Tuesday 25 May 2004
Definition: 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.
Autoimmune hepatitis (AIH) is usually a chronic portal-based hepatitis with prominent plasma cells. Although necroinflammatory activity throughout the lobule is described, centrilobular necrosis (CN) is only rarely the predominant pattern of injury.
autoimmune hepatitis type 1
- AIH type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscular (SMA) autoantibodies.
autoimmune hepatitis type 2
- AIH type 2 is characterized by liver/kidney microsomal autoantibodies (LKM).
autoimmune hepatitis type 3
- AIH type 3 may be distinguished by autoantibodies to soluble liver proteins (SLA) or the liver pancreas antigen (LP).
The autoimmune hepatitis type 2 (AIH type 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.
The autoimmune hepatitis type 1 and autoimmune hepatitis type 3 show a higher age of onset and a better long-term response to immunosuppressive treatment.
Attempts have been made to divide AIH into subtypes, depending primarily on the pattern of autoantibodies. Although useful for research purposes, these distinctions are not ideal.
Some clinical differences are seen between the subtypes, particularly in response to treatment and outcome between type 1 and type 2 AIH, but it must be appreciated that these are not distinct disease entities.
Type 1 AIH is most common. It can present at any age, is characterized by ANA, SMA, and in some cases perinuclear antineutrophil cytoplasmic antibodies (pANCA); treatment failure is rare. ANA and SMA titers of more than 1:80 are generally accepted as positive, although positive autoantibodies of uncertain clinical significance are more frequently detected in the elderly.
Type 2, which occurs in a younger age group, is associated with positive anti-liver kidney microsomal antibodies and is a more aggressive disease. Treatment failure is more frequent and relapse after drug withdrawal is almost inevitable; most of these patients need lifelong immunosuppressive therapy.
The putative type 3 autoimmune hepatitis (AIH type 3) is characterized by autoantibodies against SLA/LP (with or without ANA or SMA) and has been associated with more frequent relapse.
multifocal hepatic necrosis with bridging in the acute stage
aggressive hepatitis with mononuclear cell infiltration or macronodular cirrhosis in the late stages
chronic portal-based hepatitis with prominent plasma cells
lobular necroinflammatory activity
autoimmune active chronic hepatitis
autoimmune panlobular hepatitis
autoimmune bridging mecrosis
autoimmune massive hepatic necrosis
autoimmune hepatitis type 1 (lupoid hepatitis) (anti-smooth muscle antibody, antinuclear antibodies)
autoimmune hepatitis type 2 (LKM1-associated autoimmune hepatitis or anti-LKM1 chronic active hepatitis)
autoimmune hepatitis type 3 (soluble liver antigen, liver/pancreas antigen)
AIH is characterized by elevated serum transaminase levels reflecting hepatocyte damage with typically modest elevations in alkaline phosphatase levels.
Patients with acute presentation may have jaundice, but otherwise this is a manifestation of severe exacerbations or a feature of end-stage disease. Immunology testing reveals hypergammaglobulinemia and high-titre circulating autoantibodies indicating immune activation.
AIH has been subdivided into three main categories according to the autoantibodies detected:
Type 1 AIH, characterized by the presence of anti-smooth muscle antibodies (SMA) and/or anti-nuclear antibodies (ANA). This is the most common form.
Type 2 AIH, characterized by anti-liver kidney microsomal antibodies. This form is rare in adults.
Type 3 AIH, characterized by antibodies to soluble liver or liver-pancreas antigens.
Antibodies against cyclic citrullinated peptides (anti-CCPs) have been validated as specific diagnostic and prognostic markers of rheumatoid arthritis. Anti-CCPs have been found in 9% of patients with AIH. These patients have been reported to have a higher frequency of histological cirrhosis at presentation and to be at greater risk of dying from liver failure.
Other autoantibodies that may be found include autoantibodies to asialoglycoprotein receptor and anti-neutrophil cytoplasmic antibodies (ANCA).
Approximately 20% of patients will not have any of these autoantibodies, and they often have high immunoglobulin (IgG) and sometimes develop autoantibodies at a later stage.
- celiac disease
- primary sclerosing cholangitis
- inflammatory bowel diseases (IBDs) (9123955, 8447289)
- familial autoimmune enteropathy (7996356)
- primary biliary cirrhosis (16416210)
- autoimmune enteric leiomyositis (15948126)
primary biliary cirrhosis (PBC)
primary sclerosing cholangitis
chronic hepatitis C-immune predominant
chronic hepatitis C-immune predominant
cryptogenic chronic hepatitis
Patients presenting with chronic AIH typically have a plasma cell-rich mononuclear infiltrate mainly involving portal and periportal regions.
Plasma cells are not invariably present and a paucity of plasma cells does not therefore exclude a diagnosis of AIH.
Interface hepatitis is also a key diagnostic feature of AIH and is typically associated with ballooning and rosetting of periportal hepatocytes.
These changes lead to the development of periportal fibrosis, initially as delicate strands of immature collagen enveloping small clusters of entrapped hepatocytes.
Subsequently, there is formation of broader fibrous septa associated with bridging and nodule formation. Progression to cirrhosis occurs in 40–80% of cases.
Inflammatory activity often subsides when cirrhosis has developed, making it difficult to distinguish end-stage AIH from other causes of cirrhosis.
Varying degrees of lobular necroinflammatory activity are also commonly seen in AIH. These range from mild spotty inflammation with acidophil body formation to more severe lesions associated with confluent or bridging necrosis.
Giant cell transformation of hepatocytes is also quite common—this usually occurs to a minor degree, but in some cases is sufficiently extensive to warrant the term “giant cell hepatitis”.
Lobular necroinflammatory changes tend to be more prominent in patients with an acute presentation.
In patients presenting with fulminant hepatic failure, there are typically large areas of panacinar necrosis. Many patients with an apparently acute presentation of AIH have histological features of an underlying chronic hepatitis, including evidence of bridging fibrosis or cirrhosis.
Liver biopsy plays an important role in establishing a diagnosis of AIH. This is based both on the presence of typical features supporting a diagnosis of AIH and on the absence of atypical features (e.g., biliary abnormalities or steatosis) that might point to an alternative diagnosis.
Liver biopsy should be performed to confirm the diagnosis unless there is a good reason or contraindication.
Liver biopsy also provides valuable information about disease severity, which has implications for instigating and monitoring responses to immunosuppressive therapy. The pattern and severity of inflammatory activity at the time of presentation are predictive for subsequent progression to fibrosis and cirrhosis.
Interface hepatitis generally responds well to immunosuppression, whereas bridging necrosis more frequently progresses to fibrosis or cirrhosis.
The presence of cirrhosis at the time of presentation has also been associated with an adverse prognosis.
However, such patients frequently have ongoing inflammatory activity and still benefit from immunosuppression. Suppression of inflammatory activity is associated with reduction in fibrosis including some cases in which there appears to be reversal of an established diagnosis of cirrhosis.;
Conversely, worsening of inflammatory activity during corticosteroid therapy is associated with progression of fibrosis.
Natural history - prognosis
The seminal trials of immunosuppression in AIH were published more than 25 years ago. They revealed that untreated AIH has a poor prognosis with 5- and 10-year survival rates of 50 and 10%, respectively, whereas treatment with prednisolone is associated with excellent short- and long-term survival.
Up to 30% of adult patients have histological features of cirrhosis at diagnosis and progression of fibrosis can occur in patients with inflammatory activity despite steroid therapy.
The presence of cirrhosis at baseline significantly increases the risk of subsequent death or liver transplantation.
The risk of hepatocellular carcinoma (HCC) in autoimmune liver disease is associated with the development of cirrhosis and is no greater than in other non-viral causes of cirrhosis.
The 10-year overall survival of patients with AIH ranges between 80 and 93%.
The increasing diagnosis of AIH on routine blood testing, particularly in the elderly, has uncovered a group of patients with asymptomatic AIH who appear to have a very indolent course.
These patients are often elderly, and it is not clear what their long-term outcome is or whether they always require immunosuppressive therapy.
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