Chronic hepatitis B: pathogenesis

The hepatitis B virus itself is not cytopathogenic in relation to the hepatocyte. The development of the disease depends on changes occurring in the phase of virus 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 during the phase of viral replication

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

During the viral replication phase, hepatocytes undergo changes, and in some cases “mutant hepatocytes” appear, i.e. both viral and virus-induced neoantigens appear on the surface of hepatocytes.

In response to this, the body's immune response develops with damage to hepatocytes, which determines the form of chronic hepatitis.

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

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

In hepatology, the question of the main viral antigen expressed on the hepatocyte membrane and serving as a target for cytotoxic effector T lymphocytes has been long debated. Any hepatitis B virus antigen may be a candidate for this role. For a long time, HBsAg was considered such an antigen.

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

The main type of immunopathological reaction developing in relation to hepatocytes is delayed-type hypersensitivity (DTH) to HBeAg, HBcAg.

The development of one or another variant of chronic hepatitis depends on the severity of DTH, as well as on the ratio of T-lymphocyte subpopulations participating in this reaction.

Chronic persistent hepatitis (CPH) is characterized by a weak immune response of the body to hepatitis B virus antigens. In CPH, there is some decrease in the function of T-helpers, preservation of the function of T-suppressors, low sensitization of immunocytes to viral antigens and liver lipoprotein, hypofunction of T-killers, normal function of natural killers (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 specific liver lipoprotein, preserved function of T-suppressors), there is no pronounced cytolysis syndrome (the function of T-killers and NK is not increased).

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

In this case, a pronounced macrophage cellular reaction is observed, aimed at increased resorption of necrotic hepatocytes. However, complete elimination of the virus does not occur.

With CAH with high activity, extensive immune complex reactions also develop: vasculitis (venulitis, capillaritis, arteriolitis, arteritis). These vasculitis develop in various organs and tissues due to extrahepatic replication of the hepatitis B virus and immune complex damage to blood vessels. A reflection of these reactions is the development of arthritis, polymyositis, Sjogren's syndrome, myocarditis, and fibrosing alveolitis in CAH.

Thus, in CAH-B, the pathological immune response causes damage to hepatocytes (pronounced cytolysis syndrome), leads to HBV mutation (i.e. to the emergence of a mutant virus that cannot be eliminated and therefore supports the destruction of hepatocytes) and the development of immune complex pathology, which causes extrahepatic manifestations of CAH-B.

3. Expression of autoimmune mechanisms

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

The trigger for the development of autoimmune mechanisms is a deficiency of T-suppressor function, which can be a congenital (more common) or acquired defect. Deficiency of T-suppressor activity is especially common in HIABg.

In CAH-B, the most important is the development of autoimmune reactions to liver-specific lipoprotein (LSP) and liver membrane antigens. Liver-specific lipoprotein was first isolated by Meyer and Buschenfeld in 1971.

LSP is a heterogeneous material from hepatocyte membranes containing 7-8 antigenic determinants, some of which are liver-specific, others are non-specific. Normally, LSP is not accessible to lymphocytes, but becomes accessible during 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 (antinuclear, smooth muscle, mitochondria) are less common in CAH-B; they play a major role in CAH of an autoimmune nature.

Thus, in CAH-B, T-lymphocytes sensitized to viral antigens perceive hepatocytes modified by the virus with specific antigenic LSP determinants as foreign. Along with immune T-cell cytolysis of hepatocytes, autosensitization to LSP develops, which maintains 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 reason for the activation is unclear, 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 stepwise necrosis and self-progression of active hepatitis.

5. Activation of lipid peroxidation processes

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

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

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

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

Mechanisms of chronization

Progression depends on ongoing viral replication in the liver and the patient's status (especially the immune system). The virus has no direct cytopathic effect, and lysis of infected hepatocytes is determined by the host immune response. Viral persistence may be due to a specific T-cell defect that prevents recognition of HBV antigens.

Patients with established chronic hepatitis have an inadequate cell-mediated immune response to the virus. If the response is too weak, there is little or no liver damage, and the virus continues to replicate despite normal liver function. Such patients tend to be healthy carriers. They have significant amounts of HBsAg in their livers without hepatocellular necrosis. Patients with a more pronounced cell-mediated immune response develop hepatocellular necrosis, but the response is insufficient to eliminate the virus, resulting in chronic hepatitis.

Impairment of humoral and cellular immunity thus determines the outcome of hepatitis B. When there is a defect in the background of ongoing viral replication, a chronic carrier state with or without chronic hepatitis develops. This is especially important for patients with leukemia, renal failure, or organ transplant recipients, as well as for patients receiving immunosuppressive therapy, homosexuals with AIDS, and newborns.

The failure to lyse virus-infected hepatocytes is explained by various mechanisms. It may be due to 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-HBc, obtained in utero, which blocks the expression of the viral nuclear antigen on the hepatocyte membrane.

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

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

Cytokine involvement is possible. IFN-a, interleukin-1 (IL-1), and tumor necrosis factor-a (TNF-a) are produced locally in the liver during active HBV infection. This, however, may simply be a nonspecific reflection of inflammation.

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