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Semin Liver Dis 2009; 29(4): 412-422
DOI: 10.1055/s-0029-1240010
© Thieme Medical Publishers

Drug-Induced Liver Injury Associated with Statins

Mark W. Russo1 , Martin Scobey1 , Herbert L. Bonkovsky1
  • 1Department of Medicine, Carolinas Medical Center, Charlotte, North Carolina
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Publication History

Publication Date:
13 October 2009 (online)

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ABSTRACT

The “statins,” or hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors, are a generally safe class of drugs that are widely used throughout the world and are rarely associated with severe hepatotoxicity. In this article, two cases of severe hepatotoxicity attributed to statin use are presented. In addition, a detailed summary of previously published cases of statin hepatotoxicity and the risks and benefits of statins in patients with chronic liver disease are presented. Drug-induced liver injury (DILI) from statins typically presents with an acute hepatocellular liver injury pattern, although mixed or cholestatic injury patterns have also been reported. Nonspecific autoantibodies as well as clinical, laboratory, and histological features of an autoimmune-like hepatitis may be present in some patients with statin hepatotoxicity. Despite their widespread use, acute liver failure and death have rarely been reported in patients with statin hepatotoxicity. Multiple retrospective studies as well as a large prospective randomized controlled trial demonstrate that statins can safely be given to hyperlipidemic patients with compensated chronic liver disease.

KEYWORDS

Autoimmune hepatitis - hepatotoxicity - hydroxymethylglutaryl coenzyme A reductase - nonalcoholic fatty liver disease - lipid-lowering agents

REFERENCES

  • 1 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver.  Hepatology. 2005;  41(4) 690-695
    CrossrefPubMedGoogle Scholar
  • 2 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(4) 336-339
    CrossrefPubMedGoogle Scholar
  • 3 Alvarez F, Berg P A, Bianchi F B et al.. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.  J Hepatol. 1999;  31(5) 929-938
    CrossrefPubMedGoogle Scholar
  • 4 Geddes J A. Cholestatic jaundice associated with lovastatin (Mevacor) therapy.  CMAJ. 1990;  143(1) 13-14
    PubMedGoogle Scholar
  • 5 McQueen M J. Cholestatic jaundice associated with lovastatin (Mevacor) therapy.  CMAJ. 1990;  142(8) 841-842
    PubMedGoogle Scholar
  • 6 Ballaré M, Campanini M, Catania E, Bordin G, Zaccala G, Monteverde A. Acute cholestatic hepatitis during simvastatin administration.  Recenti Prog Med. 1991;  82(4) 233-235
    PubMedGoogle Scholar
  • 7 Feydy P, Bogomoletz W V. [A case of hepatitis caused by simvastatin].  Gastroenterol Clin Biol. 1991;  15(1) 94-95
    PubMedGoogle Scholar
  • 8 Spreckelsen U, Kirchhoff R, Haacke H. Chloestatischer ikterus während lovastatin-einnahme.  Dtsch Med Wochenschr. 1991;  116 739-740
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Raveh D, Arnon R, Israeli A, Eisenberg S. Lovastatin-induced hepatitis.  Isr J Med Sci. 1992;  28(2) 101-102
    PubMedGoogle Scholar
  • 10 Grimbert S, Pessayre D, Degott C, Benhamou J-P. Acute hepatitis induced by HMG-CoA reductase inhibitor, lovastatin.  Dig Dis Sci. 1994;  39(9) 2032-2033
    CrossrefPubMedGoogle Scholar
  • 11 Huchzermeyer H, Münzenmaier R. [Lovastatin-induced acute cholestatic hepatitis].  Dtsch Med Wochenschr. 1995;  120(8) 252-256
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Gavilán Carrasco J C, Bermúdez Recio F, Salgado Ordóñez F, González Santos P. [Hepatitis due to lovastatin].  Med Clin (Barc). 1996;  107(14) 557-558
    PubMedGoogle Scholar
  • 13 Bruguera M, Joya P, Rodés J. [Hepatitis associated with treatment with lovastatin. Presentation of 2 cases].  Gastroenterol Hepatol. 1998;  21(3) 127-128
    PubMedGoogle Scholar
  • 14 Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pravastatin.  Am J Gastroenterol. 1999;  94(5) 1388-1390
    CrossrefPubMedGoogle Scholar
  • 15 Jiménez-Alonso J, Osorio J M, Gutiérrez-Cabello F, López de la Osa A, León L, Mediavilla García J D. Atorvastatin-induced cholestatic hepatitis in a young woman with systemic lupus erythematosus. Grupo Lupus Virgen de las Nieves.  Arch Intern Med. 1999;  159(15) 1811-1812
    CrossrefPubMedGoogle Scholar
  • 16 Nakad A, Bataille L, Hamoir V, Sempoux C, Horsmans Y. Atorvastatin-induced acute hepatitis with absence of cross-toxicity with simvastatin.  Lancet. 1999;  353(9166) 1763-1764
    PubMedGoogle Scholar
  • 17 Heuer T, Gerards H, Pauw M, Gabbert H E, Reis H E. Toxischer leberschaden durch HMG-CoA-reduktase-hemmer.  Med Klin (Munich). 2000;  95 642-644
    CrossrefPubMedGoogle Scholar
  • 18 Punthakee Z, Scully L J, Guindi M M, Ooi T C. Liver fibrosis attributed to lipid lowering medications: two cases.  J Intern Med. 2001;  250(3) 249-254
    CrossrefPubMedGoogle Scholar
  • 19 Graziadei I W, Obermoser G E, Sepp N T, Erhart K H, Vogel W. Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis.  Lupus. 2003;  12(5) 409-412
    CrossrefPubMedGoogle Scholar
  • 20 Pelli N, Setti M, Ceppa P, Toncini C, Indiveri F. Autoimmune hepatitis revealed by atorvastatin.  Eur J Gastroenterol Hepatol. 2003;  15(8) 921-924
    CrossrefPubMedGoogle Scholar
  • 21 Perger L, Kohler M, Fattinger K, Flury R, Meier P J, Pauli-Magnus C. Fatal liver failure with atorvastatin.  J Hepatol. 2003;  39(6) 1095-1097
    PubMedGoogle Scholar
  • 22 Gershovich O E, Lyman Jr A E. Liver function test abnormalities and pruritus in a patient treated with atorvastatin: case report and review of the literature.  Pharmacotherapy. 2004;  24(1) 150-154
    CrossrefPubMedGoogle Scholar
  • 23 Wolters L MM, Van Buuren H R. Rosuvastatin-associated hepatitis with autoimmune features.  Eur J Gastroenterol Hepatol. 2005;  17(5) 589-590
    CrossrefPubMedGoogle Scholar
  • 24 Alla V, Abraham J, Siddiqui J et al.. Autoimmune hepatitis triggered by statins.  J Clin Gastroenterol. 2006;  40(8) 757-761
    CrossrefPubMedGoogle Scholar
  • 25 de Castro M L, Hermo J A, Baz A et al.. Hepatitis colestásica aguda tras la reintroducción atorvastatina.  Gastroenterol Hepatol. 2006;  29 21-24
    CrossrefPubMedGoogle Scholar
  • 26 Famularo G, Miele L, Minisola G, Grieco A. Liver toxicity of rosuvastatin therapy.  World J Gastroenterol. 2007;  13(8) 1286-1288
    PubMedGoogle Scholar
  • 27 Rahier J F, Rahier J, Leclercq I, Geubel A P. Severe acute cholestatic hepatitis with prolonged cholestasis and bile-duct injury following atorvastatin therapy: a case report.  Acta Gastroenterol Belg. 2008;  71(3) 318-320
    PubMedGoogle Scholar
  • 28 Ridruejo E, Mandó O G. Acute cholestatic hepatitis after reinitiating treatment with atorvastatin.  J Hepatol. 2002;  37(1) 165-166
    CrossrefPubMedGoogle Scholar
  • 29 Clarke A T, Mills P R. Atorvastatin associated liver disease.  Dig Liver Dis. 2006;  38(10) 772-777
    CrossrefPubMedGoogle Scholar
  • 30 Drug Topics. 2008 Top 200 generic drugs by total prescriptions. Available at: http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/222009/599844/article.pdf Accessed May 18, 2009
    Google Scholar
  • 31 Argo C K, Loria P, Caldwell S H, Lonardo A. Statins in liver disease: a molehill, an iceberg, or neither?.  Hepatology. 2008;  48(2) 662-669
    CrossrefPubMedGoogle Scholar
  • 32 Zimmerman H J. Hepatotoxicity. 2nd ed. Philadelphia, PA; Lippincott Williams & Wilkins 1999: 440-444
    PubMedGoogle Scholar
  • 33 Bonkovsky H L, Shedlofsky S I, Jones D P, LaBrecque D. Drug-induced liver injury. In: Boyer TD, Manns MP, Wright TL Zakim and Boyer's Hepatology—a Textbook of Liver Disease. 5th ed. Philadelphia, PA; Saunders-Elsevier 2006: 503-550
    PubMedGoogle Scholar
  • 34 Boberg K M. Prevalence and epidemiology of autoimmune hepatitis.  Clin Liver Dis. 2002;  6(3) 635-647
    CrossrefPubMedGoogle Scholar
  • 35 Rudski L, Rabinovitch M A, Danoff D. Systemic immune reactions to HMG-CoA reductase inhibitors. Report of 4 cases and review of the literature.  Medicine (Baltimore). 1998;  77(6) 378-383
    CrossrefPubMedGoogle Scholar
  • 36 Purvin V, Kawasaki A, Smith K H, Kesler A. Statin-associated myasthenia gravis: report of 4 cases and review of the literature.  Medicine (Baltimore). 2006;  85(2) 82-85
    CrossrefPubMedGoogle Scholar
  • 37 Khosla R, Butman A N, Hammer D F. Simvastatin-induced lupus erythematosus.  South Med J. 1998;  91(9) 873-874
    PubMedGoogle Scholar
  • 38 Ahmad S. Lovastatin-induced lupus erythematosus.  Arch Intern Med. 1991;  151(8) 1667-1668
    CrossrefPubMedGoogle Scholar
  • 39 Ricaurte B, Guirguis A, Taylor H C, Zabriskie D. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity.  Ann Pharmacother. 2006;  40(4) 753-757
    CrossrefPubMedGoogle Scholar
  • 40 Kanathur N, Mathai M G, Byrd Jr R P, Fields C L, Roy T M. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis.  Tenn Med. 2001;  94(9) 339-341
    PubMedGoogle Scholar
  • 41 Caldwell S H, Hespenheide E E, von Borstel R W. Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin.  Dig Dis Sci. 2001;  46(2) 376-378
    CrossrefPubMedGoogle Scholar
  • 42 Ashar U, Desai D, Bhaduri A. Flutamide-induced hepatotoxicity with possible potentiation by simvastatin.  J Assoc Physicians India. 2003;  51 75-77
    PubMedGoogle Scholar
  • 43 Bristol-Myers Squibb Company. Pravachol (pravastatin sodium) Tablets. Available at: http://packageinserts.bms.com/pi/pi_pravachol.pdf Accessed May 30, 2009
    Google Scholar
  • 44 Dunn W, Xu R, Wingard D L et al.. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study.  Am J Gastroenterol. 2008;  103(9) 2263-2271
    CrossrefPubMedGoogle Scholar
  • 45 Serfaty L, Capeau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data.  Liver Int. 2009;  29(Suppl 2) 13-25
    CrossrefPubMedGoogle Scholar
  • 46 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(5) 1287-1292
    CrossrefPubMedGoogle Scholar
  • 47 Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes.  Am J Med Sci. 2005;  329(2) 62-65
    CrossrefPubMedGoogle Scholar
  • 48 Avins A L, Manos M M, Ackerson L et al.. Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study.  Drug Saf. 2008;  31(4) 325-334
    CrossrefPubMedGoogle Scholar
  • 49 Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.  Hepatology. 2008;  47(6) 2003-2009
    CrossrefPubMedGoogle Scholar
  • 50 Russo M W, Galanko J A, Shrestha R, Fried M W, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States.  Liver Transpl. 2004;  10(8) 1018-1023
    CrossrefPubMedGoogle Scholar
  • 51 Horlander J C, Kwo P Y, Cummings O W. Atorvastatin for the treatment of NASH.  Gastroenterology. 2001;  120 A544
    PubMedGoogle Scholar
  • 52 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
    PubMedGoogle Scholar
  • 53 Rallidis L S, Drakoulis C K, Parasi A S. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study.  Atherosclerosis. 2004;  174(1) 193-196
    CrossrefPubMedGoogle Scholar
  • 54 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(4) 131-134
    PubMedGoogle Scholar
  • 55 Gómez-Domínguez E, Gisbert J P, Moreno-Monteagudo J A, García-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients.  Aliment Pharmacol Ther. 2006;  23(11) 1643-1647
    CrossrefPubMedGoogle Scholar
  • 56 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(1) 233-234
    CrossrefPubMedGoogle Scholar
  • 57 Ekstedt M, Franzén 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(1) 135-141
    CrossrefPubMedGoogle Scholar
  • 58 Andrade R J, Lucena M I, Fernández M C Spanish Group for the Study of Drug-Induced Liver Disease et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.  Gastroenterology. 2005;  129(2) 512-521
    CrossrefPubMedGoogle Scholar
  • 59 Chalasani N, Fontana R J, Bonkovsky H L Drug Induced Liver Injury Network (DILIN) et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.  Gastroenterology. 2008;  135(6) 1924-1934, 1934, e1–e4
    CrossrefPubMedGoogle Scholar
  • 60 Lewis J H, Mortensen M E, Zweig S, Fusco M J, Medoff J R, 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(5) 1453-1463
    CrossrefPubMedGoogle Scholar
  • 61 Zafra C, Abraldes J G, Turnes J et al.. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis.  Gastroenterology. 2004;  126 749-755
    CrossrefPubMedGoogle Scholar
  • 62 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(1) 242-253
    CrossrefPubMedGoogle Scholar
  • 63 Resch U, Tatzber F, Budinsky A, Sinzinger H. Reduction of oxidative stress and modulation of autoantibodies against modified low-density lipoprotein after rosuvastatin therapy.  Br J Clin Pharmacol. 2006;  61(3) 262-274
    CrossrefPubMedGoogle Scholar
  • 64 Hui J M, Hodge A, Farrell G C, Kench J G, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?.  Hepatology. 2004;  40(1) 46-54
    CrossrefPubMedGoogle Scholar
  • 65 Cohen D E, Anania F A, Chalasani N. National Lipid Association Statin Safety Task Force Liver Expert Panel . An assessment of statin safety by hepatologists.  Am J Cardiol. 2006;  97(8A, suppl) 77C-81C
    PubMedGoogle Scholar

Mark W RussoM.D. M.P.H. 

Carolinas Medical Center, Center for Liver Diseases and Transplantation

Annex Bldg 3rd Floor, 1000 Blythe Blvd., Charlotte, NC 28203

Email: Mark.Russo@carolinas.org

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