Author: Leah Farquharson
Overview
Autoimmune Hepatitis (AIH) is a rare and severe chronic inflammatory liver disease (Manns et al., 2015). AIH is usually due to genetic predisposition, may be triggered by an immune response, and may start with acute hepatitis (Manns et al., 2015). Untreated, AIH can lead to end-stage liver diseases such as cirrhosis, acute liver failure, and liver transplant, and even death (Mieli-Vergani et al., 2018).
AIH can remain untreated for long periods of time because it is often asymptomatic (Sucher et al., 2019). Many patients with AIH are only diagnosed following a liver function test (Sucher et al., 2019). At the time of diagnosis, around one-third of all patients are asymptomatic and one third have severe/ advanced AIH, even cirrhosis, and around one-quarter present with acute hepatitis (Gatsoulis et al., 2015). AIH has a higher prevalence in females than males (Pape et al., 2019). AIH is prevalent globally among all age groups and races, though slightly higher incidence in the 4th and 6th decades (Gatsoulis et al., 2015).
Etiology
The exact cause of AIH is unknown (Gatsoulis et al., 2015). AIH usually is thought to occur due to an immune response to an individual’s own liver antigens, triggered when an immune response to a pathogen becomes targeted to similar self-proteins (Mieli-Vergani et al., 2018).
The antibody, anti-LKM1, targets and causes the destruction of a liver enzyme, cytochrome P450 2D6 (CYP2D6) (Mieli-Vergani et al., 2018). The autoimmune response may result from uncommitted CD4+ helper T cells (Th0) being presented with self-antigens by antigen-presenting cells, such as B cells and macrophages (Mieli-Vergani et al., 2018).
Additionally, a decrease in the number or function of regulatory T cells decreases the self-tolerance of the liver which may induce the autoimmune response (Mieli-Vergani et al., 2018). Regulatory T cells (Tregs) are the body’s main guardians against autoimmunity and self-tolerance regulators, and therefore may or may not be impaired or abnormal in individuals with AIH (Wang et al., 2020).
Tregs may be impaired or at an insufficient quantity in individuals with AIH (Wang et al., 2020). However, some patients with AIH have an increased amount of hepatic Tregs, indicating that the Tregs are impaired rather than of insufficient amount (Wang et al., 2020). Around one quarter (12-35% (Gatsoulis et al., 2015)) of AIH cases start with acute hepatitis (Manns et al., 2015).
Symptoms
Acute Hepatitis:
- Discomfort/ malaise (Gatsoulis et al, 2015),
- Abdominal (RUQ) pain (Gatsoulis et al, 2015),
- Nausea (Gatsoulis et al, 2015)
Autoimmune Hepatitis:
- Fatigue and lethargy (Gatsoulis et al., 2015),
- Pruritus (itch) (Gatsoulis et al., 2015),
- Arthralgias/ arthritis (Manns et al., 2015),
- Abdominal pain (RUQ), (Gatsoulis et al, 2015),
- Weight loss/ Anorexia ((Gatsoulis et al, 2015),
- Nausea (Gatsoulis et al, 2015),
Advanced/ Severe AIH:
- Advanced portal hypertension (Mieli-Vergani et al., 2018),
- Gastrointestinal (GI) bleeding (Mieli-Vergani et al., 2018),
- Jaundice (yellowing of eyes and skin) (Manns et al., 2015)
Risk Factors
- Genetic predisposition (Sucher et al., 2019)
- Sex (females are at increased risk) (Sucher et al., 2019)
- Viruses and other pathogens such as microbes, xenobiotics, antibiotics (nitrofurantoin, minocycline), statins, anti-TNF agents (adalimumab, infliximab), and antibiotics (Manns et al., 2015; Gatsoulis et al., 2015)
Diagnosis
Clinical Features
Many cases of AIH are asymptomatic and only diagnosed when the patient undergoes a liver function test (Sucher et al., 2019). In mild to moderate cases, patients may present with abdominal pain (specifically right upper quadrant), nausea, and weight loss (Gatsoulis et al, 2015).
The most common symptom in patients with AIH is fatigue, which is often accompanied by lethargy (Manns et al., 2015). Some patients also experience joint pain (Manns et al., 2015). In severe cases, individuals may present with acute liver failure, jaundice, GI bleeding and abdominal pain, and advanced portal hypertension (Mieli-Vergani et al., 2018). In severe cases, patients may have progressed to the cirrhotic stage of the disease (Pape et al., 2019).
Diagnosis is confirmed based on circulating levels of immunoglobulin (IgG), transaminase and autoantibodies levels as well as liver function tests (Mieli-Vergani et al., 2018; Manns et al., 2015; Sucher et al., 2019).
Pathological Features
Patients with AIH often have hypergammaglobulinemia: increased levels of G immunoglobulins (IgG), circulating antibodies, and distinctive histology (Pape et al., 2019). Individuals have increased transaminase levels and prevalence of circulating autoantibodies, such as antinuclear antibodies, which react in both hepatic and other tissues (Mieli-Vergani et al., 2018). CD163, a protein produced during macrophage activation, is seen at elevated levels during active stages of AIH and normal when the patient is in complete remission (Mieli-Vergani et al., 2018).
Patients may have decreased Treg count compared to the average (Mieli-Vergani et al., 2018). Untreated individuals with AIH may see a higher frequency of circulating Tregs, and this may be due to a decrease in IL-2 levels (Wang et al., 2020). Patients with acute hepatitis may have elevated bilirubin levels (Manns et al., 2015).
Treatment
Treatment is recommended in almost all cases unless AIH is very mild and the patient has many comorbidities (Pape et al., 2019).
Pharmaceutical Treatment
Due to the autoimmune nature of AIH, the main treatment is the use of immunosuppressants (Mieli-Vergani et al., 2018). Immunosuppressive treatment should commence immediately following the individual’s diagnosis to ensure increased effectiveness and should be continued for two years after transaminase levels and IgG levels are normalized (Mieli-Vergani et al., 2018; Pape et al., 2019).
Pharmaceutical therapies include corticosteroids and azathioprine, either alone or in combination (Mieli-Vergani et al., 2018). Patients are considered in complete remission once transaminase levels are normalized (Mieli-Vergani et al., 2018). Following drug withdrawal, patients’ liver enzymes, transaminase levels, and IgG levels should be monitored closely (Pape et al., 2019).
For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic targeting of rapamycin (mTOR) inhibitors, and biologic agents, which should be administered only in specialized hepatology centers (Mieli-Vergani et al., 2018).
Relapse may be incited by the rapid decrease of Tregs during therapy (Wang et al., 2020). Low-dose IL-2 can be recommended for individuals with AIH type two to help increase Tregs (Wang et al., 2020). Blocking Th17 can convert Tregs into a more suppressive phenotype, and therefore may be recommended during treatment (Wang et al., 2020). Antigen-specific Treg generation may also be an effective therapy for individuals with AIH (Wang et al., 2020).
Treg therapy and therapies targeting Tregs are emerging treatments for AIH and other autoimmune diseases (Wang et al., 2020).
Non-Pharmaceutical Treatment
Patients with severe and progressed liver disease should be treated in collaboration with a transplantation center (Pape et al., 2019). Liver transplantation may also be a lifesaving treatment option, especially for individuals with severe liver disease (Mieli-Vergani et al., 2018). However, an individual may develop AIH again following transplantation (Mieli-Vergani et al., 2018).
Articles on Misdiagnosis
Calisti, G., Irish, D.N., Ijaz, S., Tedder, R.S., & M. Kevin. (2017). Acute hepatitis E mimicking a flare disease in a patient with chronic autoimmune hepatitis. Annals of Hepatology, 16(1), 160-163. DOI: 10.5604/16652681.1226952.
Jiang, W., Wu, D., Fu, S., Ran, S., & T. Zhou. (2020). Autoimmune hepatitis mimicking drug-induced liver injury: a case report and review of the literature. International Journal of Clinical and Experimental Medicine, 13(8), 6176-6181.
Pijak, M.R., & V. Csibova. (2012). 354 Autoimmune hepatitis misdiagnosed as hepatitis c responding to interferon/ribavirine therapy. World Allergy Organization Journal, 5(2), S130-S131. DOI: 10.1097/01.WOX.0000412117.18651.08.
References
Gatsoulis, N. K., Zachou, K., Koukoulis, G. K., & Dalekos, G. N. (2015). Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics. World journal of gastroenterology, 21(1), 60–83. DOI: 10.3748/wjg.v21.i1.60.
Manns, M. P., Lohse, A. W., & Vergani, D. (2015). Autoimmune hepatitis–Update 2015. Journal of hepatology, 62(1 Suppl), S100–S111. DOI: 10.1016/j.jhep.2015.03.005.
Mieli-Vergani, G., Vergani, D., Czaja, A. J., Manns, M. P., Krawitt, E. L., Vierling, J. M., Lohse, A. W., & Montano-Loza, A. J. (2018). Autoimmune hepatitis. Nature reviews. Disease primers, 4, 18017. DOI: 10.1038/nrdp.2018.17.
Pape, S., Schramm, C., & Gevers, T. J. (2019). Clinical management of autoimmune hepatitis. United European gastroenterology journal, 7(9), 1156–1163. DOI: 10.1177/2050640619872408.
Sucher, E., Sucher, R., Gradistanac, T., Brandacher, G., Schneeberger, S., & Berg, T. (2019). Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. Journal of immunology research, 2019, 9437043. DOI: 10.1155/2019/9437043.
Wang, H., Feng, X., Yan, W., & Tian, D. (2020). Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.575572
