Pathogenesis of hepatitis A

Many questions of the pathogenesis of hepatitis A have not been completely resolved to date. In the general pathogenetic concept, which can be taken as a basis, the existence of a direct cytopathic effect of the hepatitis A virus directly on the liver parenchyma is allowed.

The introduction of the hepatitis A virus

Infection almost always occurs through the mouth. The virus with saliva, food masses or water first penetrates into the stomach, and then into the small intestine, where, apparently, it is being injected, it is absorbed into the portal bloodstream. Answer the question what happens to the virus in the stomach, and then in the small intestine, it is not possible. It can be assumed that in some cases, the action of gastric juice is detrimental to the virus and, hence, complete sanation from the pathogen is already at the level of infection. However, such an outcome of the infection is theoretically possible, but it is still unlikely, since the hepatitis A virus, like other enteroviruses, is stable in the pH range 3.0-9.0, which guarantees survival, further advance into the duodenum, and then into the thin department of the intestine. According to modern ideas, the hepatitis A virus in the small intestine does not linger and, moreover, does not have a damaging effect on the mucosa. This phase of the pathogenetic chain (enteral), apparently; more characteristic of viral hepatitis of animals.

The mechanism of penetration of the hepatitis A virus from the intestine into the blood is not exactly known. More likely the active introduction of the virus through the mucosa into the lymphatic system, and then into the regional lymph nodes, but the possibility of passive transport with the participation of special "vectors" facilitating the penetration of the virus through the lipid membrane is not ruled out.

However, regardless of the mechanism of penetration through the wall of the small intestine, the virus most likely does not stay in the regional lymph nodes and, moreover, does not multiply, as it was supposed until recently, but rather quickly in the general blood flow and parenchyma of the liver. This phase of the pathogenetic chain can be conditionally called parenchymatous diffusion. There are various ideas about the mechanism of penetration of the hepatitis A virus into the hepatic parenchyma. The widely held opinion about primary damage to the hepatitis A virus of the reticuloendothelial liver system can now be considered erroneous. According to modern ideas, the virus immediately penetrates into hepatocytes, where it finds optimal conditions for reproduction. The opinion is expressed that the penetration of the virus through the hepatocyte membrane can be carried out by pinocytosis, but the active process through the related receptor is more likely. The presence of such receptors on the hepatocyte membrane will mean the susceptibility of a particular individual to hepatitis A infection, whereas their absence, on the contrary, is complete immunity. This direction in scientific research to the authors of this book seems especially promising.

The intracellularly located virus begins to interact with biological macromolecules involved in detoxification processes. The consequence of this interaction is the release of free radicals, initiating the processes of lipid peroxidation of cell membrane lipids. The intensification of the processes of lipid peroxidation leads to a change in the structural organization of the lipid components of membranes due to the formation of hydroperoxide groups, which causes the appearance of "holes" in the hydrophobic barrier of biological membranes and, consequently. Increase their permeability. There is a central link in the pathogenesis of hepatitis A - cytolysis syndrome. It becomes possible to move the biologically active substances along the concentration gradient. Since the concentration of enzymes inside the hepatocytes is tens or even hundreds of thousands of times greater than their content in the extracellular space, the activity of enzymes with cytoplasmic, mitochondrial, lysosomal and other localization increases in the serum, which indirectly indicates a decrease in their content in intracellular structures, and consequently a lowered bioenergetic regime of chemical transformations. Violated all types of metabolism (protein, fatty, carbohydrate, pigmented, etc.), resulting in a deficiency of energy-rich compounds, and the bioenergetic potential of hepatocytes decreases. The ability of hepatocytes to synthesize albumin, clotting factors (prothrombin, proconvertin, proaccelerin, fibrinogen, etc.), various vitamins is violated; deterioration of the use of glucose, amino acids for protein synthesis, complex protein complexes, biologically active compounds; the processes of transamination and deamination of amino acids are slowed down; there are difficulties in excretion of conjugated bilirubin, cholesterol esterification and glucuronization of many compounds. All this testifies to a sharp violation of the detoxifying function of the liver.

The increased permeability of all subcellular membranes, presumably, leads to the replacement of intracellular potassium by sodium and calcium ions in the mitochondria, which further enhances the "breakdown" in the oxidative phosphorylation system and promotes the development of intracellular and then extracellular acidosis-accumulation of H-ions.

The changed reaction of the environment in hepatopitites and the disruption of the structural organization of subcellular membranes lead to the activation of acid hydrolases (RNAase, leucine aminopeptidase, cathepsins O, B, C, etc.), to a certain extent, by the decrease in the activity of the proteolysis inhibitor a2-macroglobul. The final effect of proteolytic enzymes is the hydrolysis of necrotic liver cells with the possible release of protein complexes that can act as auto-antigens and, in addition to the hepatotropic virus, stimulate the T and B immunity systems by activating, on the one hand, sensitized killer cells, on the other - causing the formation of specific antibodies capable of attacking the liver parenchyma. It should be noted, however, that autoaggression mechanisms for hepatitis A are not fully realized, Heavy forms with this form of hepatitis are rare.

The phase of reconvalescence is characterized by the implementation of protective factors and reparative processes, complete elimination of the virus and restoration of the functional state of the liver. Virtually all patients recover with complete restoration of the structure and functions of the organ in the period from 1.5 to 3 months from the onset of the disease. Only in some patients (3-5%) the initial factors of protection can be insufficient, and the replicative activity of the virus in hepatocytes with a violation of their structure and function can be observed for a relatively long (from 3 to 6-8 months and longer). In such cases, a protracted course of the disease with a prolonged mechanism of structural and functional changes is formed. However, in these patients, in the end, the defense mechanisms win - the viral activity is blocked, and a full recovery comes. Formation of a chronic process in the outcome of hepatitis A infection does not occur.

The data given, of course, do not exhaust the complex pathogenesis of hepatitis A, in which all organs and systems suffer. From the first days of infection, the CNS is affected, as evidenced by the appearance of symptoms such as lethargy, adynamia, headache, insomnia, irritability and other disorders. The cause of CNS disorders is intoxication due, on the one hand, to viralemia and the effect of the virus on the CNS, on the other hand, as a result of the disintegration of affected hepatic cells and release of endogenous toxins, as well as impairment of the functional capacity of the liver.

From the first days of the disease, the function of the gastrointestinal tract is disrupted, while there is an inhibition of gastric secretion and pancreatic function. The result is a decrease in appetite, down to anorexia, often nausea, vomiting, upset of the stool, which is usually observed at the very beginning of the disease.

In general, it can be said that in hepatitis A, a pathological process undergoes a series of sequential, interdependent steps, with the virus leading the appearance of a general toxic syndrome in the first stages, and subsequent metabolic disturbances with the possible occurrence of a so-called secondary metabolic toxicosis. However, regardless of the stage of the disease, the liver is the main arena of the pathological process.

Particular questions of the pathogenesis of hepatitis A

The value of viral replication

Although some researchers report a direct cytopathic effect of the hepatitis A virus, the actual evidence supporting this position is not given in the works. In experiments on monkeys and cell cultures, the localization of the viral antigen in the cytoplasm of hepatocytes is shown with complete absence in the nuclei. When studying the dynamics of hepatitis A virus multiplication, it was revealed that the maximum production of intracellular viral antigen is observed at the 3rd-4th week from the onset of infection, which coincides with the dynamics of virus detection in patients. However, it is not possible to completely transfer the results obtained in vitro to the disease in humans. There is an opinion that the peculiarity of reproduction of the hepatitis A virus in vitro is that it is reproduced extremely long in the culture and has no cytopathic effect completely. If we still admit that the hepatitis A virus does not have a cytopathic effect, then we must admit that hepatocyte damage in hepatitis A is primarily associated with the sensitization of lymphocytes to the antigens of the pathogen and, possibly, the denatured proteins of the hepatocytes.

Importance of immunological parameters

Currently, in the pathogenesis of viral hepatitis, including hepatitis A, great importance is attached to the immunological mechanisms of hepatic cell damage. In recent studies, it has been established that the lesion of infected hepatic cells in hepatitis A is carried out by sensitized cytotoxic T-lymphocytes.

Other additional mechanisms of hepatodeficiency in hepatitis A can be K-cell cytolysis and immunocomplex lesion of hepatocytes.

According to our observations and taking into account the literature data, we can assume that for hepatitis A, the acute period of the disease is characterized by T-lymphopenia, T-lymphocytosis - active, thermostable and autoroset-forming cells. In this case, the ratio of T-lymphocytes with helper activity and T-lymphocytes with suppressor activity decreases.

The content of B cells does not change significantly. These changes in the rates of immunological response depend significantly on the severity of the disease. A particularly significant decrease in T cells is observed in severe forms of the disease, and conversely, the content of T-active, T-multiresupertal, thermostable and autoroset-forming cells is the greater, the heavier the pathological process in the liver. Proportional to the increase in the severity of the disease, specific sensitization to hepatic lipoprotein increases, and the activity of natural killers and antibody-dependent cellular cytotoxicity increase.

The noted shifts in the immunological response reflect the adequacy of the immune response in patients with hepatitis A, aimed at eliminating infected hepatocytes and providing full immunity and complete recovery.

With the development of protracted hepatitis A, there is a more pronounced decrease in the number of T-lymphocytes with a relatively weak mobilization of functionally active T-cell subpopulations and a moderate shift in the ratio of helper and suppressor T-lymphocytes towards the predominance of the former, which ultimately leads to an increase in the synthesis of IgM production, and also increase the sensitization of T cells to LP4. This type of immunological response determines the delayed cycle of the infectious process. In these cases, it can be assumed that the antigens of the hepatitis A virus located on the surface of the hepatocytes cause a weak activation of the T cells of the immune response inducers and an equally weak suppression of the suppressor T cells. This interaction of immunocompetent cells creates conditions for delayed specific immunogenesis, terminating (through a delayed cycle) by the formation of sufficiently resistant protective immunity.

In full accordance with the nature of the cellular immunological response, there are changes in the mechanisms of immunocomplex formation.

Studies have shown that in all patients with hepatitis A at the height of clinical manifestations in the blood, the concentration of immune complexes increases sharply and their complement-binding activity increases. It is important to note that during this period the diseases in the blood circulate predominantly complexes of large sizes, in whose composition immunoglobulins of class M predominate. Such immune complexes are known to bind complement easily, they are rapidly excreted from the body by cells of the mononuclear-phagocytic system. With a smooth course of hepatitis A, the dynamics of the CIC in the blood serum strictly correlates with the nature of the pathological process in the liver, whereas in patients with a prolonged course of the disease a high level of immune complexes serves as a harbinger of an unfavorable outcome. At the same time, the proportion of medium and small immune complexes that have weak complement-binding activity increases sharply in the CIC and, in addition, the proportion of immunoglobulins G increases in their composition, which makes it difficult for them to be eliminated by the cells of the macrophage system and, therefore, can become the decisive cause of the protracted course of hepatitis A.

Thus, the actual materials allow to consider hepatitis A, like hepatitis B, an immunopathological disease. However, the similarity of these diseases is only external and is seen mainly by the nature of the immunological response. Immunological shifts in hepatitis A arise on membrane antigens of hepatocytes with expressed viral antigens, which reflects the necrosogenic effect of the pathogen. In addition, although hepatitis A and specific sensitization of immunocompetent cells to the hepatic lipoprotein, but nevertheless the expressed immune cytolysis of hepatocytes does not occur, since the hepatitis A virus does not integrate into the genome of the cell. In this regard, the immune cytolysis reactions are not prolonged in time, but reflect only the adequacy of the immune response, contributing to the rapid elimination of infected hepatocytes and the elimination of the virus, which to a certain extent is also facilitated by adequate mechanisms of immunocomplex formation, which allow rapid binding of the virus antigens mainly with IgM class antibodies, with the formation of large complexes easily eliminated by the macrophage system, the aggregate of all these mechanisms ensures a self-limiting process without the risk of fulminant or chronic hepatitis.

The role of biochemical shifts

According to the figurative expression of hepatologists, the pathogenesis of viral hepatitis is the pathogenesis of metabolic disorders. Although from a modern point of view such a definition can not be completely considered correct, metabolic disorders play an important role in the pathogenesis of the disease.

With hepatitis A, all types of metabolism (protein, fat, carbohydrate, pigment, etc.) are violated. The biochemical basis of these processes is the release of intracellular enzymes and their transfer from hepatocytes to the blood. Initially, the cells leave cytoplasmic localization enzymes (ALT, ACT, F-1-FA, sorbitol dehydrogenesis, etc.), then mitochondrial (glutamate dehydrogenase, urocaninase, malate dehydrogenase, etc.) and lysosomal localization (cathepsins D, C, leucinamineoneptidase, etc.). The loss of hepatocytes by enzymes, which are the main catalysts of metabolic transformations, leads to disturbances in oxidative phosphorylation and, consequently, to a decrease in the synthesis of energy donors (ATP, NADP, etc.), which is the basis for the pro-growth metabolic disturbance. The synthesis of albumin, blood clotting factors, vitamins decreases, metabolism of microelements, hormones, carbohydrates, fats, etc. Is violated. Consequently, metabolic disorders in viral hepatitis always arise again, following a massive loss of hepatic-cell enzymes.

Schematically occurring at the level of hepatocytes can be thought of as an interdependent cascade of metabolic disorders that go through three stages: enzymatic disorders, functional shifts, necrosis and lysis of hepatocytes with their autolytic decay. The most important role in autolytic decay of affected hepatocytes is played by proteolytic enzymes released from subcellular organelles - lysosomes. Under their action, protein structures break down with the release of a large number of amino acids that play a significant role in the onset of symptoms of intoxication.

In the mechanism of the development of the pathological process, an important role is played by violations in the pigment metabolism. It is known that the liver serves as the most important organ that transforms bilirubin, as a result of which the pigment loses its toxic properties and is eliminated from the body. In physiological conditions, bilirubin is formed in the reticuloendothelial network from hemoglobin released during hemolysis of red blood cells.

In viral hepatitis, disorders in pigmentation occur primarily at the level of hepatocyte excretion of bound bilirubin. At the same time, the functions of capture and conjugation of free bilirubin in the first stages of the disease practically do not suffer. The main reason for the violation of excretion of bilirubin should be considered defeat of enzyme systems and a decrease in the energy potential of hepatocytes. The bound bilirubin formed in the course of metabolic transformations eventually does not enter the bile capillary, but directly into the blood (parachiolia). Other mechanisms, such as a mechanical obstruction due to the formation of biliary thrombi or the compression of the bile ducts, with hepatitis A are not significant. The only exception is cholestatic forms of the disease, in which mechanical factors can acquire significance in the pathogenesis of long-lasting jaundice.

Pathomorphology of hepatitis A

The morphology of hepatitis A has been studied on the basis of the data of intravital puncture liver biopsies. Changes are noted in all tissue components of the liver - parenchyma, connective tissue stroma, reticuloendothelium, bile ducts. The degree of organ damage can vary from minor dystrophic and single necrotizing changes in the epithelial tissue of the lobe of the liver in mild forms to more pronounced focal necrosis of the hepatic parenchyma in moderate to severe forms. The widespread necrosis of the hepatic parenchyma and, moreover, massive liver necrosis in hepatitis A does not happen.

By the nature of morphological changes, one can distinguish between acute and prolonged forms of the disease.

In acute cyclic form in the liver, diffuse lesions of hepatocytes, endothelial and mesenchymal elements are detected. There is a diversity of microscopic changes due to the discomplexation of the beam structure and the different nature of the lesion of hepatocytes, their significant polymorphism: along with the widespread dystrophic changes, there are also pronounced regenerations. Characterized by the presence of necrotized hepatocytes scattered along the lobule, as well as the presence of individual hepatic cells with a homogenized acidophilic cytoplasm with a pycnotic nucleus (eosinophilic corpuscle). Obesity of the hepatic cells is not noted. Lose glycogen only necrotic cells.

Changes in mesenchymal elements within the lobule are expressed in the proliferation of stellate reticuloendotheliocytes (Kupffer cells), transforming them into macrophages found in the lumen of the capillaries. The cytoplasm of these cells is basophilic, contains bile pigment and lipofuscin. Small lymphohistiocyte accumulations are noted at the site of necrotic hepatocytes scattered along the lobe. The capillaries in the center of the lobules are enlarged. Stroma with no visible changes. In the portal tract proliferation of lymphogistocyte elements with an admixture of plasma cells, eosinophils and neutrophils is noted.

Morphological changes in the liver are cyclical. By the end of the first - the beginning of the second week of the disease in the portal tracts and around the veins of the hepatic veins against the background of the edema of connective tissue structures there is already a loose, abundant infiltration. At the height of the disease (2-3 weeks of the disease), the intensity of alterative-degenerative processes increases up to the appearance of focal necrosis with a simultaneous increase in the proliferative reaction.

The structure of the liver parenchyma in this period is maximally disrupted due to discomplexation and pronounced dystrophic changes in the hepatic cells. In more severe cases, the fields of "enlightened" (balloon) cells predominate and numerous mummified cells are found (Kaunsilmen's body). Small focal or even focal necrosis scattered throughout the lobule can be detected,

In hepatitis A, in contrast to hepatitis B, inflammatory-dystrophic and proliferative changes are localized around the periphery of the lobes, extending to the center, inside the parenchyma, in the form of a fine mesh and tracks. In the peripheral zones of the lobules, multinucleated cells with a tendency to form symplastic-like structures are possible: a typical increase in the number of plasma cells

In the bile capillaries, bile ducts may appear, traces of some coarsening and collagenization of the reticular scaffold are possible, but small necroses with regenerates from multinucleated cells and growth of false bile ducts can be conserved on the periphery of the lobules, which should be regarded as manifestations of regeneration of the hepatic parenchyma.

During the 4th week, necrotic-dystrophic changes in the parenchyma disappear, mesenchymal infiltration is significantly reduced. "Enlightenment" of the cytoplasm completely disappears (balloon dystrophy).

In the former foci of necrosis, there are zones of rarefaction - the "defects" of the parenchyma. The phenomena of regeneration and restoration predominate.

According to most morphologists, by the end of the 5th-6th week of the illness all inflammatory phenomena disappear, and by the end of the 2-3rd month the pathological process in the liver with hepatitis A in the overwhelming majority of cases is completely completed. There comes a restoration of the structure and function of the liver.

The degree of destructive changes in the liver parenchyma corresponds to the severity of the clinical manifestations of the disease.

Of extrahepatic changes in hepatitis A, an increase in portal lymph nodes and spleen with reticular hyperplasia of the stroma and myelosis of the pulp of the spleen is noted. There are also reactive changes from the reticuloendothelial system of the pancreas, kidneys and other organs. Changes are described from the side of the central nervous system.

In patients with mild forms of hepatitis A, who died from accidental causes, circulatory disorders, changes in endothelial cells, serous and serous-productive meningitis, and degenerative changes in nerve cells were found in the central nervous system.

According to pathologists, the CNS lesion occurs with all viral hepatitis. In this case, the primary effect of the virus on the central nervous system is expressed primarily by the vascular endothelium (venules). In the nerve cells appear pathological changes of varying severity, up to the necrobiosis of individual cells.

The opinion is expressed that changes from the side of the central nervous system in viral hepatitis are analogous to hepatocerebral syndrome in hepatolenticular degeneration.