Autoimmune hepatitis (AIH) is a chronic, progressive liver disease caused by immune system dysregulation that targets the liver. If untreated, AIH can lead to severe complications, including cirrhosis and liver failure. First-line treatments such as immunosuppressive therapies have proven effective for most patients, but a subset remains unresponsive or intolerant to these therapies, necessitating second- and third-line options. Recent advancements in the understanding of AIH pathogenesis have paved the way for novel therapeutic strategies, offering hope to patients with difficult-to-treat forms of the disease.
Introduction
AIH manifests with elevated transaminases, hypergammaglobulinemia, and positive serum autoantibodies, alongside histological evidence of liver inflammation. The global prevalence is approximately 17.44 per 100,000 individuals, with a higher incidence in middle-aged women. AIH's etiology remains elusive, although it likely involves genetic and environmental factors. Early diagnosis and treatment are critical in preventing disease progression to more severe stages.
Indications for Treatment
AIH management guidelines across regions recommend initiating immunosuppressive treatment for patients with active disease, as defined by elevated aminotransferases, immunoglobulin G (IgG), and interface hepatitis. Close monitoring of patients with milder forms is also essential to detect worsening clinical symptoms. Treatment typically lasts at least two years post-remission, with liver biopsy recommended before discontinuation to confirm remission.
First-Line Treatments
The primary goal of AIH treatment is biochemical remission, achieved through the normalization of serum transaminases and IgG levels. Predniso(lo)ne, often combined with azathioprine (AZA), is the gold-standard first-line therapy. Recent studies suggest that low-dose steroid regimens may be as effective as higher doses, reducing the risk of steroid-induced side effects. Budesonide, a second-generation glucocorticoid, offers an alternative to predniso(lo)ne, though it is less effective and not recommended for patients with cirrhosis.
Second-Line Treatments
For patients who do not respond to or tolerate first-line therapies, second-line options like mycophenolate mofetil (MMF) and calcineurin inhibitors (CNIs) are considered. MMF is particularly effective in patients intolerant to AZA, while CNIs, such as cyclosporine A and tacrolimus, have shown promising results in achieving biochemical remission in refractory AIH cases. Additionally, purine synthesis inhibitors like 6-mercaptopurine and 6-thioguanine offer alternatives for AZA-intolerant patients.
Third-Line Treatments
Patients who fail both first- and second-line treatments may benefit from biologic therapies. Rituximab, a CD20-targeting monoclonal antibody, has demonstrated efficacy in stabilizing AIH and reducing steroid dependency. Infliximab and belimumab have also shown potential in refractory cases, although they carry risks, including infections and autoimmune-related side effects. Liver transplantation remains a viable option for AIH-related liver failure.
Emerging Therapies
Novel approaches are being explored, including treatments targeting the gut-liver axis. Gut microbiota dysbiosis has been implicated in AIH, and therapies like probiotics, fecal microbiota transplantation (FMT), and bacteriophages offer exciting potential. Additionally, new experimental drugs such as low-dose interleukin-2 (IL-2) and regulatory T cells (Tregs) are being investigated to restore immune tolerance in AIH patients.
Treatment in Special Populations
AIH in pregnant women and elderly patients poses unique challenges. Maintenance therapy with low-dose predniso(lo)ne and AZA is recommended during pregnancy to reduce relapse risk. For the elderly, treatment must balance efficacy with minimizing side effects, particularly in those with osteoporosis or diabetes. Pediatric AIH requires prompt initiation of immunosuppressive therapy to prevent long-term liver damage, and emerging therapies like JAK inhibitors show promise in genetically predisposed children.
Conclusions
The treatment landscape of AIH is rapidly evolving. While first-line therapies remain effective for most patients, ongoing research into the disease's pathogenesis is leading to the development of new, more targeted treatments. Gut microbiota-targeted therapies, biologics, and immune-modulating drugs like IL-2 and Tregs hold great potential. Tailoring treatment to individual patient needs remains essential in managing this complex and heterogeneous disease.
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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00193
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
