Autoimmune Hepatitis: Current and Evolving Therapies
Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver. Presentation can vary from the asymptomatic individual with abnormal liver function test to fulminant liver failure. The diagnosis is based on the combination of biochemical, autoimmune, and histological parameters, and exclusion of other liver diseases. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to the standard treatment and/or have unacceptable adverse effects. This review examines the role of alternative drugs (second-line agents) available for AIH treatment non-responders. These agents include budesonide, mycophenolate mofetil, cyclosporin, tacrolimus, 6-mercaptopurine, 6-thioguanine, rituximab, ursodeoxycholic acid, rapamycin, and methotrexate. In addition, the risk of opportunistic infections and malignancies are discussed. A treatment algorithm is proposed for the management of patients with AIH treatment non-responders.
Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver that primarily targets hepatocytes. It affects all age groups. The clinical, biochemical, and histological features are heterogeneous. The exact incidence and prevalence are unknown, and earlier studies might have overestimated the prevalence of AIH before the diagnosis of hepatitis C became available. However, a recent population-based epidemiological study of AIH from Canterbury, New Zealand demonstrated an incidence of 2/100 000 and a high point prevalence of 24.5/100 000. The presentation of AIH ranges from the asymptomatic patient with abnormal liver function tests to fulminant hepatic failure. AIH is common in Caucasian females, but non-classical phenotypes have been described in other racial groups and in other patient populations. Twenty percent of patients are male; while African Americans tend to present at a younger age with cirrhosis, Japanese patients generally have milder disease. AIH has been described in elderly patients.
The symptoms of chronic AIH are often non-specific and include fatigue, lethargy, loss of appetite, pruritus, and arthralgia. Clinical examination might be completely normal, but signs of cirrhosis, such as spider nevi, jaundice, splenomegaly, or hepatic encephalopathy, might be present.
The exact pathogenesis of AIH is unknown. Genetic studies have shown that HLA DR3 and DR4 polymorphisms independently increase the susceptibility for AIH in European and North American populations, while HLA DR4 is more common in Japanese patients. HLA DR4 positive people who are HLA DR3 negative have more extrahepatic manifestations, milder disease, and are more responsive to corticosteroid therapy. The female preponderance of AIH has been linked to HLA DRB1 and B8 polymorphisms. Unidentified environmental factors, and occasionally drugs, might trigger AIH in genetically-susceptible individuals. Indeed, Th-1 to Th-2 imbalance, the activation of CD8+ cells, CD4+ cells, and defective T-regulatory cells (CD4+ and CD25+) have all been demonstrated as a process of liver injury in AIH patients.
Abstract and Introduction
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver. Presentation can vary from the asymptomatic individual with abnormal liver function test to fulminant liver failure. The diagnosis is based on the combination of biochemical, autoimmune, and histological parameters, and exclusion of other liver diseases. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to the standard treatment and/or have unacceptable adverse effects. This review examines the role of alternative drugs (second-line agents) available for AIH treatment non-responders. These agents include budesonide, mycophenolate mofetil, cyclosporin, tacrolimus, 6-mercaptopurine, 6-thioguanine, rituximab, ursodeoxycholic acid, rapamycin, and methotrexate. In addition, the risk of opportunistic infections and malignancies are discussed. A treatment algorithm is proposed for the management of patients with AIH treatment non-responders.
Introduction
Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver that primarily targets hepatocytes. It affects all age groups. The clinical, biochemical, and histological features are heterogeneous. The exact incidence and prevalence are unknown, and earlier studies might have overestimated the prevalence of AIH before the diagnosis of hepatitis C became available. However, a recent population-based epidemiological study of AIH from Canterbury, New Zealand demonstrated an incidence of 2/100 000 and a high point prevalence of 24.5/100 000. The presentation of AIH ranges from the asymptomatic patient with abnormal liver function tests to fulminant hepatic failure. AIH is common in Caucasian females, but non-classical phenotypes have been described in other racial groups and in other patient populations. Twenty percent of patients are male; while African Americans tend to present at a younger age with cirrhosis, Japanese patients generally have milder disease. AIH has been described in elderly patients.
The symptoms of chronic AIH are often non-specific and include fatigue, lethargy, loss of appetite, pruritus, and arthralgia. Clinical examination might be completely normal, but signs of cirrhosis, such as spider nevi, jaundice, splenomegaly, or hepatic encephalopathy, might be present.
The exact pathogenesis of AIH is unknown. Genetic studies have shown that HLA DR3 and DR4 polymorphisms independently increase the susceptibility for AIH in European and North American populations, while HLA DR4 is more common in Japanese patients. HLA DR4 positive people who are HLA DR3 negative have more extrahepatic manifestations, milder disease, and are more responsive to corticosteroid therapy. The female preponderance of AIH has been linked to HLA DRB1 and B8 polymorphisms. Unidentified environmental factors, and occasionally drugs, might trigger AIH in genetically-susceptible individuals. Indeed, Th-1 to Th-2 imbalance, the activation of CD8+ cells, CD4+ cells, and defective T-regulatory cells (CD4+ and CD25+) have all been demonstrated as a process of liver injury in AIH patients.
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