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Semin Liver Dis 2009; 29(3): 286-296
DOI: 10.1055/s-0029-1233531
© Thieme Medical Publishers

Autoimmune Hepatitis and Liver Transplantation: Indications, Results, and Management of Recurrent Disease

Dhiraj Tripathi1 , James Neuberger1
  • 1Liver Unit, University Hospital Birmingham, NHS Foundation Trust, Birmingham, United Kingdom
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Publication History

Publication Date:
12 August 2009 (online)

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ABSTRACT

For those with autoimmune hepatitis (AIH), indications for liver transplantation include end-stage liver failure (as suggested by a MELD score >16), the onset of liver cancer, intractable symptoms that make the patient's life intolerable, and fulminant liver failure; outcomes are excellent, with 10-year survival in excess of 70%. For those with a fulminant presentation, the impact of corticosteroids is controversial and liver transplantation may be required. Autoimmune hepatitis recurs in approximately one third and may be detected up to 10 years or more post-transplant. There are no agreed-on criteria for the diagnosis, and differentiation from rejection and other causes of graft damage can be difficult. There is no strong correlation between the prevalence of recurrent AIH (rAIH) and graft loss from rAIH. Treatment of recurrent disease with the addition or increase in corticosteroids is often successful, although long-term data are lacking and some may progress to graft failure despite increased treatment. There remains controversy over the role for protocol liver biopsies to detect recurrent disease and the best immunosuppressive strategies to prevent and treat recurrence.

KEYWORDS

Autoimmune hepatitis - liver transplantation - recurrence - de novo autoimmune hepatitis

REFERENCES

  • 1 Verslype C, George C, Buchel E, Nevens F, van Steenbergen W, Fevery J. Diagnosis and treatment of autoimmune hepatitis at age 65 and older.  Aliment Pharmacol Ther. 2005;  21(6) 695-699
    CrossrefPubMedGoogle Scholar
  • 2 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
  • 3 Johnson P J, McFarlane I G. Meeting report: International Autoimmune Hepatitis Group.  Hepatology. 1993;  18(4) 998-1005
    CrossrefPubMedGoogle Scholar
  • 4 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
  • 5 Czaja A J, Bianchi F B, Carpenter H A et al.. Treatment challenges and investigational opportunities in autoimmune hepatitis.  Hepatology. 2005;  41(1) 207-215
    CrossrefPubMedGoogle Scholar
  • 6 Czaja A J, Carpenter H A. Thiopurine methyltransferase deficiency and azathioprine intolerance in autoimmune hepatitis.  Dig Dis Sci. 2006;  51(5) 968-975
    CrossrefPubMedGoogle Scholar
  • 7 Heneghan M A, Allan M L, Bornstein J D, Muir A J, Tendler D A. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis.  J Hepatol. 2006;  45(4) 584-591
    CrossrefPubMedGoogle Scholar
  • 8 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
  • 9 Cuarterolo M, Ciocca M, Velasco C C et al.. Follow-up of children with autoimmune hepatitis treated with cyclosporine.  J Pediatr Gastroenterol Nutr. 2006;  43(5) 635-639
    CrossrefPubMedGoogle Scholar
  • 10 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
  • 11 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
  • 12 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(7) 571-578
    PubMedGoogle Scholar
  • 13 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
  • 14 Kamath P S, Wiesner R H, Malinchoc M et al.. A model to predict survival in patients with end-stage liver disease.  Hepatology. 2001;  33(2) 464-470
    CrossrefPubMedGoogle Scholar
  • 15 Malinchoc M, Kamath P S, Gordon F D, Peine C J, Rank J, ter Borg P C. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.  Hepatology. 2000;  31(4) 864-871
    CrossrefPubMedGoogle Scholar
  • 16 Neuberger J, Gimson A, Davies M Liver Advisory Group et al. Selection of patients for liver transplantation and allocation of donated livers in the UK.  Gut. 2008;  57(2) 252-257
    CrossrefPubMedGoogle Scholar
  • 17 Cheng A L, Kang Y K, Chen Z et al.. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.  Lancet Oncol. 2009;  10(1) 25-34
    CrossrefPubMedGoogle Scholar
  • 18 Llovet J M, Ricci S, Mazzaferro V SHARP Investigators Study Group et al. Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;  359(4) 378-390
    CrossrefPubMedGoogle Scholar
  • 19 Polak W G, Soyama A, Slooff M J. Liver transplantation in patients with hepatocellular carcinoma.  Ann Transplant. 2008;  13(4) 5-15
    PubMedGoogle Scholar
  • 20 Mazzaferro V, Regalia E, Doci R et al.. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.  N Engl J Med. 1996;  334(11) 693-699
    CrossrefPubMedGoogle Scholar
  • 21 Yao F Y, Kerlan Jr R K, Hirose R et al.. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis.  Hepatology. 2008;  48(3) 819-827
    CrossrefPubMedGoogle Scholar
  • 22 Mazzaferro V, Llovet J M, Miceli R Metroticket Investigator Study Group et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.  Lancet Oncol. 2009;  10(1) 35-43
    CrossrefPubMedGoogle Scholar
  • 23 Toso C, Meeberg G A, Bigam D L et al.. De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects.  Transplantation. 2007;  83(9) 1162-1168
    CrossrefPubMedGoogle Scholar
  • 24 O'Grady J G, Alexander G J, Hayllar K M, Williams R. Early indicators of prognosis in fulminant hepatic failure.  Gastroenterology. 1989;  97(2) 439-445
    PubMedGoogle Scholar
  • 25 Ichai P, Duclos-Vallée J C, Guettier C et al.. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis.  Liver Transpl. 2007;  13(7) 996-1003
    CrossrefPubMedGoogle Scholar
  • 26 Amontree J S, Stuart T D, Bredfeldt J E. Autoimmune chronic active hepatitis masquerading as acute hepatitis.  J Clin Gastroenterol. 1989;  11(3) 303-307
    PubMedGoogle Scholar
  • 27 Bosch J, Coll M, Puig A et al.. Autoimmune hepatitis with fatal outcome.  J Pediatr. 1991;  118(5) 823-824
    PubMedGoogle Scholar
  • 28 Ferrari R, Pappas G, Agostinelli D et al.. Type 1 autoimmune hepatitis: patterns of clinical presentation and differential diagnosis of the ‘acute’ type.  QJM. 2004;  97(7) 407-412
    CrossrefPubMedGoogle Scholar
  • 29 Herzog D, Rasquin-Weber A M, Debray D, Alvarez F. Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual form of presentation.  J Hepatol. 1997;  27(3) 578-582
    CrossrefPubMedGoogle Scholar
  • 30 Kessler W R, Cummings O W, Eckert G, Chalasani N, Lumeng L, Kwo P Y. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis.  Clin Gastroenterol Hepatol. 2004;  2(7) 625-631
    CrossrefPubMedGoogle Scholar
  • 31 Maggiore G, Porta G, Bernard O et al.. Autoimmune hepatitis with initial presentation as acute hepatic failure in young children.  J Pediatr. 1990;  116(2) 280-282
    PubMedGoogle Scholar
  • 32 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
  • 33 Okano N, Yamamoto K, Sakaguchi K et al.. Clinicopathological features of acute-onset autoimmune hepatitis.  Hepatol Res. 2003;  25(3) 263-270
    PubMedGoogle Scholar
  • 34 Viruet E J, Torres E A. Steroid therapy in fulminant hepatic failure secondary to autoimmune hepatitis.  P R Health Sci J. 1998;  17(3) 297-300
    PubMedGoogle Scholar
  • 35 Villamil A G, Casciato P, Eduardo M et al.. Fulminant autoimmune hepatitis: Clinical presentation, outcome and prognostic factors.  Am J Transplant. 2005;  5 278
    PubMedGoogle Scholar
  • 36 Futagawa Y, Terasaki P I. An analysis of the OPTN/UNOS Liver Transplant Registry.  Clin Transpl. 2004;  315-329
    PubMedGoogle Scholar
  • 37 Molmenti E P, Netto G J, Murray N G et al.. Incidence and recurrence of autoimmune/alloimmune hepatitis in liver transplant recipients.  Liver Transpl. 2002;  8(6) 519-526
    CrossrefPubMedGoogle Scholar
  • 38 Neuberger J, Adams D H. What is the significance of acute liver allograft rejection?.  J Hepatol. 1998;  29(1) 143-150
    CrossrefPubMedGoogle Scholar
  • 39 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
  • 40 Ayata G, Gordon F D, Lewis W D et al.. Liver transplantation for autoimmune hepatitis: a long-term pathologic study.  Hepatology. 2000;  32(2) 185-192
    CrossrefPubMedGoogle Scholar
  • 41 Bahar R J, Yanni G S, Martín M G et al.. Orthotopic liver transplantation for autoimmune hepatitis and cryptogenic chronic hepatitis in children.  Transplantation. 2001;  72(5) 829-833
    CrossrefPubMedGoogle Scholar
  • 42 Birnbaum A H, Benkov K J, Pittman N S, McFarlane-Ferreira Y, Rosh J R, LeLeiko N S. Recurrence of autoimmune hepatitis in children after liver transplantation.  J Pediatr Gastroenterol Nutr. 1997;  25(1) 20-25
    CrossrefPubMedGoogle Scholar
  • 43 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
  • 44 Duclos-Vallée J C, Sebagh M, Rifai K et al.. A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence.  Gut. 2003;  52(6) 893-897
    CrossrefPubMedGoogle Scholar
  • 45 González-Koch A, Czaja A J, Carpenter H A et al.. Recurrent autoimmune hepatitis after orthotopic liver transplantation.  Liver Transpl. 2001;  7(4) 302-310
    CrossrefPubMedGoogle Scholar
  • 46 Heffron T G, Smallwood G A, Oakley B et al.. Autoimmune hepatitis following liver transplantation: relationship to recurrent disease and steroid weaning.  Transplant Proc. 2002;  34(8) 3311-3312
    CrossrefPubMedGoogle Scholar
  • 47 Khalaf H, Mourad W, El-Sheikh Y et al.. Liver transplantation for autoimmune hepatitis: a single-center experience.  Transplant Proc. 2007;  39(4) 1166-1170
    CrossrefPubMedGoogle Scholar
  • 48 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
  • 49 Narumi S, Hakamada K, Sasaki M et al.. Liver transplantation for autoimmune hepatitis: rejection and recurrence.  Transplant Proc. 1999;  31(5) 1955-1956
    CrossrefPubMedGoogle Scholar
  • 50 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
  • 51 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
  • 52 Reich D J, Fiel I, Guarrera J V et al.. Liver transplantation for autoimmune hepatitis.  Hepatology. 2000;  32(4 Pt 1) 693-700
    CrossrefPubMedGoogle Scholar
  • 53 Renz J F, Ascher N L. Liver transplantation for nonviral, nonmalignant diseases: problem of recurrence.  World J Surg. 2002;  26(2) 247-256
    CrossrefPubMedGoogle Scholar
  • 54 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
  • 55 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
  • 56 Yusoff I F, House A K, De Boer W B et al.. Disease recurrence after liver transplantation in Western Australia.  J Gastroenterol Hepatol. 2002;  17(2) 203-207
    CrossrefPubMedGoogle Scholar
  • 57 Kerkar N, Hadzić N, Davies E T et al.. De-novo autoimmune hepatitis after liver transplantation.  Lancet. 1998;  351(9100) 409-413
    CrossrefPubMedGoogle Scholar
  • 58 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
  • 59 Mottershead M, Neuberger J. Transplantation in autoimmune liver diseases.  World J Gastroenterol. 2008;  14(21) 3388-3395
    CrossrefPubMedGoogle Scholar
  • 60 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
  • 61 Hübscher S G. Recurrent autoimmune hepatitis after liver transplantation: diagnostic criteria, risk factors, and outcome.  Liver Transpl. 2001;  7(4) 285-291
    CrossrefPubMedGoogle Scholar
  • 62 Evans H M, Kelly D A, McKiernan P J, Hübscher S. Progressive histological damage in liver allografts following pediatric liver transplantation.  Hepatology. 2006;  43(5) 1109-1117
    CrossrefPubMedGoogle Scholar
  • 63 Junge G, Neuhaus R, Schewior L et al.. Withdrawal of steroids: a randomized prospective study of prednisone and tacrolimus versus mycophenolate mofetil and tacrolimus in liver transplant recipients with autoimmune hepatitis.  Transplant Proc. 2005;  37(4) 1695-1696
    CrossrefPubMedGoogle Scholar
  • 64 Uemura T, Ikegami T, Sanchez E Q et al.. Late acute rejection after liver transplantation impacts patient survival.  Clin Transplant. 2008;  22(3) 316-323
    CrossrefPubMedGoogle Scholar
  • 65 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
  • 66 Milkiewicz P, Ahmed M, Hathaway M, Elias E. Factors associated with progression of the disease before transplantation in patients with autoimmune hepatitis.  Liver. 1999;  19(1) 50-54
    PubMedGoogle Scholar
  • 67 Hurtova M, Duclos-Vallée J C, Johanet C et al.. Successful tacrolimus therapy for a severe recurrence of type 1 autoimmune hepatitis in a liver graft recipient.  Liver Transpl. 2001;  7(6) 556-558
    CrossrefPubMedGoogle Scholar
  • 68 Kerkar N, Dugan C, Rumbo C et al.. Rapamycin successfully treats post-transplant autoimmune hepatitis.  Am J Transplant. 2005;  5(5) 1085-1089
    CrossrefPubMedGoogle Scholar
  • 69 Rodríguez-Diaz Y, Reyes-Rodriguez R, Dorta-Francisco M C et al.. De novo autoimmune hepatitis following liver transplantation for primary biliary cirrhosis.  Transplant Proc. 2006;  38(5) 1467-1470
    CrossrefPubMedGoogle Scholar
  • 70 Seyam M, Neuberger J M, Gunson B K, Hübscher S G. Cirrhosis after orthotopic liver transplantation in the absence of primary disease recurrence.  Liver Transpl. 2007;  13(7) 966-974
    CrossrefPubMedGoogle Scholar
  • 71 Di Cocco P, Barletta A, Clemente K et al.. De novo autoimmune hepatitis following liver transplantation: a case report.  Transplant Proc. 2008;  40(6) 2073-2074
    CrossrefPubMedGoogle Scholar
  • 72 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
  • 73 Aguilera I, Sousa J M, Gavilan F, Bernardos A, Wichmann I, Nuñez-Roldan A. Glutathione S-transferase T1 genetic mismatch is a risk factor for de novo immune hepatitis in liver transplantation.  Transplant Proc. 2005;  37(9) 3968-3969
    CrossrefPubMedGoogle Scholar
  • 74 Tan C K, Sian Ho J M. Concurrent de novo autoimmune hepatitis and recurrence of primary biliary cirrhosis post-liver transplantation.  Liver Transpl. 2001;  7(5) 461-465
    CrossrefPubMedGoogle Scholar
  • 75 Gao E K, Lo D, Cheney R, Kanagawa O, Sprent J. Abnormal differentiation of thymocytes in mice treated with cyclosporin A.  Nature. 1988;  336(6195) 176-179
    CrossrefPubMedGoogle Scholar
  • 76 Czaja A J. Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.  Liver Transpl. 2002;  8(6) 505-513
    CrossrefPubMedGoogle Scholar
  • 77 Neuberger J, Gunson B, Hubscher S, Nightingale P. Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation.  Liver Transpl. 2004;  10(4) 488-491
    CrossrefPubMedGoogle Scholar
  • 78 Petz W, Sonzogni A, Bertani A et al.. A cause of late graft dysfunction after pediatric liver transplantation: de novo autoimmune hepatitis.  Transplant Proc. 2002;  34(5) 1958-1959
    CrossrefPubMedGoogle Scholar
  • 79 Venick R S, McDiarmid S V, Farmer D G et al.. Rejection and steroid dependence: unique risk factors in the development of pediatric posttransplant de novo autoimmune hepatitis.  Am J Transplant. 2007;  7(4) 955-963
    CrossrefPubMedGoogle Scholar
  • 80 D'Antiga L, Dhawan A, Portmann B et al.. Late cellular rejection in paediatric liver transplantation: aetiology and outcome.  Transplantation. 2002;  73(1) 80-84
    PubMedGoogle Scholar
  • 81 Miyagawa-Hayashino A, Haga H, Egawa H et al.. Outcome and risk factors of de novo autoimmune hepatitis in living-donor liver transplantation.  Transplantation. 2004;  78(1) 128-135
    PubMedGoogle Scholar
  • 82 Aguilera I, Wichmann I, Sousa J M et al.. Antibodies against glutathione S-transferase T1 (GSTT1) in patients with de novo immune hepatitis following liver transplantation.  Clin Exp Immunol. 2001;  126(3) 535-539
    CrossrefPubMedGoogle Scholar
  • 83 Gupta P, Hart J, Millis J M, Cronin D, Brady L. De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation.  Transplantation. 2001;  71(5) 664-668
    CrossrefPubMedGoogle Scholar
  • 84 Riva S, Sonzogni A, Bravi M et al.. Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience.  Liver Transpl. 2006;  12(4) 573-577
    CrossrefPubMedGoogle Scholar
  • 85 Andries S, Casamayou L, Sempoux C et al.. Posttransplant immune hepatitis in pediatric liver transplant recipients: incidence and maintenance therapy with azathioprine.  Transplantation. 2001;  72(2) 267-272
    CrossrefPubMedGoogle Scholar
  • 86 Hernandez H M, Kovarik P, Whitington P F, Alonso E M. Autoimmune hepatitis as a late complication of liver transplantation.  J Pediatr Gastroenterol Nutr. 2001;  32(2) 131-136
    CrossrefPubMedGoogle Scholar

James NeubergerD.M. F.R.C.P. 

Liver Unit, University Hospital Birmingham, NHS Foundation Trust

Birmingham B15 2TH, United Kingdom

Email: James.Neuberger@uhb.nhs.uk