Hepatology International

, Volume 13, Issue 4, pp 510–518 | Cite as

Biliary features in liver histology of children with autoimmune liver disease

  • Angelo Di GiorgioEmail author
  • A. D’Adda
  • A. Marseglia
  • A. Sonzogni
  • L. Licini
  • E. Nicastro
  • L. D’Antiga
Original Article


Objectives and study

Various degrees of biliary changes are considered to be part of the histological picture of children with pediatrics autoimmune liver disease (AILD), but the literature is scarce and confusing. We aimed to describe the characteristics of children with AILD (autoimmune hepatitis, AIH, and autoimmune sclerosing cholangitis, ASC) focusing on the prevalence and type of biliary abnormalities on initial biopsy to see whether ASC was predictable on histological ground.


The files of children diagnosed with AILD were reviewed. The Ishak score was used to grade inflammation and fibrosis on biopsy; a biliary score was built to grade bile duct injury. Demographic, laboratory and histological features at diagnosis were reported and compared between the two groups (AIH vs ASC).


Forty-one patients were diagnosed with AIH (n = 24), ASC (n = 13) and PSC (n = 4) between 2009 and 2018. Twenty-nine patients [F = 76%, AIH = 20, ASC = 9, median age at diagnosis 11.7 (range 2.2–17.8)] were included in the study; 12 (4 with PSC) were excluded. Prevalence of inflammatory bowel disease was higher in ASC group (56% vs 10% in AIH, p < 0.05). On histology 17% had cirrhosis. The grade of biliopathy with AILD was moderate in 72% and severe in 31%, and overall more prominent in ASC (p = 0.031). The inflammation of the bile ducts was classified as “multifocal” or “diffuse” mainly in ASC patients (89% vs 45% in AIH, p = 0.043). Periductular fibrosis was reported in 52% of AILD patients, with a higher mean score in ASC group (p < 0.05). However, ductular reaction, biliary metaplasia and granulomatous cholangitis were equally reported in AIH and ASC, providing no clear-cut for the distinction of the two entities in the global histological evaluation.


Majority of patients with pediatrics AILD have “moderate” or “severe” features of biliopathy; AIH and ASC are not easily distinguishable on histological ground at diagnosis, and therefore, the cholangiogram remains the only effective tool to differentiate patients with AIH from those with ASC. Further prospective studies are needed to better define histological biliary features in AILD, assess if the biliopathy responds to immunosuppressive treatment and evaluate its impact on long-term outcome.


Autoimmune hepatitis Autoimmune sclerosing cholangitis Overlap syndrome Children 



Autoimmune liver disease


Autoimmune hepatitis


Autoimmune sclerosing cholangitis


Primary sclerosing cholangitis


Primary biliary cirrhosis


Sclerosing cholangitis


Anti-nuclear antibodies


Anti-smooth muscle antibodies


Anti-liver/kidney microsomes antibodies


Anti-liver cytosol antibodies


Magnetic resonance cholangiopancreatography



We would like to acknowledge the contribution of Arianna Ghirardi for the statistical analysis carried out for this study.

Author contributions

The idea for this study originated from AG and LD’A. The manuscript was written by AG and LD’A, eventually reviewed and approved by the other authors. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript.

Compliance with ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare no conflict of interest and no financial support for this study.


  1. 1.
    Mieli-Vergani G, Vergani D. Autoimmune liver diseases in children—what is different from adulthood? Best Pract Res Clin Gastroenterol 2011;25:783–795CrossRefPubMedGoogle Scholar
  2. 2.
    Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544–553CrossRefPubMedGoogle Scholar
  3. 3.
    Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–2213CrossRefPubMedGoogle Scholar
  4. 4.
    European Association for the Study of the Liver. EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol 2015;63:971–1004CrossRefGoogle Scholar
  5. 5.
    Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, et al. Diagnosis and management of pediatric autoimmune liver disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2018;66:345–360CrossRefPubMedGoogle Scholar
  6. 6.
    Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54:374–385CrossRefPubMedGoogle Scholar
  7. 7.
    Verdonk RC, Lozano MF, van den Berg AP, et al. Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis. Liver Int 2016;36:1362–1369CrossRefPubMedGoogle Scholar
  8. 8.
    Mieli-Vergani G, Vergani D. Sclerosing cholangitis in children and adolescents. Clin Liver Dis 2016;20:99–111CrossRefPubMedGoogle Scholar
  9. 9.
    Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–678CrossRefPubMedGoogle Scholar
  10. 10.
    Jolliff CR, Cost KM, Stivrins PC, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem 1982;28:126–128PubMedGoogle Scholar
  11. 11.
    Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–176CrossRefPubMedGoogle Scholar
  12. 12.
    Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, International Autoimmune Hepatitis Group, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol 2004;41:677–683CrossRefPubMedGoogle Scholar
  13. 13.
    Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22(6):696–699CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ludwig J. Surgical pathology of the syndrome of primary sclerosing cholangitis. Am J Surg Pathol 1989;13(Suppl 1):43–49PubMedGoogle Scholar
  15. 15.
    Bateman AC, Hubscher SG. Cytokeratin expression as an aid to diagnosis in medical liver biopsies. Histopathology 2010;56:415–425CrossRefPubMedGoogle Scholar
  16. 16.
    Mieli-Vergani G, Heller S, Jara P, et al. Autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2009;49:158–164CrossRefPubMedGoogle Scholar
  17. 17.
    Jiménez-Rivera C, Ling SC, Ahmed N, Yap J, Aglipay M, Barrowman N, et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics 2015;136:1237–1248CrossRefGoogle Scholar
  18. 18.
    Di Giorgio A, Bravi M, Bonanomi E, et al. Fulminant hepatic failure of autoimmune aetiology in children. J Pediatr Gastroenterol Nutr 2015;60:159–164CrossRefPubMedGoogle Scholar
  19. 19.
    Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 1997;25:541–547CrossRefPubMedGoogle Scholar
  20. 20.
    Rodrigues AT, Liu PM, Fagundes ED, Queiroz TC, de Souza Haueisen Barbosa P, Silva SL, et al. Clinical characteristics and prognosis in children and adolescents with autoimmune hepatitis and overlap syndrome. J Pediatr Gastroenterol Nutr 2016;63:76–81CrossRefPubMedGoogle Scholar
  21. 21.
    Smolka V, Karaskova E, Tkachyk O, Aiglova K, Ehrmann J, Michalkova K, et al. Long-term follow- up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis. Hepatobiliary Pancreat Dis Int 2016;15:412–418CrossRefPubMedGoogle Scholar
  22. 22.
    Burt AD, Ferrell LD, Hübscher S. Mac Sween’s Pathology of the Liver. Philadelphia: Elsevier; 2018Google Scholar
  23. 23.
    Deneau M, Jensen MK, Holmen J, et al. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in utah children: epidemiology and natural history. Hepatology 2013;58:1392–1400CrossRefPubMedGoogle Scholar
  24. 24.
    Karakoyun M, Ecevit CO, Kilicoglu E, Aydogdu S, Yagci RV, Ozgenc F. Autoimmune hepatitis and long-term disease course in children in Turkey, a single-center experience. Eur J Gastroenterol Hepatol 2016;28:927–930CrossRefPubMedGoogle Scholar
  25. 25.
    Radhakrishnan KR, Alkhouri N, Worley S, Arrigain S, Hupertz V, Kay M, et al. Autoimmune hepatitis in children–impact of cirrhosis at presentation on natural history and long-term outcome. Dig Liver Dis 2010;42(10):724–728CrossRefPubMedGoogle Scholar
  26. 26.
    Ludwig J, Czaja AJ, Dickson ER, et al. Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology. Liver 1984;4:105–116CrossRefPubMedGoogle Scholar
  27. 27.
    Czaja AJ, Carpenter HA. Autoimmune hepatitis with incidental histologic features of bile duct injury. Hepatology 2001;34:659–665CrossRefPubMedGoogle Scholar
  28. 28.
    de Boer YS, van Nieuwkerk CMJ, Witte BI, et al. Assessment of the histopathological key features in autoimmune hepatitis. Histopathology 2015;66:351–362CrossRefPubMedGoogle Scholar
  29. 29.
    Gurung A, Assis DN, McCarty TR, Mitchell KA, Boyer JL, Jain D. Histologic features of autoimmune hepatitis: a critical appraisal. Hum Pathol 2018;82:51–60CrossRefPubMedGoogle Scholar
  30. 30.
    Balitzer D, Shafizadeh N, Peters MG, Ferrell LD, Alshak N, Kakar S. Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria. Mod Pathol 2017;30(5):773–783CrossRefPubMedGoogle Scholar
  31. 31.
    Czaja AJ. Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014;12:1430–1438CrossRefPubMedGoogle Scholar
  32. 32.
    Gouw ASH, Clouston AD, Theise ND. Ductular reactions in human liver: diversity at the interface. Hepatology 2011;54:1853–1863CrossRefPubMedGoogle Scholar
  33. 33.
    Stueck AE, Wanless IR. Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis. Hepatology 2015;61:1696–1707CrossRefPubMedGoogle Scholar
  34. 34.
    Beland K, Marceau G, Labardy A, et al. Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. Hepatology 2015;62:1511–1523CrossRefPubMedGoogle Scholar
  35. 35.
    Sogo T, Takahashi A, Inui A, Fujisawa T, Ohira H, Takikawa H, Japan AIH Study Group (JAIHSG). Clinical features of pediatric autoimmune hepatitis in Japan: a nationwide survey. Hepatol Res 2018;48:286–294CrossRefPubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  • Angelo Di Giorgio
    • 1
    Email author
  • A. D’Adda
    • 1
  • A. Marseglia
    • 1
  • A. Sonzogni
    • 2
  • L. Licini
    • 2
  • E. Nicastro
    • 1
  • L. D’Antiga
    • 1
  1. 1.Paediatric Hepatology, Gastroenterology and TransplantationHospital Papa Giovanni XXIIIBergamoItaly
  2. 2.Liver PathologyHospital Papa Giovanni XXIIIBergamoItaly

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