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Lankisch, T. O.1; Strassburg, C. P.1; Debray, D.2; Manns, M. P.1; Jacquemin, E.2

Journal of Pediatric Gastroenterology and Nutrition: June 2004 - Volume 39 - Issue - p S45
ABSTRACTS: Oral Presentation Abstracts

1Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany,2Pediatric Hepatology, CHU Bicêtre, AP-HP, Le Kremlin Bicêtre, France

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Introduction: Autoimmune hepatitis (AIH) may be associated with extrahepatic autoimmune diseases (EHAD) and is a component of autoimmune polyendocrine syndrome type 1 (APS-1). APS-1 is associated with mutations of the AIRE gene, a transcription factor and putative immune regulator which represents a candidate gene for general predisposition to autoimmunity. We have searched for AIRE mutations and characterized autoanti-bodies in 3 patients with AIH and EHAD.

Methods: Patient 1 presented with liver failure and anti LKM1 antibodies at age 3 years. Evolution was characterized by a positive response of AIH under steroids and azathioprine and appearance of endocrine disorders suggestive of APS-1. She is doing well at age 20 years. Patient 2 presented with liver failure and anti LC1 antibodies at age 6 months, not responding to immunosuppression. Liver transplantation (LT) was performed. Evolution was characterized by appearance of autoimmune enteropathy and by recurrence of immune hepatitis and of anti LC1 antibodies. Despite immunosuppressive therapy, he died at 3.5 years. Patient 3 presented with autoimmune enteropathy and anti gut antibodies at age 10 months, complicated by autoimmune nephropathy and liver failure with anti kidney and anti LKM1 antibodies responding to steroids, azathioprine and cyclosporine. He is doing well at age 13 years, unless nephropathy. The 14 exons and adjoining intronic junctions of AIRE were sequenced in all patients. Classical autoantibody screening was performed, in addition to the specific analysis of LM (CYP1A2), CYP450 SCC and CYP450 C17, which represent APS-1 related autoantibodies. Two patients with AIH type 2 but without EHAD, served as controls.

Results: Patient 1 had a homozygous deletion in exon 10, leading to a frame shift and to a stop codon at amino acid 448 (P398fsX448). Patient 2 harboured an APS-1 associated homozygous nonsense mutation in exon 6 (R257X). Patient 3 carried a heterozygous missense mutation in exon 12 (R441C), which was found in 3 out of 50 healthy blood donors and may represent AIRE polymorphism. Anti-CYP450 SCC and -CYP450 C17 were detected in patients 1 and 3, and anti-CYP1A2 was undetectable in all patients. No AIRE mutation was found in control patients.

Conclusion: These findings show that children with AIH type 2 and EHAD, may have AIRE mutations, irrespective of the full clinical picture of APS-1. In addition, AIRE single nucleotide polymorphisms may be of relevance in AIH patients with extrahepatic manifestations. AIRE analysis allows to identify APS-1 patients among AIH patients with extrahepatic disease and may predict a very severe clinical course, such as recurrence of immune hepatitis after LT.

© 2004 Lippincott Williams & Wilkins, Inc.