Autoimmune Hepatitis - Causes and Pathogenesis

The cause of autoimmune hepatitis is unknown. Immune changes are evident. Serum gamma globulin levels are extremely high. Positive LE cell test results in approximately 15% of patients led to the term "lupoid hepatitis". Tissue antibodies are found in a significant proportion of patients.

Chronic (lupoid) hepatitis and classical systemic lupus erythematosus are not identical diseases, since classical lupus rarely shows any changes in the liver. Moreover, patients with systemic lupus erythematosus do not have antibodies to smooth muscles and mitochondria in their blood.

In the pathogenesis of autoimmune hepatitis, an important role belongs to defects in immune regulation, in particular, a decrease in the T-suppressor function of lymphocytes and the appearance of various autoantibodies. These antibodies are fixed on the membrane of hepatocytes, due to which conditions are created for the development of antibody-dependent cytotoxic reactions that damage the liver and cause the development of immune inflammation.

Immune mechanisms and autoantibodies

Autoimmune chronic hepatitis is a disease with impaired immune regulation, represented by a defect in suppressor (regulatory) T cells. This results in the production of autoantibodies to hepatocyte surface antigens. It is unknown whether the defect in the immune regulatory apparatus is primary or a consequence of acquired changes in the antigen structure of tissues.

The mononuclear infiltrate in the portal zone consists of B lymphocytes and T helper cells with relatively rare cytotoxic/suppressor cells. This is consistent with the view that antibody-dependent cytotoxicity is the major effector mechanism.

Patients have persistently high levels of circulating measles virus antibodies, probably due to immune hyperfunction rather than reactivation of persistent virus.

The nature of the hepatocyte membrane target antigen remains to be elucidated. One possible antigen, liver membrane protein (LMP), appears to play a significant role in the development of stepwise necrosis. Cell-mediated immunity to membrane proteins has been demonstrated. Peripheral blood T cells activated to liver membranes may be important for the autoimmune attack in chronic hepatitis.

A large number of autoantibodies are detected in the serum of patients. Their role in the pathogenesis and course of the disease is unknown, but they have great diagnostic value. There is no obvious data in favor of the fact that antibodies to cellular antigens can independently mediate an autoimmune attack.

Antinuclear antibodies are present in the serum of approximately 80% of patients. Homogeneous (diffuse) and "speckled" immunofluorescence patterns are equivalent. The "speckled" pattern is more common in young patients with high serum transaminase levels.

The content of double-stranded DNA increases in all types of chronic hepatitis, and the highest titers are observed in patients with autoimmune hepatitis, in whom it disappears after corticosteroid therapy. This is a non-specific manifestation of inflammatory activity.

Antibodies to smooth muscles (actin) are present in approximately 70% of patients with autoimmune hepatitis and are detected in approximately 50% of patients with PBC. They are also detected in low titers in acute hepatitis A and B or infectious mononucleosis. Titers exceeding 1:40 are rarely detected, with the exception of autoimmune chronic hepatitis type I. The antibodies belong to the IgM class, the antigen is to S-actin of smooth and skeletal muscles. It is also present in the cell membrane and cytoskeleton of the liver cell. Therefore, the appearance of antibodies to smooth muscles can be considered as a consequence of liver cell damage.

Antibodies to the human asialoglycoprotein receptor. The antigen is a component of the liver-specific protein (LSP). Its presence is closely associated with inflammation and hepatitis activity.

Antimitochondrial antibodies are usually absent or their titer is very low.

Genetics

As with other autoimmune diseases, women predominate among patients (8:1). The disease can be familial.

Effector T lymphocytes recognize an antigen only if it is presented by autologous HLA molecules on the surface of damaged hepatocytes. The interaction between HLA molecules, antigenic peptides presented in their bed region, and T cell receptors is decisive. Some alleles at HLA loci indicate a predisposition of individuals to the corresponding disease. Only the predisposition is inherited, not the disease itself, which can be “triggered” by an antigen.

The major histocompatibility complex (MHC) is located on the short arm of chromosome 6. The MHC class I and II genes are highly polymorphic. Autoimmune hepatitis type I in whites is associated with HLA-A1-B8-DR3 or HLA-DR4. In the Japanese, the disease is associated mainly with HLA-DR4. Information on autoimmune hepatitis type II is limited. Analysis of the hypervariable region of HLA class II has shown that in whites, lysine at position 71 is critical for the development of autoimmune hepatitis type I, while position 13 is important in the Japanese.

The genes encoding complement are also polymorphic and are known as HLA class III genes. The C4A-QO allele of HLA class III is markedly elevated in autoimmune hepatitis types I and II. In the future, HLA typing may be used to determine susceptibility to autoimmune chronic hepatitis. However, for further progress, it is essential to elucidate the nature of the antigenic peptide in the HLA bed presented to lymphocytes.

Morphological changes in the liver

The morphological picture corresponds to severe chronic hepatitis. The activity of the process is expressed unevenly, and some areas may be practically normal.

In zone 1, cellular infiltrates are visible, mainly of lymphocytes and plasma cells, which penetrate between the liver cells. Increased septal formation isolates groups of liver cells in the form of rosettes. Fatty degeneration is absent. Collapse zones can be seen. Connective tissue is introduced into the parenchyma. Cirrhosis develops rapidly, usually of the macronodular type. Apparently, chronic hepatitis and cirrhosis develop almost simultaneously.

Over time, the activity of the process decreases, cellular infiltration and the number of step necroses decrease, and fibrous tissue becomes denser. At autopsy, in advanced cases, a picture of inactive cirrhosis is noted. However, in most cases, a thorough search allows us to identify step necrosis zones and rosette formation on the periphery of the nodes.

Although inflammation and necrosis may completely disappear during remissions and the disease remains inactive for varying periods of time, regeneration is inadequate because the perilobular architecture does not return to normal and the pattern of damage is still detectable at later stages.

At the onset of the disease, cirrhosis develops in only a third of patients, but is usually detected 2 years after its onset. Repeated episodes of necrosis followed by stromal collapse and fibrosis aggravate cirrhosis. Over time, the liver becomes small and undergoes gross cirrhotic changes.

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