Chronic hepatitis B: pathogenesis

The hepatitis B virus itself is not cytopathogenic for hepatocyte. The development of the disease depends on the changes occurring in the phase of viral replication; the nature and severity of the immune response; the severity of autoimmune mechanisms; activation of connective tissue in the liver and processes of activation of lipid peroxidation.

1. Changes in hepatocytes. Occurring in the phase of viral replication

After the hepatitis B virus enters the bloodstream, it penetrates into the hepatocyte with the help of pre-Sl and S2 proteins, where the virus replication phase occurs, i.e. A large number of new viral particles are produced in hepatocytes.

During the replication phase of the virus, there is a change in hepatocytes, in a number of cases, "mutant hepatocytes" appear, i. Both viral and virus-induced neoantigens appear on the surface of the hepatocytes.

In response, the immune response of the organism develops with damage to hepatocytes, which determines the form of chronic hepatitis.

2. The nature and severity of the body's immune response

With chronic hepatitis of the viral etiology, immune reactions develop, the degree of expression of which largely depends on the genetic characteristics of the immune response, as well as the characteristics of the HLA system; in particular, the presence of HLA B ₈ predisposes to a more pronounced immune response.

In hepatology, there is a long discussion about the main viral antigen expressed on the hepatocyte membrane and serves as a target for cytotoxic effector T lymphocytes. The candidate for this role can be any antigen of the hepatitis B virus. For a long time, this antigen was considered HBsAg.

Currently, the main target of immune aggression in chronic viral hepatitis is HBcAg, to which the cytotoxicity of T lymphocytes and antibody-dependent cellular cytotoxicity are directed. Along with this, a huge role is played by the second HBeAg antigen, which is actually a subcomponent of HBcAg.

The main type of immunopathological reaction, developing with respect to hepatocytes, is the delayed type hypersensitivity (HRT) to HBeAg, HBcAg.

The development of this or that variant of chronic hepatitis depends on the severity of HRT, as well as on the ratio of the subpopulations of T-lymphocytes taking part in this reaction.

Chronic persistent hepatitis (HPV) is characterized by a weak immune response of the body to hepatitis B virus antigens. With CPG, there is some decrease in T-helper function, safety of T-suppressor function, low sensitivity of immunocytes to antigens of the virus and hepatic lipoprotein, hypo-function of T-killers, normal function natural killer (NK). In this case, conditions are created for the persistence of the hepatitis B virus (insufficient formation of antiviral antibodies), there are no pronounced autoimmune processes (low and transient sensitization to a specific hepatic lipoprotein, a preserved function of T suppressors), there is no pronounced cytolysis syndrome (T-killer function and NK not increased ).

In chronic active hepatitis B (XAG), there is a decrease in T-suppressor function, high sensitization of T-lymphocytes to viral antigens and liver specific lipoprotein, increased production of antibodies to them, increased function of T-killers and NK. These circumstances create conditions for the development of an active immune-inflammatory process in the liver, a marked cytolysis syndrome. With CAG with high activity, the immune response is strained, RGZT is very pronounced, significant necrosis of the hepatic tissue develops.

In this case, a pronounced macrophage cellular reaction is observed, aimed at enhanced resorption of necrotic hepatocytes. However, there is no complete elimination of the virus.

When XAG with high activity, also develop extensive immunocomplex reactions: vasculitis (venules, capillaritis, arteriolitis, arteritis). These vasculitis develop in various organs and tissues due to extrahepatic replication of the hepatitis B virus and immunocomplex vascular lesions. Reflection of these reactions is the development of arthritis, polymyositis, Sjogren's syndrome, myocarditis, fibrosing alveolitis with CAG.

Thus, with XAG-B, the pathological immune response causes damage to hepatocytes (pronounced cytolysis syndrome), leads to a mutation of HBV (i.e., a mutant virus that can not be eliminated and therefore supports the destruction of hepatocytes) and the development of an immunocomplex pathology that determines extrahepatic manifestations of XAG-B.

3. The severity of autoimmune mechanisms

Autoimmune reactions have the greatest pathological significance in chronic autoimmune hepatitis, but play a great role in chronic viral hepatitis B.

The trigger mechanism for the development of autoimmune mechanisms is a deficit of T-suppressor function, which can be a congenital (more often) or acquired defect. Especially often deficiency of T-suppressor activity takes place with HIABg.

With XAG-B, the development of autoimmune reactions to hepatic specific lipoprotein (LSP) and liver membrane antigens is most important. For the first time, hepatic specific lipoprotein was isolated by Meyer, Buschenfeld in 1971

LSP is a heterogeneous material from hepatocyte membranes containing 7-8 antigenic determinants, some of which are hepatic specific, others are non-specific. Normally LSP is not available for lymphocytes, it becomes available with cytolysis. Antibodies to LSP cause an autoimmune reaction with the development of antibody-dependent cellular cytolysis of hepatocytes.

In chronic viral liver diseases, the frequency of sensitization to LSP is in the range of 48-97%.

Other antibodies (anti-nuclear, to smooth muscles, mitochondria) with XAG-B are less common, they play a big role in autoimmune nature of XAG.

So, with XAG-B, T-lymphocytes sensitized to viral antigens perceive virus-modified hepatocytes with specific antigenic LSP determinants, like strangers. Along with immune T-cell cytolysis of hepatocytes, autosensitivity to LSP develops, which supports the inflammatory process in the liver.

4. Activation of connective tissue in the liver

In chronic hepatitis, connective tissue in the liver is activated. The cause of activation is not clear, but it is assumed that it is caused by the death of hepatocytes, liver parenchyma.

Activated connective tissue has a damaging effect on intact hepatocytes, which contributes to the development of step necrosis and self-progression of active hepatitis.

5. Activation of processes of lipid peroxidation

Lipid peroxidation (LPO) is significantly activated in chronic hepatitis B, especially in chronic autoimmune hepatitis.

As a result of LPO activation free radicals and peroxides are formed, which stimulate the processes of fibrosis in the liver and promote cytolysis of hepatocytes.

The pathogenesis of extrahepatic manifestations of chronic hepatitis B is as follows:

• replication of hepatitis B virus not only in hepatocytes, but also in peripheral mononuclears, pancreatic cells, endothelium, leukocytes and other tissues;
• microthrombosis of different localization, developing as a result of the circulation of immune complexes;
• the HBsAg-anti-HBs immune complex is of major importance as the largest. The immune complex HBeAg-anti-HBe and others have a smaller value and therefore have a less damaging effect;
• direct inhibitory effect of HBV on the function of certain organs and systems.

Chronization mechanisms

Progression depends on the continued replication of the virus in the liver and the condition of the patient (especially the immune system). The virus has no direct cytopathic effect, and the lysis of infected hepatocytes is determined by the host's immune response. The persistence of the virus may be associated with a specific defect in T cells that prevents recognition of HBV antigens.

In patients with developed chronic hepatitis, an inadequate cell-mediated immune response to the virus is detected. If the answer is too weak, then the liver damage is insignificant or it is absent, and the virus continues to replicate against the background of normal liver function. Such patients mainly become healthy carriers. In their liver, a significant amount of HBsAg is detected in the absence of hepatocellular necrosis. In patients with a more pronounced cellular-mediated immune response, hepatocellular necrosis develops, but the response is not sufficient to eliminate the virus, and as a result, chronic hepatitis develops.

Violation of humoral and cellular immunity, thus, determines the outcome of hepatitis B. When there is a defect against the background of continued replication of the virus, a state of chronic carrier with chronic hepatitis develops or without it. This is especially important for patients with leukemia, kidney failure or organ transplantation, as well as for patients receiving immunosuppressive therapy for homosexuals with AIDS and newborns.

Lack of lysis of viruses infected with hepatocytes is explained by various mechanisms. It can be associated with enhanced suppressor (regulatory) T-cell function, a defect in cytotoxic (killer) lymphocytes, or the presence of blocking antibodies on the cell membrane. In neonates, infection may be due to maternal intrauterine anti-HBs obtained in utero that block the expression of the viral nuclear antigen on the hepatocyte membrane.

Some patients who become ill with chronic hepatitis B in adulthood have a decreased ability to produce interferons (IFN), which disrupts the expression of class I HLA antigens on the hepatocyte membrane.

However, the lack of IFN-a has not been proved. Viral Ag on the hepatocyte membrane, may be HBc, HBe or HBs.

Possible involvement of cytokines. IFN-a, interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a) are locally produced in the liver with active HBV infection. This, however, can simply be a nonspecific reflection of inflammation.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]