Lecture Notes: Classification of Autoimmune Hepatitis

Autoimmune hepatitis is a chronic hepatitis of unknown etiology, which can progress to cirrhosis. It is characterized by autoimmune features, hyperglobulinemia and the presence of circulating autoantibodies. Most cases respond to therapy with immunomodulating drugs.

Since it was first described in the 1950s, this disorder has been known by a variety of terms, including active chronic hepatitis, chronic active hepatitis, chronic aggressive hepatitis, lupoid hepatitis, plasma cell hepatitis, and, most commonly, autoimmune chronic active hepatitis. In 1992, the International Autoimmune Hepatitis Group recommended autoimmune hepatitis as the most appropriate and least redundant term for this disease.

Autoimmune hepatitis is characterized by considerable heterogeneity, as illustrated by the variety of clinical features, histologic findings, immunogenetic phenotypes, and circulating autoantibodies. Since the discovery of a distinct form of autoimmune hepatitis seen primarily in children and young adults that is generally characterized by antibodies to a specific cytochrome P450 (IID6) located in liver and kidney microsomes, a classification of autoimmune hepatitis based upon circulating autoantibodies has been proposed.

Although extensions of this autoantibody-based classification have been proposed from time to time, none has proven to provide a valid, clinically useful classification for predicting disease course or response to treatment. In addition, there is little evidence to support a role for these antibodies in the pathogenesis of this disorder.

The current classification of autoimmune hepatitis according to the type of autoantibodies present are:
  • Type 1 (classic)
    • Antinuclear
    • Anti-smooth muscle
    • Anti-actin
    • Anti-soluble liver/ liver pancreas antigen (Anti-SLA/LP)
    • Atypical pANCA
    • Antimitochondrial
  • Type 2
    • Anti-LKM-1
    • Anti-liver cytosol -1 (Anti-LC1)
    • Anti-soluble liver/liver pancreas antigen (Anti-SLA/LP)

Type 1 autoimmune hepatitis 
Type 1, or classic autoimmune hepatitis, is characterized by circulating antibodies to nuclei (ANA) and/or smooth muscle (ASMA); the latter are thought to be reflective of more specific antiactin antibodies (AAA). ASMA titers of 1:320 or greater almost always reflect the presence of AAA. IgG anti F actin AAA measured by ELISA appear to be more sensitive than ASMA measured by immunofluorescence.

In addition, antibodies to soluble liver antigens (SLA) occur in approximately 10 to 30 percent of patients with type 1 and type 2 autoimmune hepatitis. When SLA antibodies were first described, they were incorrectly thought to represent a distinct third form of autoimmune hepatitis. However, it now appears that a variety of antibodies appear in the two major forms of the disease, but SLA antibodies are the most specific.

Other antibodies described in type 1 autoimmune hepatitis include those directed against DNA (including double-stranded DNA), Saccharomyces cerevisiae (ASCA), a plasma-membrane sulfatide, the nuclear envelope proteins lamins A and C, a number of cytoskeleton antigens, and antineutrophil cytoplasmic antibodies (ANCA), which characterize primary sclerosing cholangitis and inflammatory bowel disease. ANCA are commonly present in type 1 but not type 2 autoimmune hepatitis; they have a P-ANCA pattern on immunofluorescence, and are directed against a myeloid 50 kilodalton nuclear envelope protein rather than myeloperoxidase with typical ANCA. On occasion, they appear as isolated antibodies.

Circulating antibodies against the liver-specific asialoglycoprotein receptor are found in a large percentage of European, Asian, and North American patients with autoimmune hepatitis. At present, these antibodies serve primarily as a research tool.

On occasion, antimitochondrial antibodies (AMA), which are generally seen in primary biliary cirrhosis, accompany ANA, SLA, and/or ASMA in autoimmune hepatitis. In contrast, the isolated presence of AMA almost always signifies primary biliary cirrhosis, except in those rare instances in which an overlap syndrome occurs.

Type 2 autoimmune hepatitis 
Type 2 autoimmune hepatitis is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1), which are directed at an epitope of CYP2D6 (cytochrome P450IID6), and/or antibodies to a liver cytosol antigen (ALC-1 or LC1) and to SLA. On occasion, type 2 autoimmune hepatitis may be marked exclusively by ALC-1.

ALKM-2 antibodies, seen in ticrynafen-induced hepatitis, and ALKM-3 antibodies, seen in chronic delta hepatitis, are not characteristic of type 2 autoimmune hepatitis.

References: UTD

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