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  • The recommendation of the European

    2019-07-08

    The recommendation of the European Association for the Study of the Liver (EASL) for the standard therapy of AIH is a glucocorticoid treatment with prednisone or prednisolone alone or in combination with azathioprine [37]. Alternative treatments include the next generation glucocorticoid budesonide [38] as well as the calcineurin inhibitors cyclosporine A and tacrolimus [12,39]. It has been reported that a combination therapy with budesonide and azathioprine resulted in fewer side effects than the conventional prednisone/azathioprine therapy in AIH patients without cirrhosis [38]. However, the EASL clinical guidelines do not recommend budesonide for patients with cirrhosis or peri-hepatic shunting, since the lack of efficient first-pass hepatic clearing of budesonide might result in undesired side effects [37]. A further alternative is the cytostatic immunosuppressant drug mycophenolate mofetil (MMF), which interferes with the purine biosynthesis and has been demonstrated to be safe and effective as first-line or rescue therapy [40]. However, the EASL clinical practice guidelines suggest using MMF mainly as a second-line therapy in cases of azathioprine-intolerance [37]. Unfortunately, long-term standard therapies with glucocorticoids and cytostatic drugs carry the risk of significant steroid-specific and azathioprine-related side effects. This is problematic since standard treatment for only a short period of time is not very effective. Adults rarely achieve resolution in less than 12 months and withdrawal of therapy after only two years of treatment results in relapses in 85% of cases [10].
    Autoimmune hepatitis: susceptibility and possible environmental triggers Just like in virtually all other autoimmune diseases the HLA haplotype is the predominant risk factor for AIH. Both AIH-1 and AIH-2 are associated with HLA-B8 (MHC class I) and HLA-DR3 [DRB1*03:01] (MHC class II). Further associations are with HLA-DR4 [DRB1*04:01] (MHC class II) for AIH-1 as well as HLA-DR7 [DRB1*07:01)] and HLA-DQ2 [DQB1*02:01] (both MHC class I) for AIH-2 [[41], [42], [43], [44], [45], [46], [47]]. Recently DRB1*03:01 and DRB1*04:01 have been confirmed as the primary and secondary susceptibility loci for AIH-1 in Dutch and German cohorts by Seladelpar wide association study (GWAS) [48]. Distinctive susceptibility variants have been reported for different ethnic groups (see [47] for a more detailed listing of HLA associations) and the HLA-haplotype seems to also influence the course of the disease in that presence of the HLA-B8 allele is associated with a more severe inflammation. Patients carrying an HLA-B8 allele are also more likely to suffer relapses after treatment. Similarly, patients with an HLA-DR3 allele display a lower frequency of remission and a higher probability for relapses [49]. In contrast, presence of an HLA-DR4 allele seems to have a somewhat protective effect, since HLA-DR4-positive patients have a higher rate of complete remissions and a lower frequency of cirrhosis [50]. Several environmental factors that might induce and/or accelerate a detrimental activation of an aggressive immune response in the liver have been suggested in the past. Such triggers include pathogen infections, drugs, alcohol, and obesity. It has been reported that about 50% (26 out of 54) of patients with non-alcoholic steatohepatitis (NASH) also carry ANA or AMA and display besides features of NASH, also histological signs of AIH or PBC, respectively [51]. However, the influence of obesity on the development of autoimmune liver disease is a matter of debate. On the one hand, a study with patients with non-alcoholic fatty liver disease (NAFLD) demonstrates that a substantial fraction of patients (23% of 225 patients) carried ANA or SMA. The majority (88%) of those ANA or SMA-positive NAFLD patients fulfilled the diagnostic criteria for AIH [52]. On the other hand, another study demonstrated the presence of ANA in 33% of 212 NAFLD patients, but only one has been also classified as definite AIH after liver biopsy [53]. To date there is no firm proof that NAFLD or NASH indeed play a role in the immunopathogenesis of human AIH, a situation that is quite similar to alcoholic liver disease and its influence on autoimmunity [54]. However, it has been shown in a mouse model for AIH (the CYP2D6 model, see section below) that pre-existing NAFLD exacerbates AIH characterized by an increased frequency of liver autoantigen-specific T cells and a higher degree of cellular infiltration and liver fibrosis [55]. Many drugs have been identified to cause acute and/or chronic damage to the liver. Whereas some drugs are toxins that cause direct cellular damage, some drugs are enzymatically converted to reactive metabolites that form protein adducts. Such modified self-proteins might cause autoimmune-mediated hepatitis with similar manifestations as AIH. However, due to their known etiology, drug-induced hepatitis, such as Halothane hepatitis [56], are classified separate from AIH [57]. The question if such drug-induced hepatitis may also break tolerance to AIH-related liver autoantigens and thereby induce or accelerate AIH has yet to be answered. In PBC however, it has been suggested that the cosmetic and food additive 2-octynoic acid (2-OA) can trigger an immune response against the main PBC autoantigen, namely the E2-subunit of the pyruvate dehydrogenase complex (PDH-E2) [58]. Patients with PBC carry autoantibodies directed against the PDH-E2 that cross-react with 2-OA [58] and immunization with a 2-OA conjugated carrier protein induces a PBC-like disease in mice [59]. The structural similarity between 2-OA and the lipoic acid moiety in PDH-E2 is a typical example of a phenomenon called ‘molecular mimicry’, in which antibodies and/or T cells cross-react to trigger and target.