmacol 2003; 58 (10) 669-675
    CrossrefPubMedGoogle Scholar
  • 32 Wright AP, Adusumalli S, Corey KE. Statin therapy in patients with cirrhosis. Frontline Gastroenterol 2015; 6 (04) 255-261
    CrossrefPubMedGoogle Scholar
  • 33 Theile D, Haefeli WE, Seitz HK, Millonig G, Weiss J, Mueller S. Association of liver stiffness with hepatic expression of pharmacokinetically important genes in alcoholic liver disease. Alcohol Clin Exp Res 2013; 37 (Suppl. 01) E17-E22
    PubMedGoogle Scholar
  • 34 Link E, Parish S, Armitage J. et al; SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy–a genome wide study. N Engl J Med 2008; 359 (08) 789-799
    CrossrefPubMedGoogle Scholar
  • 35 More VR, Cheng Q, Donepudi AC. et al. Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver. Drug Metab Dispos 2013; 41 (05) 1148-1155
    CrossrefPubMedGoogle Scholar
  • 36 Voora D, Baye J, McDermaid A. et al. SLCO1B1*5 allele is associated with atorvastatin discontinuation and adverse muscle symptoms in the context of routine care. Clin Pharmacol Ther 2022; 111 (05) 1075-1083
    CrossrefPubMedGoogle Scholar
  • 37 Wang LY, Huang YS, Perng CL, Huang B, Lin HC. Statin-induced liver injury in an area endemic for hepatitis B virus infection: risk factors and outcome analysis. Br J Clin Pharmacol 2016; 82 (03) 823-830
    CrossrefPubMedGoogle Scholar
  • 38 Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011; 106 (01) 71-77
    CrossrefPubMedGoogle Scholar
  • 39 Cho Y, Rhee H, Kim YE. et al. Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study). BMC Med 2022; 20 (01) 93
    CrossrefPubMedGoogle Scholar
  • 40 Abdallah M, Brown L, Provenza J, Tariq R, Gowda S, Singal AK. Safety and efficacy of dyslipidemia treatment in NAFLD patients: a meta-analysis of randomized controlled trials. Ann Hepatol 2022; 27 (06) 100738
    CrossrefPubMedGoogle Scholar
  • 41 Hatzitolios A, Savopoulos C, Lazaraki G. et al. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol 2004; 23 (04) 131-134
    PubMedGoogle Scholar
  • 42 Abel T, Fehér J, Dinya E, Eldin MG, Kovács A. Safety and efficacy of combined ezetimibe/simvastatin treatment and simvastatin monotherapy in patients with non-alcoholic fatty liver disease. Med Sci Monit 2009; 15 (12) MS6-MS11
    PubMedGoogle Scholar
  • 43 Athyros VG, Tziomalos K, Gossios TD. et al; GREACE Study Collaborative Group. 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 (9756) 1916-1922
    CrossrefPubMedGoogle Scholar
  • 44 Kiyici M, Gulten M, Gurel S. et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 2003; 17 (12) 713-718
    CrossrefPubMedGoogle Scholar
  • 45 Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis 2007; 16 (01) 39-46
    PubMedGoogle Scholar
  • 46 Hyogo H, Tazuma S, Arihiro K. et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008; 57 (12) 1711-1718
    CrossrefPubMedGoogle Scholar
  • 47 Kargiotis K, Athyros VG, Giouleme O. et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol 2015; 21 (25) 7860-7868
    CrossrefPubMedGoogle Scholar
  • 48 Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R. Pravastatin in Chronic Liver Disease Study Investigators. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46 (05) 1453-1463
    CrossrefPubMedGoogle Scholar
  • 49 Abraldes JG, Villanueva C, Aracil C. et al; BLEPS Study Group. 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 (05) 1160-1170.e3
    CrossrefPubMedGoogle Scholar
  • 50 Abraldes JG, Albillos A, Bañares R. et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136 (05) 1651-1658
    CrossrefPubMedGoogle Scholar
  • 51 Muñoz AE, Pollarsky F, Marino M. et al. Baseline severity and inflammation would influence the effect of simvastatin on clinical outcomes in cirrhosis patients. Dig Dis Sci 2023; 68 (08) 3442-3450
    CrossrefPubMedGoogle Scholar
  • 52 Vijayaraghavan R, Jindal A, Arora V, Choudhary A, Kumar G, Sarin SK. Hemodynamic effects of adding simvastatin to carvedilol for primary prophylaxis of variceal bleeding: a randomized controlled trial. Am J Gastroenterol 2020; 115 (05) 729-737
    CrossrefPubMedGoogle Scholar
  • 53 Pose E, Napoleone L, Amin A. et al. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol 2020; 5 (01) 31-41
    CrossrefPubMedGoogle Scholar
  • 54 Blanc JF, Khemissa F, Bronowicki JP. et al; PRODIGE 21 Collaborators. Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis. Hepatol Int 2021; 15 (01) 93-104
    CrossrefPubMedGoogle Scholar
  • 55 Terrault NA, Lok ASF, McMahon BJ. et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67 (04) 1560-1599
    CrossrefPubMedGoogle Scholar
  • 56 Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin North Am 2015; 44 (04) 717-734
    CrossrefPubMedGoogle Scholar
  • 57 Rusu E, Jinga M, Enache G. et al. Effects of lifestyle changes including specific dietary intervention and physical activity in the management of patients with chronic hepatitis C – a randomized trial. Nutr J 2013; 12: 119
    CrossrefPubMedGoogle Scholar
  • 58 Bader T, Korba B. Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro. Antiviral Res 2010; 86 (03) 241-245
    CrossrefPubMedGoogle Scholar
  • 59 Wu C. Hepatitis B virus reactivation associated with atorvastatin. Int J Infect Dis 2013; 17 (11) e1069-e1070
    CrossrefPubMedGoogle Scholar
  • 60 Hayashi M, Abe K, Fujita M, Okai K, Takahashi A, Ohira H. Hepatitis B virus reactivation in a patient with nonalcoholic steatohepatitis 41 months after rituximab-containing chemotherapy. Intern Med 2019; 58 (03) 375-380
    CrossrefPubMedGoogle Scholar
  • 61 Harrison SA, Rossaro L, Hu KQ. et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology 2010; 52 (03) 864-874
    CrossrefPubMedGoogle Scholar
  • 62 Bader T, Fazili J, Madhoun M. et al. Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008; 103 (06) 1383-1389
    CrossrefPubMedGoogle Scholar
  • 63 Sheridan DA, Bridge SH, Crossey MME. et al. Omega-3 fatty acids and/or fluvastatin in hepatitis C prior non-responders to combination antiviral therapy - a pilot randomised clinical trial. Liver Int 2014; 34 (05) 737-747
    CrossrefPubMedGoogle Scholar
  • 64 O'Leary JG, Chan JL, McMahon CM, Chung RT. Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial. Hepatology 2007; 45 (04) 895-898
    CrossrefPubMedGoogle Scholar
  • 65 Kondo C, Atsukawa M, Tsubota A. et al. An open-label randomized controlled study of pegylated interferon/ribavirin combination therapy for chronic hepatitis C with versus without fluvastatin. J Viral Hepat 2012; 19 (09) 615-622
    CrossrefPubMedGoogle Scholar
  • 66 Atsukawa M, Tsubota A, Kondo C. et al. Combination of fluvastatin with pegylated interferon/ribavirin therapy reduces viral relapse in chronic hepatitis C infected with HCV genotype 1b. J Gastroenterol Hepatol 2013; 28 (01) 51-56
    CrossrefPubMedGoogle Scholar
  • 67 Yun B, Ahn SH, Yoon JH, Kim BK. Statin use and risk of progression to liver cirrhosis in chronic hepatitis B independent of conventional risk factors: a nationwide study. Hepatol Commun 2022; 6 (09) 2455-2464
    CrossrefPubMedGoogle Scholar
  • 68 Huang YW, Lee CL, Yang SS. et al. Statins reduce the risk of cirrhosis and its decompensation in chronic hepatitis B patients: a nationwide cohort study. Am J Gastroenterol 2016; 111 (07) 976-985
    CrossrefPubMedGoogle Scholar
  • 69 Chang FM, Wang YP, Lang HC. et al. Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study. Hepatology 2017; 66 (03) 896-907
    CrossrefPubMedGoogle Scholar
  • 70 Cheung KS, Mak LY, Lam LK. et al. Statins associate with better clinical outcomes in chronic hepatitis B patients with HBsAg seroclearance. Hepatol Int 2021; 15 (04) 881-891
    CrossrefPubMedGoogle Scholar
  • 71 Butt AA, Yan P, Bonilla H. et al; ERCHIVES (Electronically Retrieved Cohort of HCV Infected Veterans) Study Team. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: Results from ERCHIVES. Hepatology 2015; 62 (02) 365-374
    CrossrefPubMedGoogle Scholar
  • 72 Simon TG, King LY, Zheng H, Chung RT. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C. J Hepatol 2015; 62 (01) 18-23
    CrossrefPubMedGoogle Scholar
  • 73 Milazzo L, Meroni L, Galazzi M. et al. Does fluvastatin favour HCV replication in vivo? A pilot study on HIV-HCV coinfected patients. J Viral Hepat 2009; 16 (07) 479-484
    CrossrefPubMedGoogle Scholar
  • 74 Milazzo L, Caramma I, Mazzali C. et al. Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C virus genotype 1 co-infected patients: an open-label randomized controlled study. J Antimicrob Chemother 2010; 65 (04) 735-740
    CrossrefPubMedGoogle Scholar
  • 75 Oliver NT, Hartman CM, Kramer JR, Chiao EY. Statin drugs decrease progression to cirrhosis in HIV/hepatitis C virus coinfected individuals. AIDS 2016; 30 (16) 2469-2476
    CrossrefPubMedGoogle Scholar
  • 76 Byrne DD, Tate JP, Forde KA. et al. Risk of acute liver injury after statin initiation by human immunodeficiency virus and chronic hepatitis C virus infection status. Clin Infect Dis 2017; 65 (09) 1542-1550
    CrossrefPubMedGoogle Scholar
  • 77 Rosenson RS, Colantonio LD, Burkholder GA, Chen L, Muntner P. Trends in utilization of statin therapy and contraindicated statin use in HIV–infected adults treated with antiretroviral therapy from 2007 through 2015. J Am Heart Assoc 2018; 7 (24) e010345
    CrossrefPubMedGoogle Scholar
  • 78 Chastain DB, Stover KR, Riche DM. Evidence-based review of statin use in patients with HIV on antiretroviral therapy. J Clin Transl Endocrinol 2017; 8: 6-14
    PubMedGoogle Scholar
  • 79 Wohl DA, McComsey G, Tebas P. et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006; 43 (05) 645-653
    CrossrefPubMedGoogle Scholar
  • 80 Ikeda M, Abe K, Yamada M, Dansako H, Naka K, Kato N. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006; 44 (01) 117-125
    CrossrefPubMedGoogle Scholar
  • 81 El Kamari V, Hileman CO, Gholam PM, Kulkarni M, Funderburg N, McComsey GA. Statin therapy does not reduce liver fat scores in patients receiving antiretroviral therapy for HIV infection. Clin Gastroenterol Hepatol 2019; 17 (03) 536-542.e1
    CrossrefPubMedGoogle Scholar
  • 82 Aberg JA, Zackin RA, Brobst SW. et al; ACTG 5087 Study Team. A randomized trial of the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities: AIDS Clinical Trials Group Study 5087. AIDS Res Hum Retroviruses 2005; 21 (09) 757-767
    CrossrefPubMedGoogle Scholar
  • 83 Bremer CM, Bung C, Kott N, Hardt M, Glebe D. Hepatitis B virus infection is dependent on cholesterol in the viral envelope. Cell Microbiol 2009; 11 (02) 249-260
    CrossrefPubMedGoogle Scholar
  • 84 Dorobantu C, Macovei A, Lazar C, Dwek RA, Zitzmann N, Branza-Nichita N. Cholesterol depletion of hepatoma cells impairs hepatitis B virus envelopment by altering the topology of the large envelope protein. J Virol 2011; 85 (24) 13373-13383
    CrossrefPubMedGoogle Scholar
  • 85 Lin YL, Shiao MS, Mettling C, Chou CK. Cholesterol requirement of hepatitis B surface antigen (HBsAg) secretion. Virology 2003; 314 (01) 253-260
    CrossrefPubMedGoogle Scholar
  • 86 Zhao H, Yu Y, Wang Y. et al. Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction. Cell Mol Immunol 2022; 19 (12) 1347-1360
    CrossrefPubMedGoogle Scholar
  • 87 Norouzi A, Taziki S, Najafipasandi A, Mohammadi S, Roshandel G. Rosuvastatin intervention decreased the frequencies of the TIM-3+ population of NK cells and NKT cells among patients with chronic hepatitis B. Iran J Immunol 2022; 19 (03) 255-262
    PubMedGoogle Scholar
  • 88 Li H, Wu K, Tao K. et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2012; 56 (04) 1342-1351
    CrossrefPubMedGoogle Scholar
  • 89 Ju Y, Hou N, Meng J. et al. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 2010; 52 (03) 322-329
    CrossrefPubMedGoogle Scholar
  • 90 Aizaki H, Lee KJ, Sung VMH, Ishiko H, Lai MMC. Characterization of the hepatitis C virus RNA replication complex associated with lipid rafts. Virology 2004; 324 (02) 450-461
    CrossrefPubMedGoogle Scholar
  • 91 Peng LF, Schaefer EAK, Maloof N. et al. Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase. J Infect Dis 2011; 204 (04) 609-616
    CrossrefPubMedGoogle Scholar
  • 92 Kapadia SB, Chisari FV. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A 2005; 102 (07) 2561-2566
    CrossrefPubMedGoogle Scholar
  • 93 Ye J, Wang C, Sumpter Jr R, Brown MS, Goldstein JL, Gale Jr M. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci U S A 2003; 100 (26) 15865-15870
    CrossrefPubMedGoogle Scholar
  • 94 Harrison SA, Bedossa P, Guy CD. et al; MAESTRO-NASH Investigators. A Phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024; 390 (06) 497-509
    CrossrefPubMedGoogle Scholar
  • 95 Ayada I, van Kleef LA, Zhang H. et al. Dissecting the multifaceted impact of statin use on fatty liver disease: a multidimensional study. EBioMedicine 2023; 87: 104392
    CrossrefPubMedGoogle Scholar
  • 96 Sfikas G, Psallas M, Koumaras C. et al. Prevalence, diagnosis, and treatment with 3 different statins of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in military personnel. Do genetics play a role?. Curr Vasc Pharmacol 2021; 19 (05) 572-581
    CrossrefPubMedGoogle Scholar
  • 97 Blais P, Lin M, Kramer JR, El-Serag HB, Kanwal F. Statins are underutilized in patients with nonalcoholic fatty liver disease and dyslipidemia. Dig Dis Sci 2016; 61 (06) 1714-1720
    CrossrefPubMedGoogle Scholar
  • 98 Ioannou GN, Haigh WG, Thorning D, Savard C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J Lipid Res 2013; 54 (05) 1326-1334
    CrossrefPubMedGoogle Scholar
  • 99 Ioannou GN, Subramanian S, Chait A. et al. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. J Lipid Res 2017; 58 (06) 1067-1079
    CrossrefPubMedGoogle Scholar
  • 100 Min HK, Kapoor A, Fuchs M. et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab 2012; 15 (05) 665-674
    CrossrefPubMedGoogle Scholar
  • 101 Song Y, Liu J, Zhao K, Gao L, Zhao J. Cholesterol-induced toxicity: an integrated view of the role of cholesterol in multiple diseases. Cell Metab 2021; 33 (10) 1911-1925
    CrossrefPubMedGoogle Scholar
  • 102 Ekstedt M, Franzén LE, Mathiesen UL, 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 (01) 135-141
    CrossrefPubMedGoogle Scholar
  • 103 Taylor RS, Taylor RJ, Bayliss S. et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 2020; 158 (06) 1611-1625.e12
    CrossrefPubMedGoogle Scholar
  • 104 Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009; 43 (10) 990-994
    CrossrefPubMedGoogle Scholar
  • 105 Kim D, Adejumo AC, Yoo ER. et al. Trends in mortality from extrahepatic complications in patients with chronic liver disease, from 2007 through 2017. Gastroenterology 2019; 157 (04) 1055-1066.e11
    CrossrefPubMedGoogle Scholar
  • 106 Adams LA, Lymp JF, St Sauver J. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129 (01) 113-121
    CrossrefPubMedGoogle Scholar
  • 107 Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008; 118 (03) 829-838
    CrossrefPubMedGoogle Scholar
  • 108 Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM 2010; 103 (02) 71-83
    CrossrefPubMedGoogle Scholar
  • 109 Orime K, Shirakawa J, Togashi Y. et al. Lipid-lowering agents inhibit hepatic steatosis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma mouse model. Eur J Pharmacol 2016; 772: 22-32
    CrossrefPubMedGoogle Scholar
  • 110 Langhi C, Marquart TJ, Allen RM, Baldán A. Perilipin-5 is regulated by statins and controls triglyceride contents in the hepatocyte. J Hepatol 2014; 61 (02) 358-365
    CrossrefPubMedGoogle Scholar
  • 111 Gao X, Nan Y, Zhao Y. et al. Atorvastatin reduces lipid accumulation in the liver by activating protein kinase A-mediated phosphorylation of perilipin 5. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862 (12) 1512-1519
    CrossrefPubMedGoogle Scholar
  • 112 Marchianò S, Biagioli M, Roselli R. et al. Atorvastatin protects against liver and vascular damage in a model of diet induced steatohepatitis by resetting FXR and GPBAR1 signaling. FASEB J 2022; 36 (01) e22060
    CrossrefPubMedGoogle Scholar
  • 113 Fraulob JC, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet. Clin Sci (Lond) 2012; 123 (04) 259-270
    CrossrefPubMedGoogle Scholar
  • 114 Zhang W, Yang X, Chen Y. et al. Activation of hepatic Nogo-B receptor expression - a new anti-liver steatosis mechanism of statins. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863 (02) 177-190
    CrossrefPubMedGoogle Scholar
  • 115 Zhang X, Zhou H, Su Y. Targeting truncated RXRα for cancer therapy. Acta Biochim Biophys Sin (Shanghai) 2016; 48 (01) 49-59
    CrossrefPubMedGoogle Scholar
  • 116 Ioannou GN, Van Rooyen DM, Savard C. et al. Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH. J Lipid Res 2015; 56 (02) 277-285
    CrossrefPubMedGoogle Scholar
  • 117 Inia JA, Stokman G, Pieterman EJ. et al. Atorvastatin attenuates diet-induced non-alcoholic steatohepatitis in APOE*3-Leiden mice by reducing hepatic inflammation. Int J Mol Sci 2023; 24 (09) 7818
    CrossrefPubMedGoogle Scholar
  • 118 Van Rooyen DM, Gan LT, Yeh MM. et al. Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. J Hepatol 2013; 59 (01) 144-152
    CrossrefPubMedGoogle Scholar
  • 119 Seif El-Din SH, El-Lakkany NM, El-Naggar AA. et al. Effects of rosuvastatin and/or β-carotene on non-alcoholic fatty liver in rats. Res Pharm Sci 2015; 10 (04) 275-287
    PubMedGoogle Scholar
  • 120 Yao L, Romero MJ, Toque HA, Yang G, Caldwell RB, Caldwell RW. The role of RhoA/Rho kinase pathway in endothelial dysfunction. J Cardiovasc Dis Res 2010; 1 (04) 165-170
    CrossrefPubMedGoogle Scholar
  • 121 Trebicka J, Hennenberg M, Laleman W. et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46 (01) 242-253
    CrossrefPubMedGoogle Scholar
  • 122 Schierwagen R, Maybüchen L, Hittatiya K. et al. Statins improve NASH via inhibition of RhoA and Ras. Am J Physiol Gastrointest Liver Physiol 2016; 311 (04) G724-G733
    CrossrefPubMedGoogle Scholar
  • 123 Tripathi DM, Vilaseca M, Lafoz E. et al. Simvastatin prevents progression of acute on chronic liver failure in rats with cirrhosis and portal hypertension. Gastroenterology 2018; 155 (05) 1564-1577
    CrossrefPubMedGoogle Scholar
  • 124 Chong LW, Hsu YC, Lee TF. et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol 2015; 15: 22
    CrossrefPubMedGoogle Scholar
  • 125 Wang W, Zhao C, Zhou J, Zhen Z, Wang Y, Shen C. Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. PLoS One 2013; 8 (10) e76538
    CrossrefPubMedGoogle Scholar
  • 126 Kimura Y, Hyogo H, Yamagishi S. et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010; 45 (07) 750-757
    CrossrefPubMedGoogle Scholar
  • 127 Park HS, Jang JE, Ko MS. et al. Statins increase mitochondrial and peroxisomal fatty acid oxidation in the liver and prevent non-alcoholic steatohepatitis in mice. Diabetes Metab J 2016; 40 (05) 376-385
    CrossrefPubMedGoogle Scholar
  • 128 Rodrigues G, Moreira AJ, Bona S. et al. Simvastatin reduces hepatic oxidative stress and endoplasmic reticulum stress in nonalcoholic steatohepatitis experimental model. Oxid Med Cell Longev 2019; 2019: 3201873
    CrossrefPubMedGoogle Scholar
  • 129 Bravo M, Raurell I, Hide D. et al. Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH. Sci Rep 2019; 9 (01) 20183
    CrossrefPubMedGoogle Scholar
  • 130 Ciric D, Kravic-Stevovic T, Bumbasirevic V. et al. Effects of metformin and simvastatin treatment on ultrastructural features of liver macrophages in HFD mice. Ultrastruct Pathol 2023; 47 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 131 Samy W, Hassanian MA. Paraoxonase-1 activity, malondialdehyde and glutathione peroxidase in non-alcoholic fatty liver disease and the effect of atorvastatin. Arab J Gastroenterol 2011; 12 (02) 80-85
    CrossrefPubMedGoogle Scholar
  • 132 Longo M, Crosignani A, Battezzati PM. et al. Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut 2002; 51 (02) 265-269
    CrossrefPubMedGoogle Scholar
  • 133 Takeyama Y, Uehara Y, Anan A. et al. Increased hepatic ABCA1 transporter is associated with hypercholesterolemia in a cholestatic rat model and primary biliary cholangitis patients. Med Mol Morphol 2017; 50 (04) 227-237
    CrossrefPubMedGoogle Scholar
  • 134 Loaeza-Del Castillo AM, Gaytán-Santillán A, López-Tello A. et al. Patterns of serum lipids derangements and cardiovascular risk assessment in patients with primary biliary cholangitis. Ann Hepatol 2019; 18 (06) 879-882
    CrossrefPubMedGoogle Scholar
  • 135 Zhang Y, Hu X, Chang J. et al. The liver steatosis severity and lipid characteristics in primary biliary cholangitis. BMC Gastroenterol 2021; 21 (01) 395
    CrossrefPubMedGoogle Scholar
  • 136 Jang H, Han N, Staatz CE, Kwak JH, Baek IH. Effect on lipid profile and clinical outcomes of obeticholic acid for the treatment of primary biliary cholangitis and metabolic dysfunction-associated steatohepatitis: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2023; 47 (10) 102227
    CrossrefPubMedGoogle Scholar
  • 137 Siddiqui MS, Van Natta ML, Connelly MA. et al; NASH CRN. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol 2020; 72 (01) 25-33
    CrossrefPubMedGoogle Scholar
  • 138 Stojakovic T, Putz-Bankuti C, Fauler G. et al. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology 2007; 46 (03) 776-784
    CrossrefPubMedGoogle Scholar
  • 139 Stanca CM, Bach N, Allina J, Bodian C, Bodenheimer Jr H, Odin JA. Atorvastatin does not improve liver biochemistries or Mayo Risk Score in primary biliary cirrhosis. Dig Dis Sci 2008; 53 (07) 1988-1993
    CrossrefPubMedGoogle Scholar
  • 140 Stojakovic T, Claudel T, Putz-Bankuti C. et al. Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment. Atherosclerosis 2010; 209 (01) 178-183
    CrossrefPubMedGoogle Scholar
  • 141 Ritzel U, Leonhardt U, Näther M, Schäfer G, Armstrong VW, Ramadori G. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers. J Hepatol 2002; 36 (04) 454-458
    CrossrefPubMedGoogle Scholar
  • 142 Del Puppo M, Galli Kienle M, Crosignani A. et al. Cholesterol metabolism in primary biliary cirrhosis during simvastatin and UDCA administration. J Lipid Res 2001; 42 (03) 437-441
    CrossrefPubMedGoogle Scholar
  • 143 Cash WJ, O'Neill S, O'Donnell ME. et al. Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis. Liver Int 2013; 33 (08) 1166-1174
    CrossrefPubMedGoogle Scholar
  • 144 Meireles CZ, Pasarin M, Lozano JJ. et al. Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation. Shock 2017; 47 (03) 370-377
    CrossrefPubMedGoogle Scholar
  • 145 Kim Y, Lee EJ, Jang HK. et al. Statin pretreatment inhibits the lipopolysaccharide-induced epithelial-mesenchymal transition via the downregulation of toll-like receptor 4 and nuclear factor-κB in human biliary epithelial cells. J Gastroenterol Hepatol 2016; 31 (06) 1220-1228
    CrossrefPubMedGoogle Scholar
  • 146 Desmet VJ. Ludwig symposium on biliary disorders – part I. Pathogenesis of ductal plate abnormalities. Mayo Clin Proc 1998; 73 (01) 80-89
    CrossrefPubMedGoogle Scholar
  • 147 Park SM. The crucial role of cholangiocytes in cholangiopathies. Gut Liver 2012; 6 (03) 295-304
    CrossrefPubMedGoogle Scholar
  • 148 Pollo-Flores P, Soldan M, Santos UC. et al. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: a randomized controlled trial. Dig Liver Dis 2015; 47 (11) 957-963
    CrossrefPubMedGoogle Scholar
  • 149 Bishnu S, Ahammed SM, Sarkar A. et al. 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 (01) 54-59
    CrossrefPubMedGoogle Scholar
  • 150 Kronborg TM, Schierwagen R, Trošt K. et al. Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial. Hepatol Commun 2023; 7 (12) e0332
    CrossrefPubMedGoogle Scholar
  • 151 Kumar S, Grace ND, Qamar AA. Statin use in patients with cirrhosis: a retrospective cohort study. Dig Dis Sci 2014; 59 (08) 1958-1965
    CrossrefPubMedGoogle Scholar
  • 152 Chen YC, Li YD, Lu CM, Huang WC, Kao SS, Chen WC. Propranolol use in patients with cirrhosis and refractory ascites: a nationwide study. Saudi J Gastroenterol 2022; 28 (02) 108-114
    CrossrefPubMedGoogle Scholar
  • 153 Hung TH, Tsai CC, Lee HF. Statin use in cirrhotic patients with infectious diseases: a population-based study. PLoS One 2019; 14 (04) e0215839
    CrossrefPubMedGoogle Scholar
  • 154 Tapper EB, Parikh ND, Sengupta N. et al. A risk score to predict the development of hepatic encephalopathy in a population-based cohort of patients with cirrhosis. Hepatology 2018; 68 (04) 1498-1507
    CrossrefPubMedGoogle Scholar
  • 155 Watts KL, Spiteri MA. Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism. Am J Physiol Lung Cell Mol Physiol 2004; 287 (06) L1323-L1332
    CrossrefPubMedGoogle Scholar
  • 156 Eberlein M, Heusinger-Ribeiro J, Goppelt-Struebe M. Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins). Br J Pharmacol 2001; 133 (07) 1172-1180
    CrossrefPubMedGoogle Scholar
  • 157 Boerma M, Fu Q, Wang J. et al. Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin. Blood Coagul Fibrinolysis 2008; 19 (07) 709-718
    CrossrefPubMedGoogle Scholar
  • 158 Gardner JL, Turner SM, Bautista A, Lindwall G, Awada M, Hellerstein MK. Measurement of liver collagen synthesis by heavy water labeling: effects of profibrotic toxicants and antifibrotic interventions. Am J Physiol Gastrointest Liver Physiol 2007; 292 (06) G1695-G1705
    CrossrefPubMedGoogle Scholar
  • 159 Klein S, Klösel J, Schierwagen R. et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest 2012; 92 (10) 1440-1450
    CrossrefPubMedGoogle Scholar
  • 160 Trebicka J, Hennenberg M, Odenthal M. et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010; 53 (04) 702-712
    CrossrefPubMedGoogle Scholar
  • 161 Olteanu D, Nagy A, Dudea M. et al. Hepatic and systemic effects of rosuvastatin on an experimental model of bile duct ligation in rats. J Physiol Pharmacol 2012; 63 (05) 483-496
    PubMedGoogle Scholar
  • 162 Yang JI, Yoon JH, Bang YJ. et al. Synergistic antifibrotic efficacy of statin and protein kinase C inhibitor in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2010; 298 (01) G126-G132
    CrossrefPubMedGoogle Scholar
  • 163 Zafra C, Abraldes JG, Turnes J. et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004; 126 (03) 749-755
    CrossrefPubMedGoogle Scholar
  • 164 Uschner FE, Ranabhat G, Choi SS. et al. 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
    CrossrefPubMedGoogle Scholar
  • 165 Choi SS, Omenetti A, Witek RP. et al. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol 2009; 297 (06) G1093-G1106
    CrossrefPubMedGoogle Scholar
  • 166 Singal AG, Llovet JM, Yarchoan M. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023; 78 (06) 1922-1965
    CrossrefPubMedGoogle Scholar
  • 167 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
    Google Scholar
  • 168 Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: current status and future perspectives. World J Gastroenterol 2023; 29 (06) 1054-1075
    CrossrefPubMedGoogle Scholar
  • 169 Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet 2022; 400 (10360): 1345-1362
    CrossrefPubMedGoogle Scholar
  • 170 Shah RH, Chyou D, Goldberg DS. Impact of major hepatocellular carcinoma policy changes on liver transplantation for hepatocellular carcinoma in the United States. Liver Transpl 2022; 28 (12) 1857-1864
    CrossrefPubMedGoogle Scholar
  • 171 Younossi Z, Stepanova M, Ong JP. et al; Global Nonalcoholic Steatohepatitis Council. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol 2019; 17 (04) 748-755.e3
    CrossrefPubMedGoogle Scholar
  • 172 Kanwal F, Kramer JR, Asch SM, Cao Y, Li L, El-Serag HB. Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents. Hepatology 2020; 71 (01) 44-55
    CrossrefPubMedGoogle Scholar
  • 173 Singal AG, Rich NE, Mehta N. et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019; 157 (05) 1253-1263.e2
    CrossrefPubMedGoogle Scholar
  • 174 Choi WM, Kim HJ, Jo AJ. et al. Association of aspirin and statin use with the risk of liver cancer in chronic hepatitis B: a nationwide population-based study. Liver Int 2021; 41 (11) 2777-2785
    CrossrefPubMedGoogle Scholar
  • 175 Goh MJ, Sinn DH, Kim S. et al. Statin use and the risk of hepatocellular carcinoma in patients with chronic hepatitis B. Hepatology 2020; 71 (06) 2023-2032
    CrossrefPubMedGoogle Scholar
  • 176 Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 2012; 30 (06) 623-630
    CrossrefPubMedGoogle Scholar
  • 177 Hsiang JC, Wong GLH, Tse YK, Wong VWS, Yip TCF, Chan HLY. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: a propensity score landmark analysis. J Hepatol 2015; 63 (05) 1190-1197
    CrossrefPubMedGoogle Scholar
  • 178 Yang X, Wang Y, Luk AOY. et al. Enhancers and attenuators of risk associations of chronic hepatitis B virus infection with hepatocellular carcinoma in type 2 diabetes. Endocr Relat Cancer 2013; 20 (02) 161-171
    CrossrefPubMedGoogle Scholar
  • 179 Kim HW, Joo YS, Kang SC. et al. Association of statin treatment with hepatocellular carcinoma risk in end-stage kidney disease patients with chronic viral hepatitis. Sci Rep 2022; 12 (01) DOI: 10.1038/s41598-022-14713-w.
    CrossrefPubMedGoogle Scholar
  • 180 Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol 2013; 31 (12) 1514-1521
    CrossrefPubMedGoogle Scholar
  • 181 Vell MS, Loomba R, Krishnan A. et al. Association of statin use with risk of liver disease, hepatocellular carcinoma, and liver-related mortality. JAMA Netw Open 2023; 6 (06) e2320222
    CrossrefPubMedGoogle Scholar
  • 182 Kraglund F, Christensen DH, Eiset AH, Villadsen GE, West J, Jepsen P. Effects of statins and aspirin on HCC risk in alcohol-related cirrhosis: nationwide emulated trials. Hepatol Commun 2023; 7 (01) e0013
    CrossrefPubMedGoogle Scholar
  • 183 Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J Hepatol 2018; 68 (03) 476-484
    CrossrefPubMedGoogle Scholar
  • 184 McGlynn KA, Divine GW, Sahasrabuddhe VV. et al. Statin use and risk of hepatocellular carcinoma in a U.S. population. Cancer Epidemiol 2014; 38 (05) 523-527
    CrossrefPubMedGoogle Scholar
  • 185 Tran KT, McMenamin ÚC, Coleman HG. et al. Statin use and risk of liver cancer: evidence from two population-based studies. Int J Cancer 2020; 146 (05) 1250-1260
    CrossrefPubMedGoogle Scholar
  • 186 Lai SW, Liao KF, Lai HC, Muo CH, Sung FC, Chen PC. Statin use and risk of hepatocellular carcinoma. Eur J Epidemiol 2013; 28 (06) 485-492
    CrossrefPubMedGoogle Scholar
  • 187 Simon TG, Duberg AS, Aleman S. et al. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann Intern Med 2019; 171 (05) 318-327
    CrossrefPubMedGoogle Scholar
  • 188 Yi SW, Kim SH, Han KJ, Yi JJ, Ohrr H. Higher cholesterol levels, not statin use, are associated with a lower risk of hepatocellular carcinoma. Br J Cancer 2020; 122 (05) 630-633
    CrossrefPubMedGoogle Scholar
  • 189 Thrift AP, Natarajan Y, Liu Y, El-Serag HB. Statin use after diagnosis of hepatocellular carcinoma is associated with decreased mortality. Clin Gastroenterol Hepatol 2019; 17 (10) 2117-2125.e3
    CrossrefPubMedGoogle Scholar
  • 190 Kawata S, Yamasaki E, Nagase T. et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 2001; 84 (07) 886-891
    CrossrefPubMedGoogle Scholar
  • 191 Jeon CY, Goodman MT, Cook-Wiens G, Sundaram V. Statin use and survival with early-stage hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 2016; 25 (04) 686-692
    CrossrefPubMedGoogle Scholar
  • 192 Morris TJ, Palm SL, Furcht LL, Buchwald H. Effect of lovastatin alone and as an adjuvant chemotherapeutic agent on hepatoma tissue culture-4 cell growth. Ann Surg Oncol 1995; 2 (03) 266-274
    CrossrefPubMedGoogle Scholar
  • 193 Huether A, Höpfner M, Baradari V, Schuppan D, Scherübl H. EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol 2005; 70 (11) 1568-1578
    CrossrefPubMedGoogle Scholar
  • 194 Riaño I, Martín L, Varela M. et al. Efficacy and Safety of the combination of pravastatin and sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial). Cancers (Basel) 2020; 12 (07) 1900
    CrossrefPubMedGoogle Scholar
  • 195 Jouve JL, Lecomte T, Bouché O. et al; PRODIGE-11 Investigators/Collaborators. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol 2019; 71 (03) 516-522
    CrossrefPubMedGoogle Scholar
  • 196 Higashi T, Hayashi H, Kitano Y. et al. Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. Med Oncol 2016; 33 (11) 123
    CrossrefPubMedGoogle Scholar
  • 197 Benhammou JN, Qiao B, Ko A, Sinnett-Smith J, Pisegna JR, Rozengurt E. Lipophilic statins inhibit YAP coactivator transcriptional activity in HCC cells through Rho-mediated modulation of actin cytoskeleton. Am J Physiol Gastrointest Liver Physiol 2023; 325 (03) G239-G250
    CrossrefPubMedGoogle Scholar
  • 198 Wang ST, Ho HJ, Lin JT, Shieh JJ, Wu CY. Simvastatin-induced cell cycle arrest through inhibition of STAT3/SKP2 axis and activation of AMPK to promote p27 and p21 accumulation in hepatocellular carcinoma cells. Cell Death Dis 2017; 8 (02) e2626
    CrossrefPubMedGoogle Scholar
  • 199 Abukhdeir AM, Park BH. P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med 2008; 10: e19
    CrossrefPubMedGoogle Scholar
  • 200 Relja B, Meder F, Wilhelm K, Henrich D, Marzi I, Lehnert M. Simvastatin inhibits cell growth and induces apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. Int J Mol Med 2010; 26 (05) 735-741
    CrossrefPubMedGoogle Scholar
  • 201 Kah J, Wüstenberg A, Keller AD. et al. Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression. Oncol Rep 2012; 28 (03) 1077-1083
    CrossrefPubMedGoogle Scholar
  • 202 Qi R, An H, Yu Y. et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res 2003; 63 (23) 8323-8329
    PubMedGoogle Scholar
  • 203 Huang X, Ma J, Xu J, Su Q, Zhao J. Simvastatin induces growth inhibition and apoptosis in HepG2 and Huh7 hepatocellular carcinoma cells via upregulation of Notch1 expression. Mol Med Rep 2015; 11 (03) 2334-2340
    CrossrefPubMedGoogle Scholar
  • 204 Zhou TY, Zhou YL, Qian MJ. et al. Interleukin-6 induced by YAP in hepatocellular carcinoma cells recruits tumor-associated macrophages. J Pharmacol Sci 2018; 138 (02) 89-95
    CrossrefPubMedGoogle Scholar
  • 205 Yokohama K, Fukunishi S, Ii M. et al. Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice. Int J Mol Med 2016; 38 (05) 1499-1506
    CrossrefPubMedGoogle Scholar
  • 206 Deza Z, Caimi GR, Noelia M, Coli L, Ridruejo E, Alvarez L. Atorvastatin shows antitumor effect in hepatocellular carcinoma development by inhibiting angiogenesis via TGF-β1/pERK signaling pathway. Mol Carcinog 2023; 62 (03) 398-407
    CrossrefPubMedGoogle Scholar
  • 207 Sutter AP, Maaser K, Höpfner M, Huether A, Schuppan D, Scherübl H. Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor. J Hepatol 2005; 43 (05) 808-816
    CrossrefPubMedGoogle Scholar
  • 208 Zhang W, Wu J, Zhou L, Xie HY, Zheng SS. Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway. Indian J Exp Biol 2010; 48 (12) 1167-1174
    PubMedGoogle Scholar
  • 209 Wang J, Xu Z, Zhang M. Downregulation of survivin expression and elevation of caspase-3 activity involved in pitavastatin-induced HepG 2 cell apoptosis. Oncol Rep 2007; 18 (02) 383-387
    PubMedGoogle Scholar
  • 210 Elleithi YA, El-Gayar AM, Amin MN. Simvastatin induces apoptosis and suppresses hepatocellular carcinoma induced in rats. Appl Biochem Biotechnol 2023; 195 (03) 1656-1674
    CrossrefPubMedGoogle Scholar
  • 211 Decaudin D, Castedo M, Nemati F. et al. Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo. Cancer Res 2002; 62 (05) 1388-1393
    PubMedGoogle Scholar
  • 212 Arasanz H, Gato-Cañas M, Zuazo M. et al. PD1 signal transduction pathways in T cells. Oncotarget 2017; 8 (31) 51936-51945
    CrossrefPubMedGoogle Scholar
  • 213 Shwe TH, Pothacharoen P, Phitak T, Wudtiwai B, Kongtawelert P. Atorvastatin attenuates programmed death ligand-1 (PD-L1) induction in human hepatocellular carcinoma cells. Int J Mol Sci 2021; 22 (16) 8755
    CrossrefPubMedGoogle Scholar
  • 214 Cheng Y, Luo R, Zheng H. et al. Synergistic anti-tumor efficacy of sorafenib and fluvastatin in hepatocellular carcinoma. Oncotarget 2017; 8 (14) 23265-23276
    CrossrefPubMedGoogle Scholar
  • 215 Shao WQ, Zhu WW, Luo MJ. et al. Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma. Cell Rep 2022; 39 (03) 110712
    CrossrefPubMedGoogle Scholar
  • 216 Wong TL, Ng KY, Tan KV. et al. CRAF methylation by PRMT6 regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation. Hepatology 2020; 71 (04) 1279-1296
    CrossrefPubMedGoogle Scholar
  • 217 Feng J, Dai W, Mao Y. et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis. J Exp Clin Cancer Res 2020; 39 (01) 24
    CrossrefPubMedGoogle Scholar
  • 218 Mok EHK, Leung CON, Zhou L. et al. Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma. Cancer Res 2022; 82 (17) 3102-3115
    CrossrefPubMedGoogle Scholar
  • 219 Nguyen CDK, Yi C. YAP/TAZ signaling and resistance to cancer therapy. Trends Cancer 2019; 5 (05) 283-296
    CrossrefPubMedGoogle Scholar
  • 220 Jeon D, Cha HR, Chung SW. et al. Association between statin use and the prognosis of hepatocellular carcinoma after resection: a nationwide cohort study. EClinicalMedicine 2023; 65: 102300
    CrossrefPubMedGoogle Scholar
  • 221 Khajeh E, Aminizadeh E, Moghadam AD. et al. Association of perioperative use of statins, metformin, and aspirin with recurrence after curative liver resection in patients with hepatocellular carcinoma: a propensity score matching analysis. Cancer Med 2023; 12 (19) 19548-19559
    CrossrefPubMedGoogle Scholar
  • 222 Yun B, Ahn SH, Oh J, Yoon JH, Kim BK. Statin use is associated with better post-operative prognosis among patients with hepatitis B virus-related hepatocellular carcinoma. Eur J Clin Invest 2023; 53 (04) e13936
    CrossrefPubMedGoogle Scholar
  • 223 Yang SY, Wang CC, Chen KD. et al. Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma. BMC Cancer 2021; 21 (01) 70
    CrossrefPubMedGoogle Scholar
  • 224 Nishio T, Taura K, Nakamura N. et al. 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 (02) 264-269
    CrossrefPubMedGoogle Scholar
  • 225 Kawaguchi Y, Sakamoto Y, Ito D. et al. Statin use is associated with a reduced risk of hepatocellular carcinoma recurrence after initial liver resection. Biosci Trends 2017; 11 (05) 574-580
    CrossrefPubMedGoogle Scholar
  • 226 Lee O, Rhu J, Choi GS, Kim JM, Kim K, Joh JW. Impact of statins on hepatocellular carcinoma recurrence after living-donor liver transplantation. Ann Transplant 2022; 27: e935604
    PubMedGoogle Scholar
  • 227 Wu LL, Hsieh MC, Chow JM, Liu SH, Chang CL, Wu SY. Statins improve outcomes of nonsurgical curative treatments in hepatocellular carcinoma patients. Medicine (Baltimore) 2016; 95 (36) e4639
    CrossrefPubMedGoogle Scholar
  • 228 Dasari BVM, Pathanki A, Hodson J. et al. Propensity-matched analysis of the influence of perioperative statin therapy on outcomes after liver resection. BJS Open 2019; 3 (04) 509-515
    CrossrefPubMedGoogle Scholar
  • 229 Young SH, Chau GY, Lee IC. et al. Aspirin is associated with low recurrent risk in hepatitis B virus-related hepatocellular carcinoma patients after curative resection. J Formos Med Assoc 2020; 119 (1, Pt 2): 218-229
    CrossrefPubMedGoogle Scholar
  • 230 Cho Y, Kim MS, Nam CM, Kang ES. Statin use is associated with decreased hepatocellular carcinoma recurrence in liver transplant patients. Sci Rep 2019; 9 (01) 1467
    CrossrefPubMedGoogle Scholar
  • 231 Becchetti C, Dirchwolf M, Schropp J. et al; Swiss Transplant Cohort Study. Use of statins after liver transplantation is associated with improved survival: results of a nationwide study. Aliment Pharmacol Ther 2022; 56 (07) 1194-1204
    CrossrefPubMedGoogle Scholar
  • 232 Graf H, Jüngst C, Straub G. et al. Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma. Digestion 2008; 78 (01) 34-38
    CrossrefPubMedGoogle Scholar
  • 233 Singal AG, Manjunath H, Yopp AC. et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109 (03) 325-334
    CrossrefPubMedGoogle Scholar
  • 234 Lelkes PI, Friedman JE. Interaction of French-pressed liposomes with isolated bovine adrenal chromaffin cells. Characterization of the cell-liposome interactions. J Biol Chem 1985; 260 (03) 1796-1803
    CrossrefPubMedGoogle Scholar
  • 235 Dongiovanni P, Petta S, Mannisto V. et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015; 63 (03) 705-712
    CrossrefPubMedGoogle Scholar