The diagnosis of autoimmune hepatitis (AIH) is based on a combination of biochemical, immunological and histological features and exclusion of other causes of liver disease. Typical histological features include a chronic hepatitis pattern of injury with portal inflammation and interface activity, predominance of plasma cells in the portal infiltrate, emperipolesis, and hepatocellular rosette formation. Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation is now recognised in the histological spectrum of AIH and may represent an early stage of the disease. Liver histology plays a major role in clinical diagnostic scoring systems and is important to confirm or support the clinical diagnosis of AIH. This review focuses on the role of histopathology in AIH and highlights the contribution of histological interpretation to the diagnosis of AIH, differential diagnosis from other entities, recognition of concurrent liver disease, and identification of the so-called overlap or variant syndromes, and addresses the importance of liver biopsy in the management and prognosis of patients with AIH.

Keywords:
Autoimmune hepatitis, Autoimmune liver disease, Diagnosis, Histopathology, Liver biopsy
1.
Guindi M: Histology of autoimmune hepatitis and its variants. Clin Liver Dis 2010;14:577-590.
2.
Schiano TD, Fiel MI: To b(iopsy) or not to b(iopsy). Clin Gastroenterol Hepatol 2011;9:3-4.
3.
Washington MK, Manns MP: Autoimmune hepatitis; in Burt AD, Portmann B, Ferrel L (eds): MacSween's Pathology of the Liver. Edinburgh, Churchill Livingstone, 2012, pp 467-490.
4.
Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al: International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929-938.
5.
Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW; International Autoimmune Hepatitis Group: Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169-176.
6.
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM; American Association for the Study of Liver Diseases: Diagnosis and management of autoimmune hepatitis. Hepatology 2010:51;2193-2213.
7.
Manns MP, Lohse AW, Vergani D: Autoimmune hepatitis - update 2015. J Hepatol 2015;62(1 suppl):S100-S111.
8.
Weiler-Normann C, Lohse AW: Acute autoimmune hepatitis: many open questions. J Hepatol 2014;61:727-729.
9.
Gleeson D, Heneghan MA; British Society of Gastroenterology: British society of gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut 2011;60:1611-1629. 9a EASL: EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol 2015;63:971-1004.
10.
Czaja AJ: Comparability of probable and definite autoimmune hepatitis by international diagnostic scoring criteria. Gastroenterology 2011;140:1472-1480.
11.
Björnsson E, Talwalkar J, Treeprasertsuk S, Neuhauser M, Lindor K: Patients with typical laboratory features of autoimmune hepatitis rarely need a liver biopsy for diagnosis. Clin Gastroenterol Hepatol 2011;9:57-63.
12.
Czaja AJ: Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013;38:343-364.
13.
de Boer YS, van Nieuwkerk CM, Witte BI, Mulder CJ, Bouma G, Bloemena E: Assessment of the histopathological key features in autoimmune hepatitis. Histopathology 2015;66:351-362.
14.
Abe K, Takahashi A, Nozawa Y, Imaizumi H, Hayashi M, Okai K, Kanno Y, Watanabe H, Ohira H: The utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of autoimmune liver diseases. Med Mol Morphol 2014;47:162-168.
15.
Miao Q, Bian Z, Tang R, Zhang H, Wang Q, Huang S, Xiao X, Shen L, Qiu D, Krawitt EL, Gershwin ME, Ma X: Emperipolesis mediated by CD8 T cells is a characteristic histopathologic feature of autoimmune hepatitis. Clin Rev Allergy Immunol 2015;48:226-235.
16.
Benseler V, Warren A, Vo M, Holz LE, Tay SS, Le Couteur DG, Breen E, Allison AC, van Rooijen N, McGuffog C, Schlitt HJ, Bowen DG, McCaughan GW, Bertolino P: Hepatocyte entry leads to degradation of autoreactive CD8 T cells. Proc Natl Acad Sci U S A 2011;108:16735-16740.
17.
Kumari N, Kathuria R, Srivastav A, Krishnani N, Poddar U, Yachha SK: Significance of histopathological features in differentiating autoimmune liver disease from nonautoimmune chronic liver disease in children. Eur J Gastroenterol Hepatol 2013;25:333-337.
18.
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;59:246-249.
19.
Miyake Y, Iwasaki Y, Terada R, Onishi T, Okamoto R, Takaguchi K, Ikeda H, Makino Y, Kobashi H, Sakaguchi K, Shiratori Y: Clinical features of Japanese type 1 autoimmune hepatitis patients with zone III necrosis. Hepatol Res 2007;37:801-805.
20.
Czaja AJ: Challenges in the diagnosis and management of autoimmune hepatitis. Can J Gastroenterol 2013;27:531-539.
21.
Gaya DR, Thorburn D, Oien KA, Morris AJ, Stanley AJ: Hepatic granulomas: a 10 year single centre experience. J Clin Pathol 2003;56:850-853.
22.
Bihari C, Rastogi A, Sarin SK: Postinfantile giant cell hepatitis: an etiological and prognostic perspective. Hepat Res Treat 2013;2013:601290.
23.
Czaja AJ: Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis Sci 2013;58:897-914.
24.
Fujiwara K, Fukuda Y, Yokosuka O: Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute-onset autoimmune hepatitis. J Gastroenterol 2008;43:951-958.
25.
Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, Manns MP, Norman GL, Lee WM; Acute Liver Failure Study Group: Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011;53:517-526.
26.
Yasui S, Fujiwara K, Yonemitsu Y, Oda S, Nakano M, Yokosuka O: Clinicopathological features of severe and fulminant forms of autoimmune hepatitis. J Gastroenterol 2011;46:378-390.
27.
Bernal W, Lee WM, Wendon J, Larsen FS, Williams R: Acute liver failure: a curable disease by 2024? J Hepatol 2015;62(1 suppl):S112-S120.
28.
Lee WM: Etiologies of acute liver failure. Semin Liver Dis 2008;28:142-152.
29.
Ngu JH, Gearry RB, Frampton CM, Stedman CA: Predictors of poor outcome in patients with autoimmune hepatitis: a population-based study. Hepatology 2013;57:2399-2406.
30.
Grønbæk L, Vilstrup H, Jepsen P: Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J Hepatol 2014;60:612-617.
31.
Czaja AJ: Cryptogenic chronic hepatitis and its changing guise in adults. Dig Dis Sci 2011;56:3421-3438.
32.
Werner M, Wallerstedt S, Lindgren S, Almer S, Björnsson E, Bergquist A, Prytz H, Sandberg-Gertzén H, Hultcrantz R, Sangfelt P, Weiland O, Ohlsson B, Danielsson A: Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response. Scand J Gastroenterol 2010;45:457-467.
33.
Romanque P, Stickel F, Dufour JF: Disproportionally high results of transient elastography in patients with autoimmune hepatitis. Liver Int 2008;28:177-178.
34.
Czaja AJ: Hepatocellular carcinoma and other malignancies in autoimmune hepatitis. Dig Dis Sci 2013;58:1459-1476.
35.
Danielsson Borssén Å, Almer S, Prytz H, Wallerstedt S, Friis-Liby IL, Bergquist A, et al: Hepatocellular and extrahepatic cancer in patients with autoimmune hepatitis - a long-term follow-up study in 634 Swedish patients. Scand J Gastroenterol 2015;50:217-223.
36.
Couto CA, Bittencourt PL, Porta G, Abrantes-Lemos CP, Carrilho FJ, Guardia BD, Cançado EL: Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis. Hepatology 2014;59:592-600.
37.
Serpaggi J, Carnot F, Nalpas P, Canioni D, Guéchot J, Lebray P, Vallet-Pichard A, Fontaine H, Bedossa P, Pol S: Direct and indirect evidence for the reversibility of cirrhosis. Hum Pathol 2006;37:1519-1526.
38.
Czaja AJ: Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014;39:385-406.
39.
Czaja AJ: Autoantibody-negative autoimmune hepatitis. Dig Dis Sci 2012;57:610-624.
40.
O'Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ: Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology 2008;48:550-556.
41.
Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417.
42.
Scheuer PJ: Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991;13:372-374.
43.
Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR cooperative study group. Hepatology 1994;20:15-20.
44.
Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN, et al: Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-699.
45.
deLemos AS, Foureau DM, Jacobs C, Ahrens W, Russo MW, Bonkovsky HL: Drug-induced liver injury with autoimmune features. Semin Liver Dis 2014;34:194-204.
46.
Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Björnsson E: The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology 2011;54:931-939.
47.
Tsuneyama K, Baba H, Kikuchi K, Nishida T, Nomoto K, Hayashi S, Miwa S, Nakajima T, Nakanishi Y, Masuda S, Terada M, Imura J, Selmi C: Autoimmune features in metabolic liver disease: a single-center experience and review of the literature. Clin Rev Allergy Immunol 2013;45:143-148.
48.
Efe C, Ozaslan E, Purnak T, Ozseker B, Kav T, Bayraktar Y: Liver biopsy is a superior diagnostic method in some patients showing the typical laboratory features of autoimmune hepatitis. Clin Res Hepatol Gastroenterol 2012;36:185-188.
49.
Pischke S, Gisa A, Suneetha PV, Wiegand SB, Taubert R, Schlue J, Wursthorn K, Bantel H, Raupach R, Bremer B, Zacher BJ, Schmidt RE, Manns MP, Rifai K, Witte T, Wedemeyer H: Increased HEV seroprevalence in patients with autoimmune hepatitis. PLoS One 2014;9:e85330.
50.
Vergani D, Mieli-Vergani G: Autoimmune manifestations in viral hepatitis. Semin Immunopathol 2013;35:73-85.
51.
Efe C, Wahlin S, Ozaslan E, Purnak T, Muratori L, Quarneti C, et al: Diagnostic difficulties, therapeutic strategies, and performance of scoring systems in patients with autoimmune hepatitis and concurrent hepatitis B/C. Scand J Gastroenterol 2013;48:504-508.
52.
Rigopoulou EI, Zachou K, Gatselis N, Koukoulis GK, Dalekos GN: Autoimmune hepatitis in patients with chronic HBV and HCV infections: patterns of clinical characteristics, disease progression and outcome. Ann Hepatol 2014;13:127-135.
53.
Burt AD, Lackner C, Tiniakos D: Diagnosis and assessment of NAFLD: definitions and histopathological classification. Semin Liv Dis 2015, in press.
54.
Yener S, Akarsu M, Karacanci C, Sengul B, Topalak O, Biberoglu K, Akpinar H: Wilson's disease with coexisting autoimmune hepatitis. J Gastroenterol Hepatol 2004;19:114-116.
55.
Höhler T, Leininger S, Köhler HH, Schirmacher P, Galle PR: Heterozygosity for the hemochromatosis gene in liver diseases - prevalence and effects on liver histology. Liver 2000;20:482-486.
56.
Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E; International Autoimmune Hepatitis Group: Overlap syndromes: the international autoimmune hepatitis group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54:374-385.
57.
Efe C, Ozaslan E, Heurgué-Berlot A, Kav T, Masi C, Purnak T, et al: Sequential presentation of primary biliary cirrhosis and autoimmune hepatitis. Eur J Gastroenterol Hepatol 2014;26:532-537.
58.
Kobayashi M, Kakuda Y, Harada K, Sato Y, Sasaki M, Ikeda H, et al: Clinicopathological study of primary biliary cirrhosis with interface hepatitis compared to autoimmune hepatitis. World J Gastroenterol 2014;20:3597-3608.
59.
Czaja AJ: Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci 2012;57:1996-2010.
60.
van Gerven NM, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ, van Erpecum KJ, et al; Dutch Autoimmune Hepatitis Working Group: Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J Hepatol 2013;58:141-147.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.