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Human leucocyte antigens and pediatric autoimmune liver disease: diagnosis and prognosis

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Abstract

An association of human leukocyte antigen (HLA) class II alleles with autoimmune conditions is increasingly being used for diagnostic purposes. The aim of our study was to examine whether HLA class II alleles in pediatric-onset autoimmune liver disease (pAILD) may serve as diagnostic markers and if they correlate with clinical outcome parameters. HLA-DRB1 alleles of 76 children with pAILD (autoimmune hepatitis [AIH], autoimmune sclerosing cholangitis [AISC], primary sclerosing cholangitis [PSC]) and of 50 healthy blood donors as control group were analyzed retrospectively. Diagnosis of these patients was confirmed by the autoimmune hepatitis score including liver histology, which has been re-evaluated by a blinded liver pathologist, and by bile duct imaging, as appropriate. Our results showed significant association of HLA-DRB1*03 with AIH1 and AISC with 82 % specificity for AIH. For pAILD (excluding AIH2), HLA-DRB1*03 homozygosity had specificity of 98 %, whereas sensitivity is low. Remission in HLA-DRB1*03-positive patients appears to be less likely. HLA-DRB1*13 is significantly associated with PSC and also with AIH1.

Conclusion: HLA-DRB1 alleles provide supportive information for diagnostic workup in patients with liver disease, but they were not suitable for differentiation within pAILD. Their prognostic value could be helpful but needs to be evaluated further.

What is Known:

• HLA-DRB1*03 is NOT associated with pediatric AIH in a previous national study.

• In other studies, HLA-DRB1*03 is associated with AIH1.

• HLA-DRB1*13 is associated with PSC.

• HLA-DRB1*04 is described as protective for AILD.

What is New:

• HLA-DRB1 four-digit typing for all alleles and for all subgroups of pAILD combined with re-assessment of liver histology

• HLA-DRB1*03:01 is associated with pediatric AIH1 and AISC.

• HLA-DRB1*03:01 appears to be a prognostic marker.

• HLA-DRB1*13:01 is associated with pediatric AIH1 in mixed ethnicity cohort.

• HLA-DRB1*04 does not show any protective effect for pAILD.

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Abbreviations

AIH1:

Autoimmune hepatitis type 1

AIH2:

Autoimmune hepatitis type 2

AIHS:

Autoimmune hepatitis score

AILD:

Autoimmune liver disease

AISC:

Autoimmune sclerosing cholangitis

CG:

Control group

HLA:

Human leukocyte antigen

LT:

Liver transplantation

pAILD:

Pediatric-onset autoimmune liver disease

PSC:

Primary sclerosing cholangitis

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Authors’ contributions

Norman Junge: Conception and design of the study; coordination of the study; acquisition, analysis, and interpretation of data for the study; drafting the paper; final approval of the version to be published. Miriam Tiedau: Substantial contributions to the acquisition, analysis, and interpretation of data for the study; critically revising the paper for important intellectual content. Eva Pfister: Critically revising the paper for important intellectual content and final approval of the version to be published. Imeke Goldschmidt: Critically revising the paper for important intellectual content and final approval of the version to be published. Michael Hallensleben: Critically revising the paper for important intellectual content and final approval of the version to be published. Rainer Blasczyk: Critically revising the paper for important intellectual content and final approval of the version to be published. Murielle Verboom: Performing high resolution typing for HLA alleles; critically revising the paper for important intellectual content and final approval of the version to be published. Jerome Schlue: Re-evaluation of histopathology from liver biopsies and final approval of the version to be published. Ulrich Baumann: Substantial contributions to the conception and design of the work; critically revising the paper for important intellectual content and final approval of the version to be published

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Authors and Affiliations

  1. Pediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl- Neuberg-Str 1, 30625, Hannover, Niedersachsen, Germany

    Norman Junge, Miriam Tiedau, Imeke Goldschmidt, Eva-Doreen Pfister & Ulrich Baumann

  2. Institute for Transfusion Medicine, Hannover Medical School, Carl- Neuberg-Str 1, 30625, Hannover, Niedersachsen, Germany

    Murielle Verboom, Michael Hallensleben & Rainer Blasczyk

  3. Institute for Pathology, Hannover Medical School, Carl- Neuberg-Str 1, 30625, Hannover, Niedersachsen, Germany

    Jerome Schlue

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  1. Norman Junge
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Correspondence to Norman Junge.

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There are no conflicts of interest for any of the authors regarding this work. There are no sources of funding for this work.

This research was conducted as an observational study approved by local ethical committee. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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The authors declare that they have no conflict of interest.

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There was no funding source for this study

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Communicated by Peter de Winter

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Junge, N., Tiedau, M., Verboom, M. et al. Human leucocyte antigens and pediatric autoimmune liver disease: diagnosis and prognosis. Eur J Pediatr 175, 527–537 (2016). https://doi.org/10.1007/s00431-015-2662-x

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  • DOI: https://doi.org/10.1007/s00431-015-2662-x

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