Download PDF
Semin Liver Dis 2009; 29(3): 273-285
DOI: 10.1055/s-0029-1233534
© Thieme Medical Publishers

Treatment of Autoimmune Hepatitis

Christian P. Strassburg1 , Michael P. Manns1
  • 1Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
Further Information

Publication History

Publication Date:
12 August 2009 (online)

    Permissions and Reprints

ABSTRACT

First described in 1950, autoimmune hepatitis (AIH) was the first chronic liver disease with a favorable response to drug therapy and a dismal prognosis when left untreated. In the decades since the first treatment studies, the basic strategic principle of inducing remission with steroids and azathioprine has not been modified. The main problems are a timely diagnosis before cirrhosis develops, the avoidance of immunosuppressant side effects, nonresponders to standard induction therapy, and adherence to therapy. Alternative drugs for immunosuppression have been tested in small series and include transplant immunosuppressants. A large multicenter prospective treatment trial suggests that budesonide may offer an alternative in noncirrhotic AIH patients and can minimize unwanted steroid effects. The ultimate treatment approach upon drug treatment failure is liver transplantation. Although only 4% of transplant candidates are AIH patients, the risk for graft loss because of recurrence has to be considered, and recurrent AIH should be treated after transplantation.

KEYWORDS

Immunosuppression - first pass effect - corticosteroids - budesonide - transplantation

REFERENCES

  • 1 Waldenström J. Leber, Blutproteine und Nahrungseiweisse.  Dtsch Gesellsch Verd Stoffw. 1950;  15 113-119
    PubMedGoogle Scholar
  • 2 Cowling I, Mackay I R, Taft L I. Lupoid hepatitis.  Lancet. 1956;  271 1323-1326
    PubMedGoogle Scholar
  • 3 Strassburg C P, Obermayer-Straub P, Manns M P. Autoimmunity in liver diseases.  Clin Rev Allergy Immunol. 2000;  18(2) 127-139
    PubMedGoogle Scholar
  • 4 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
  • 5 Hennes E M, Zeniya M, Czaja A J International Autoimmune Hepatitis Group et al. Simplified criteria for the diagnosis of autoimmune hepatitis.  Hepatology. 2008;  48(1) 169-176
    CrossrefPubMedGoogle Scholar
  • 6 Strassburg C P, Manns M P. Autoantibodies and autoantigens in autoimmune hepatitis.  Semin Liver Dis. 2002;  22(4) 339-352
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Johnson P J, McFarlane I G. Meeting report: International autoimmune hepatitis group.  Hepatology. 1993;  18(4) 998-1005
    CrossrefPubMedGoogle Scholar
  • 8 Strassburg C P, Manns M P. Autoimmune hepatitis in the elderly: what is the difference?.  J Hepatol. 2006;  45(4) 480-482
    CrossrefPubMedGoogle Scholar
  • 9 Strassburg C P, Manns M P. Autoimmune hepatitis versus viral hepatitis C.  Liver. 1995;  15(5) 225-232
    PubMedGoogle Scholar
  • 10 Manns M P, Griffin K J, Sullivan K F, Johnson E F. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase.  J Clin Invest. 1991;  88(4) 1370-1378
    PubMedGoogle Scholar
  • 11 Manns M P, Johnson E F, Griffin K J, Tan E M, Sullivan K F. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.  J Clin Invest. 1989;  83(3) 1066-1072
    PubMedGoogle Scholar
  • 12 Strassburg C P, Obermayer-Straub P, Alex B et al.. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis.  Gastroenterology. 1996;  111(6) 1576-1586
    CrossrefPubMedGoogle Scholar
  • 13 Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Büschenfelde K H. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen.  Lancet. 1987;  1(8528) 292-294
    PubMedGoogle Scholar
  • 14 Stechemesser E, Klein R, Berg P A. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis.  Hepatology. 1993;  18(1) 1-9
    CrossrefPubMedGoogle Scholar
  • 15 Gelpi C SE, Sontheimer E J, Rodriguez-Sanchez J L. Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion.  Proc Natl Acad Sci U S A. 1992;  89(20) 9739-9743
    PubMedGoogle Scholar
  • 16 Volkmann M, Martin L, Bäurle A et al.. Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis.  Hepatology. 2001;  33(3) 591-596
    CrossrefPubMedGoogle Scholar
  • 17 Wies I, Brunner S, Henninger J et al.. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis [see comment].  Lancet. 2000;  355(9214) 1510-1515
    CrossrefPubMedGoogle Scholar
  • 18 Dienes H P, Popper H, Manns M et al.. Histologic features in autoimmune hepatitis.  Z Gastroenterol. 1989;  27 325-330
    PubMedGoogle Scholar
  • 19 Nishioka M, Morshed S A, Kono K et al.. Frequency and significance of antibodies to P450IID6 protein in Japanese patients with chronic hepatitis C.  J Hepatol. 1997;  26(5) 992-1000
    CrossrefPubMedGoogle Scholar
  • 20 Nishioka M, Morshed S A, McFarlane I G. Geographical Variation in the Frequency and Characteristics of Autoimmune Liver Diseases. Amsterdam; Elsevier 1998: 413-424
    Google Scholar
  • 21 Cancado E LR, Porta G. Autoimmune Hepatitis in South America. Dordrecht, Boston, London; Kluwer Academic Publishers 2000: 82-92
    Google Scholar
  • 22 Kirk A P, Jain S, Pocock S, Thomas H C, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis.  Gut. 1980;  21 78-83
    CrossrefPubMedGoogle Scholar
  • 23 Geall M G, Schoenfield L J, Summerskill W HJ. Classification and treatment of chronic active liver disease.  Gastroenterology. 1968;  55(6) 724-729
    PubMedGoogle Scholar
  • 24 Soloway R D, Summerskill W H, Baggenstoss A H 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
  • 25 Gregorio G V, Portmann B, Reid F et al.. Autoimmune hepatitis in childhood: a 20-year experience.  Hepatology. 1997;  25(3) 541-547
    CrossrefPubMedGoogle Scholar
  • 26 Homberg J C, Abuaf N, Bernard O et al.. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis.  Hepatology. 1987;  7(6) 1333-1339
    PubMedGoogle Scholar
  • 27 Manns M P, Strassburg C P. Autoimmune hepatitis: clinical challenges.  Gastroenterology. 2001;  120(6) 1502-1517
    CrossrefPubMedGoogle Scholar
  • 28 Johnson P J, McFarlane I G, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis.  N Engl J Med. 1995;  333(15) 958-963
    CrossrefPubMedGoogle Scholar
  • 29 Nikias G A, Batts K P, Czaja A J. The nature and prognostic implications of autoimmune hepatitis with an acute presentation.  J Hepatol. 1994;  21(5) 866-871
    CrossrefPubMedGoogle Scholar
  • 30 Newton J L, Burt A D, Park J B, Mathew J, Bassendine M F, James O F. Autoimmune hepatitis in older patients.  Age Ageing. 1997;  26(6) 441-444
    CrossrefPubMedGoogle Scholar
  • 31 Schramm C, Kanzler S, zum Büschenfelde K H, Galle P R, Lohse A W. Autoimmune hepatitis in the elderly.  Am J Gastroenterol. 2001;  96(5) 1587-1591
    CrossrefPubMedGoogle Scholar
  • 32 Czaja A J, Carpenter H A. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly.  Hepatology. 2006;  43(3) 532-538
    CrossrefPubMedGoogle Scholar
  • 33 Czaja A J, Carpenter H A, Santrach P J, Moore S B. Significance of HLA DR4 in type 1 autoimmune hepatitis.  Gastroenterology. 1993;  105(5) 1502-1507
    PubMedGoogle Scholar
  • 34 Al-Chalabi T, Boccato S, Portmann B C, McFarlane I G, Heneghan M A. 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(4) 575-583
    CrossrefPubMedGoogle Scholar
  • 35 Prelog M. Aging of the immune system: a risk factor for autoimmunity?.  Autoimmun Rev. 2006;  5(2) 136-139
    CrossrefPubMedGoogle Scholar
  • 36 Talor E, Rose N R. Hypothesis: the aging paradox and autoimmune disease.  Autoimmunity. 1991;  8(3) 245-249
    PubMedGoogle Scholar
  • 37 Thalén A, Brattsand R. Synthesis and anti-inflammatory properties of budesonide, a new non-halogenated glucocorticoid with high local activity.  Arzneimittelforschung. 1979;  29(11) 1687-1690
    PubMedGoogle Scholar
  • 38 Danielsson A, Prytz H. Oral budesonide for treatment of autoimmune chronic active hepatitis.  Aliment Pharmacol Ther. 1994;  8(6) 585-590
    PubMedGoogle Scholar
  • 39 Czaja A J, Lindor K D. Failure of budesonide in a pilot study of treatment-dependent autoimmune hepatitis.  Gastroenterology. 2000;  119(5) 1312-1316
    PubMedGoogle Scholar
  • 40 Wiegand J, Schüler A, Kanzler S et al.. Budesonide in previously untreated autoimmune hepatitis.  Liver Int. 2005;  25(5) 927-934
    CrossrefPubMedGoogle Scholar
  • 41 Rebollo Bernárdez J, Cifuentes Mimoso C, Piñar Moreno A et al.. Deflazacort for long-term maintenance of remission in type I autoimmune hepatitis.  Rev Esp Enferm Dig. 1999;  91(9) 630-638
    PubMedGoogle Scholar
  • 42 Strassburg C P, Bahr M J, Becker T, Klempnauer J, Manns M P. [Progress in immunosuppression].  Chirurg. 2008;  79(2) 149-156
    CrossrefPubMedGoogle Scholar
  • 43 Alvarez F, Ciocca M, Cañero-Velasco C et al.. Short-term cyclosporine induces a remission of autoimmune hepatitis in children.  J Hepatol. 1999;  30(2) 222-227
    CrossrefPubMedGoogle Scholar
  • 44 Debray D, Maggiore G, Girardet J P, Mallet E, Bernard O. Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis.  J Pediatr. 1999;  135(1) 111-114
    PubMedGoogle Scholar
  • 45 Fernandes N F, Redeker A G, Vierling J M, Villamil F G, Fong T-L. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis.  Am J Gastroenterol. 1999;  94(1) 241-248
    CrossrefPubMedGoogle Scholar
  • 46 Heneghan M A, McFarlane I G. Current and novel immunosuppressive therapy for autoimmune hepatitis.  Hepatology. 2002;  35(1) 7-13
    CrossrefPubMedGoogle Scholar
  • 47 Van Thiel D H, Wright H, Carroll P et al.. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial.  Am J Gastroenterol. 1995;  90(5) 771-776
    PubMedGoogle Scholar
  • 48 Aqel B A, Machicao V, Rosser B, Satyanarayana R, Harnois D M, Dickson R C. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis.  J Clin Gastroenterol. 2004;  38(9) 805-809
    PubMedGoogle Scholar
  • 49 Richardson P D, James P D, Ryder S D. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine.  J Hepatol. 2000;  33(3) 371-375
    CrossrefPubMedGoogle Scholar
  • 50 Hennes E M, Oo Y H, Schramm C et al.. Mycophenolate mofetil as second line therapy in autoimmune hepatitis?.  Am J Gastroenterol. 2008;  103(12) 3063-3070
    CrossrefPubMedGoogle Scholar
  • 51 Kanzler S, Gerken G, Dienes H P, Meyer zum Büschenfelde K-H, Lohse A W. Cyclophosphamide as alternative immunosuppressive therapy for autoimmune hepatitis-- report of three cases.  Z Gastroenterol. 1997;  35 571-578
    PubMedGoogle Scholar
  • 52 Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid.  Hepatology. 1990;  11(1) 12-15
    CrossrefPubMedGoogle Scholar
  • 53 Czaja A J, Carpenter H A, Lindor K D. Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial.  Hepatology. 1999;  30(6) 1381-1386
    CrossrefPubMedGoogle Scholar
  • 54 Nakamura K, Yoneda M, Yokohama S et al.. Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis [see comments].  J Gastroenterol Hepatol. 1998;  13(5) 490-495
    PubMedGoogle Scholar
  • 55 Strassburg C P. [Autoimmune liver diseases and their overlap syndromes].  Praxis. 2006;  95 1363-1381
    CrossrefPubMedGoogle Scholar
  • 56 Rust C, Beuers U. Overlap syndromes among autoimmune liver diseases.  World J Gastroenterol. 2008;  14(21) 3368-3373
    CrossrefPubMedGoogle Scholar
  • 57 Ben-Ari Z, Dhillon A P, Sherlock S. Autoimmune cholangiopathy: part of the spectrum of autoimmune chronic active hepatitis.  Hepatology. 1993;  18(1) 10-15
    CrossrefPubMedGoogle Scholar
  • 58 Angulo P, El-Amin O, Carpenter H A, Lindor K D. Development of autoimmune hepatitis in the setting of long-standing primary biliary cirrhosis.  Am J Gastroenterol. 2001;  96(10) 3021-3027
    CrossrefPubMedGoogle Scholar
  • 59 Colombato L A, Alvarez F, Côté J, Huet P M. Autoimmune cholangiopathy: the result of consecutive primary biliary cirrhosis and autoimmune hepatitis?.  Gastroenterology. 1994;  107(6) 1839-1843
    PubMedGoogle Scholar
  • 60 Chazouillères O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy.  Hepatology. 1998;  28(2) 296-301
    CrossrefPubMedGoogle Scholar
  • 61 Duclos-Vallée J C, Hadengue A, Ganne-Carrié N, Robin E, Degott C, Erlinger S. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. Corticoresistance and effective treatment by cyclosporine A.  Dig Dis Sci. 1995;  40(5) 1069-1073
    CrossrefPubMedGoogle Scholar
  • 62 Al-Chalabi T, Portmann B C, Bernal W, McFarlane I G, Heneghan M A. Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival.  Aliment Pharmacol Ther. 2008;  28(2) 209-220
    CrossrefPubMedGoogle Scholar
  • 63 Silveira M G, Talwalkar J A, Angulo P, Lindor K D. Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes.  Am J Gastroenterol. 2007;  102(6) 1244-1250
    CrossrefPubMedGoogle Scholar
  • 64 Gossard A A, Lindor K D. Development of autoimmune hepatitis in primary biliary cirrhosis.  Liver Int. 2007;  27(8) 1086-1090
    CrossrefPubMedGoogle Scholar
  • 65 Poupon R, Chazouilleres O, Corpechot C, Chrétien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis.  Hepatology. 2006;  44(1) 85-90
    CrossrefPubMedGoogle Scholar
  • 66 Michieletti P, Wanless I R, Katz A et al.. Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis.  Gut. 1994;  35(2) 260-265
    PubMedGoogle Scholar
  • 67 Gregorio G V, Portmann B, Karani J et al.. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.  Hepatology. 2001;  33(3) 544-553
    CrossrefPubMedGoogle Scholar
  • 68 Potthoff A, Deterding K, Trautwein C et al.. Steroid treatment for severe acute cryptogenic hepatitis.  Z Gastroenterol. 2007;  45(1) 15-19
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Chazouillères O, Wendum D, Serfaty L, Rosmorduc O, Poupon R. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome.  J Hepatol. 2006;  44(2) 400-406
    CrossrefPubMedGoogle Scholar
  • 70 Strassburg C P, Becker T, Klempnauer J, Manns M P. [Liver transplantation: deciding between need and donor allocation].  Internist (Berl). 2004;  45(11) 1233-1245
    CrossrefPubMedGoogle Scholar
  • 71 Ahmed M, Mutimer D, Hathaway M, Hubscher S, McMaster P, Elias E. Liver transplantation for autoimmune hepatitis: a 12-year experience.  Transplant Proc. 1997;  29(1-2) 496
    PubMedGoogle Scholar
  • 72 Neuberger J, Portmann B, Calne R, Williams R. Recurrence of autoimmune chronic active hepatitis following orthotopic liver grafting.  Transplantation. 1984;  37(4) 363-365
    PubMedGoogle Scholar
  • 73 Prados E, Cuervas-Mons V, de la Mata M et al.. Outcome of autoimmune hepatitis after liver transplantation.  Transplantation. 1998;  66(12) 1645-1650
    CrossrefPubMedGoogle Scholar
  • 74 Sanchez-Urdazpal L, Czaja A J, van Holk B, Krom R A, Wiesner R H. Prognostic features and role of liver transplantation in severe corticoid-treated autoimmune chronic active hepatitis.  Hepatology. 1992;  15 215-221
    PubMedGoogle Scholar
  • 75 Tillmann H L, Jäckel E, Manns M P. Liver transplantation in autoimmune liver disease—selection of patients.  Hepatogastroenterology. 1999;  46(30) 3053-3059
    PubMedGoogle Scholar
  • 76 Vogel A, Heinrich E, Bahr M J et al.. Long-term outcome of liver transplantation for autoimmune hepatitis.  Clin Transplant. 2004;  18(1) 62-69
    CrossrefPubMedGoogle Scholar
  • 77 Strassburg C P, Manns M P. [Liver transplantation: indications and results].  Internist (Berl). 2009;  50(5) 550-560
    CrossrefPubMedGoogle Scholar
  • 78 Ratziu V, Samuel D, Sebagh M et al.. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease.  J Hepatol. 1999;  30(1) 131-141
    CrossrefPubMedGoogle Scholar
  • 79 Schreuder T C, Hübscher S G, Neuberger J. Autoimmune liver diseases and recurrence after orthotopic liver transplantation: what have we learned so far?.  Transpl Int. 2009;  22(2) 144-152
    CrossrefPubMedGoogle Scholar
  • 80 Devlin J, Donaldson P, Portmann B, Heaton N, Tan K C, Williams R. Recurrence of autoimmune hepatitis following liver transplantation.  Liver Transpl Surg. 1995;  1(3) 162-165
    CrossrefPubMedGoogle Scholar
  • 81 Manns M P, Bahr M J. Recurrent autoimmune hepatitis after liver transplantation-when non-self becomes self.  Hepatology. 2000;  32(4 Pt 1) 868-870
    CrossrefPubMedGoogle Scholar
  • 82 Milkiewicz P, Hubscher S G, Skiba G, Hathaway M, Elias E. Recurrence of autoimmune hepatitis after liver transplantation.  Transplantation. 1999;  68(2) 253-256
    CrossrefPubMedGoogle Scholar
  • 83 Wright H L, Bou-Abboud C F, Hassanein T et al.. Disease recurrence and rejection following liver transplantation for autoimmune chronic active liver disease.  Transplantation. 1992;  53(1) 136-139
    PubMedGoogle Scholar
  • 84 Götz G, Neuhaus R, Bechstein W O et al.. Recurrence of autoimmune hepatitis after liver transplantation.  Transplant Proc. 1999;  31(1-2) 430-431
    CrossrefPubMedGoogle Scholar
  • 85 Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review.  Liver Transpl. 2006;  12(12) 1813-1824
    CrossrefPubMedGoogle Scholar
  • 86 Rowe I A, Webb K, Gunson B K, Mehta N, Haque S, Neuberger J. The impact of disease recurrence on graft survival following liver transplantation: a single centre experience.  Transpl Int. 2008;  21(5) 459-465
    CrossrefPubMedGoogle Scholar
  • 87 Campsen J, Zimmerman M A, Trotter J F et al.. Liver transplantation for autoimmune hepatitis and the success of aggressive corticosteroid withdrawal.  Liver Transpl. 2008;  14(9) 1281-1286
    CrossrefPubMedGoogle Scholar
  • 88 Kerkar N, Hadzić N, Davies E T et al.. De-novo autoimmune hepatitis after liver transplantation.  Lancet. 1998;  351(9100) 409-413
    CrossrefPubMedGoogle Scholar
  • 89 Salcedo M, Vaquero J, Bañares R et al.. Response to steroids in de novo autoimmune hepatitis after liver transplantation.  Hepatology. 2002;  35(2) 349-356
    CrossrefPubMedGoogle Scholar
  • 90 Jones D E, James O F, Portmann B, Burt A D, Williams R, Hudson M. Development of autoimmune hepatitis following liver transplantation for primary biliary cirrhosis.  Hepatology. 1999;  30(1) 53-57
    CrossrefPubMedGoogle Scholar

Christian P StrassburgM.D. 

Professor of Gastroenterology and Hepatology, Department of Gastroenterology

Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

Email: strassburg.christian@mh-hannover.de

      >