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Drug-Induced Autoimmune-Like Hepatitis

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Abstract

The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.

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References

  1. Manns MP, Czaja AJ, Gorham JD, et al. Practice guidelines of the American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–2213.

    PubMed  CAS  Google Scholar 

  2. Czaja AJ. Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci. 2010 [Epub ahead of print].

  3. Czaja A, Carpenter HA. Validation of scoring system for diagnosis of autoimmune hepatitis. Dig Dis Sci. 1996;41:305–314.

    PubMed  CAS  Google Scholar 

  4. Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology. 1993;105:1824–1832.

    PubMed  CAS  Google Scholar 

  5. Czaja AJ, Davis GL, Ludwig J, Taswell HF. Complete resolution of inflammatory activity following corticosteroid treatment of HBsAg-negative chronic active hepatitis. Hepatology. 1984;4:622–627.

    PubMed  CAS  Google Scholar 

  6. Hegarty JE, Nouri Aria KT, Portmann B, Eddleston AL, Williams R. Relapse following treatment withdrawal in patients with autoimmune chronic active hepatitis. Hepatology. 1983;3:685–689.

    PubMed  CAS  Google Scholar 

  7. Czaja AJ, Menon KV, Carpenter HA. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology. 2002;35:890–897.

    PubMed  CAS  Google Scholar 

  8. Montano-Loza AJ, Carpenter HA, Czaja AJ. Improving the end point of corticosteroid therapy in type 1 autoimmune hepatitis to reduce the frequency of relapse. Am J Gastroenterol. 2007;102:1005–1012.

    PubMed  CAS  Google Scholar 

  9. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938.

    PubMed  CAS  Google Scholar 

  10. Czaja AJ. Autoimmune hepatitis. Part B: diagnosis. Expert Rev Gastroenterol Hepatol. 2007;1:129–143.

    PubMed  CAS  Google Scholar 

  11. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513–1520.

    PubMed  CAS  Google Scholar 

  12. Czaja AJ, Carpenter HA, Santrach PJ, et al. Evidence against hepatitis viruses as important causes of severe autoimmune hepatitis in the United States. J Hepatol. 1993;18:342–352.

    PubMed  CAS  Google Scholar 

  13. Czaja AJ. Extrahepatic immunologic features of chronic viral hepatitis. Dig Dis. 1997;15:125–144.

    PubMed  CAS  Google Scholar 

  14. Czaja AJ, Carpenter HA. Histological findings in chronic hepatitis C with autoimmune features. Hepatology. 1997;26:459–466.

    PubMed  CAS  Google Scholar 

  15. Okano N, Yamamoto K, Sakaguchi K, et al. Clinicopathological features of acute-onset autoimmune hepatitis. Hepatol Res. 2003;25:263–270.

    PubMed  Google Scholar 

  16. Kessler WR, Cummings OW, Eckert G, et al. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol. 2004;2:625–631.

    PubMed  Google Scholar 

  17. Nikias GA, Batts KP, Czaja AJ. The nature and prognostic implications of autoimmune hepatitis with an acute presentation. J Hepatol. 1994;21:866–871.

    PubMed  CAS  Google Scholar 

  18. Burgart LJ, Batts KP, Ludwig J, Nikias GA, Czaja AJ. Recent-onset autoimmune hepatitis. Biopsy findings and clinical correlations. Am J Surg Pathol. 1995;19:699–708.

    PubMed  CAS  Google Scholar 

  19. Kogan J, Safadi R, Ashur Y, Shouval D, Ilan Y. Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients. J Clin Gastroenterol. 2002;35:75–81.

    PubMed  Google Scholar 

  20. Feld JJ, Dinh H, Arenovich T, et al. Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology. 2005;42:53–62.

    PubMed  Google Scholar 

  21. Czaja AJ, Taswell HF, Rakela J, Schimek CM. Frequency and significance of antibody to hepatitis C virus in severe corticosteroid-treated autoimmune chronic active hepatitis. Mayo Clin Proc. 1991;66:572–582.

    PubMed  CAS  Google Scholar 

  22. Czaja AJ, Magrin S, Fabiano C, et al. Hepatitis C virus infection as a determinant of behavior in type 1 autoimmune hepatitis. Dig Dis Sci. 1995;40:33–40.

    PubMed  CAS  Google Scholar 

  23. Czaja AJ, Carpenter HA. Autoimmune hepatitis with incidental histologic features of bile duct injury. Hepatology. 2001;34:659–665.

    PubMed  CAS  Google Scholar 

  24. Czaja AJ, Muratori P, Muratori L, Carpenter HA, Bianchi FB. Diagnostic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int. 2004;24:322–329.

    PubMed  Google Scholar 

  25. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol. 1998;29:198–206.

    PubMed  CAS  Google Scholar 

  26. Magrin S, Craxi A, Fiorentino G, et al. Is autoimmune chronic active hepatitis a HCV-related disease? J Hepatol. 1991;13:56–60.

    PubMed  CAS  Google Scholar 

  27. Bjornsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51:2040–2048.

    PubMed  Google Scholar 

  28. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–176.

    PubMed  Google Scholar 

  29. Czaja AJ. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology. 2008;48:1540–1548.

    PubMed  Google Scholar 

  30. Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology. 2010;52:730–742.

    PubMed  Google Scholar 

  31. Lewis JH, Zimmerman HJ. Drug-induced autoimmune liver disease. In: Krawitt EL, Wiesner RH, Nishioka K, eds. Autoimmune Liver Diseases. 2nd ed. Amsterdam: Elsevier; 1998:627–649.

    Google Scholar 

  32. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002;6:755–774.

    PubMed  Google Scholar 

  33. Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–521.

    PubMed  Google Scholar 

  34. Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006;43:618–631.

    PubMed  Google Scholar 

  35. Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis. 2000;4:73–96. (vi).

    PubMed  CAS  Google Scholar 

  36. Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol. 2009;62:481–492.

    PubMed  CAS  Google Scholar 

  37. Dienes HP, Drebber U. Pathology of immune-mediated liver injury. Dig Dis. 2010;28:57–62.

    PubMed  Google Scholar 

  38. Meier Y, Cavallaro M, Roos M, et al. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol. 2005;61:135–143.

    PubMed  Google Scholar 

  39. Chalasani N, Bjornsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology. 2010;138:2246–2259.

    PubMed  CAS  Google Scholar 

  40. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36:451–455.

    PubMed  Google Scholar 

  41. Dossing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol. 1982;17:205–211.

    PubMed  CAS  Google Scholar 

  42. De Valle MB, Av Klinteberg V, Alem N, Olsson R, Bjornsson E. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther. 2006;24:1187–1195.

    PubMed  Google Scholar 

  43. Bjorneboe M, Iversen O, Olsen S. Infective hepatitis and toxic jaundice in a municipal hospital during a five-year period. Incidence and prognosis. Acta Med Scand. 1967;182:491–501.

    PubMed  CAS  Google Scholar 

  44. Miller RR. Hospital admissions due to adverse drug reactions. A report from the Boston Collaborative Drug Surveillance Program. Arch Intern Med. 1974;134:219–223.

    PubMed  CAS  Google Scholar 

  45. Lewis JH, Zimmerman HJ. Drug-induced liver disease. Med Clin North Am. 1989;73:775–792.

    PubMed  CAS  Google Scholar 

  46. Williams R. Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis. 1996;16:343–348.

    PubMed  CAS  Google Scholar 

  47. Williams R. Changing clinical patterns in acute liver failure. J Hepatol. 2003;39:660–661.

    PubMed  Google Scholar 

  48. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349:474–485.

    PubMed  CAS  Google Scholar 

  49. Hussaini SH, O’Brien CS, Despott EJ, Dalton HR. Antibiotic therapy: a major cause of drug-induced jaundice in southwest England. Eur J Gastroenterol Hepatol. 2007;19:15–20.

    PubMed  CAS  Google Scholar 

  50. de Abajo FJ, Montero D, Madurga M, Garcia Rodriguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58:71–80.

    PubMed  Google Scholar 

  51. Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–1934, 1934:e1921–e1924.

    Google Scholar 

  52. Devarbhavi H, Dierkhising R, Kremers WK, et al. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010;105:2396–2404.

    PubMed  Google Scholar 

  53. Njoku DB. Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury: a review. Expert Opin Drug Metab Toxicol. 2010;6:519–531.

    PubMed  CAS  Google Scholar 

  54. Boberg KM, Aadland E, Jahnsen J, et al. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33:99–103.

    PubMed  CAS  Google Scholar 

  55. Werner M, Prytz H, Ohlsson B, et al. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand J Gastroenterol. 2008;43:1232–1240.

    PubMed  Google Scholar 

  56. Agarwal VK, McHutchison JG, Hoofnagle JH. Important elements for the diagnosis of drug-induced liver injury. Clin Gastroenterol Hepatol. 2010;8:463–470.

    PubMed  Google Scholar 

  57. Goldstein GB, Lam KC, Mistilis SP. Drug-induced active chronic hepatitis. Am J Dig Dis. 1973;18:177–184.

    PubMed  CAS  Google Scholar 

  58. Maddrey WC, Boitnott JK. Drug-induced chronic liver disease. Gastroenterology. 1977;72:1348–1353.

    PubMed  CAS  Google Scholar 

  59. Seeff LB. Drug-induced chronic liver disease, with emphasis on chronic active hepatitis. Semin Liver Dis. 1981;1:104–115.

    PubMed  CAS  Google Scholar 

  60. Shoenfeld Y, Vilner Y, Reshef T, et al. Increased presence of common systemic lupus erythematosus (SLE) anti-DNA idiotypes (16/6 Id, 32/15 Id) is induced by procainamide. J Clin Immunol. 1987;7:410–419.

    PubMed  CAS  Google Scholar 

  61. Silva MO, Reddy KR, Jeffers LJ, Hill M, Schiff ER. Interferon-induced chronic active hepatitis? Gastroenterology. 1991;101:840–842.

    PubMed  CAS  Google Scholar 

  62. Garcia-Buey L, Garcia-Monzon C, Rodriguez S, et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology. 1995;108:1770–1777.

    PubMed  CAS  Google Scholar 

  63. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 2003;100:8372–8377.

    PubMed  CAS  Google Scholar 

  64. Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol. 2010;37:499–507.

    PubMed  CAS  Google Scholar 

  65. Takahashi A, Kanno Y, Takahashi Y, et al. Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report. World J Gastroenterol. 2008;14:5474–5477.

    PubMed  CAS  Google Scholar 

  66. Babany G, Larrey D, Pessayre D, et al. Chronic active hepatitis caused by benzarone. J Hepatol. 1987;5:332–335.

    PubMed  CAS  Google Scholar 

  67. Scully LJ, Clarke D, Barr RJ. Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis. Dig Dis Sci. 1993;38:744–751.

    PubMed  CAS  Google Scholar 

  68. Bernard PH, Lamouliatte H, Le Bail B, et al. Chronic active hepatitis associated with antinuclear antibodies induced by fenofibrate. Gastroenterol Clin Biol. 1994;18:1048–1049.

    PubMed  CAS  Google Scholar 

  69. Martinez-Odriozola P, Gutierrez-Macias A, Ibarmia-Lahuerta J, Munoz-Sanchez J. Meloxicam as a cause of drug-induced autoimmune hepatitis. Dig Dis Sci. 2010;55:1191–1192.

    PubMed  Google Scholar 

  70. Lewis JJ, Iezzoni JC, Berg CL. Methylphenidate-induced autoimmune hepatitis. Dig Dis Sci. 2007;52:594–597.

    PubMed  Google Scholar 

  71. Poncin E, Silvain C, Touchard G, Barbier J, Beauchant M. Papaverine-induced chronic liver disease. Gastroenterology. 1986;90:1051–1053.

    PubMed  CAS  Google Scholar 

  72. Sterling MJ, Kane M, Grace ND. Pemoline-induced autoimmune hepatitis. Am J Gastroenterol. 1996;91:2233–2234.

    PubMed  CAS  Google Scholar 

  73. Fedotin MS, Lefer LG. Liver disease caused by propylthiouracil. Arch Intern Med. 1975;135:319–321.

    PubMed  CAS  Google Scholar 

  74. Maggiore G, Larizza D, Lorini R, et al. Propylthiouracil hepatotoxicity mimicking autoimmune chronic active hepatitis in a girl. J Pediatr Gastroenterol Nutr. 1989;8:547–548.

    PubMed  CAS  Google Scholar 

  75. Graziadei IW, Obermoser GE, Sepp NT, Erhart KH, Vogel W. Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis. Lupus. 2003;12:409–412.

    PubMed  CAS  Google Scholar 

  76. Pelli N, Setti M, Ceppa P, Toncini C, Indiveri F. Autoimmune hepatitis revealed by atorvastatin. Eur J Gastroenterol Hepatol. 2003;15:921–924.

    PubMed  Google Scholar 

  77. Noel B. Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review. J Eur Acad Dermatol Venereol. 2007;21:17–24.

    PubMed  CAS  Google Scholar 

  78. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis. 2009;29:412–422.

    PubMed  CAS  Google Scholar 

  79. Wolters LM, Van Buuren HR. Rosuvastatin-associated hepatitis with autoimmune features. Eur J Gastroenterol Hepatol. 2005;17:589–590.

    PubMed  CAS  Google Scholar 

  80. Hinrichsen H, Luttges J, Kloppel G, Folsch UR, Schmidt WE. Idiosyncratic drug allergic phenprocoumon-induced hepatitis with subacute liver failure initially misdiagnosed as autoimmune hepatitis. Scand J Gastroenterol. 2001;36:780–783.

    PubMed  CAS  Google Scholar 

  81. Paredes AH, Lewis JH. Terbinafine-induced acute autoimmune hepatitis in the setting of hepatitis B virus infection. Ann Pharmacother. 2007;41:880–884.

    PubMed  CAS  Google Scholar 

  82. Abraham C, Hart J, Locke SM, Baker AL. A case of indometacin-induced acute hepatitis developing into chronic autoimmune hepatitis. Nat Clin Pract Gastroenterol Hepatol. 2008;5:172–176.

    PubMed  Google Scholar 

  83. Aliberti S, Grignani G, Allione P, et al. An acute hepatitis resembling autoimmune hepatitis occurring during imatinib therapy in a gastrointestinal stromal tumor patient. Am J Clin Oncol. 2009;32:640–641.

    PubMed  Google Scholar 

  84. Germano V, Picchianti Diamanti A, Baccano G, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis. 2005;64:1519–1520.

    PubMed  CAS  Google Scholar 

  85. Tobon GJ, Canas C, Jaller JJ, Restrepo JC, Anaya JM. Serious liver disease induced by infliximab. Clin Rheumatol. 2007;26:578–581.

    PubMed  Google Scholar 

  86. Carlsen KM, Riis L, Madsen OR. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept. Clin Rheumatol. 2009;28:1001–1003.

    PubMed  CAS  Google Scholar 

  87. Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol. 2010;44:e20–e22.

    PubMed  Google Scholar 

  88. Efe C, Purnak T, Ozaslan E, Wahlin S. Drug-induced autoimmune hepatitis caused by anti-tumor necrosis factor alpha agents. Hepatology. 2010 [Epub ahead of print].

  89. Fong TL, Klontz KC, Canas-Coto A, et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol. 2010;105:1561–1566.

    PubMed  Google Scholar 

  90. Kamiyama T, Nouchi T, Kojima S, et al. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol. 1997;92:703–704.

    PubMed  CAS  Google Scholar 

  91. Guzman G, Kallwitz ER, Wojewoda C, et al. Liver injury with features mimicking autoimmune hepatitis following the use of black cohosh. Case Report Med. 2009:918156.

  92. Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of ma huang. Am J Gastroenterol. 2001;96:1654–1655.

    PubMed  CAS  Google Scholar 

  93. Cohen SM, O’Connor AM, Hart J, Merel NH, Te HS. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause. 2004;11:575–577.

    PubMed  Google Scholar 

  94. Ben Yahia M, Mavier P, Metreau JM, et al. Chronic active hepatitis and cirrhosis induced by wild germander. 3 cases. Gastroenterol Clin Biol. 1993;17:959–962.

    PubMed  CAS  Google Scholar 

  95. Larrey D, Vial T, Pauwels A, et al. Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity. Ann Intern Med. 1992;117:129–132.

    PubMed  CAS  Google Scholar 

  96. Gilbert KM, Przybyla B, Pumford NR, et al. Delineating liver events in trichloroethylene-induced autoimmune hepatitis. Chem Res Toxicol. 2009;22:626–632.

    PubMed  CAS  Google Scholar 

  97. Reynolds TB, Peters RL, Yamada S. Chronic active and lupoid hepatitis caused by a laxative, oxyphenisatin. N Engl J Med. 1971;285:813–820.

    PubMed  CAS  Google Scholar 

  98. Lecoeur S, Bonierbale E, Challine D, et al. Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity: comparison with two directly hepatotoxic drugs. Chem Res Toxicol. 1994;7:434–442.

    PubMed  CAS  Google Scholar 

  99. 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;42:280–285.

    PubMed  CAS  Google Scholar 

  100. Bourdi M, Tinel M, Beaune PH, Pessayre D. Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies. Mol Pharmacol. 1994;45:1287–1295.

    PubMed  CAS  Google Scholar 

  101. Neuberger J, Kenna JG. Halothane hepatitis: a model of immune mediated drug hepatotoxicity. Clin Sci (Lond). 1987;72:263–270.

    CAS  Google Scholar 

  102. Christen U, Quinn J, Yeaman SJ, et al. Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis. Molecular mimicry of trifluoroacetyl-lysine by lipoic acid. Eur J Biochem. 1994;223:1035–1047.

    PubMed  CAS  Google Scholar 

  103. Herzog D, Hajoui O, Russo P, Alvarez F. Study of immune reactivity of minocycline-induced chronic active hepatitis. Dig Dis Sci. 1997;42:1100–1103.

    PubMed  CAS  Google Scholar 

  104. Lawrenson RA, Seaman HE, Sundstrom 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;23:333–349.

    PubMed  CAS  Google Scholar 

  105. Czaja AJ, dos Santos RM, Porto A, Santrach PJ, Moore SB. Immune phenotype of chronic liver disease. Dig Dis Sci. 1998;43:2149–2155.

    PubMed  CAS  Google Scholar 

  106. Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum. 1999;28:392–397.

    PubMed  CAS  Google Scholar 

  107. Goldstein NS, Bayati N, Silverman AL, Gordon SC. Minocycline as a cause of drug-induced autoimmune hepatitis. Report of four cases and comparison with autoimmune hepatitis. Am J Clin Pathol. 2000;114:591–598.

    PubMed  CAS  Google Scholar 

  108. Ford TJ, Dillon JF. Minocycline hepatitis. Eur J Gastroenterol Hepatol. 2008;20:796–799.

    PubMed  CAS  Google Scholar 

  109. 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;152:1132–1136.

    PubMed  CAS  Google Scholar 

  110. Abe M, Furukawa S, Takayama S, et al. Drug-induced hepatitis with autoimmune features during minocycline therapy. Intern Med. 2003;42:48–52.

    PubMed  Google Scholar 

  111. Eichenfield AH. Minocycline and autoimmunity. Curr Opin Pediatr. 1999;11:447–456.

    PubMed  CAS  Google Scholar 

  112. Ramakrishna J, Johnson AR, Banner BF. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol. 2009;43:787–790.

    PubMed  Google Scholar 

  113. 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;8:599–606.

    PubMed  CAS  Google Scholar 

  114. Amit G, Cohen P, Ackerman Z. Nitrofurantoin-induced chronic active hepatitis. Isr Med Assoc J. 2002;4:184–186.

    PubMed  Google Scholar 

  115. Hatoff DE, Cohen M, Schweigert BF, Talbert WM. Nitrofurantoin: another cause of drug-induced chronic active hepatitis? A report of a patient with HLA-B8 antigen. Am J Med. 1979;67:117–121.

    PubMed  CAS  Google Scholar 

  116. Aithal PG, Day CP. The natural history of histologically proved drug induced liver disease. Gut. 1999;44:731–735.

    PubMed  CAS  Google Scholar 

  117. Andrade RJ, Lucena MI, Kaplowitz N, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology. 2006;44:1581–1588.

    PubMed  CAS  Google Scholar 

  118. Rodman JS, Deutsch DJ, Gutman SI. Methyldopa hepatitis. A report of six cases and review of the literature. Am J Med. 1976;60:941–948.

    PubMed  CAS  Google Scholar 

  119. Arranto AJ, Sotaniemi EA. Morphologic alterations in patients with alpha-methyldopa-induced liver damage after short- and long-term exposure. Scand J Gastroenterol. 1981;16:853–863.

    PubMed  CAS  Google Scholar 

  120. Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ. 1996;312:169–172.

    PubMed  CAS  Google Scholar 

  121. Czaja AJ, Manns MP. The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol. 1995;90:1206–1211.

    PubMed  CAS  Google Scholar 

  122. Homberg JC, Andre C, Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin Exp Immunol. 1984;55:561–570.

    PubMed  CAS  Google Scholar 

  123. Beaune P, Dansette PM, Mansuy D, et al. Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci USA. 1987;84:551–555.

    PubMed  CAS  Google Scholar 

  124. Beaune PH, Lecoeur S, Bourdi M, et al. Anti-cytochrome P450 autoantibodies in drug-induced disease. Eur J Haematol Suppl. 1996;60:89–92.

    PubMed  CAS  Google Scholar 

  125. Lecoeur S, Andre C, Beaune PH. Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol Pharmacol. 1996;50:326–333.

    PubMed  CAS  Google Scholar 

  126. Bourdi M, Larrey D, Nataf J, et al. Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis. J Clin Invest. 1990;85:1967–1973.

    PubMed  CAS  Google Scholar 

  127. Belloc C, Gauffre A, Andre C, Beaune PH. Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis. Pharmacogenetics. 1997;7:181–186.

    PubMed  CAS  Google Scholar 

  128. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax. 1996;51:132–136.

    PubMed  CAS  Google Scholar 

  129. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis. 2002;22:145–155.

    PubMed  CAS  Google Scholar 

  130. Fountain FF, Tolley E, Chrisman CR, Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic. Chest. 2005;128:116–123.

    PubMed  CAS  Google Scholar 

  131. Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet. 2005;44:33–60.

    PubMed  CAS  Google Scholar 

  132. Bjornsson E, Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice. J Hepatol. 2009;50:511–517.

    PubMed  Google Scholar 

  133. Lucena MI, Andrade RJ, Kaplowitz N, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology. 2009;49:2001–2009.

    PubMed  Google Scholar 

  134. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis. 2007;11:477–505. (v).

    PubMed  Google Scholar 

  135. Uetrecht JP. New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system. Chem Res Toxicol. 1999;12:387–395.

    PubMed  CAS  Google Scholar 

  136. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol. 2007;47:513–539.

    PubMed  CAS  Google Scholar 

  137. Lammert C, Einarsson S, Saha C, et al. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47:2003–2009.

    PubMed  CAS  Google Scholar 

  138. Otani K, Kaneko S, Tasaki H, Fukushima Y. Hepatic injury caused by mianserin. BMJ. 1989;299:519.

    PubMed  CAS  Google Scholar 

  139. Lewis JH. The rational use of potentially hepatotoxic medications in patients with underlying liver disease. Expert Opin Drug Saf. 2002;1:159–172.

    PubMed  CAS  Google Scholar 

  140. Russo MW, Watkins PB. Are patients with elevated liver tests at increased risk of drug-induced liver injury? Gastroenterology. 2004;126:1477–1480.

    PubMed  Google Scholar 

  141. Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol. 2006;62:423–429.

    PubMed  CAS  Google Scholar 

  142. Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132:272–281.

    PubMed  CAS  Google Scholar 

  143. Rieder MJ, Shear NH, Kanee A, Tang BK, Spielberg SP. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther. 1991;49:13–17.

    PubMed  CAS  Google Scholar 

  144. Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology. 2003;37:924–930.

    PubMed  CAS  Google Scholar 

  145. Huang YS, Su WJ, Huang YH, et al. Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol. 2007;47:128–134.

    PubMed  CAS  Google Scholar 

  146. Lucena MI, Andrade RJ, Martinez C, et al. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology. 2008;48:588–596.

    PubMed  Google Scholar 

  147. Lucena MI, Garcia-Martin E, Andrade RJ, et al. Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology. 2010;52:303–312.

    PubMed  CAS  Google Scholar 

  148. Aithal GP, Ramsay L, Daly AK, et al. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology. 2004;39:1430–1440.

    PubMed  CAS  Google Scholar 

  149. Ong MM, Latchoumycandane C, Boelsterli UA. Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci. 2007;97:205–213.

    PubMed  CAS  Google Scholar 

  150. Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics of drug-induced liver injury. Hepatology. 2010;52:748–761.

    PubMed  CAS  Google Scholar 

  151. Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008;134:1203–1214.

    PubMed  CAS  Google Scholar 

  152. Strettell MD, Donaldson PT, Thomson LJ, et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology. 1997;112:2028–2035.

    PubMed  CAS  Google Scholar 

  153. Czaja AJ. Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:379–388.

    PubMed  CAS  Google Scholar 

  154. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology. 2010;51:615–620.

    PubMed  CAS  Google Scholar 

  155. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46:1331–1336.

    PubMed  CAS  Google Scholar 

  156. Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–1330.

    PubMed  CAS  Google Scholar 

  157. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26:664–669.

    PubMed  CAS  Google Scholar 

  158. Rochon J, Protiva P, Seeff LB, et al. Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury. Hepatology. 2008;48:1175–1183.

    PubMed  Google Scholar 

  159. Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel–Uclaf causality assessment method. Hepatology. 2010;51:2117–2126.

    PubMed  Google Scholar 

  160. Ransohoff DF, Jacobs G. Terminal hepatic failure following a small dose of sulfamethoxazole-trimethoprim. Gastroenterology. 1981;80:816–819.

    PubMed  CAS  Google Scholar 

  161. Shear NH, Spielberg SP, Grant DM, Tang BK, Kalow W. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med. 1986;105:179–184.

    PubMed  CAS  Google Scholar 

  162. Gennis MA, Vemuri R, Burns EA, et al. Familial occurrence of hypersensitivity to phenytoin. Am J Med. 1991;91:631–634.

    PubMed  CAS  Google Scholar 

  163. Victorino RM, Maria VA. Modifications of the lymphocyte transformation test in a case of drug-induced cholestatic hepatitis. Diagn Immunol. 1985;3:177–181.

    PubMed  CAS  Google Scholar 

  164. Victorino RM, Maria VA, Pinto LA. Evidence for prostaglandin-producing suppressor cells in drug-induced liver injury and implications in the diagnosis of drug sensitization. Clin Exp Immunol. 1992;87:132–137.

    PubMed  CAS  Google Scholar 

  165. Maria VA, Pinto L, Victorino RM. Lymphocyte reactivity to ex vivo drug antigens in drug-induced hepatitis. J Hepatol. 1994;21:151–158.

    PubMed  CAS  Google Scholar 

  166. Berg PA, Becker EW. The lymphocyte transformation test—a debated method for the evaluation of drug allergic hepatic injury. J Hepatol. 1995;22:115–118.

    PubMed  CAS  Google Scholar 

  167. Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology. 2001;33:308–310.

    PubMed  CAS  Google Scholar 

  168. Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11:272–276.

    PubMed  CAS  Google Scholar 

  169. Benichou C, Solal Celigny P. Standardization of definitions and criteria for causality assessment of adverse drug reactions. Drug-induced blood cytopenias: report of an international consensus meeting. Nouv Rev Fr Hematol. 1991;33:257–262.

    PubMed  CAS  Google Scholar 

  170. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.

    PubMed  CAS  Google Scholar 

  171. Garcia-Cortes M, Lucena MI, Pachkoria K, et al. Evaluation of naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther. 2008;27:780–789.

    PubMed  CAS  Google Scholar 

  172. Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol. 2000;33:949–952.

    PubMed  CAS  Google Scholar 

  173. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001;33:123–130.

    PubMed  CAS  Google Scholar 

  174. Takikawa H, Takamori Y, Kumagi T, et al. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the International Consensus Meeting. Hepatol Res. 2003;27:192–195.

    PubMed  Google Scholar 

  175. Bjornsson E, Kalaitzakis E, Av Klinteberg V, Alem N, Olsson R. Long-term follow-up of patients with mild to moderate drug-induced liver injury. Aliment Pharmacol Ther. 2007;26:79–85.

    PubMed  CAS  Google Scholar 

  176. Czaja AJ, Ammon HV, Summerskill WH. Clinical features and prognosis of severe chronic active liver disease (CALD) after corticosteroid-induced remission. Gastroenterology. 1980;78:518–523.

    PubMed  CAS  Google Scholar 

  177. Lindon JC, Holmes E, Nicholson JK. Metabonomics and its role in drug development and disease diagnosis. Expert Rev Mol Diagn. 2004;4:189–199.

    PubMed  CAS  Google Scholar 

  178. Ruepp S, Boess F, Suter L, et al. Assessment of hepatotoxic liabilities by transcript profiling. Toxicol Appl Pharmacol. 2005;207:161–170.

    PubMed  Google Scholar 

  179. Njoku DB, Mellerson JL, Talor MV, et al. Role of CYP2E1 immunoglobulin G4 subclass antibodies and complement in pathogenesis of idiosyncratic drug-induced hepatitis. Clin Vaccine Immunol. 2006;13:258–265.

    PubMed  CAS  Google Scholar 

  180. Czaja AJ. Autoimmune hepatitis. Part A: pathogenesis. Expert Rev Gastroenterol Hepatol. 2007;1:113–128.

    PubMed  CAS  Google Scholar 

  181. Robin MA, Le Roy M, Descatoire V, Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. J Hepatol. 1997;26:23–30.

    PubMed  CAS  Google Scholar 

  182. Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol. 2008;21:84–92.

    PubMed  CAS  Google Scholar 

  183. Liebler DC, Guengerich FP. Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov. 2005;4:410–420.

    PubMed  CAS  Google Scholar 

  184. Dansette PM, Bonierbale E, Minoletti C, et al. Drug-induced immunotoxicity. Eur J Drug Metab Pharmacokinet. 1998;23:443–451.

    PubMed  CAS  Google Scholar 

  185. Czaja AJ. Animal models of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2010;4:429–443.

    PubMed  CAS  Google Scholar 

  186. Wilke RA, Lin DW, Roden DM, et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov. 2007;6:904–916.

    PubMed  CAS  Google Scholar 

  187. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Semin Liver Dis. 2009;29:400–411.

    PubMed  CAS  Google Scholar 

  188. Longhi MS, Ma Y, Bogdanos DP, et al. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol. 2004;41:31–37.

    PubMed  CAS  Google Scholar 

  189. Longhi MS, Ma Y, Mitry RR, et al. Effect of CD4 + CD25 + regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun. 2005;25:63–71.

    PubMed  CAS  Google Scholar 

  190. Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of CD4 + CD25 + regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176:4484–4491.

    PubMed  CAS  Google Scholar 

  191. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.

    PubMed  CAS  Google Scholar 

  192. Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16:3041–3053.

    PubMed  CAS  Google Scholar 

  193. Luyendyk JP, Maddox JF, Green CD, Ganey PE, Roth RA. Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats. Hepatology. 2004;40:1342–1351.

    PubMed  CAS  Google Scholar 

  194. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4:489–499.

    PubMed  CAS  Google Scholar 

  195. Cohen IR, Lohse AW. Physiology and pathophysiology of autoimmunity. Semin Liver Dis. 1991;11:183–186.

    PubMed  CAS  Google Scholar 

  196. Godfrey DI, Hammond KJ, Poulton LD, Smyth MJ, Baxter AG. NKT cells: facts, functions and fallacies. Immunol Today. 2000;21:573–583.

    PubMed  CAS  Google Scholar 

  197. Wu Z, Han M, Chen T, Yan W, Ning Q. Acute liver failure: mechanisms of immune-mediated liver injury. Liver Int. 2010;30:782–794.

    PubMed  CAS  Google Scholar 

  198. Donaldson PT, Doherty DG, Hayllar KM, et al. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology. 1991;13:701–706.

    PubMed  CAS  Google Scholar 

  199. Cookson S, Constantini PK, Clare M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology. 1999;30:851–856.

    PubMed  CAS  Google Scholar 

  200. Agarwal K, Czaja AJ, Jones DE, Donaldson PT. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology. 2000;31:49–53.

    PubMed  CAS  Google Scholar 

  201. Hiraide A, Imazeki F, Yokosuka O, et al. Fas polymorphisms influence susceptibility to autoimmune hepatitis. Am J Gastroenterol. 2005;100:1322–1329.

    PubMed  CAS  Google Scholar 

  202. Agarwal K, Czaja AJ, Donaldson PT. A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis. Tissue Antigens. 2007;69:227–235.

    PubMed  CAS  Google Scholar 

  203. Fan LY, Tu XQ, Zhu Y, et al. Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. World J Gastroenterol. 2005;11:2768–2772.

    PubMed  CAS  Google Scholar 

  204. Milks MW, Cripps JG, Lin H, et al. The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis. Liver Int. 2009;29:1307–1315.

    PubMed  CAS  Google Scholar 

  205. Schramm C, Protschka M, Kohler HH, et al. Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2003;284:G525–G535.

    PubMed  CAS  Google Scholar 

  206. Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35:126–131.

    PubMed  CAS  Google Scholar 

  207. Fan L, Tu X, Zhu Y, et al. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol. 2005;20:249–255.

    PubMed  CAS  Google Scholar 

  208. Czaja AJ. Current and future treatments of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2009;3:269–291.

    PubMed  CAS  Google Scholar 

  209. Czaja AJ. Safety issues in the management of autoimmune hepatitis. Expert Opin Drug Saf. 2008;7:319–333.

    PubMed  CAS  Google Scholar 

  210. Czaja AJ. Features and consequences of untreated type 1 autoimmune hepatitis. Liver Int. 2009;29:816–823.

    PubMed  CAS  Google Scholar 

  211. Czaja AJ. Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol. 2009;51:161–167.

    PubMed  CAS  Google Scholar 

  212. Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology. 1988;95:448–453.

    PubMed  CAS  Google Scholar 

  213. Kanzler S, Gerken G, Lohr H, et al. Duration of immunosuppressive therapy in autoimmune hepatitis. J Hepatol. 2001;34:354–355.

    PubMed  CAS  Google Scholar 

  214. Kanzler S, Lohr H, Gerken G, Galle PR, Lohse AW. Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience. Z Gastroenterol. 2001;39:339–341, 344–348.

    Google Scholar 

  215. 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;63:820–833.

    PubMed  CAS  Google Scholar 

  216. 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;80:687–692.

    PubMed  CAS  Google Scholar 

  217. Luth S, Herkel J, Kanzler S, et al. Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis. J Clin Gastroenterol. 2008;42:926–930.

    PubMed  Google Scholar 

  218. Paiva LA, Wright PJ, Koff RS. Long-term hepatic memory for hypersensitivity to nitrofurantoin. Am J Gastroenterol. 1992;87:891–893.

    PubMed  CAS  Google Scholar 

  219. Aleksunes LM, Slitt AM, Cherrington NJ, et al. Differential expression of mouse hepatic transporter genes in response to acetaminophen and carbon tetrachloride. Toxicol Sci. 2005;83:44–52.

    PubMed  CAS  Google Scholar 

  220. Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15:241–243.

    PubMed  Google Scholar 

  221. Venulet J. Critical reflection on the collection and evaluation of adverse drug reaction data. Int J Clin Pharmacol Ther Toxicol. 1985;23:S48–S53.

    PubMed  Google Scholar 

  222. Kelly WN. The quality of published adverse drug event reports. Ann Pharmacother. 2003;37:1774–1778.

    PubMed  Google Scholar 

  223. van Heyningen C. Drug-induced acute autoimmune hepatitis during combination therapy with atorvastatin and ezetimibe. Ann Clin Biochem. 2005;42:402–404.

    PubMed  Google Scholar 

  224. Eliasson E, Gardner I, Hume-Smith H, et al. Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis. Chem Biol Interact. 1998;116:123–141.

    PubMed  CAS  Google Scholar 

  225. Pessayre D, Degos F, Feldmann G, et al. Chronic active hepatitis and giant multinucleated hepatocytes in adults treated with clometacin. Digestion.. 1981;22:66–72.

    PubMed  CAS  Google Scholar 

  226. Pariente EA, Hamoud A, Goldfain D, et al. Hepatitis caused by clometacin (Duperan). Retrospective study of 30 cases. A model of autoimmune drug-induced hepatitis? Gastroenterol Clin Biol. 1989;13:769–774.

    PubMed  CAS  Google Scholar 

  227. Shalev O, Mosseri M, Ariel I, Stalnikowicz R. Methyldopa-induced immune hemolytic anemia and chronic active hepatitis. Arch Intern Med. 1983;143:592–593.

    PubMed  CAS  Google Scholar 

  228. Helfgott SM, Sandberg-Cook J, Zakim D, Nestler J. Diclofenac-associated hepatotoxicity. JAMA. 1990;264:2660–2662.

    PubMed  CAS  Google Scholar 

  229. Bhat G, Jordan J Jr, Sokalski S, et al. Minocycline-induced hepatitis with autoimmune features and neutropenia. J Clin Gastroenterol. 1998;27:74–75.

    PubMed  CAS  Google Scholar 

  230. Fairhurst DA, Sheehan-Dare R. Autoimmune hepatitis associated with infliximab in a patient with palmoplantar pustular psoriaisis. Clin Exp Dermatol. 2009;34:421–422.

    PubMed  CAS  Google Scholar 

  231. Marques M, Magro F, Cardoso H, et al. Infliximab-induced lupus-like syndrome associated with autoimmune hepatitis. Inflamm Bowel Dis. 2008;14:723–725.

    PubMed  CAS  Google Scholar 

  232. Ozorio G, McGarity B, Bak H, et al. Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis. Med J Aust. 2007;187:524–526.

    PubMed  Google Scholar 

  233. Sharp JR, Ishak KG, Zimmerman HJ. Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin. Ann Intern Med. 1980;92:14–19.

    PubMed  CAS  Google Scholar 

  234. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology. 1975;69:289–302.

    PubMed  CAS  Google Scholar 

  235. Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol. 1996;91:1436–1438.

    PubMed  CAS  Google Scholar 

  236. Schramm C, Kanzler S, zum Buschenfelde KH, Galle PR, Lohse AW. Autoimmune hepatitis in the elderly. Am J Gastroenterol. 2001;96:1587–1591.

    PubMed  CAS  Google Scholar 

  237. Al-Chalabi T, Boccato S, Portmann BC, McFarlane IG, Heneghan MA. Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre. J Hepatol. 2006;45:575–583.

    PubMed  Google Scholar 

  238. Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology. 2006;43:532–538.

    PubMed  Google Scholar 

  239. Davis GL, Czaja AJ, Baggenstoss AH, Taswell HF. Prognostic and therapeutic implications of extreme serum aminotransferase elevation in chronic active hepatitis. Mayo Clin Proc. 1982;57:303–309.

    PubMed  CAS  Google Scholar 

  240. Kenny RP, Czaja AJ, Ludwig J, Dickson ER. Frequency and significance of antimitochondrial antibodies in severe chronic active hepatitis. Dig Dis Sci. 1986;31:705–711.

    PubMed  CAS  Google Scholar 

  241. Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology. 1996;110:848–857.

    PubMed  CAS  Google Scholar 

  242. Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol. 2004;40:646–652.

    PubMed  CAS  Google Scholar 

  243. Davis GL, Czaja AJ, Ludwig J. Development and prognosis of histologic cirrhosis in corticosteroid-treated hepatitis B surface antigen-negative chronic active hepatitis. Gastroenterology. 1984;87:1222–1227.

    PubMed  CAS  Google Scholar 

  244. Czaja AJ, Carpenter HA. Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. Hepatology. 2004;39:1631–1638.

    PubMed  Google Scholar 

  245. Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology. 2007;46:1138–1145.

    PubMed  CAS  Google Scholar 

  246. Montano-Loza AJ, Carpenter HA, Czaja AJ. Consequences of treatment withdrawal in type 1 autoimmune hepatitis. Liver Int. 2007;27:507–515.

    PubMed  CAS  Google Scholar 

  247. Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97:2051–2057.

    PubMed  CAS  Google Scholar 

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Czaja, A.J. Drug-Induced Autoimmune-Like Hepatitis. Dig Dis Sci 56, 958–976 (2011). https://doi.org/10.1007/s10620-011-1611-4

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