Semin Liver Dis 2011; 31(1): 071-081
DOI: 10.1055/s-0031-1272834
© Thieme Medical Publishers

De Novo Autoimmune Hepatitis after Liver Transplantation

Maria Guido1 , Patrizia Burra2
  • 1Department of Medical Sciences and Special Therapies - Pathology Unit, University of Padova, Padova, Italy
  • 2Department of Gastroenterological and Surgical Sciences, University of Padova, Padova, Italy
Further Information

Publication History

Publication Date:
22 February 2011 (online)

ABSTRACT

Allograft dysfunction with clinical, serologic, and histologic features resembling autoimmune hepatitis (AIH) may develop in pediatric and adult patients who have received a liver transplant (LT) for end-stage diseases other than AIH. This condition is now known as de novo AIH, although its pathophysiology is still uncertain and whether it represents a specific type of rejection or a genuine form of AIH is under debate. The occurrence of de novo AIH seems to be unrelated to the etiology of the disease necessitating liver transplantation, but it has been correlated with antiviral treatment in cases of hepatitis C virus (HCV) infection recurring after LT. Several investigators have reported adverse outcome of de novo AIH, including graft failure, particularly in cases with late diagnosis. Prompt treatment with prednisone, with or without azathioprine (in addition to the basic immunosuppressive regimen), seems to be the best option. The histology of de novo AIH is characterized by an infiltrate rich in plasma cells with significant interface hepatitis and perivenular necro-inflammatory activity. These features are not specific for autoimmune damage; therefore, other causes of graft dysfunction must be excluded. The final diagnosis may be a challenge in patients with recurrent hepatitis C, and requires careful clinical and pathologic assessment.

REFERENCES

  • 1 Kerkar N, Hadzić N, Davies E T et al.. De-novo autoimmune hepatitis after liver transplantation.  Lancet. 1998;  351 (9100) 409-413
  • 2 Heneghan M A, Portmann B C, Norris S M et al.. Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults.  Hepatology. 2001;  34 (3) 464-470
  • 3 Conti F, Dousset B, Levillayer H, Gruska I, Weill B, Calmus Y. Autoantibodies after liver transplantation: a marker of allograft disease.  J Hepatol. 1997;  26 (S1) 150A
  • 4 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
  • 5 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
  • 6 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
  • 7 Spada M, Bertani A, Sonzogni A et al.. A cause of late graft dysfunction after liver transplantation in children: de-novo autoimmune hepatitis.  Transplant Proc. 2001;  33 (1–2) 1747-1748
  • 8 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
  • 9 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
  • 10 Yoshizawa K, Shirakawa H, Ichijo T et al.. De novo autoimmune hepatitis following living-donor liver transplantation for primary biliary cirrhosis.  Clin Transplant. 2008;  22 (3) 385-390
  • 11 Oya H, Sato Y, Yamamoto S et al.. De novo autoimmune hepatitis after living donor liver transplantation in a 25-day-old newborn baby: a case report.  Transplant Proc. 2009;  41 (1) 433-434
  • 12 Berardi S, Lodato F, Gramenzi A et al.. High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?.  Gut. 2007;  56 (2) 237-242
  • 13 Rifle G, Mousson C, Martin L, Guignier F, Hajji K. Donor-specific antibodies in allograft rejection: clinical and experimental data.  Transplantation. 2005;  79 (3, Suppl) S14-S18
  • 14 Mieli-Vergani G, Vergani D. De novo autoimmune hepatitis after liver transplantation.  J Hepatol. 2004;  40 (1) 3-7
  • 15 Hübscher S G. Recurrent autoimmune hepatitis after liver transplantation: diagnostic criteria, risk factors, and outcome.  Liver Transpl. 2001;  7 (4) 285-291
  • 16 Jones DEJ, James OFW, 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
  • 17 Czaja A J. Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.  Liver Transpl. 2002;  8 (6) 505-513
  • 18 Vanderlugt C L, Miller S D. Epitope spreading in immune-mediated diseases: implications for immunotherapy.  Nat Rev Immunol. 2002;  2 (2) 85-95
  • 19 Aichele P, Bachmann M F, Hengartner H, Zinkernagel R M. Immunopathology or organ-specific autoimmunity as a consequence of virus infection.  Immunol Rev. 1996;  152 21-45
  • 20 Oldstone MBA. Molecular mimicry and immune-mediated diseases.  FASEB J. 1998;  12 (13) 1255-1265
  • 21 Choudhuri K, Gregorio G V, Mieli-Vergani G, Vergani D. Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis.  Hepatology. 1998;  28 (5) 1177-1181
  • 22 Zhao Z S, Granucci F, Yeh L, Schaffer P A, Cantor H. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection.  Science. 1998;  279 (5355) 1344-1347
  • 23 Albert L J, Inman R D. Molecular mimicry and autoimmunity.  N Engl J Med. 1999;  341 (27) 2068-2074
  • 24 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
  • 25 Bucy R P, Xu X Y, Li J, Huang G Q. Cyclosporin A-induced autoimmune disease in mice.  J Immunol. 1993;  151 (2) 1039-1050
  • 26 Glazier A, Tutschka P J, Farmer E R, Santos G W. Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution.  J Exp Med. 1983;  158 (1) 1-8
  • 27 Hess A D, Fischer A C. Immune mechanisms in cyclosporine-induced syngeneic graft-versus-host disease.  Transplantation. 1989;  48 (6) 895-900
  • 28 Hess A D, Horwitz L R, Laulis M K. Cyclosporine-induced syngeneic graft-versus-host disease: recognition of self MHC class II antigens in vivo.  Transplant Proc. 1993;  25 (1 Pt 2) 1218-1221
  • 29 Hess A D, Horwitz L R, Laulis M K, Fuchs E. Cyclosporine-induced syngeneic graft-vs-host disease: prevention of autoaggression by treatment with monoclonal antibodies to T lymphocyte cell surface determinants and to MHC class II antigens.  Clin Immunol Immunopathol. 1993;  69 (3) 341-350
  • 30 Cooper M H, Hartman G G, Starzl T E, Fung J J. The induction of pseudo-graft-versus-host disease following syngeneic bone marrow transplantation using FK 506.  Transplant Proc. 1991;  23 (6) 3234-3235
  • 31 Cholongitas E, Samonakis D, Patch D et al.. Induction of autoimmune hepatitis by pegylated interferon in a liver transplant patient with recurrent hepatitis C virus.  Transplantation. 2006;  81 (3) 488-490
  • 32 Kontorinis N, Agarwal K, Elhajj N, Fiel M I, Schiano T D. Pegylated interferon-induced immune-mediated hepatitis post-liver transplantation.  Liver Transpl. 2006;  12 (5) 827-830
  • 33 Stanca C M, Fiel M I, Kontorinis N, Agarwal K, Emre S, Schiano T D. Chronic ductopenic rejection in patients with recurrent hepatitis C virus treated with pegylated interferon alfa-2a and ribavirin.  Transplantation. 2007;  84 (2) 180-186
  • 34 Fiel M I, Agarwal K, Stanca C et al.. Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus.  Liver Transpl. 2008;  14 (6) 861-871
  • 35 Ward S C, Schiano T D, Thung S N, Fiel M I. Plasma cell hepatitis in hepatitis C virus patients post-liver transplantation: case-control study showing poor outcome and predictive features in the liver explant.  Liver Transpl. 2009;  15 (12) 1826-1833
  • 36 Clifford B D, Donahue D, Smith L et al.. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C.  Hepatology. 1995;  21 (3) 613-619
  • 37 Muratori P, Muratori L, Stroffolini T et al.. Prevalence of non-organ specific autoantibodies in HCV-infected subjects in the general population.  Clin Exp Immunol. 2003;  131 (1) 118-121
  • 38 Ferri S, Muratori L, Lenzi M, Granito A, Bianchi F B, Vergani D. HCV and autoimmunity.  Curr Pharm Des. 2008;  14 (17) 1678-1685
  • 39 García-Buey L, García-Monzón C, Rodriguez S et al.. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C.  Gastroenterology. 1995;  108 (6) 1770-1777
  • 40 Bayraktar Y, Bayraktar M, Gurakar A, Hassanein T I, Van Thiel D H. A comparison of the prevalence of autoantibodies in individuals with chronic hepatitis C and those with autoimmune hepatitis: the role of interferon in the development of autoimmune diseases.  Hepatogastroenterology. 1997;  44 (14) 417-425
  • 41 Noda K, Enomoto N, Arai K et al.. Induction of antinuclear antibody after interferon therapy in patients with type-C chronic hepatitis: its relation to the efficacy of therapy.  Scand J Gastroenterol. 1996;  31 (7) 716-722
  • 42 Pileri P, Uematsu Y, Campagnoli S et al.. Binding of hepatitis C virus to CD81.  Science. 1998;  282 (5390) 938-941
  • 43 Stroffolini T, Colloredo G, Gaeta G B et al.. Does an ‘autoimmune’ profile affect the clinical profile of chronic hepatitis C? An Italian multicentre survey.  J Viral Hepat. 2004;  11 (3) 257-262
  • 44 Narciso-Schiavon J L, Freire F C, Suarez M M et al.. Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon?.  Eur J Gastroenterol Hepatol. 2009;  21 (4) 440-446
  • 45 Bianchi F B, Muratori P, Granito A, Pappas G, Ferri S, Muratori L. Hepatitis C and autoreactivity.  Dig Liver Dis. 2007;  39 (Suppl 1) S22-S24
  • 46 Czaja A J, Carpenter H A. Histological findings in chronic hepatitis C with autoimmune features.  Hepatology. 1997;  26 (2) 459-466
  • 47 Chrétien P, Chousterman M, Abd Alsamad I et al.. Non-organ-specific autoantibodies in chronic hepatitis C patients: association with histological activity and fibrosis.  J Autoimmun. 2009;  32 (3–4) 201-205
  • 48 Khettry U, Huang W Y, Simpson M A et al.. Patterns of recurrent hepatitis C after liver transplantation in a recent cohort of patients.  Hum Pathol. 2007;  38 (3) 443-452
  • 49 Czaja A J, Manns M P. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis.  Gastroenterology. 2010;  139 (1) 58-72, e4
  • 50 Wiegard C, Schramm C, Lohse A W. Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future.  Semin Liver Dis. 2009;  29 (3) 254-261
  • 51 Demetris A J, Adeyi O, Bellamy C O Banff Working Group et al. Liver biopsy interpretation for causes of late liver allograft dysfunction.  Hepatology. 2006;  44 (2) 489-501
  • 52 Bogdanos D P, Mieli-Vergani G, Vergani D. Autoantibodies and their antigens in autoimmune hepatitis.  Semin Liver Dis. 2009;  29 (3) 241-253
  • 53 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
  • 54 Aguilera I, Sousa J M, Gavilán F, Bernardos A, Wichmann I, Nuñez-Roldán A. Glutathione S-transferase T1 mismatch constitutes a risk factor for de novo immune hepatitis after liver transplantation.  Liver Transpl. 2004;  10 (9) 1166-1172
  • 55 Dubel L, Farges O, Johanet C, Sebagh M, Bismuth H. High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection.  Transplantation. 1998;  65 (8) 1072-1075
  • 56 Duclos-Vallée J C, Johanet C, Bach J F, Yamamoto A M. Autoantibodies associated with acute rejection after liver transplantation for type-2 autoimmune hepatitis.  J Hepatol. 2000;  33 (1) 163-166
  • 57 Lohse A W, Obermayer-Straub P, Gerken G et al.. Development of cytochrome P450 2D6-specific LKM-autoantibodies following liver transplantation for Wilson's disease — possible association with a steroid-resistant transplant rejection episode.  J Hepatol. 1999;  31 (1) 149-155
  • 58 Dubel L, Farges O, Johanet C, Sebagh M, Bismuth H. High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection.  Transplantation. 1998;  65 (8) 1072-1075
  • 59 Duclos-Vallée J C, Johanet C, Bach J F, Yamamoto A M. Autoantibodies associated with acute rejection after liver transplantation for type-2 autoimmune hepatitis.  J Hepatol. 2000;  33 (1) 163-166
  • 60 Shinkura N, Ikai I, Egawa H et al.. Presence of anti-FKBP12 autoantibodies in patients with liver allografts: its association with allograft rejection.  Transplantation. 1997;  64 (9) 1336-1342
  • 61 Salcedo M, Vaquero J, Banares R et al.. Serum autoantibodies after liver transplantation. Prevalence and associated immunologic disorders.  J Hepatol. 2003;  34 47A
  • 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
  • 63 Avitzur Y, Ngan B Y, Lao M, Fecteau A, Ng V L. Prospective evaluation of the prevalence and clinical significance of positive autoantibodies after pediatric liver transplantation.  J Pediatr Gastroenterol Nutr. 2007;  45 (2) 222-227
  • 64 Richter A, Grabhorn E, Helmke K, Manns M P, Ganschow R, Burdelski M. Clinical relevance of autoantibodies after pediatric liver transplantation.  Clin Transplant. 2007;  21 (3) 427-432
  • 65 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
  • 66 Hadzic N, Srinivasan R, Rela M et al.. De novo autoimmune hepatitis after liver transplantation in children; a single centre experience.  Hepatology. 2003;  38 202A
  • 67 Bogdanos D P, Invernizzi P, Mackay I R, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges.  World J Gastroenterol. 2008;  14 (21) 3374-3387
  • 68 Bach N, Thung S N, Schaffner F. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis.  Hepatology. 1992;  15 (4) 572-577
  • 69 Czaja A J, Carpenter H A. Autoimmune Hepatitis. In: McSween R NM, Burt A D, Portmann B C, Ishak K I, Scheuer P J, Anthony P P, eds. Pathology of the Liver. London: Churchill Livingstone; 2002: 415-434
  • 70 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
  • 71 Misdraji J, Thiim M, Graeme-Cook F M. Autoimmune hepatitis with centrilobular necrosis.  Am J Surg Pathol. 2004;  28 (4) 471-478
  • 72 Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation.  J Clin Pathol. 2006;  59 (3) 246-249
  • 73 Zen Y, Notsumata K, Tanaka N, Nakanuma Y. Hepatic centrilobular zonal necrosis with positive antinuclear antibody: a unique subtype or early disease of autoimmune hepatitis?.  Hum Pathol. 2007;  38 (11) 1669-1675
  • 74 Demetris A J, Crawford J M, Minervini M I et al.. Transplantation pathology of the liver. In: Odze R D, Goldblum J R, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia: Saunders/Elsevier; 2009: 1177-1180
  • 75 Hubscher S GPB. Transplantation pathology. In: MacSween R NM, Burt A D, Ferrell L D, eds. Pathology of the Liver. 5th ed. London: Churchill Livingstone; 2007: 815-879
  • 76 Adeyi O, Fischer S E, Guindi M. Liver allograft pathology: approach to interpretation of needle biopsies with clinicopathological correlation.  J Clin Pathol. 2010;  63 (1) 47-74
  • 77 Czaja A J, Carpenter H A. Autoimmune hepatitis with incidental histologic features of bile duct injury.  Hepatology. 2001;  34 (4 Pt 1) 659-665
  • 78 Krasinskas A M, Ruchelli E D, Rand E B, Chittams J L, Furth E E. Central venulitis in pediatric liver allografts.  Hepatology. 2001;  33 (5) 1141-1147
  • 79 Nakazawa Y, Walker N I, Kerlin P et al.. Clinicopathological analysis of liver allograft biopsies with late centrilobular necrosis: a comparative study in 54 patients.  Transplantation. 2000;  69 (8) 1599-1608
  • 80 Tsamandas A C, Jain A B, Felekouras E S, Fung J J, Demetris A J, Lee R G. Central venulitis in the allograft liver: a clinicopathologic study.  Transplantation. 1997;  64 (2) 252-257
  • 81 Ludwig J, Gross Jr J B, Perkins J D, Moore S B. Persistent centrilobular necroses in hepatic allografts.  Hum Pathol. 1990;  21 (6) 656-661
  • 82 Turlin B, Slapak G I, Hayllar K M, Heaton N, Williams R, Portmann B. Centrilobular necrosis after orthotopic liver transplantation: a longitudinal clinicopathologic study in 71 patients.  Liver Transpl Surg. 1995;  1 (5) 285-289
  • 83 Demetris A J. Central venulitis in liver allografts: considerations of differential diagnosis.  Hepatology. 2001;  33 (5) 1329-1330
  • 84 Demetris A J, Eghtesad B, Marcos A et al.. Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis.  Am J Surg Pathol. 2004;  28 (5) 658-669
  • 85 Ziarkiewicz-Wróblewska B, Wróblewski T, Wasiutyński A. Morphological features and differential diagnosis of hepatitis C recurrence after liver transplantation - literature review and results of single transplantation center.  Ann Transplant. 2008;  13 (2) 12-20
  • 86 Manns M P, Czaja A J, Gorham J D American Association for the Study of Liver Diseases et al. Diagnosis and management of autoimmune hepatitis.  Hepatology. 2010;  51 (6) 2193-2213

Maria GuidoM.D. 

Istituto di Anatomia Patologica

Via Gabelli, 61, 35100 Padova

Email: mguido@unipd.it

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