Hepatitis B virus serologic markers

HBsAg is 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, and disappears during recovery. Determination of HBsAg in the blood is a sign of persistence of the hepatitis B virus. This is observed in patients with chronic liver diseases. There may be cases of "healthy carriage" of HBsAg.

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

When the inflammatory process in the liver becomes chronic, HBeAg remains together with HBsAg in the blood for a long period of time.

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

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

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

The first to appear are antibodies to HbcAg - HBcAb (НbсАgАbо-dy), already 2-4 weeks after the appearance of HBsAg. Most of the antibodies at this time are represented by the IgM class (HBcAblgM), which remain in the blood serum of patients for 6-9 months. The presence of HBcAblgM indicates acute or chronic hepatitis with ongoing replication of the hepatitis B virus. Somewhat later, HBcAb of the IgG class appear in the blood, which can be determined for many years. The detection of HBcAblgG may indicate both a past and completely 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 patient's recovery or the transition of acute viral hepatitis to chronic, while the replication of the hepatitis B virus ceases or significantly decreases, the integration of the hepatitis B virus genome into the hepatocyte genome occurs, 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 indicates immune resolution of the infection, but the presence of the hepatitis B virus in hepatocytes is not excluded.

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

The hepatitis B virus itself does not have a direct cytopathic effect (i.e. the virus itself does not destroy hepatocytes); liver damage is explained by the body's pronounced immune response to the introduction of the virus into the hepatocyte.

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

During the replication phase, the virus is reproduced (multiplied). The hepatotropism of the hepatitis B virus, its ability to penetrate the hepatocyte, is determined by the proteins of the outer membrane 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 to the hepatocyte. In the replication phase, the viral DNA penetrates the hepatocyte nucleus and on it, as on a matrix, with the help of DNA polymerase, the viral nucleocapsid is synthesized, containing the viral DNA, HBcAg, HBeAg, HBxAg antigens. The HBcAg and HBeAg antigens are the main target of the immune system. Then the nucleocapsid migrates from the nucleus to the cytoplasm, where the proteins of the outer membrane (HBsAg) are replicated and thus the complete virion is assembled. In this case, the excess HBsAg, not used for the assembly of the virus, enters the blood through the intercellular space. Complete assembly (replication) of the virus ends with the presentation of its soluble nucleocapsid antigen - HBeAg on the hepatocyte membrane, where it is "recognized" by immunocytes. Secretion of HBeAg into the blood plays a huge role in protecting the virus from the effects of the immune system. 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 a key role in the process of recognizing hepatitis B virus antigens by T-lymphocytes), humoral immunity - due to the suppression of antibody formation by B-lymphocytes. Thus, HBeAg is able to induce a state of immunotolerance and this slows down its removal from infected hepatocytes.

The ability of the hepatitis B virus to mutate has now been established. Mutations of varying frequency can occur in virtually all genes of the hepatitis B virus, but most often in the region of the gene encoding the synthesis of HBeAg. As a result of mutation, the virus loses the ability to synthesize HBeAg, and this allows the virus to escape the surveillance of the immune system and avoid elimination. Thus, it can be considered that mutation of the virus can be considered as a way to protect against the immune system and the survival (preservation) of the virus in the human body. Bonino (1994) defines the mutated hepatitis B virus as "HBV minus HBeAg". It is often detected in the most severe liver diseases caused by the hepatitis B virus, in particular, in the HbeAg-negative variant of chronic hepatitis, which has the following features:

• absence of HBeAg in the blood in the presence of HBV replication markers;
• detection of HBV DNA in 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 with HBeAg-positive chronic hepatitis B.

Therefore, the HBV minus HBeAg type virus is more pathogenic than the wild-type HBV, possibly due to higher cytopathogenicity or greater efficiency of cytotoxic T lymphocytes.

Currently, the point of view that "HBV minus HBeAg" is usually detected in the absence of tolerance to the virus is more substantiated, while populations of the unmutated ("wild") virus predominate in the presence of tolerance to it. The unrecognizability of mutant HBV causes the inadequacy of the immune response, which changes the course and outcome of viral hepatitis B.

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

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

In 7-12% of patients with chronic viral hepatitis B, a spontaneous transition of the replication phase to the non-replicative phase is possible (in this case, HBeAg disappears from the blood and HBeAb appears). It is the replication phase that determines the severity of liver damage and the contagiousness of the patient.

It has been established that hepatitis B virus replication occurs not only in the liver, but also in hematopoietic progenitor cells (in the bone marrow); endothelium; monocytes, macrophages of the lymph nodes and spleen, endothelium of the renal vessels; glandular epithelium and fibroblasts of the stomach and intestine stroma; in stromal fibroblasts of the testicles; neurocytes and stromal fibroblasts of the peripheral, nerve ganglia; fibroblasts of the dermis. In 1995-1996, hepatitis B virus replication was shown in the tissues of the heart, lungs, brain, sex glands, adrenal glands, thyroid and pancreas.

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

During the integration phase, the hepatitis B virus fragment carrying the HBsAg gene is integrated (embedded) into the genome (DNA) of the hepatocyte, with subsequent formation of predominantly HBsAg. In this case, virus replication ceases, but the genetic apparatus of the hepatocyte continues to synthesize HBsAg in large quantities.

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

The integration phase is accompanied by the establishment of clinical and morphological remission. In this phase, in most cases, a state of immunological tolerance to the virus is formed, which leads to the suppression of the process activity and the carriage of HBsAg. Integration makes the virus inaccessible to immune control.

Serological markers of the integration phase:

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

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

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