Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

Boer, Ynto S. de; Gerven, Nicole M. F. van; Zwiers, Antonie; Verwer, Bart J.; Hoek, Bart van; Erpecum, Karel J. van; Beuers, Ulrich; Buuren, Henk R. van; Drenth, Joost P.H.; Ouden, Jannie W. den; Verdonk, Robert C.; Koek, Ger H.; Brouwer, Johannes T.; Guichelaar, Maureen M. J.; Vrolijk, Jan Maarten; Kraal, Georg; Mulder, Chris J.; Nieuwkerk, C.M.J. van; Fischer, Janett; Berg, Thomas; Stickel, Felix; Sarrazin, Christoph; Schramm, Christoph; Lohse, Ansgar W.; Weiler‐Normann, Christina; Lerch, Markus M.; Nauck, Matthias; Völzke, Henry; Homuth, Georg; Bloemena, Elisabeth; Verspaget, Hein W.; Kumar, Vinod; Zhernakova, Alexandra; Wijmenga, Cisca; Franke, Lude; Bouma, Gerd

doi:10.1053/j.gastro.2014.04.022

Cited by 278 publications

(231 citation statements)

References 58 publications

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“…They tended to have earlier disease onset and lower frequency of concurrent immune diseases [39] . Beyond HLA-related genes, a recent genome-wide association study in AIH verified the association of AIH-1 with variants in the MHC region, but also identified SH2B3 as the first non-HLA genetic factor for AIH and indicated that AIH-1 shares part of the genetic susceptibility with other immune-mediated diseases [40] . Its relevance to the prevalence of concurrent AIDs is as yet uncertain.…”

Section: Effects Of Aih Types Age Gender and Genetic Backgroundmentioning

confidence: 93%

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Wong

Heneghan²

2015

Dig Dis

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For many patients with autoimmune hepatitis (AIH), the presence of extrahepatic features is well recognised both at the time of presentation and during long-term follow-up. Concomitant ‘autoimmune disorders' have been described in 20-50% of patients with AIH, both in adults and children. Indeed, the presence of these associated phenomena has been incorporated into both the original and revised International AIH group scoring systems as an aid to codifying the diagnosis. In acute index presentations, non-specific joint pains sometimes flitting in nature have been reported in 10-60% of patients, and while joint swelling is uncommon, rheumatoid arthritis and mixed connective tissue disease have been reported in 2-4% of patients with AIH. For a majority of patients, these joint symptoms resolve within days of the introduction of immunosuppressive therapy. Rarer features at index presentation include a maculopapular skin rash and unexplained fever, which are features that tend to resolve quickly with treatment. Interestingly, joint pain and stiffness are also well recognised in the context of steroid withdrawal and cessation in AIH. The occasional co-presentation of AIH with coeliac disease is clinically important (1-6%), since for some patients, there is a risk of immunosuppression malabsorption, thus delaying effective treatment. Similarly, the co-existence of selective IgA deficiency (IgAD) can occur in patients with coeliac disease or in isolation. Selective IgAD as a co-existing extraheaptic feature seems to be more common in paediatric patients with AIH. For these patients, they are at an increased risk of respiratory and sinus infections. Although, typically associated with primary sclerosing cholangitis, the presence of inflammatory bowel disease (IBD; both Crohn's disease and ulcerative colitis) has been described in 2-8% of patients with AIH. Interestingly, for patients with autoimmune sclerosing cholangitis, a distinct pattern of IBD has been recently described. Other conditions have been reported at a lower frequency, including Sjogren's syndrome 1-7%, systemic lupus erythematosus 1-3% and glomerulonephritis 1%. Rarer still and at a frequency of <1% include fibrosing alveolitis, haemolytic anaemia, uveitis, mononeuritis multiplex, polymyositis and multiple sclerosis. In contrast, the reported associations between AIH and thyroiditis 8-23%, diabetes 1-10% and psoriasis 3% are commonly seen and notable in clinical practice.

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Section: Effects Of Aih Types Age Gender and Genetic Backgroundmentioning

confidence: 93%

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Wong

Heneghan²

2015

Dig Dis

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“…Hence the conflictory evidence of inflammation not resulting in fibrosis in pediatric LT versus other inflammatory hepatic diseases. In AIH, the HLA-DRB1*03/04 allele is considered an independent predictor of portal fibrosis (Montano-Loza et al, 2006;de Boer et al, 2014;Liberal et al, 2015). As AIH is the prototype of immune dysregulation-mediated hepatic disease, examining its role in LT recipients is the next logical step: we sought to evaluate "idiopathic" allograft changes by analysing serial PBs in a complication-free LT recipient cohort.…”

Section: Introductionmentioning

confidence: 99%

Progressive Fibrosis is Driven by Genetic Predisposition, Allo-Immunity, and Inflammation in Pediatric Liver Transplant Recipients

Varma

Ambroise

Komuta

et al. 2016

Journal of Clinical and Experimental Hepatology

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“…These associations have been recently confirmed in the first AIH genome-wide association study [27] . In paediatrics, AIH-1 is associated with the possession of HLA-DRB1 * 03 [3] , while susceptibility to AIH-2 is associated with HLA-DR * 03 and HLA-DR * 07 [28,29] .…”

Section: Geneticsmentioning

confidence: 61%

Paediatric Autoimmune Liver Disease

Liberal¹,

Vergani²,

Mieli‐Vergani³

2015

Dig Dis

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In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: ‘classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4^pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the bile duct damage characteristic of this condition. Since a substantial difference between these 2 pathologies is the frequent association of ASC with inflammatory bowel disease, it can be speculated that lymphocytes of intestinal origin are present in patients with a diagnosis of ASC rather than in those with AIH. Animal models faithfully representing the human conditions are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AILD is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.

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Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

Cited by 278 publications

References 58 publications

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Progressive Fibrosis is Driven by Genetic Predisposition, Allo-Immunity, and Inflammation in Pediatric Liver Transplant Recipients

Paediatric Autoimmune Liver Disease

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