Serological markers of hepatitis B virus

HBsAg - an external component of the hepatitis B virus, appears in the blood of patients with acute hepatitis in the prodromal period of the disease, persists for about 1-4 months, disappears upon recovery. The determination of HBsAg in the blood is a sign of the persistence of the hepatitis B virus. This is observed in the uz of patients with chronic liver diseases. There may be cases of "healthy carrier" HBsAg.

HBeAg - is determined in the blood of patients with positive HbsAg, is detected in the early stages of acute hepatitis B virus soon after the appearance of HBsAg and disappears by the time of the unfolded clinical picture.

When the inflammatory process is chronicized in the liver, HBeAg is preserved together with HBsAg in the blood for a long time.

The presence of HBeAg reflects the phase of replication of the hepatitis B virus and correlates with the high activity of the inflammatory process in the liver and the contagiousness of the patient.

HBcAg - is not found in the blood, is located in the nuclei of hepatocytes. In recent years, using immunoelectronic microscopy, HBcAg has also been detected in the cytoplasm of hepatocytes in patients.

After infection with the hepatitis B virus during the immune response, antibodies to the antigens of the virus appear in the blood.

The first antibodies to HbcAg-HBcAb (HbcAgAb-dy) appear, 2-4 weeks after the appearance of HBsAg. Most of the antibodies at this time are represented by the class IgM (HBcAblgM), which persist in the serum of patients 6-9 months. The presence of HBcAblgM indicates an acute or chronic hepatitis with continued replication of the hepatitis B virus. Somewhat later, HBcAb of IgG class appears in the blood, which can be determined for many years. The detection of HBcAblgG can indicate both the transferred and fully resolved acute viral hepatitis B and the persistence of the hepatitis B virus.

Antibodies to HbeAg-HBeAb-appear approximately 2 weeks after the onset of acute viral hepatitis B and, as the concentration of HBeAg decreases, remain in the blood for 1 to 5 years or more. The appearance of HBeAb indicates the recovery of the patient or the transition of acute viral hepatitis to the chronic, with the replication of the hepatitis B virus terminated or significantly reduced, the hepatitis B virus genome integrates into the genome of the hepatocyte, which is accompanied by a decrease in the activity of the inflammatory process.

Antibodies to HBsAg - HBsAb - are detected 3-5 months after the onset of acute hepatitis B. They can be detected in the patient's blood for 5-10 years or more. The appearance of these antibodies suggests an immune resolution of the infection, but the presence of hepatitis B virus in hepatocytes is not excluded.

Some doctors believe that only these antibodies have protective properties, they provide immunity to the hepatitis B virus.

The hepatitis B virus itself does not have a direct cytopathic effect (ie the hepatocyte virus itself does not destroy), liver damage is due to a pronounced immune response of the body to the introduction into the hepatocyte of the virus.

In the life of the hepatitis B virus, two phases are distinguished: the replication phase and the integration phase.

During the replication phase, reproduction (multiplication) of the virus takes place. Hepatotropicity of the hepatitis B virus, its ability to penetrate into the hepatocyte is determined by the proteins of the outer shell of the pre-S region. On the membranes of hepatocytes there are zones of polymerized albumin corresponding to the pre-S 1 receptors.

Due to the interaction of pre-S proteins with their receptors on the surface of the hepatocyte, the virus attaches itself to the hepatocyte. In the replication phase, the DNA of the virus penetrates into the nucleus of the hepatocyte, and on it, as on the template, a nucleocapsid of the virus containing the virus DNA, HBcAg, HBeAg, and HBxAg antigens is synthesized using DNA polymerase. Antigens HBcAg and HBeAg are the main target of the immune system. Then the nucleocapsid migrates from the nucleus to the cytoplasm, where outer envelope proteins (HBsAg) are replicated and thus the complete virion is assembled. In this case, excess HBsAg, not used to assemble the virus, through the intercellular space enters the blood. Complete assembly (replication) of the virus ends with the presentation of its soluble nucleocapsid antigen - HBeAg on the hepatocyte membrane, where it "recognizes" the immunocytes. In the protection of the virus from the effects of the immune system, the secretion of HBeAg in the blood plays a huge role. It has been established that circulating HBeAg suppresses both links of immunity. Cellular immunity is inhibited by reducing the synthesis of y-interferon (it plays the most important role in the process of recognition of hepatitis B virus antigens by T lymphocytes), humoral immunity by suppressing the formation of antibodies by B lymphocytes. Thus, HBeAg is able to induce a state of immunotolerance and this slows its removal from infected hepatocytes.

Currently, the ability of the hepatitis B virus to mutations has been established. Mutations with different frequencies can occur in almost all genes of the hepatitis B virus, but most often in the region of the gene that codes for the synthesis of HBeAg. As a result of the mutation, the virus loses the ability to synthesize HBeAg and this allows the virus to get rid of the immune system and avoid elimination. Thus, it can be considered that mutation of the virus can be considered as a method of protection from the immune system and the survival (conservation) of the virus in the human body. Bonino (1994) identifies a mutated hepatitis B virus as "HBVminus HBeAg". It is often detected in the most serious liver diseases caused by the hepatitis B virus, in particular, with HbeAg-negative variant of chronic hepatitis, which has the following features:

• the absence of HBeAg in the blood in the presence of HBV replication markers;
• detection of HBV DNA in blood serum and HBcAg in hepatocytes;
• the presence of both cytoplasmic and nuclear HBV nucleocapsid antigens in infected hepatocytes;
• more severe clinical course of the disease;
• less pronounced response to interferon treatment compared to the HBeAg-positive variant of chronic hepatitis B.

Consequently, the virus type "HBV minus HBeAg" is more pathogenic than the unmutated type of HBV, possibly because of higher cytopathogenicity or greater efficacy of cytoxic T lymphocytes.

Currently, the point of view according to which "HBV minus HBeAg" is usually found in the absence of tolerance to the virus is more justified, and the populations of the unmutated ("wild") virus prevail in the presence of tolerance to it. The unrecognizability of mutant HBV causes an inferiority of the immune response, which changes the course and outcome of viral hepatitis B.

Markers of the phase of replication of the hepatitis B virus are:

• detection of HBeAg, HBcAblgM (HBcAbG / HBcAbM <1.2), viral DNA at a concentration of> 200 ng / l (determined by polymerase chain reaction), DNA polymerase and pre-S antigens (characterizing the functional activity of albumin susceptibility of receptors);
• detection of hepatocytes HBeAg and HBV-DNA.

In 7-12% of patients with chronic viral hepatitis B, a spontaneous transition of the replication phase to the non-replicative phase is possible (with HBeAg disappearing from the blood and HBeAb appearing). It is the phase of replication that determines the severity of liver damage and the contagious nature of the patient.

It has been established that the replication of the hepatitis B virus occurs not only in the liver - in hematopoietic progenitor cells (in the bone marrow); endothelium; monocytes, macrophages of the lymph nodes and spleen, endothelium of the kidney vessels; glandular epithelium and fibroblasts of the stroma of the stomach and intestines; in stromal fibroblasts of testicles; neurocytes and stromal fibroblasts of peripheral, nervous ganglia; fibroblasts of the dermis. In 1995-1996, hepatitis B virus was replicated in the tissues of the heart, lungs, brain, gonads, adrenals, thyroid and pancreas.

Extrahepatic replication of the hepatitis B virus can be the cause of the development of a variety of extrahepatic (systemic) manifestations of the disease - a chronic generalized infection.

In the integration phase, the fragment of the hepatitis B virus carrying the HBsAg gene is integrated into the hepatocyte genome (DNA), followed by the formation of predominantly HBsAg. At the same time, virus replication ceases, but the genetic apparatus of the hepatocyte continues to synthesize HBsAg in large numbers.

Viral DNA can be integrated not only in hepatocytes, but also in cells of the pancreas, salivary glands, leukocytes, spermatozoa, kidney cells.

The integration phase is accompanied by the formation of clinical and morphological remission. In this phase, in most cases, a state of immunological tolerance to the virus is formed, which leads to a reduction in the activity of the process and the carrier of HBsAg. Integration makes the virus unreachable for immune control.

Serologic markers of the integration phase:

• presence in the blood only HBsAg or in combination with HBcAblgG;
• absence of viral DNA polymerase and DNA virus in the blood;
• seroconversion of HBeAg in HBeAb (ie, disappearance of HBeAg from the blood and the appearance of HBeAb).

In recent years, it has been established that in the case of hepatitis B, the integration of the genome of the virus with the hepatocyte genome is not mandatory, but optional. The overwhelming majority of patients with acute hepatitis B it does not develop. In rare cases, chronicization of HBV infection can occur without integration with the genome of infected hepatocytes. In such patients, continuous active replication of HBV is recorded.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]