Autoimmune hepatitis: causes and pathogenesis

The cause of autoimmune hepatitis is unknown. Immune changes are evident. Levels of y-globulin in the serum are extremely high. Positive results of LE-cell test in about 15% of patients led to the emergence of 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, as in classical lupus in the liver, there are rarely any changes. Moreover, in the blood of patients with systemic lupus erythematosus there are no antibodies to smooth muscles and mitochondria.

In the pathogenesis of autoimmune hepatitis, immunoregulation defects, in particular, a decrease in T-suppressor function of lymphocytes and the appearance of various autoantibodies, are of great importance. These antibodies are fixed on the membrane of hepatocytes, which creates conditions for the development of antibody-dependent cytotoxic reactions damaging the liver and causing the development of immune inflammation.

Immune mechanisms and autoantibodies

Autoimmune chronic hepatitis is a disease with impaired immunoregulation, represented by a defect of suppressor (regulatory) T cells. The result of this is the production of autoantibodies to the surface antigens of the hepatocyte. It is not known whether the defect in the immune regulatory apparatus is primary or it is a consequence of the acquired changes in the antigenic tissue structure.

Mononuclear infiltration in the portal zone consists of B-lymphocytes and T-helpers with relatively rare cytotoxic / suppressor cells. This correlates with the view that antibody-dependent cytotoxicity is the main effector mechanism.

Patients have consistently high levels of circulating antibodies to the measles virus. This is probably due to the hyperfunction of the immune system, rather than the reactivation of the persistent virus.

The nature of the target antigen-target of the hepatocyte membrane is to be determined. One possible antigen, the hepatic membrane protein (LMP), appears to play a significant role in the occurrence of step necroses. Cell-mediated immunity with respect to membrane proteins has been proved. The peripheral blood T cells, activated with respect to the hepatic membranes, may be important for an autoimmune attack in chronic hepatitis.

Serum of patients reveals a large number of autoantibodies. Their role in the pathogenesis and course of the disease is unknown, but they have great diagnostic value. There is no obvious evidence 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 "mottled" pictures of imunofluorescence are equivalent. The "speckled" pattern is more common in young patients with high serum transaminase levels.

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

Antibodies to smooth muscle (actin) are present in approximately 70% of patients with autoimmune hepatitis and are found in approximately 50% of patients with PBC. In low titers, they are also detected in acute hepatitis A and B or infectious mononucleosis. Titres exceeding 1:40 are rare, except for autoimmune chronic hepatitis type I. Antibodies are classified as IgM, antigen is for the S-actin of smooth and skeletal muscles. It is also present in the cell membrane and the cytoskeleton of the hepatic cell. Consequently, the appearance of antibodies to smooth muscles can be considered as a consequence of damage to the liver cells.

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

Antimitochondrial antibodies, as a rule, are 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 the antigen only if it is represented by autologous HLA molecules on the surface of damaged hepatocytes. The interaction between HLA molecules, antigenic peptides present in the region of their bed, and T-cell receptors is decisive. Some alleles at HLA-loci indicate a predisposition of individuals to the corresponding disease. Only predisposition is inherited, and not actually a disease that can be "triggered" by an antigen.

The main histocompatibility complex (MHC) is located on the short arm of chromosome 6. The genes of MHC class I and II are highly polymorphic. Autoimmune hepatitis type I in representatives of the white race is associated with HLA-A1-B8-DR3 or with HLA-DR4. In Japanese, the disease is associated mainly with HLA-DR4. Information regarding autoimmune hepatitis type II is limited. Analysis of the hypervariable region of class II HLA showed that the representatives of the white race have the decisive role for the occurrence of autoimmune hepatitis type I lysine at position 71, while the Japanese have an important position 13.

Genes coding for complement are also polymorphic and are known as HLA class III genes. The C4A-QO allele of Class III HLA is markedly elevated for autoimmune hepatitis type I and II. In the future, HLA typing can be used to determine the predisposition to autoimmune chronic hepatitis. However, for further progress, it is essential to clarify the nature of the antigenic peptide in the HLA lymphocyte bed.

Morphological changes in the liver

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

In zone 1, cell infiltrates, mainly from lymphocytes and plasma cells, that penetrate between the hepatic cells are visible. The intensive formation of partitions isolates groups of liver cells in the form of rosettes. Fat dystrophy is absent. You can see the collapse zones. The connective tissue is introduced into the parenchyma. Cirrhosis develops rapidly, usually macronodular type. Obviously, chronic hepatitis and cirrhosis develop almost simultaneously.

Over time, the activity of the process decreases, cell infiltration and the number of step necroses decrease, fibrous tissue becomes more dense. At autopsy in far-gone cases, a picture of inactive cirrhosis is noted. However, in most cases, a thorough search makes it possible to identify step necks on the periphery of nodes and the formation of rosettes.

Although inflammation and necrosis can completely disappear during remissions and the disease remains inactive for various time intervals, regeneration is inadequate, since perilobular architectonics does not return to normal, and the damage pattern is detected at a later date.

At the onset of the disease, cirrhosis only develops in a third of patients, but usually occurs within 2 years after its debut. Repeated episodes of necrosis followed by stroma collapse and fibrosis aggravate cirrhosis. Over time, the liver becomes small and is subjected to coarse cirrhotic changes.

[1], [2], [3], [4], [5], [6], [7]