Drug-Induced Liver Injury with Autoimmune Features

 

 Buy Article Permissions and Reprints

Abstract

Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, α-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-α agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis.

• References

• 1 Boyer TD, Manns MP, Sanyal AJ. Zakim and Boyer's Hepatology - A Textbook of Liver Disease. 6th ed. Philadelphia, PA: Elsevier; 2012
  Google Scholar
• 2 Surh CD, Coppel R, Gershwin ME. Structural requirement for autoreactivity on human pyruvate dehydrogenase-E2, the major autoantigen of primary biliary cirrhosis. Implication for a conformational autoepitope. J Immunol 1990; 144 (9) 3367-3374
  PubMedGoogle Scholar
• 3 Shimoda S, Nakamura M, Ishibashi H , et al. Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Gastroenterology 2003; 124 (7) 1915-1925
  CrossrefPubMedGoogle Scholar
• 4 Andrade RJ, Agúndez JA, Lucena MI, Martínez C, Cueto R, García-Martín E. Pharmacogenomics in drug induced liver injury. Curr Drug Metab 2009; 10 (9) 956-970
  CrossrefPubMedGoogle Scholar
• 5 Urban TJ, Shen Y, Stolz A , et al; Drug-Induced Liver Injury Network; DILIGEN; EUDRAGENE; Spanish DILI Registry; International Serious Adverse Events Consortium. Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet Genomics 2012; 22 (11) 784-795
  CrossrefPubMedGoogle Scholar
• 6 Lawson JA, Farhood A, Hopper RD, Bajt ML, Jaeschke H. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci 2000; 54 (2) 509-516
  CrossrefPubMedGoogle Scholar
• 7 Murphy EJ, Davern TJ, Shakil AO , et al; Acute Liver Failure Study Group. Troglitazone-induced fulminant hepatic failure. Dig Dis Sci 2000; 45 (3) 549-553
  CrossrefPubMedGoogle Scholar
• 8 Alla V, Abraham J, Siddiqui J , et al. Autoimmune hepatitis triggered by statins. J Clin Gastroenterol 2006; 40 (8) 757-761
  CrossrefPubMedGoogle Scholar
• 9 García-Buey L, García-Monzón C, Rodriguez S , et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 1995; 108 (6) 1770-1777
  CrossrefPubMedGoogle Scholar
• 10 Zhou S, Chan E, Duan W, Huang M, Chen YZ. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 2005; 37 (1) 41-213
  CrossrefPubMedGoogle Scholar
• 11 Ju C, Uetrecht JP. Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr Drug Metab 2002; 3 (4) 367-377
  CrossrefPubMedGoogle Scholar
• 12 Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics of drug-induced liver injury. Hepatology 2010; 52 (2) 748-761
  CrossrefPubMedGoogle Scholar
• 13 Pichler WJ, Beeler A, Keller M , et al. Pharmacological interaction of drugs with immune receptors: the p-i concept. Allergol Int 2006; 55 (1) 17-25
  CrossrefPubMedGoogle Scholar
• 14 Kelly BD, Heneghan MA, Bennani F, Connolly CE, O'Gorman TA. Nitrofurantoin-induced hepatotoxicity mediated by CD8+ T cells. Am J Gastroenterol 1998; 93 (5) 819-821
  PubMedGoogle Scholar
• 15 Norcross MA, Luo S, Lu L , et al. Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity. AIDS 2012; 26 (11) F21-F29
  CrossrefPubMedGoogle Scholar
• 16 Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A 1999; 96 (1) 185-190
  CrossrefPubMedGoogle Scholar
• 17 Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 1996; 24 (5) 1068-1073
  CrossrefPubMedGoogle Scholar
• 18 Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci 2010; 55 (8) 2144-2161
  CrossrefPubMedGoogle Scholar
• 19 Xiao X, Zhao P, Rodriguez-Pinto D , et al. Inflammatory regulation by TLR3 in acute hepatitis. J Immunol 2009; 183 (6) 3712-3719
  CrossrefPubMedGoogle Scholar
• 20 Imaeda AB, Watanabe A, Sohail MA , et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 2009; 119 (2) 305-314
  PubMedGoogle Scholar
• 21 Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012; 143 (5) 1158-1172
  CrossrefPubMedGoogle Scholar
• 22 Aithal GP, Ramsay L, Daly AK , et al. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 2004; 39 (5) 1430-1440
  CrossrefPubMedGoogle Scholar
• 23 Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol 2009; 27: 147-163
  CrossrefPubMedGoogle Scholar
• 24 Li J, Zhu X, Liu F , et al. Cytokine and autoantibody patterns in acute liver failure. J Immunotoxicol 2010; 7 (3) 157-164
  CrossrefPubMedGoogle Scholar
• 25 Steuerwald NM, Foureau DM, Norton HJ , et al. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance. PLoS ONE 2013; 8 (12) e81974
  CrossrefPubMedGoogle Scholar
• 26 Sutherland AP, Joller N, Michaud M, Liu SM, Kuchroo VK, Grusby MJ. IL-21 promotes CD8+ CTL activity via the transcription factor T-bet. J Immunol 2013; 190 (8) 3977-3984
  CrossrefPubMedGoogle Scholar
• 27 Ghabril M, Bonkovsky HL, Kum C , et al; US Drug-Induced Liver Injury Network. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol 2013; 11 (5) 558-564 , e3
  CrossrefPubMedGoogle Scholar
• 28 Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29 (4) 412-422
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 de Jong HJ, Tervaert JW, Saldi SR , et al. Association between statin use and lupus-like syndrome using spontaneous reports. Semin Arthritis Rheum 2011; 41 (3) 373-381
  CrossrefPubMedGoogle Scholar
• 30 Jiménez-Alonso J, Jaimez L, Sabio JM, Hidalgo C, Leon L. Atorvastatin-induced reversible positive antinuclear antibodies. Am J Med 2002; 112 (4) 329-330
  CrossrefPubMedGoogle Scholar
• 31 Lucena MI, Kaplowitz N, Hallal H , et al. Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis. J Hepatol 2011; 55 (4) 820-827
  CrossrefPubMedGoogle Scholar
• 32 von Felden J, Montani M, Kessebohm K, Stickel F. Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate. Int J Clin Pharmacol Ther 2013; 51 (3) 219-223
  CrossrefPubMedGoogle Scholar
• 33 Fontana RJ, Hayashi P, Bonkovsky HL , et al. Presentation and outcomes with clinically apparent interferon beta hepatotoxicity. Dig Dis Sci 2013; 58 (6) 1766-1775
  CrossrefPubMedGoogle Scholar
• 34 Moreno-Otero R, García-Buey L, García-Sanchez A, Trapero-Marugán M. Autoimmune hepatitis after long-term methotrexate therapy for rheumatoid arthritis. Curr Drug Saf 2011; 6 (3) 197-200
  CrossrefPubMedGoogle Scholar
• 35 Lucena MI, Andrade RJ, Kaplowitz N , et al; Spanish Group for the Study of Drug-Induced Liver Disease. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology 2009; 49 (6) 2001-2009
  CrossrefPubMedGoogle Scholar
• 36 Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144 (7) 1419-1425 , e1–e3, quiz e19–e20
  CrossrefPubMedGoogle Scholar
• 37 Chalasani N, Fontana RJ, Bonkovsky HL , et al; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135 (6) 1924-1934 , e1–e4
  CrossrefPubMedGoogle Scholar
• 38 Björnsson E, Talwalkar J, Treeprasertsuk S , et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51 (6) 2040-2048
  CrossrefPubMedGoogle Scholar
• 39 Lawrenson RA, Seaman HE, Sundström A, Williams TJ, Farmer RD. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf 2000; 23 (4) 333-349
  CrossrefPubMedGoogle Scholar
• 40 Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology 1988; 8 (3) 599-606
  CrossrefPubMedGoogle Scholar
• 41 Teitelbaum JE, Perez-Atayde AR, Cohen M, Bousvaros A, Jonas MM. Minocycline-related autoimmune hepatitis: case series and literature review. Arch Pediatr Adolesc Med 1998; 152 (11) 1132-1136
  PubMedGoogle Scholar
• 42 Ramakrishna J, Johnson AR, Banner BF. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol 2009; 43 (8) 787-790
  CrossrefPubMedGoogle Scholar
• 43 Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009; 62 (6) 481-492
  CrossrefPubMedGoogle Scholar
• 44 Appleyard S, Saraswati R, Gorard DA. Autoimmune hepatitis triggered by nitrofurantoin: a case series. J Med Case Reports 2010; 4: 311
  CrossrefPubMedGoogle Scholar
• 45 Hebert MF, Roberts JP. Endstage liver disease associated with nitrofurantoin requiring liver transplantation. Ann Pharmacother 1993; 27 (10) 1193-1194
  PubMedGoogle Scholar
• 46 Bourdi M, Gautier JC, Mircheva J , et al. Anti-liver microsomes autoantibodies and dihydralazine-induced hepatitis: specificity of autoantibodies and inductive capacity of the drug. Mol Pharmacol 1992; 42 (2) 280-285
  PubMedGoogle Scholar
• 47 Belloc C, Gauffre A, André C, Beaune PH. Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis. Pharmacogenetics 1997; 7 (3) 181-186
  CrossrefPubMedGoogle Scholar
• 48 Bartoli E, Massarelli G, Solinas A, Faedda R, Chiandussi L. Acute hepatitis with bridging necrosis due to hydralazine intake. Report of a case. Arch Intern Med 1979; 139 (6) 698-699
  CrossrefPubMedGoogle Scholar
• 49 Itoh S, Ichinoe A, Tsukada Y, Itoh Y. Hydralazine-induced hepatitis. Hepatogastroenterology 1981; 28 (1) 13-16
  PubMedGoogle Scholar
• 50 Rodman JS, Deutsch DJ, Gutman SI. Methyldopa Hepatitis. A report of six cases and review of the literature. Am J Med 1976; 60 (7) 941-948
  CrossrefPubMedGoogle Scholar
• 51 Suzuki A, Brunt EM, Kleiner DE , et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology 2011; 54 (3) 931-939
  CrossrefPubMedGoogle Scholar
• 52 Heurgué-Berlot A, Bernard-Chabert B, Diebold MD, Thiéfin G. Drug-induced autoimmune-like hepatitis: a case of chronic course after drug withdrawal. Dig Dis Sci 2011; 56 (8) 2504-2505 , author reply 2505
  CrossrefPubMedGoogle Scholar
• 53 Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011; 56 (4) 958-976
  CrossrefPubMedGoogle Scholar
• 54 Davern TJ, Chalasani N, Fontana RJ , et al; Drug-Induced Liver Injury Network (DILIN). Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology 2011; 141 (5) 1665-1672 , e1–e9
  CrossrefPubMedGoogle Scholar
• 55 Manoussakis MN, Tzioufas AG, Silis MP, Pange PJ, Goudevenos J, Moutsopoulos HM. High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol 1987; 69 (3) 557-565
  PubMedGoogle Scholar
• 56 Manns MP, Czaja AJ, Gorham JD , et al; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51 (6) 2193-2213
  CrossrefPubMedGoogle Scholar
• 57 Gleeson D, Heneghan MA ; British Society of Gastroenterology. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut 2011; 60 (12) 1611-1629
  CrossrefPubMedGoogle Scholar
• 58 Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38 (4) 343-364
  CrossrefPubMedGoogle Scholar
• 59 Manns MP, Woynarowski M, Kreisel W , et al; European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010; 139 (4) 1198-1206
  CrossrefPubMedGoogle Scholar
• 60 Soloway RD, Summerskill WH, Baggenstoss AH , et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology 1972; 63 (5) 820-833
  PubMedGoogle Scholar
• 61 Czaja AJ, Wolf AM, Baggenstoss AH. Laboratory assessment of severe chronic active liver disease during and after corticosteroid therapy: correlation of serum transaminase and gamma globulin levels with histologic features. Gastroenterology 1981; 80 (4) 687-692
  PubMedGoogle Scholar
• 62 Lüth S, Herkel J, Kanzler S , et al. Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis. J Clin Gastroenterol 2008; 42 (8) 926-930
  CrossrefPubMedGoogle Scholar
• 63 Amit G, Cohen P, Ackerman Z. Nitrofurantoin-induced chronic active hepatitis. Isr Med Assoc J 2002; 4 (3) 184-186
  PubMedGoogle Scholar
• 64 Paiva LA, Wright PJ, Koff RS. Long-term hepatic memory for hypersensitivity to nitrofurantoin. Am J Gastroenterol 1992; 87 (7) 891-893
  PubMedGoogle Scholar