Pathogenesis of hepatitis B

In the pathogenesis of hepatitis B, several leading links of the pathogenetic chain can be distinguished:

• introduction of the pathogen - infection;
• fixation on the hepatocyte and penetration into the cell;
• multiplication of the virus and "pushing" it onto the surface of the hepatocyte, and also into the blood;
• inclusion of immunological reactions aimed at eliminating the pathogen;
• immunocomplex lesion of organs and systems;
• formation of immunity, release from the pathogen, recovery.

Since infection with hepatitis B always occurs parenterally, we can assume that the moment of infection is almost equivalent to the penetration of the virus into the blood. Attempts of some researchers to isolate in hepatitis B enteral and regional phase are poorly grounded. There are more reasons to believe that with the bloodstream, the virus immediately enters the liver.

Tropism of the hepatitis B virus to liver tissue is predetermined by the presence in the HBsAg of a special receptor - a polypeptide with a molecular weight of 31 000 Da (RZ1), which has albumin binding activity. A similar zone of albumin is found on the membrane of hepatocytes of human liver and chimpanzee than in essence and is determined by the tropism of HBV to human liver and chimpanzee.

When a virus enters the hepatocyte, a viral DNA is released, which, entering the nucleus of the hepatocyte and acting as a template for the synthesis of nucleic acids, triggers a series of consecutive biological reactions, which result in the assembly of the nucleocapsid of the virus. Nucleocapsid migrates through the nuclear membrane into the cytoplasm, where the final assembly of Dane particles - the total hepatitis B virus - takes place.

It should be noted, however, that when a hepatocyte is infected, the process can go two ways - replicative and integrative. In the first case, a picture of acute or chronic hepatitis develops, and in the second case, a virus carrying.

The causes that predetermine the two types of interaction of viral DNA and hepatocyte are not exactly established. Most likely, the type of response is genetically determined.

The result of replicative interaction is the assembly of structures of the cow antigen (in the nucleus) and the assembly of the complete virus (in the cytoplasm) followed by the presentation of the complete virus or its antigens on the membrane or in the structure of the hepatocyte membrane.

It is believed that replication of the virus does not lead to cell damage at the hepatocyte level, since the hepatitis B virus does not have cytopathic action. This provision can not be considered indisputable, since it is based on experimental data, which, although it indicates the absence of cytopathic effect of the hepatitis B virus, is obtained on tissue cultures and therefore can not be fully extrapolated to viral hepatitis B in humans. In any case, the question of the absence of lesion of hepatocytes during the replicative phase requires additional study.

However, regardless of the nature of the interaction of the virus with the cell, the liver is subsequently included in the immunopathological process. In this case, the damage to hepatocytes is due to the fact that as a result of the expression of viral antigens on the hepatocyte membrane and the release of viral antigens into the free circulation, a chain of consecutive cellular and humoral immune reactions is directed ultimately to remove the virus or body. This process is carried out in full accordance with the general patterns of the immune response in viral infections. To eliminate the pathogen include cellular cytotoxic reactions mediated by different classes of effector cells: K cells, T cells, natural killers, macrophages. During these reactions, the infected hepatocytes are destroyed, which is accompanied by the release of viral antigens (HBcAg, HBeAg, HBsAg) triggering the system of antigenigenesis, resulting in the accumulation of specific antibodies in the blood, primarily to the cortex - anti-HBc and e-antigen - anti-HBE . Consequently, the release of the hepatic cell from the virus occurs during its death due to the reactions of cellular cytolysis.

Simultaneously, specific antibodies accumulating in the blood bind antigens of the virus, forming immune complexes phagocytosed by macrophages and secreted by the kidneys. In this case, various immunocomplex lesions may occur in the form of glomerulonephritis, arteritis, arthralgia, skin rashes, etc. With the participation of specific antibodies, the organism cleanses of the pathogen and a full recovery occurs.

In accordance with the above concept of the pathogenesis of hepatitis B, it is customary to explain the diversity of clinical variants of the disease course by the features of the interaction of the virus and the cooperation of immunocompetent cells, in other words, the strength of the immune response to the presence of viral antigens. According to modern ideas, the strength of the immune response is genetically determined and linked to the histocompatibility antigens of the first class HLA locus.

It is generally believed that in conditions of an adequate immune response to the virus antigens, acute hepatitis with a cyclic course and complete recovery is clinically developed. Against the background of a decrease in the immune response to antigens of the virus, immuno-mediated cytolysis is not significantly expressed, therefore, there is no effective elimination of infected liver cells, which leads to mild clinical manifestations with a prolonged persistence of the virus and, possibly, the development of chronic hepatitis. At the same time, on the contrary, in the case of a genetically determined strong immune response and massive infection (hemotransfusion), extensive zones of damage to hepatic cells arise, which clinically correspond to severe and malignant forms of the disease.

The presented scheme of the pathogenesis of hepatitis B is notable for its harmony, nevertheless, there are a number of controversial and little-researched moments in it.

If we follow the concept of hepatitis B as an immunopathological disease, we could expect an increase in the reactions of cellular cytotoxicity with an increase in the severity of the disease. However, in severe forms, the indices of the cell link of immunity are sharply reduced, including a multiple drop, in comparison with those in healthy children, and an index of K-cell cytotoxicity. With malignant form in the period of massive hepatic necrosis and especially hepatic coma, complete inability of lymphocytes to blast transformation is observed under the influence of phytohematlutinin, staphylococcal endotoxin and HBsAg. In addition, there is no ability of leukocytes to migrate according to the inhibition of migration of leukocytes (RTML), and a sharp increase in the permeability of lymphocyte membranes is revealed from the results of their studies using a fluorescent tetracycline probe.

So, if the fluorescence indices of healthy human lymphocytes are 9.9 ± 2%, and for typical hepatitis B with benign course they increase to 22.3 ± 2.7%, then in malignant forms the number of fluorescent lymphocytes reaches on the average 63.5 ± 5.8%. Since the increase in permeability of cell membranes is unambiguously evaluated in the literature as a reliable indicator of their functional inferiority, it can be concluded that in hepatitis B, especially in malignant form, gross damage to lymphocytes occurs. This is also evidenced by the indices of K-cell cytotoxic activity. In severe form, at the first or second week of the disease, cytotoxicity is 15.5 ± 8.8%, and in the case of malignant form, 6.0 ± 2.6 in the 1st week, and 22.0 ± 6.3% in the second week. The norm is 44.8 ± 2.6%.

The presented data unequivocally testify to the expressed disturbances in the cell link of immunity in patients with severe forms of hepatitis B. It is also obvious that these changes occur again, as a result of the defeat of immunocompetent cells by toxic metabolites and, possibly, circulating immune complexes.

As studies have shown, in patients with severe forms of hepatitis B, especially in the case of the development of massive liver necrosis, the serum of HBsAg and HBeAg titer decreases and simultaneously begins to be detected in high titres of the antibody to the surface antigen, which is completely uncharacteristic for benign forms of the disease, which anti-HBV only appear on the 3-5th month of the disease.

The rapid disappearance of hepatitis B virus antigens with the simultaneous occurrence of high titres of antiviral antibodies allows one to assume the intensive formation of immune complexes and their possible participation in the pathogenesis of the development of massive liver necrosis.

Thus, the actual materials do not allow unequivocal interpretation of hepatitis B only from the standpoint of immunopathological aggression. And the point is not only that there is no correlation between the depth and prevalence of morphological changes in the liver, on the one hand, and the severity of the cellular immunity factors, on the other. Theoretically, this circumstance could be explained by the late terms of the study of the indices of cellular immunity, when immunocompetent cells underwent a powerful toxic effect in connection with the increasing functional insufficiency of the liver. It can, of course, be assumed that the immune cytolysis of hepatocytes occurs at the earliest stages of the infectious process, perhaps even before the onset of clinical symptoms of severe liver damage. However, such an assumption is unlikely, since in patients with acute (lightning) course of the disease, similar indices of cellular immunity were detected and, in addition, morphological examination of liver tissue showed no massive lymphocytic infiltration, at the same time, solid fields of necrotic epithelium without resorption and lymphocyte aggression.

Explain the morphological picture in acute hepatitis only from the standpoint of immune cell cytolysis is very difficult, so in the early works did not exclude the cytotoxic effect of the hepatitis B virus.

Currently, this assumption has been partially confirmed by the discovery of the hepatitis B virus. As studies have shown, the frequency of detection of hepatitis D markers is directly related to the severity of the disease: in a mild form they are found in 14%, moderate - in 18, severe - 30, malignant - in 52% of patients. Given that the hepatitis D virus has a necrosogenic cytopathic effect, it can be considered established that in the development of fulminant forms of hepatitis B, co-infection with hepatitis B and D viruses is of great importance.

The pathogenesis of hepatitis B can be represented as follows. After penetration of the hepatitis B virus into hepatocytes, an immunological attack is induced on infected hepatocytes of T-killers, which release lymphotoxins towards the hepatic cells.

Intimate mechanisms of hepatocyte damage in hepatitis B have not been established to date. The leading role is played by activated processes of lipid peroxidation and lysosomal hydrolases. The starting point may be lymphotoxins released from effector cells when they come into contact with hepatocytes, but it is possible that the virus itself may be the initiator of re-oxidation processes. In the future, the pathological process most likely develops in the following sequence.

• The interaction of the aggression factor (lymphotoxins or virus) with biological macromolecules (possibly with the components of membranes of the endoplasmic reticulum, capable of taking part in detoxification processes, by analogy with other damaging agents, as has been shown with respect to carbon tetrachloride).
• Formation of free radicals, activation of processes of lipid peroxidation and increase in permeability of all hepatocellular membranes (cytolysis syndrome).
• The movement of biologically active substances along the concentration gradient is the loss of enzymes of various intracellular localization, energy donors, potassium, etc. Accumulation in sodium, calcium, and pH shifts towards intracellular acidosis.
• Activation and yield of lysosomal hydrolases (RNA-ase, DNA-ase, cathepsins, etc.) with the decay of the hepatic cell and the release of autoantigens.
• Stimulation of T- and B-systems of immunity with the formation of specific sensitization of T-lymphocytes to hepatic lipoprotein, as well as the formation of anti-hepatic humoral autoantibodies.

In the proposed scheme of hepatitis B pathogenesis, viral antigens act as a trigger factor, whose intensive production is observed at the earliest stages of the disease and the entire acute period, with the exception of malignant forms in which the production of viral antigens practically ceases at the time of massive necrosis of the liver, which predetermines rapid reduction in viral replication.

It is also evident that viral antigens activate the T- and B-systems of immunity. During this process, a characteristic redistribution of T-lymphocyte subpopulations arises, aimed at arranging an adequate immune response, eliminating infected hepatocytes, neutralizing viral antigens, sanogenesis and recovery

In the interaction of immunocompetent cells with viral antigens on membranes of hepatocytes or during the reproduction of the virus within the hepatocyte, conditions arise for the activation of lipid peroxidation processes that control, as is known, the permeability of all cellular and subcellular membranes,

From this perspective, it becomes understandable that such a natural and highly characteristic for viral hepatitis emergence of cytolysis syndrome - increased permeability of cell membranes

The final outcome of the cytolysis syndrome can be a complete dissociation of oxidative phosphorylation, the outflow of the cell material, the death of the hepatic parenchyma.

However, in the overwhelming majority of cases, these processes do not acquire such fatal development. Only in malignant forms of the disease, the pathological process proceeds in an avalanche-like and irreversible manner, since massive infection, a pronounced immune process, excessive activation of reoxidation and lysosomal hydro-doses, and autoimmune aggression occur.

The same mechanisms are also observed in the favorable course of hepatitis B, with the only peculiarity that all of them are realized at a qualitatively different level. Unlike cases of massive liver necrosis, with a favorable disease course, the number of infected hepatocytes and, consequently, the zone of immunopathological cytolysis is less, the processes of lipid peroxidation are not so much increased, activation of acid hydrolases leads only to limited autolysis with an insignificant release of autoantigens, without a massive autoaggression, that is, all stages of pathogenesis in a favorable current are carried out within the framework of a continuing structural organization na liver rhenhimas and are restrained by protective systems (antioxidants, inhibitors, etc.) and therefore do not have such destructive effects.

The causes of symptoms of intoxication in viral hepatitis are not fully investigated. The proposal to distinguish between the so-called primary, or viral, intoxication and secondary (metabolic or metabolic) can be considered positive, although this does not reveal the intimate mechanism of the occurrence of general toxic syndrome. First, hepatitis viruses do not have toxic properties, and, secondly, the concentration of many metabolites does not always correlate with the severity of the disease and the degree of symptoms of toxicosis. It is also known that the concentration of viral antigens is not strictly correlated with the severity of intoxication. On the contrary, with an increase in the severity of the disease and, consequently, an increase in the degree of toxicosis, the concentration of HBsAg decreases and is the lowest in malignant forms at the time of the onset of deep hepatic coma. However, the frequency of detection and titres of specific antiviral antibodies directly depend on the severity of the disease.

Intoxication does not appear at the time of registration of viral antigens, but in the circulation period in the blood of antiviral antibodies of the IgM class to the cow antigen and the antigen of the E system. Moreover, in severe and especially malignant forms, even a significant proportion of patients in the blood even have anti-HBs, which is usually never observed with mild and moderate forms of the disease.

The presented data allow us to conclude that the toxicosis syndrome in viral hepatitis, and hepatitis B in particular, does not arise as a result of the appearance of viral antigens in the blood, but is the result of the interaction of viral antigens with antiviral antibodies of IgM class. The result of such interaction, as is known, is the formation of immune complexes and, possibly, active toxic substances.

Symptoms of intoxication occur at the time of the appearance of immune complexes in free circulation, but in the future such a correlation can not be traced.

A partial explanation for this can be found in the study of the composition of immune complexes. In patients with severe forms, medium-sized complexes circulate predominantly in the blood, and in their composition at the height of the toxic syndrome, class antibodies predominate whereas in the period of the decline in clinical manifestations and convalescence the complexes become larger, and antibodies of the IgG class predominate in their composition.

The presented data concern the mechanisms of development of a toxic syndrome in the initial period of the disease, but with toxicosis occurring at the height of clinical manifestations, they are only of partial importance and especially in the development of hepatic coma.

By the method of hemocultures it was possible to show that in hepatitis B, the blood constantly accumulates toxins released from the affected decaying hepatic tissue. The concentration of these toxins is proportional to the severity of the disease, they are of a protein nature.

In the period of convalescence, antibodies to this toxin appear in the blood; but in the case of a hepatic coma, the concentration of the toxin in the blood rises sharply, and antibodies in the blood are not detected.

Pathomorphology of hepatitis B

By the nature of morphological changes, there are three forms of acute hepatitis B:

• cyclic form,
• massive necrosis of the liver;
• cholestatic pericholangiolytic hepatitis.

With cyclic form of hepatitis B, dystrophic, inflammatory and proliferative changes are more pronounced in the center of the lobules, while in hepatitis A they are localized along the periphery of the lobule, extending to the center. These differences are explained by different ways of penetration of the virus into the parenchyma of the liver. The hepatitis A virus enters the liver through the portal vein and spreads to the center of the lobules, the hepatitis B virus penetrates the hepatic artery and the branches of the capillaries uniformly supplying all the lobules to their center.

The degree of defeat of the liver parenchyma in most cases corresponds to the severity of the clinical manifestations of the disease. In mild forms focal necrosis of hepatocytes is usually observed, and for moderate and severe forms - zonal necrosis (with a tendency to fusion and the formation of bridge necrosis in severe forms of the disease).

The greatest morphological changes in the parenchyma are observed at the height of clinical manifestations, which usually coincides with the 1 st decade of the disease. During the 2nd and especially the third decade, regeneration processes are intensified. By this time, necrobiotic changes are almost completely disappearing and the processes of cellular infiltration with a slow subsequent restoration of the structure of the hepatic cell plates begin to predominate. However, complete restoration of the structure and function of the hepatic parenchyma occurs only 3 to 6 months after the onset of the disease and not all patients.

The generalized nature of infection in hepatitis B is confirmed by the detection of HBsAg not only in hepatocytes, but also in the kidneys, lungs, spleen, pancreas, bone marrow cells, etc.

Cholestatic (pericholangiolytic) hepatitis is a special form of the disease, in which the greatest morphological changes are detected from the intrahepatic bile ducts, with a picture of cholangiolitis and pericholangiolitis. With the cholestatic form, cholestasis develops with the expansion of the bile capillaries with stasis of bile in them, with the proliferation of cholangiol and cell infiltrates around them. Hepatic cells with this form of hepatitis are slightly affected. Clinically, the disease is characterized by a protracted course with prolonged jaundice. It is shown that the cause of such a peculiar course of the disease is the predominant effect of the virus on the walls of cholangiol with insignificant effect on hepatocytes.