Diagnostic Considerations

Because autoimmune hepatitis is a potentially treatable condition, a missed diagnosis can have serious consequences. The diagnosis should be considered in all patients with hepatitis, especially females. Untreated autoimmune hepatitis can result in death due to liver failure.

Similarly, a wrong diagnosis of autoimmune hepatitis can expose the patient to unnecessary complications of immunosuppressant therapy, which can be serious and life threatening.

Regardless of the mode of presentation (ie, acute vs chronic), autoimmune hepatitis usually becomes a chronic disease. It is unnecessary to wait 6 months to prove the chronic nature of the disease.

The differential diagnosis for autoimmune hepatitis should include many causes of chronic liver disease, including α₁-antitrypsin deficiency, Wilson disease, viral hepatitis, hepatotoxic drugs, and excessive alcohol consumption.

Autoimmune hepatitis and hepatitis C

The prevalence rate of hepatitis C virus (HCV) infection in patients with autoimmune hepatitis is similar to that in the general population. This implies that HCV is not an important factor in the etiology of autoimmune hepatitis.

Positive tests for antibodies to liver-kidney microsome type 1 (anti-LKM1) have been described in patients with HCV infection; they have biopsy findings of chronic hepatitis C and no evidence for autoimmune hepatitis.^[54]

False-positive results on anti-HCV enzyme-linked immunoassay (ELISA) tests are described in the setting of hypergammaglobulinemia, including that observed in patients with autoimmune hepatitis. In these patients, hepatitis C is rule out by the performance of HCV RNA testing using a polymerase chain reaction (PCR) assay.

In general, patients with definite autoimmune hepatitis have median serum titers of anti-smooth muscle antibody (ASMA) and antinuclear antibody (ANA) of 1:160 and 1:320, respectively. In contrast, ASMA and ANA titers may be in the range of 1:80 or less in patients with chronic viral hepatitis and in other liver diseases.

Histologically, both autoimmune hepatitis and chronic hepatitis C are marked by portal inflammation. However, moderate-to-severe plasma cell infiltration of the portal tracts and lobular inflammation are more common in patients with autoimmune hepatitis. Portal lymphoid aggregates, steatosis, and bile duct damage are more common in patients with chronic HCV.

Overlap syndromes

Patients with autoimmune hepatitis may present with features that overlap with those classically associated with patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

About 7% of patients with autoimmune hepatitis have a disease that overlaps with PBC. They may have detectable anti-mitochondrial antibody (AMA) (usually in low titer), histologic findings of bile duct injury and/or destruction, and the presence of hepatic copper. The natural history of the disease tends to echo type 1 autoimmune hepatitis. Patients with the autoimmune hepatitis–PBC overlap syndrome may improve with steroid therapy. However, there should be a low threshold to institute treatment with ursodiol.

About 6% of patients with autoimmune hepatitis have a disease that overlaps with PSC. Patients with the autoimmune hepatitis–PSC overlap syndrome frequently have concurrent inflammatory bowel disease. Liver chemistries usually have a mixed hepatocellular and cholestatic pattern. Liver biopsy findings reveal bile duct injury. As in PSC, magnetic resonance cholangiopancreatography (MRCP) may reveal bile duct beading and structuring. Typically, cases of autoimmune hepatitis-PSC overlap syndrome are resistant to steroid therapy. Treatment with ursodiol should be considered.

Autoimmune cholangitis is characterized by mixed hepatic and cholestatic liver chemistries, positive ANA and/or ASMA, negative AMA, antibodies to carbonic anhydrase, and histology that resembles PBC. Some authors contend that this condition is AMA-negative PBC. Patients may have an unpredictable response to therapy with steroids or ursodiol.

Differential Diagnoses

Workup

Oettinger R, Brunnberg A, Gerner P, Wintermeyer P, Jenke A, Wirth S. Clinical features and biochemical data of Caucasian children at diagnosis of autoimmune hepatitis. J Autoimmun. 2005 Feb. 24(1):79-84. [QxMD MEDLINE Link].
Strassburg CP, Manns MP. Treatment of autoimmune hepatitis. Semin Liver Dis. 2009 Aug. 29(3):273-85. [QxMD MEDLINE Link].
[Guideline] Mack CL, Adams D, Assis DN, et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases. Hepatology. 2020 Aug. 72(2):671-722. [QxMD MEDLINE Link]. [Full Text].
Montano-Loza AJ, Carpenter HA, Czaja AJ. Consequences of treatment withdrawal in type 1 autoimmune hepatitis. Liver Int. 2007 May. 27(4):507-15. [QxMD MEDLINE Link].
Waldenstrom J. The diagnostic importance of ACTH. Acta Endocrinol (Copenh). 1950. 5(3):235-42. [QxMD MEDLINE Link].
Kunkel HG, Ahrens EH, Eisenmenger WJ. Extreme hypergammaglobulinemia in young women with liver disease of unknown etiology. J Clin Invest. 1950. 30:654.
Bearn AG, Kunkel HG, Slater RJ. The problems of chronic liver disease in young women. Am J Med. 1956. 21:3-15.
Joske RA, King WE. The L.E.-cell phenomenon in active chronic viral hepatitis. Lancet. 1955 Sep 3. 269(6888):477-80. [QxMD MEDLINE Link].
Cowling DC, Mackay IR, Taft LI. Lupoid hepatitis. Lancet. 1956 Dec 29. 271(6957):1323-6. [QxMD MEDLINE Link].
Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology. 1993 Oct. 18(4):998-1005. [QxMD MEDLINE Link].
Scully LJ, Toze C, Sengar DP, et al. Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Gastroenterology. 1993 May. 104(5):1478-84. [QxMD MEDLINE Link].
Czaja AJ, Carpenter HA, Santrach PJ, et al. Genetic predispositions for the immunological features of chronic active hepatitis. Hepatology. 1993 Oct. 18(4):816-22. [QxMD MEDLINE Link].
Oo YH, Hubscher SG, Adams DH. Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. Hepatol Int. 2010 May 19. 4(2):475-93. [QxMD MEDLINE Link]. [Full Text].
Floreani A, Restrepo-Jimenez P, Secchi MF, et al. Etiopathogenesis of autoimmune hepatitis. J Autoimmun. 2018 Dec. 95:133-43. [QxMD MEDLINE Link].
Umemura T, Ota M. Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis. Clin J Gastroenterol. 2015 Dec. 8(6):360-6. [QxMD MEDLINE Link].
Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X. The clinical phenotypes of autoimmune hepatitis: A comprehensive review. J Autoimmun. 2016 Jan. 66:98-107. [QxMD MEDLINE Link].
Czaja AJ. Diagnosis and management of autoimmune hepatitis. Clin Liver Dis. 2015 Feb. 19(1):57-79. [QxMD MEDLINE Link].
Pathmakanthan S, Kay EW, Murray FE. Autoimmune chronic active hepatitis associated with the presence of antiphospholipid antibodies. Eur J Gastroenterol Hepatol. 1998 Feb. 10(2):155-7. [QxMD MEDLINE Link].
Ben-Ari Z, Czaja AJ. Autoimmune hepatitis and its variant syndromes. Gut. 2001 Oct. 49(4):589-94. [QxMD MEDLINE Link]. [Full Text].
Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci. 2012 Mar. 57(3):610-24. [QxMD MEDLINE Link].
Czaja AJ. Autoimmune hepatitis. Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa: WB Saunders Company; 1998. 1265-74.
Ramakrishna J, Johnson AR, Banner BF. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol. 2009 Sep. 43(8):787-90. [QxMD MEDLINE Link].
Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol. 2010 Jan. 44(1):e20-2. [QxMD MEDLINE Link].
Fairhurst DA, Sheehan-Dare R. Autoimmune hepatitis associated with infliximab in a patient with palmoplantar pustular psoriaisis. Clin Exp Dermatol. 2009 Apr. 34(3):421-2. [QxMD MEDLINE Link].
Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002 Aug. 6(3):755-74. [QxMD MEDLINE Link].
Casswall TH, Nemeth A, Nilsson I, Wadstrom T, Nilsson HO. Helicobacter species DNA in liver and gastric tissues in children and adolescents with chronic liver disease. Scand J Gastroenterol. 2010. 45(2):160-7. [QxMD MEDLINE Link].
Tunio NA, Mansoor E, Sheriff MZ, Cooper GS, Sclair SN, Cohen SM. Epidemiology of autoimmune hepatitis (AIH) in the United States between 2014 and 2019: a population-based national study. J Clin Gastroenterol. 2021 Nov-Dec 01. 55(10):903-10. [QxMD MEDLINE Link].
Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV. Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol. 2002 Sep. 97(9):2402-7. [QxMD MEDLINE Link].
Ngu JH, Bechly K, Chapman BA, et al. Population-based epidemiology study of autoimmune hepatitis: a disease of older women?. J Gastroenterol Hepatol. 2010 Oct. 25(10):1681-6. [QxMD MEDLINE Link].
Czaja AJ. Special clinical challenges in autoimmune hepatitis: the elderly, males, pregnancy, mild disease, fulminant onset, and nonwhite patients. Semin Liver Dis. 2009 Aug. 29(3):315-30. [QxMD MEDLINE Link].
Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children: what is different from adult AIH?. Semin Liver Dis. 2009 Aug. 29(3):297-306. [QxMD MEDLINE Link].
Haider AS, Kaye G, Thomson A. Autoimmune hepatitis in a demographically isolated area of Australia. Intern Med J. 2010 Apr. 40(4):281-5. [QxMD MEDLINE Link].
Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology. 2006 Mar. 43(3):532-8. [QxMD MEDLINE Link].
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 Oct. 46(4):1138-45. [QxMD MEDLINE Link].
Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. 1997 Mar. 25(3):541-7. [QxMD MEDLINE Link].
Mieli-Vergani G, Vergani D, Baumann U, et al. Diagnosis and management of pediatric autoimmune liver disease: ESPGHAN Hepatology Committee position statement. J Pediatr Gastroenterol Nutr. 2018 Feb. 66(2):345-60. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Gleeson D, Heneghan MA, British Society of Gastroenterology. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011 Dec. 60(12):1611-29. [QxMD MEDLINE Link].
Buechter M, Manka P, Heinemann FM, et al. Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients. World J Gastroenterol. 2018 Apr 7. 24(13):1410-8. [QxMD MEDLINE Link]. [Full Text].
Kirk AP, Jain S, Pocock S, et al. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut. 1980 Jan. 21(1):78-83. [QxMD MEDLINE Link].
Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology. 1988 Aug. 95(2):448-53. [QxMD MEDLINE Link].
Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology. 1996 Mar. 110(3):848-57. [QxMD MEDLINE Link].
Ferreira AR, Roquete ML, Toppa NH, de Castro LP, Fagundes ED, Penna FJ. Effect of treatment of hepatic histopathology in children and adolescents with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2008 Jan. 46(1):65-70. [QxMD MEDLINE Link].
Czaja AJ, Menon KV, Carpenter HA. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology. 2002 Apr. 35(4):890-7. [QxMD MEDLINE Link].
[Guideline] Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010 Jun. 51(6):2193-213. [QxMD MEDLINE Link].
Hoeroldt B, McFarlane E, Dube A, et al. Long-term outcomes of patients with autoimmune hepatitis managed at a nontransplant center. Gastroenterology. 2011 Jun. 140(7):1980-9. [QxMD MEDLINE Link]. [Full Text].
Gleeson D. Long-term outcomes of autoimmune hepatitis. Clin Liver Dis (Hoboken). 2019 Jul. 14(1):24-8. [QxMD MEDLINE Link]. [Full Text].
Rahim MN, Miquel R, Heneghan MA. Approach to the patient with acute severe autoimmune hepatitis. JHEP Rep. 2020 Dec. 2(6):100149. [QxMD MEDLINE Link]. [Full Text].
Sharma S, Agarwal S, Kaushal K, et al. Presence and type of decompensation affects outcomes in autoimmune hepatitis upon treatment with corticosteroids. JGH Open. 2021 Jan. 5(1):81-90. [QxMD MEDLINE Link]. [Full Text].
Caprai S, Vajro P, Ventura A, et al. Autoimmune liver disease associated with celiac disease in childhood: a multicenter study. Clin Gastroenterol Hepatol. 2008 Jul. 6(7):803-6. [QxMD MEDLINE Link].
Mieli-Vergani G, Vergani D. Budesonide for juvenile autoimmune hepatitis? Not yet. J Pediatr. 2013 Nov. 163(5):1246-8. [QxMD MEDLINE Link]. [Full Text].
Greene MT, Whitington PF. Outcomes in pediatric autoimmune hepatitis. Curr Gastroenterol Rep. 2009 Jun. 11(3):248-51. [QxMD MEDLINE Link].
Mieli-Vergani G, Vergani D. Autoimmune hepatitis in childhood. Clin Liver Dis (Hoboken). 2014 Jan. 3(1):6-8. [QxMD MEDLINE Link]. [Full Text].
Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008 Jun 7. 14(21):3360-7. [QxMD MEDLINE Link]. [Full Text].
Marceau G, Lapierre P, Beland K, Soudeyns H, Alvarez F. LKM1 autoantibodies in chronic hepatitis C infection: a case of molecular mimicry?. Hepatology. 2005 Sep. 42(3):675-82. [QxMD MEDLINE Link]. [Full Text].
Frenzel C, Herkel J, Luth S, Galle PR, Schramm C, Lohse AW. Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis. Am J Gastroenterol. 2006 Dec. 101(12):2731-6. [QxMD MEDLINE Link].
Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology. 1993 Dec. 105(6):1824-32. [QxMD MEDLINE Link].
Hennes EM, Zeniya M, Czaja AJ, et al, for the International Autoimmune Hepatitis Group. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008 Jul. 48(1):169-76. [QxMD MEDLINE Link]. [Full Text].
Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999 Nov. 31(5):929-38. [QxMD MEDLINE Link].
Wiegard C, Schramm C, Lohse AW. Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future. Semin Liver Dis. 2009 Aug. 29(3):254-61. [QxMD MEDLINE Link].
Muratori P, Lalanne C, Barbato E, et al. Features and progression of asymptomatic autoimmune hepatitis in Italy. Clin Gastroenterol Hepatol. 2016 Jan. 14(1):139-46. [QxMD MEDLINE Link].
Manns MP, Woynarowski M, Kreisel W, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010 Oct. 139(4):1198-206. [QxMD MEDLINE Link].
Woynarowski M, Nemeth A, Baruch Y, et al, for the European Autoimmune Hepatitis-Budesonide Study Group. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr. 2013 Nov. 163(5):1347-53.e1. [QxMD MEDLINE Link].
Schoon EJ, Bollani S, Mills PR, et al, for the Matrix Study Group. Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn's disease. Clin Gastroenterol Hepatol. 2005 Feb. 3(2):113-21. [QxMD MEDLINE Link]. [Full Text].
Zachou K, Gatselis N, Papadamou G, Rigopoulou EI, Dalekos GN. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naïve patients. J Hepatol. 2011 Sep. 55(3):636-46. [QxMD MEDLINE Link].
Alvarez F, Ciocca M, Canero-Velasco C, et al. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol. 1999 Feb. 30(2):222-7. [QxMD MEDLINE Link].
Sciveres M, Caprai S, Palla G, Ughi C, Maggiore G. Effectiveness and safety of ciclosporin as therapy for autoimmune diseases of the liver in children and adolescents. Aliment Pharmacol Ther. 2004 Jan 15. 19(2):209-17. [QxMD MEDLINE Link].
Van Thiel DH, 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 May. 90(5):771-6. [QxMD MEDLINE Link].
Chazouilleres O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol. 2006 Feb. 44(2):400-6. [QxMD MEDLINE Link].
Floreani A, Rizzotto ER, Ferrara F, et al. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005 Jul. 100(7):1516-22. [QxMD MEDLINE Link].
Czaja AJ, Carpenter HA. Histological features associated with relapse after corticosteroid withdrawal in type 1 autoimmune hepatitis. Liver Int. 2003 Apr. 23(2):116-23. [QxMD MEDLINE Link].
Guirguis J, Alonso Y, Lopez R, Carey W. Well-controlled autoimmune hepatitis treatment withdrawal may be safely accomplished without liver-biopsy guidance. Gastroenterol Rep (Oxf). 2018 Nov. 6(4):284-90. [QxMD MEDLINE Link]. [Full Text].
Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med. 1995 Oct 12. 333(15):958-63. [QxMD MEDLINE Link].
Fernandes NF, Redeker AG, Vierling JM, et al. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol. 1999 Jan. 94(1):241-8. [QxMD MEDLINE Link].
Aqel BA, Machicao V, Rosser B, et al. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol. 2004 Oct. 38(9):805-9. [QxMD MEDLINE Link].
Devlin SM, Swain MG, Urbanski SJ, et al. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy. Can J Gastroenterol. 2004 May. 18(5):321-6. [QxMD MEDLINE Link].
Inductivo-Yu I, Adams A, Gish RG, et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol. 2007 Jul. 5(7):799-802. [QxMD MEDLINE Link].
Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol. 2000 Sep. 33(3):371-5. [QxMD MEDLINE Link].
Wolf DC, Bojito L, Facciuto M, Lebovics E. Mycophenolate mofetil for autoimmune hepatitis: a single practice experience. Dig Dis Sci. 2009 Nov. 54(11):2519-22. [QxMD MEDLINE Link].
Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up. J Hepatol. 2009 Jul. 51(1):156-60. [QxMD MEDLINE Link].
Than NN, Wiegard C, Weiler-Normann C, et al. Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on tacrolimus therapy. Scand J Gastroenterol. 2016 Mar. 51(3):329-36. [QxMD MEDLINE Link].
Osterman MT, Kundu R, Lichtenstein GR, et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology. 2006 Apr. 130(4):1047-53. [QxMD MEDLINE Link].
Wright HL, Bou-Abboud CF, Hassanein T, et al. Disease recurrence and rejection following liver transplantation for autoimmune chronic active liver disease. Transplantation. 1992 Jan. 53(1):136-9. [QxMD MEDLINE Link]. [Full Text].
Montano-Loza AJ, Mason AL, Ma M, Bastiampillai RJ, Bain VG, Tandon P. Risk factors for recurrence of autoimmune hepatitis after liver transplantation. Liver Transpl. 2009 Sep 29. 15(10):1254-1261. [QxMD MEDLINE Link].
Tripathi D, Neuberger J. Autoimmune hepatitis and liver transplantation: indications, results, and management of recurrent disease. Semin Liver Dis. 2009 Aug. 29(3):286-96. [QxMD MEDLINE Link].
Molmenti EP, Netto GJ, Murray NG, et al. Incidence and recurrence of autoimmune/alloimmune hepatitis in liver transplant recipients. Liver Transpl. 2002 Jun. 8(6):519-26. [QxMD MEDLINE Link]. [Full Text].
Post DJ, Douglas DD, Mulligan DC. Immunosuppression in liver transplantation. Liver Transpl. 2005 Nov. 11(11):1307-14. [QxMD MEDLINE Link]. [Full Text].
Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012 Aug 17. 61:1-32. [QxMD MEDLINE Link]. [Full Text].
Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Aetiopathogenesis of autoimmune hepatitis. J Autoimmun. 2010 Feb. 34(1):7-14. [QxMD MEDLINE Link].
Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis?. Autoimmun Rev. 2004 Jan. 3(1):61-9. [QxMD MEDLINE Link].
Wen L, Peakman M, Lobo-Yeo A, et al. T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet. 1990 Dec 22-29. 336(8730):1527-30. [QxMD MEDLINE Link].
Michitaka K, Nishiguchi S, Aoyagi Y, et al, for the Japan Etiology of Liver Cirrhosis Study Group. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 2010. 45(1):86-94. [QxMD MEDLINE Link].
Seki T, Kiyosawa K, Inoko H, et al. Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology. 1990 Dec. 12(6):1300-4. [QxMD MEDLINE Link].
Boberg KM. Prevalence and epidemiology of autoimmune hepatitis. Clin Liver Dis. 2002 Aug. 6(3):635-47. [QxMD MEDLINE Link].
McFarlane IG, Heneghan MA. Autoimmunity and the female liver. Hepatol Res. 2004 Apr. 28(4):171-6. [QxMD MEDLINE Link].
Czaja AJ. Autoimmune hepatitis and viral infection. Gastroenterol Clin North Am. 1994 Sep. 23(3):547-66. [QxMD MEDLINE Link].
Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology. 1996 Nov. 24(5):1068-73. [QxMD MEDLINE Link].
Tucker SM, Jonas MM, Perez-Atayde AR. Hyaline droplets in Kupffer cells: a novel diagnostic clue for autoimmune hepatitis. Am J Surg Pathol. 2015 Jun. 39(6):772-8. [QxMD MEDLINE Link].
Lichtenstein GR. Use of laboratory testing to guide 6-mercaptopurine/azathioprine therapy. Gastroenterology. 2004 Nov. 127(5):1558-64. [QxMD MEDLINE Link].
Czaja AJ, Lindor KD. Failure of budesonide in a pilot study of treatment-dependent autoimmune hepatitis. Gastroenterology. 2000 Nov. 119(5):1312-6. [QxMD MEDLINE Link].
Zandieh I, Krygier D, Wong V, et al. The use of budesonide in the treatment of autoimmune hepatitis in Canada. Can J Gastroenterol. 2008 Apr. 22(4):388-92. [QxMD MEDLINE Link]. [Full Text].
Faisal N, Renner EL. Recurrence of autoimmune liver diseases after liver transplantation. World J Hepatol. 2015 Dec 18. 7(29):2896-905. [QxMD MEDLINE Link].
Reich DJ, Fiel I, Guarrera JV, et al. Liver transplantation for autoimmune hepatitis. Hepatology. 2000 Oct. 32(4 Pt 1):693-700. [QxMD MEDLINE Link].
Duclos-Vallee JC, 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 Jun. 52(6):893-7. [QxMD MEDLINE Link].
Douglas D. Budesonide helpful in pediatric autoimmune hepatitis. July 10, 2013. Medscape from WebMD. Available at https://www.medscape.com/viewarticle/807623. Accessed: July 22, 2013.
[Guideline] Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol. 2019 Jan-Feb. 32(1):1-23. [QxMD MEDLINE Link]. [Full Text].
Sebode M, Hartl J, Vergani D, Lohse AW, for the International Autoimmune Hepatitis Group (IAIHG). Autoimmune hepatitis: From current knowledge and clinical practice to future research agenda. Liver Int. 2018 Jan. 38(1):15-22. [QxMD MEDLINE Link].
Vinnitskaya EV, Abdulkhakov SR, Abdurakhmanov DT, et al. Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018). Ter Arkh. 2019 Mar 17. 91(2):9-15. [QxMD MEDLINE Link].
Valota M, Thienemann F, Misselwitz B. False-positive serologies for acute hepatitis A and autoimmune hepatitis in a patient with acute Epstein-Barr virus infection. BMJ Case Rep. 2019 May 10. 12(5):[QxMD MEDLINE Link].
Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet. 1973 Apr 7. 1(7806):735-7. [QxMD MEDLINE Link].

Media Gallery

of 0

Table 1. Clinical Characteristics of Autoimmune Hepatitis ^[21]

Clinical Features	Type 1	Type 2	Type 3
Diagnostic autoantibodies	ASMA ANA Anti-actin	Anti-LKM P-450 IID6 Synthetic core motif peptides 254-271	Soluble liver-kidney antigen Cytokeratins 8 and 18
Age	10 y - elderly	Pediatric (2-14 y) Rare in adults	Adults (30-50 y)
Women (%)	78	89	90
Concurrent immune disease (%)	41	34	58
Gamma globulin elevation	+++	+	++
Low IgA	No	Occasional	No
HLA association	B8, DR3, DR4	B14, Dr3, C4AQO	Uncertain
Steroid response	+++	++	+++
Progression to cirrhosis (%)	45	82	75
ANA = antinuclear antibody; anti-LKM = anti-liver-kidney microsomal antibody; ASMA = anti-smooth muscle antibody; HLA = human leukocyte antigen; IgA = immunoglobulin A.

Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults

Absolute Indications	Relative Indications
Serum aspartate transaminase (AST) ≥10-fold the upper limit of normal (ULN)	Symptoms (eg, fatigue, arthralgia, jaundice)
Serum AST ≥5-fold the ULN and gamma-globulin level ≥2-fold the ULN	Serum AST and/or gamma-globulin less than absolute criteria
Bridging necrosis or multiacinar necrosis on histologic examination	Interface hepatitis

Table 3. Treatment Regimens for Adults

	Prednisone Only (mg/d)	Combination Therapy
	Prednisone Only (mg/d)	Prednisone (mg/d)	Azathioprine (mg/d)
Week 1	60	30	50
Week 2	40	20	50
Week 3	30	15	50
Week 4	30	15	50
Maintenance until end point	20	10	50
Reasons for preference	Cytopenia Thiopurine methyltransferase deficiency Pregnancy Malignancy Short course (≤6 months)	Postmenopausal state Osteoporosis Brittle diabetes Obesity Acne Emotional lability Hypertension

Table 4. Treatment Regimens for Children

Initial Regimen

Maintenance Regimen

End Point

Prednisone, 1-2 mg/kg/day (up to 60 mg/day), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/day

a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily

b. Azathioprine at constant dose if added initially

c. Continue daily prednisone dose with or without azathioprine, or switch to alternate day prednisone dose adjusted to response with or without azathioprine

a. Normal liver tests for 1-2 years during treatment

b. No flare during entire interval

c. Liver biopsy examination discloses no inflammation

Back to List

Author

David C Wolf, MD, FACP, FACG, AGAF, FAASLD Medical Director of Liver Transplantation, Westchester Medical Center; Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College

David C Wolf, MD, FACP, FACG, AGAF, FAASLD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Salix; Gilead; Abbvie; Intercept; Merck.

Coauthor(s)

Unnithan V Raghuraman, MD, FACG, FACP, FRCP Consulting Staff, Department of Gastroenterology, St John Medical Center

Unnithan V Raghuraman, MD, FACG, FACP, FRCP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy