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01-04-2016 | Original Article

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

Authors: Norman Junge, Miriam Tiedau, Murielle Verboom, Michael Hallensleben, Rainer Blasczyk, Jerome Schlue, Imeke Goldschmidt, Eva-Doreen Pfister, Ulrich Baumann

Published in: European Journal of Pediatrics | Issue 4/2016

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.

Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Buschenfelde KH M z, Zeniya M (1999) International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31:929–938CrossRefPubMed

Bellomo-Brandao MA, Costa-Pinto EA, De Tommaso AM, Hessel G (2006) Clinical and biochemical features of autoimmune hepatitis in 36 pediatric patients. Arq Gastroenterol 43:45–49CrossRefPubMed

Bittencourt PL, Goldberg AC, Cancado EL, Porta G, Carrilho FJ, Farias AQ, Palacios SA, Chiarella JM, Abrantes-Lemos CP, Baggio VL, Laudanna AA, Kalil J (1999) Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol 94:1906–1913CrossRefPubMed

Bittencourt PL, Palacios SA, Cancado EL, Carrilho FJ, Porta G, Kalil J, Goldberg AC (2002) Susceptibility to primary sclerosing cholangitis in Brazil is associated with HLA-DRB1*13 but not with tumour necrosis factor alpha −308 promoter polymorphism. Gut 51:609–610CrossRefPubMedPubMedCentral

Bowlus CL, Li CS, Karlsen TH, Lie BA, Selmi C (2010) Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: unique clinical and human leukocyte antigen associations. Liver Transpl 16:1324–1330CrossRefPubMedPubMedCentral

Czaja AJ (2009) Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol 51:161–167CrossRefPubMed

Czaja AJ (2011) Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci 56:545–554CrossRefPubMed

Czaja AJ, Freese DK, American Association for the Study of Liver Disease (2002) Diagnosis and treatment of autoimmune hepatitis. Hepatology 36:479–497CrossRef

Czaja AJ, Kruger M, Santrach PJ, Moore SB, Manns MP (1997) Genetic distinctions between types 1 and 2 autoimmune hepatitis. Am J Gastroenterol 92:2197–2200PubMed

10.

Djilali-Saiah I, Fakhfakh A, Louafi H, Caillat-Zucman S, Debray D, Alvarez F (2006) HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis. J Hepatol 45:844–850CrossRefPubMed

11.

Donaldson PT (2002) Genetics in autoimmune hepatitis. Semin Liver Dis 22:353–364CrossRefPubMed

12.

Donaldson PT, Norris S (2002) Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity 35:555–564CrossRefPubMed

13.

Eberhard HP, Feldmann U, Bochtler W, Baier D, Rutt C, Schmidt AH, Muller CR (2010) Estimating unbiased haplotype frequencies from stem cell donor samples typed at heterogeneous resolutions: a practical study based on over 1 million German donors. Tissue Antigens 76:352–361CrossRefPubMed

14.

Elfaramawy AA, Elhossiny RM, Abbas AA, Aziz HM (2010) HLA-DRB1 as a risk factor in children with autoimmune hepatitis and its relation to hepatitis A infection. Ital J Pediatr 36:73CrossRefPubMedPubMedCentral

15.

Fainboim L, Canero Velasco MC, Marcos CY, Ciocca M, Roy A, Theiler G, Capucchio M, Nuncifora S, Sala L, Zelazko M (2001) Protracted, but not acute, hepatitis a virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis. Hepatology 33:1512–1517CrossRefPubMed

16.

Fainboim L, Marcos Y, Pando M, Capucchio M, Reyes GB, Galoppo C, Badia I, Remondino G, Ciocca M, Ramonet M (1994) Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype. Hum Immunol 41:146–150CrossRefPubMed

17.

Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, Mieli-Vergani G (2001) Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 33:544–553CrossRefPubMed

18.

Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, Mowat AP, Vergani D, Mieli-Vergani G (1997) Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 25:541–547CrossRefPubMed

19.

Hadzic N, Hierro L (2014) Autoimmune liver disease: novelties in management. Clin Res Hepatol Gastroenterol 38:273–276CrossRefPubMed

20.

Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22:696–699CrossRefPubMed

21.

Liberal R, Grant CR, Longhi MS, Mieli-Vergani G, Vergani D (2014) Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev 13:435–440CrossRefPubMed

22.

Maggiore G, Riva S, Sciveres M (2009) Autoimmune diseases of the liver and biliary tract and overlap syndromes in childhood. Minerva Gastroenterol Dietol 55:53–70PubMed

23.

Mieli-Vergani G, Vergani D (2011) Autoimmune liver diseases in children—what is different from adulthood? Best Pract Res Clin Gastroenterol 25:783–795CrossRefPubMed

24.

Mieli-Vergani G, Vergani D (2013) Paediatric autoimmune liver disease. Arch Dis Child

25.

Montano-Loza AJ, Carpenter HA, Czaja AJ (2007) Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 46:1138–1145CrossRefPubMed

26.

Murasko DM, Goonewardene IM (1990) T-cell function in aging: mechanisms of decline. Annu Rev Gerontol Geriatr 10:71–96PubMed

27.

Ngu JH, Gearry RB, Frampton CM, Stedman CA (2013) Predictors of poor outcome in patients with autoimmune hepatitis: a population-based study. Hepatology 57:2399–2406CrossRefPubMed

28.

Oettinger R, Brunnberg A, Gerner P, Wintermeyer P, Jenke A, Wirth S (2005) Clinical features and biochemical data of Caucasian children at diagnosis of autoimmune hepatitis. J Autoimmun 24:79–84CrossRefPubMed

29.

Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M, Ramonet M, Badia I, Daruich J, Findor J, Tanno H, Canero-Velasco C, Fainboim L (1999) Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 30:1374–1380CrossRefPubMed

30.

Roberts EA (2011) Autoimmune hepatitis from the paediatric perspective. Liver Int 31:1424–1431CrossRefPubMed

31.

Schwab R, Russo C, Weksler ME (1992) Altered major histocompatibility complex-restricted antigen recognition by T cells from elderly humans. Eur J Immunol 22:2989–2993CrossRefPubMed

32.

Spurkland A, Saarinen S, Boberg KM, Mitchell S, Broome U, Caballeria L, Ciusani E, Chapman R, Ercilla G, Fausa O, Knutsen I, Pares A, Rosina F, Olerup O, Thorsby E, Schrumpf E (1999) HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens 53:459–469CrossRefPubMed

33.

Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M (2014) Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One 9, e100565CrossRefPubMedPubMedCentral

34.

Underhill JA, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D (2002) Different immunogenetic background in autoimmune hepatitis type 1, type 2 and autoimmune sclerosing cholangitis. J Hepatol 36:156CrossRef

35.

Verboom M, Hallensleben M, Horn PA, Blasczyk R (2007) Bioinformatic integration of biomechanics makes HLA sequencing universally applicable. Tissue Antigens 70:338–339CrossRefPubMed

36.

Wang P, Su H, Underhill J, Blackmore LJ, Longhi MS, Grammatikopoulos T, Okokon EV, Davies ET, Vergani D, Mieli-Vergani G, Ma Y (2014) Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives. J Pediatr Gastroenterol Nutr 58:457–462CrossRefPubMed

37.

Wilschanski M, Chait P, Wade JA, Davis L, Corey M, St Louis P, Griffiths AM, Blendis LM, Moroz SP, Scully L (1995) Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 22:1415–1422PubMed

Title: Human leucocyte antigens and pediatric autoimmune liver disease: diagnosis and prognosis
Authors: Norman Junge
Miriam Tiedau
Murielle Verboom
Michael Hallensleben
Rainer Blasczyk
Jerome Schlue
Imeke Goldschmidt
Eva-Doreen Pfister
Ulrich Baumann
Publication date: 01-04-2016
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Pediatrics / Issue 4/2016
Print ISSN: 0340-6199
Electronic ISSN: 1432-1076
DOI: https://doi.org/10.1007/s00431-015-2662-x

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

Abstract

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Abstract

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