Obermayer-Straub P, Strassburg C P, Manns M P
Department of Gastroenterology and Hepatology, Hannover Medical School, Germany.
J Hepatol. 2000;32(1 Suppl):181-97. doi: 10.1016/s0168-8278(00)80425-0.
Autoimmune hepatitis (AIH) is a rare disease, characterized by female predominance, hypergammaglobulinemia, autoantibodies, association with HLA DR3 and HLA DR4 and a good response to immunosuppression. Different subtypes of AIH may be distinguished, based on differences in the autoantibody patterns. AIH type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscular (SMA) autoantibodies. AIH type 2 is characterized by liver/kidney microsomal autoantibodies (LKM). AIH type 3 may be distinguished by autoantibodies to soluble liver proteins (SLA) or the liver pancreas antigen (LP). AIH-2 affects predominantly pediatric patients and is characterized by a more severe clinical course, a higher frequency of relapse under immunosuppressive treatment and a more frequent progression to cirrhosis. In contrast, AIH types 1 and 3 show a higher age of onset and a better long-term response to immunosuppressive treatment. At present, the treatment of choice is prednisone alone or a combination with prednisone and azathioprine. Both treatment protocols show high survival rates. However, a rate of 13% of treatment failures and the failure to induce permanent remission in most patients underlines the urgent need to develop additional treatment regimens. A yet unknown genetic predisposition is believed to act as the underlying etiological factor in AIH. This genetic predisposition includes a few known risk factors such as the presence of HLA DR3 or HLA DR4, deletions of C4A alleles and female gender. Furthermore, it has to be postulated that defects in immunoregulatory genes exist. A model for such defects may be the autoimmune polyglandular syndrome type 1 (APS1), which results from the defects in a single gene, the autoimmune regulator type 1 (AIRE-1). Patients with APS1 suffer from mucocutaneous candidiasis and a number of organ-specific autoimmune diseases. Characteristic is a high variability in the number and character of the disease components in APS1, indicating that other genetic and environmental factors may strongly modulate the outcome of disease. Environmental factors may comprise chemical influences, such as nutritional compounds and drugs, or virus infections. Several drugs or chemicals were shown to induce hepatitis with autoimmune involvement, e.g. tienilic acid, dihydralazine and halothane. Adduct formation of an activated metabolite is believed to act as a trigger and to induce a specific immune response. Similarly, viruses were repeatedly shown to trigger autoimmune hepatitis. In virus infections, sequence similarities between viral and self-proteins may trigger autoimmune processes and the simultaneous presence of inflammatory cytokines during virus infection may further increase the risk of developing self-perpetuating autoimmune reactions which overshoot.
自身免疫性肝炎（AIH）是一种罕见疾病，其特征为女性居多、高球蛋白血症、自身抗体、与HLA DR3和HLA DR4相关以及对免疫抑制治疗反应良好。根据自身抗体模式的差异，可区分AIH的不同亚型。1型AIH的特征是抗核（ANA）和/或抗平滑肌（SMA）自身抗体。2型AIH的特征是肝肾微粒体自身抗体（LKM）。3型AIH可通过针对可溶性肝蛋白（SLA）或肝胰抗原（LP）的自身抗体来区分。AIH-2主要影响儿童患者，其临床病程更严重，免疫抑制治疗下复发频率更高，进展为肝硬化的情况更常见。相比之下，1型和3型AIH发病年龄较高，对免疫抑制治疗的长期反应较好。目前，治疗的选择是单独使用泼尼松或泼尼松与硫唑嘌呤联合使用。两种治疗方案的生存率都很高。然而，13%的治疗失败率以及大多数患者无法诱导永久性缓解凸显了迫切需要开发其他治疗方案。一种尚不清楚的遗传易感性被认为是AIH潜在的病因。这种遗传易感性包括一些已知的风险因素，如HLA DR3或HLA DR4的存在、C4A等位基因的缺失以及女性性别。此外，必须假定免疫调节基因存在缺陷。这种缺陷的一个模型可能是1型自身免疫性多腺体综合征（APS1），它由单个基因自身免疫调节因子1（AIRE-1）的缺陷引起。APS1患者患有皮肤黏膜念珠菌病和多种器官特异性自身免疫性疾病。APS1疾病组成部分的数量和特征具有高度变异性，这表明其他遗传和环境因素可能强烈调节疾病的结果。环境因素可能包括化学影响，如营养化合物和药物，或病毒感染。几种药物或化学物质已被证明可诱发伴有自身免疫参与的肝炎，例如替尼酸、肼屈嗪和氟烷。活化代谢产物的加合物形成被认为是触发因素，并诱导特异性免疫反应。同样，病毒多次被证明可引发自身免疫性肝炎。在病毒感染中，病毒蛋白与自身蛋白之间的序列相似性可能触发自身免疫过程，并且病毒感染期间炎症细胞因子的同时存在可能进一步增加发生过度的自我持续自身免疫反应的风险。
