The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis

  • Carlos Moctezuma-Velázquez
  • Juan G. Abraldes
  • Aldo J. Montano-Loza
Liver (J Bajaj, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Liver

Abstract

Purpose of review

Statins are drugs developed to treat hypercholesterolemia. Its use in patients with liver disease has been limited because one of its potential and most feared side effects is hepatotoxicity. However, there is robust evidence that supports the safety of statins in this population in the absence of severe liver dysfunction. In this review, we will summarize the efficacy and safety of statins in cirrhosis.

Recent findings

Statins are effective in the treatment of dyslipidemia in patients with liver disease, because of their pleiotropic properties. These properties are independent of their effect on cholesterol levels, such as improving endothelial dysfunction or having antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, proapoptotic, or immunomodulation properties. Statins have been studied in other areas such as in treatment of portal hypertension, prevention of hepatocellular carcinoma, and/or protection against ischemia/reperfusion injury.

Summary

Approved indications for statins in patients with cirrhosis are those of the general population, including dyslipidemia and increased cardiovascular risk. Compensated cirrhosis is not a contraindication. In patients with decompensated cirrhosis, statins should be prescribed with extreme caution at low doses, and with frequent monitoring of creatinine phosphokinase levels in order to detect adverse events in a timely fashion.

Keywords

Hydroxymethylglutaryl-CoA reductase inhibitors Liver cirrhosis End-stage liver disease Chemical- and drug-induced liver injury Hypertension, portal Dyslipidemias 

Notes

Compliance with Ethical Standards

Conflict of Interest

Carlos Moctezuma-Velázquez declares that he has no conflict of interest. Juan Abraldes declares that he has no conflict of interest. Aldo Montano-Loza declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Cabrera L, Abraldes J. Statins: The panacea of cirrhosis? Curr Hepatol Rep. 2016;15:1–7.CrossRefGoogle Scholar
  2. 2.
    Moreno M, Ramalho LN, Sancho-Bru P, Ruiz-Ortega M, Ramalho F, Abraldes JG, et al. Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G147–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Marrone G, Maeso-Diaz R, Garcia-Cardena G, Abraldes JG, Garcia-Pagan JC, Bosch J, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut. 2015;64(9):1434–43.CrossRefPubMedGoogle Scholar
  4. 4.
    Bosch J, Abraldes JG, Fernandez M, Garcia-Pagan JC. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol. 2010;53(3):558–67.CrossRefPubMedGoogle Scholar
  5. 5.
    Abraldes JG, Rodriguez-Vilarrupla A, Graupera M, Zafra C, Garcia-Caldero H, Garcia-Pagan JC, et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol. 2007;46(6):1040–6.CrossRefPubMedGoogle Scholar
  6. 6.
    •• Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, Genesca J, et al. 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(5):1160–70 e3. Prospective study that showed a lower mortality in patients that received statins.CrossRefPubMedGoogle Scholar
  7. 7.
    Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernandez M, Garca-Pagan JC, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004;126(3):749–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009;136(5):1651–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Pollo-Flores P, Soldan M, Santos UC, Kunz DG, Mattos DE, da Silva AC, 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):957–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Wani ZA, Mohapatra S, Khan AA, Mohapatra A, Yatoo GN. Addition of simvastatin to carvedilol non responders: a new pharmacological therapy for treatment of portal hypertension. World J Hepatol. 2017;9(5):270–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Del Puppo M, Galli Kienle M, Crosignani A, Petroni ML, Amati B, Zuin M, et al. Cholesterol metabolism in primary biliary cirrhosis during simvastatin and UDCA administration. J Lipid Res. 2001;42(3):437–41.PubMedGoogle Scholar
  12. 12.
    Kurihara T, Akimoto M, Abe K, Ishiguro H, Niimi A, Maeda A, et al. Experimental use of pravastatin in patients with primary biliary cirrhosis associated with hypercholesterolemia. Clin Ther. 1993;15(5):890–8.PubMedGoogle Scholar
  13. 13.
    Ritzel U, Leonhardt U, Nather M, Schafer G, Armstrong VW, Ramadori G. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers. J Hepatol. 2002;36(4):454–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Stojakovic T, Claudel T, Putz-Bankuti C, Fauler G, Scharnagl H, Wagner M, et al. Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment. Atherosclerosis. 2010;209(1):178–83.CrossRefPubMedGoogle Scholar
  15. 15.
    Stojakovic T, Putz-Bankuti C, Fauler G, Scharnagl H, Wagner M, Stadlbauer V, et al. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology. 2007;46(3):776–84.CrossRefPubMedGoogle Scholar
  16. 16.
    Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;12:CD008623.  https://doi.org/10.1002/14651858.CD008623.pub2.Google Scholar
  17. 17.
    •• Kargiotis K, Athyros VG, Giouleme O, Katsiki N, Katsiki E, Anagnostis P, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol. 2015;21(25):7860–8. This article shows that further investigation is needed regarding the role of statins in the treatment of NAFLD.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Simon TG, Bonilla H, Yan P, Chung RT, Butt AA. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: results from ERCHIVES. Hepatology. 2016;64(1):47–57.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    •• Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis c-related compensated cirrhosis. Gastroenterology. 2016;150(2):430–40 e1. One of the largest observational studies showing a benefit of statins in patients with cirrhosis.CrossRefPubMedGoogle Scholar
  20. 20.
    Harrison SA, Rossaro L, Hu KQ, Patel K, Tillmann H, Dhaliwal S, et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology. 2010;52(3):864–74.CrossRefPubMedGoogle Scholar
  21. 21.
    Manzano-Robleda Mdel C, Ornelas-Arroyo V, Barrientos-Gutierrez T, Mendez-Sanchez N, Uribe M, Chavez-Tapia NC. Boceprevir and telaprevir for chronic genotype 1 hepatitis C virus infection. A systematic review and meta-analysis. Ann Hepatol. 2015;14(1):46–57.PubMedGoogle Scholar
  22. 22.
    Chang FM, Wang YP, Lang HC, Tsai CF, Hou MC, Lee FY, et al. Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study. Hepatology. 2017;66:896–907.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen CI, Kuan CF, Fang YA, Liu SH, Liu JC, Wu LL, et al. Cancer risk in HBV patients with statin and metformin use: a population-based cohort study. Medicine (Baltimore). 2015;94(6):e462.CrossRefGoogle Scholar
  24. 24.
    Hsiang JC, Wong GL, Tse YK, Wong VW, Yip TC, Chan HL. 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(5):1190–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Huang YW, Lee CL, Yang SS, Fu SC, Chen YY, Wang TC, 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(7):976–85.CrossRefPubMedGoogle Scholar
  26. 26.
    Butt AA, Yan P, Bonilla H, Abou-Samra AB, Shaikh OS, Simon TG, et al. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: results from ERCHIVES. Hepatology. 2015;62(2):365–74.CrossRefPubMedGoogle Scholar
  27. 27.
    Lai SW, Liao KF, Lai HC, Muo CH, Sung FC, Chen PC. Statin use and risk of hepatocellular carcinoma. Eur J Epidemiol. 2013;28(6):485–92.CrossRefPubMedGoogle Scholar
  28. 28.
    Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144(2):323–32.CrossRefPubMedGoogle Scholar
  29. 29.
    Drolz A, Horvatits T, Michl B, Roedl K, Schellongowski P, Holzinger U, et al. Statin therapy is associated with reduced incidence of hypoxic hepatitis in critically ill patients. J Hepatol. 2014;60(6):1187–93.CrossRefPubMedGoogle Scholar
  30. 30.
    Kumar S, Grace ND, Qamar AA. Statin use in patients with cirrhosis: a retrospective cohort study. Dig Dis Sci. 2014;59(8):1958–65.CrossRefPubMedGoogle Scholar
  31. 31.
    Motzkus-Feagans C, Pakyz AL, Ratliff SM, Bajaj JS, Lapane KL. Statin use and infections in veterans with cirrhosis. Aliment Pharmacol Ther. 2013;38(6):611–8.CrossRefPubMedGoogle Scholar
  32. 32.
    •• Jose J. Statins and its hepatic effects: newer data, implications, and changing recommendations. J Pharm Bioallied Sci. 2016;8(1):23–8. Complete review mainly focused on the safety of statins from the liver perspectiveCrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med. 1998;158(6):577–84.CrossRefPubMedGoogle Scholar
  34. 34.
    Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology. 2014;60(2):679–86.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Reuben A, Koch DG, Lee WM. Acute Liver Failure Study G. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065–76.  https://doi.org/10.1002/hep.23937. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bjornsson ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver Int. 2017;37(2):173–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Alla V, Abraham J, Siddiqui J, Raina D, Wu GY, Chalasani NP, et al. Autoimmune hepatitis triggered by statins. J Clin Gastroenterol. 2006;40(8):757–61.CrossRefPubMedGoogle Scholar
  38. 38.
  39. 39.
    Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology. 2004;126(5):1287–92.CrossRefPubMedGoogle Scholar
  40. 40.
    Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R, et al. 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(5):1453–63.CrossRefPubMedGoogle Scholar
  41. 41.
    Onofrei MD, Butler KL, Fuke DC, Miller HB. Safety of statin therapy in patients with preexisting liver disease. Pharmacotherapy. 2008;28(4):522–9.CrossRefPubMedGoogle Scholar
  42. 42.
    •• Bays H, Cohen DE, Chalasani N, Harrison SA, The National Lipid Association’s Statin Safety Task F. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S47–57. Specific recommendations of a panel of experts about the liver safety of statins; the strength of the recommendations and quality of evidence are given.CrossRefPubMedGoogle Scholar
  43. 43.
    Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc. 2010;85(4):349–56.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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 1):E17–22.CrossRefPubMedGoogle Scholar
  45. 45.
    Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol. 2003;38(Suppl 1):S54–68.CrossRefPubMedGoogle Scholar
  46. 46.
    Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, 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(1):242–53.CrossRefPubMedGoogle Scholar
  47. 47.
    Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol. 2007;46(6):1126–32.CrossRefPubMedGoogle Scholar
  48. 48.
    Berzigotti A, Erice E, Gilabert R, Reverter E, Abraldes JG, Garcia-Pagan JC, et al. Cardiovascular risk factors and systemic endothelial function in patients with cirrhosis. Am J Gastroenterol. 2013;108(1):75–82.CrossRefPubMedGoogle Scholar
  49. 49.
    Longo M, Crosignani A, Battezzati PM, Squarcia Giussani C, Invernizzi P, Zuin M, et al. Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut. 2002;51(2):265–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sorokin A, Brown JL, Thompson PD. Primary biliary cirrhosis, hyperlipidemia, and atherosclerotic risk: a systematic review. Atherosclerosis. 2007;194(2):293–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients. 2013;5(5):1544–60.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Syed GH, Amako Y, Siddiqui A. Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab. 2010;21(1):33–40.CrossRefPubMedGoogle Scholar
  53. 53.
    Bosch J, Forns X. Therapy Statins and liver disease: from concern to ‘wonder’ drugs? Nat Rev Gastroenterol Hepatol. 2015;12(6):320–1.CrossRefPubMedGoogle Scholar
  54. 54.
    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(1):117–25.CrossRefPubMedGoogle Scholar
  55. 55.
    Sheridan DA, Bridge SH, Crossey MM, Felmlee DJ, Fenwick FI, Thomas HC, 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(5):737–47.CrossRefPubMedGoogle Scholar
  56. 56.
    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(1):18–23.CrossRefPubMedGoogle Scholar
  57. 57.
    Bader T, Korba B. Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro. Antivir Res. 2010;86(3):241–5.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    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(6):623–30.CrossRefPubMedGoogle Scholar
  59. 59.
    •• Kim RG, Loomba R, Prokop LJ, 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. 2017;15:1521–30. Meta-analysis that reinforces the concept that statins may probably decrease mortality in patients with cirrhosis.CrossRefPubMedGoogle Scholar
  60. 60.
    Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160–4.CrossRefPubMedGoogle Scholar
  61. 61.
    La Mura V, Pasarin M, Meireles CZ, Miquel R, Rodriguez-Vilarrupla A, Hide D, et al. Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology. 2013;57(3):1172–81.CrossRefPubMedGoogle Scholar
  62. 62.
    Gracia-Sancho J, Garcia-Caldero H, Hide D, Marrone G, Guixe-Muntet S, Peralta C, et al. Simvastatin maintains function and viability of steatotic rat livers procured for transplantation. J Hepatol. 2013;58(6):1140–6.CrossRefPubMedGoogle Scholar
  63. 63.
    Chang CC, Wang SS, Hsieh HG, Lee WS, Chuang CL, Lin HC, et al. Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung. Clin Sci (Lond). 2015;129(6):449–60.CrossRefGoogle Scholar
  64. 64.
    Relja B, Lehnert M, Seyboth K, Bormann F, Hohn C, Czerny C, et al. Simvastatin reduces mortality and hepatic injury after hemorrhage/resuscitation in rats. Shock. 2010;34(1):46–54.CrossRefPubMedGoogle Scholar
  65. 65.
    Meireles CZ, Pasarin M, Lozano JJ, Garcia-Caldero H, Gracia-Sancho J, Garcia-Pagan JC, et al. Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation. Shock. 2017;47(3):370–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Trebicka J, Hennenberg M, Odenthal M, Shir K, Klein S, Granzow M, et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol. 2010;53(4):702–12.CrossRefPubMedGoogle Scholar
  67. 67.
    Abraldes JG, Burak KW. STAT order: should patients with chronic liver disease be prescribed statins to prevent fibrosis progression and hepatocellular carcinoma? Hepatology. 2016;64(1):13–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Carlos Moctezuma-Velázquez
    • 1
  • Juan G. Abraldes
    • 1
  • Aldo J. Montano-Loza
    • 1
  1. 1.Division of Gastroenterology and Liver UnitUniversity of AlbertaEdmontonCanada

Personalised recommendations