Pathogenesis of hepatitis A

Many issues of the pathogenesis of hepatitis A have not yet been finally resolved. The general pathogenetic concept, which can be taken as a basis, allows for the existence of a direct cytopathic effect of the hepatitis A virus directly on the liver parenchyma.

Introduction of the hepatitis A virus

Infection almost always occurs through the mouth. The virus with saliva, food masses or water penetrates first into the stomach, and then into the small intestine, where, apparently, it is introduced or absorbed into the portal bloodstream. It is not possible to answer the question of what happens to the virus in the stomach, and then in the small intestine. It can be assumed that in some cases the action of gastric juice is destructive for the virus and, therefore, complete sanitation from the pathogen is possible already at the level of infection. However, such an outcome of infection, although theoretically possible, is still unlikely, since the hepatitis A virus, like other enteroviruses, is stable in the pH range of 3.0-9.0, which guarantees its survival, further advancement into the duodenum, and then into the small intestine. According to modern concepts, the hepatitis A virus does not linger in the small intestine and, moreover, does not have a damaging effect on the mucous membrane. This phase of the pathogenetic chain (enteric) is apparently more characteristic of viral hepatitis in animals.

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

However, regardless of the mechanism of penetration through the wall of the small intestine, the virus most likely does not linger in the regional lymph nodes and, moreover, does not multiply, as was assumed until recently, but rather quickly appears in the general bloodstream and liver parenchyma. This phase of the pathogenetic chain can be conventionally called parenchymatous diffusion. There are different ideas about the mechanism of penetration of the hepatitis A virus into the liver parenchyma. The widespread opinion about the primary lesion of the reticuloendothelial system of the liver by the hepatitis A virus can currently be considered erroneous. According to modern concepts, the virus immediately penetrates hepatocytes, where it finds optimal conditions for reproduction. It is believed that penetration of the virus through the hepatocyte membrane can be carried out by pinocytosis, but an active process through a 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, while their absence, on the contrary, means complete immunity. The authors of this book consider this direction in scientific research to be particularly promising.

The intracellularly located virus begins to interact with biological macromolecules involved in detoxification processes. The consequence of such interaction is the release of free radicals, which initiate the processes of lipid peroxidation of cell membranes. Increased lipid peroxidation processes lead 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, an increase in their permeability. The central link in the pathogenesis of hepatitis A arises - cytolysis syndrome. The movement of biologically active substances along the concentration gradient becomes possible. Since the concentration of enzymes inside hepatocytes is tens and even hundreds of thousands of times higher than their content in the extracellular space, the activity of enzymes with cytoplasmic, mitochondrial, lysosomal and other localization increases in the blood serum, which indirectly indicates a decrease in their content in intracellular structures, and, consequently, a reduced bioenergetic mode of chemical transformations. All types of metabolism (protein, fat, carbohydrate, pigment, etc.) are disrupted, resulting in a deficit of energy-rich compounds, and the bioenergetic potential of hepatocytes decreases. The ability of hepatocytes to synthesize albumin, blood clotting factors (prothrombin, proconvertin, proaccelerin, fibrinogen, etc.), various vitamins is impaired; the use of glucose, amino acids for the synthesis of protein, complex protein complexes, biologically active compounds is impaired; the processes of transamination and deamination of amino acids are slowed down; difficulties arise in the excretion of conjugated bilirubin, cholesterol esterification and glucuronidation of many compounds. All this indicates a sharp disruption of the detoxifying function of the liver.

Increased permeability of all subcellular membranes, presumably, leads to the replacement of intracellular potassium with sodium and calcium ions in the mitochondria, which further increases the “breakdowns” in the oxidative phosphorylation system and promotes the development of intracellular and then extracellular acidosis - the accumulation of H-ions.

The changed reaction of the environment in hepatopites and the disruption of the structural organization of subcellular membranes lead to the activation of acid hydrolases (RNAse, leucine aminopeptidase, cathepsins O, B, C, etc.), which is to a certain extent facilitated by a decrease in the activity of the proteolysis inhibitor a2-macroglobules. The final action of proteolytic enzymes is the hydrolysis of necrotic liver cells with the possible release of protein complexes that can act as autoantigens and, along with the hepatotropic virus, stimulate the T- and B-systems of immunity, activating, on the one hand, sensitized killer cells, and on the other, causing the formation of specific antibodies capable of attacking the liver parenchyma. It should be said, however, that the mechanisms of autoaggression in hepatitis A are not fully realized, so severe forms of this type of hepatitis are rare.

The convalescence phase 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. Almost all patients recover with complete restoration of the structure and functions of the organ within 1.5 to 3 months from the onset of the disease. Only in some patients (3-5%) the initial protective factors may be insufficient, and a relatively long (from 3 to 6-8 months and longer) replicative activity of the virus in hepatocytes with a violation of their structure and function may be observed. In such cases, a protracted course of the disease with a prolonged mechanism of structural and functional changes is formed. However, even in these patients, the protective mechanisms ultimately win - viral activity is blocked, and complete recovery occurs. The formation of a chronic process in the outcome of hepatitis A infection does not occur.

The above data, 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 central nervous system is affected, as evidenced by the appearance of symptoms such as lethargy, adynamia, headache, insomnia, irritability and other disorders. The cause of disorders on the part of the central nervous system is intoxication, which occurs, on the one hand, as a result of viremia and the effect of the virus on the central nervous system, and on the other hand, as a result of the disintegration of affected liver cells and the release of endogenous toxins, as well as a violation of the functional capacity of the liver.

From the first days of the disease, the function of the gastrointestinal tract is disrupted, with gastric secretion and pancreatic function being suppressed. This results in decreased appetite, up to anorexia, often nausea, vomiting, and bowel disorder, which is usually observed at the very beginning of the disease.

In general, it can be said that with hepatitis A, the pathological process goes through a series of successive, interdependent stages, and at the first stages, the leading one is the action of the virus, causing the appearance of a general toxic syndrome, and at the subsequent stages - metabolic disorders with the possible occurrence of the so-called secondary metabolic toxicosis. However, regardless of the stage of the disease, the liver serves as the main arena of the pathological process.

Particular issues of the pathogenesis of hepatitis A

The Importance of Viral Replication

Although some researchers report a direct cytopathic effect of the hepatitis A virus, there is no factual evidence to support this position. Experiments on monkeys and cell cultures have shown the localization of the viral antigen in the cytoplasm of hepatocytes with its complete absence in the nuclei. When studying the dynamics of hepatitis A virus reproduction, it was found that the maximum production of intracellular viral antigen is observed on 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. It is believed that the peculiarity of hepatitis A virus reproduction in vitro is that it reproduces in culture for an exceptionally long time and has no cytopathic effect at all. If we nevertheless admit that the hepatitis A virus does not have a cytopathic effect, then we must admit that the damage to hepatocytes in hepatitis A is associated primarily with the sensitization of lymphocytes to the antigens of the causative virus and, possibly, denatured proteins of hepatocytes.

The importance of immunological indicators

Currently, immunological mechanisms of liver cell damage are of great importance in the pathogenesis of viral hepatitis, including hepatitis A. Recent studies have established that the damage to infected liver cells in hepatitis A is carried out by sensitized cytotoxic T-lymphocytes.

Other additional mechanisms of hepatic destruction in hepatitis A may be K-cell cytolysis and immune complex damage to hepatocytes.

According to our observations and taking into account the literature data, it can be considered that hepatitis A in the acute period of the disease is characterized by T-lymphopenia, T-lymphocytosis - active, thermostable and autorosette-forming cells. At the same time, the ratio of T-lymphocytes with helper activity and T-lymphocytes with suppressor activity decreases.

The content of B cells does not change significantly. The indicated shifts in the indices of the immune 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-multireceptor, thermostable and autorosette-forming cells is the greater, the more severe the pathological process in the liver. Proportionately to the increase in the severity of the disease, specific sensitization to liver lipoprotein increases, and the indices of natural killer activity and antibody-dependent cellular cytotoxicity increase.

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

In the development of protracted hepatitis A, a more pronounced decrease in the number of T-lymphocytes is observed with a relatively weak mobilization of functionally active subpopulations of T-cells 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 products, as well as an increase in the sensitization of T-cells to LP4. This type of immunological response predetermines a slow cycle of the infectious process. In these cases, it can be assumed that hepatitis A virus antigens located on the surface of hepatocytes cause weak activation of T-cells inducers of the immune response and equally weak suppression of suppressor T-cells. This interaction of immunocompetent cells creates conditions for slow specific immunogenesis, ending (through a slow cycle) with the formation of a fairly stable protective immunity.

Changes in the mechanisms of immune complex formation are in complete accordance with the nature of the cellular immunological response.

The conducted studies have shown that in all patients with hepatitis A, at the height of clinical manifestations, the concentration of immune complexes in the blood sharply increases and their complement-binding activity increases. It is important to note that during this period of the disease, mainly large-sized complexes circulate in the blood, in whose composition class M immunoglobulins predominate. Such immune complexes, as is known, easily bind complement and are quickly eliminated from the body by cells of the mononuclear-phagocytic system. In the 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 protracted 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 with weak complement-binding activity sharply increases in the composition of the CIC, and, in addition, the proportion of immunoglobulins G increases in their composition, which complicates their elimination by cells of the macrophage system and, consequently, can become a decisive cause of the protracted course of hepatitis A.

Thus, the factual materials allow us to consider hepatitis A, like hepatitis B, an immunopathological disease. However, the similarity of these diseases is only external and is seen mainly in the nature of the immunological response. Immunological shifts in hepatitis A occur on membrane antigens of hepatocytes with expressed viral antigens, which reflects the necrosogenic effect of the pathogen. In addition, although hepatitis A causes specific sensitization of immunocompetent cells to the lipoprotein of hepatocytes, there is still no pronounced immune cytolysis of hepatocytes, since the hepatitis A virus does not integrate into the cell genome. In this regard, the reactions of immune cytolysis are not prolonged in time, but reflect only the adequacy of the immune response, promoting the rapid elimination of infected hepatocytes and the elimination of the virus, which is also facilitated to a certain extent by adequate mechanisms of immune complex formation, ensuring the rapid binding of virus antigens mainly by IgM antibodies, with the formation of large complexes that are easily eliminated by the macrophage system. The combination of all these mechanisms ensures a self-limiting process without the risk of developing 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 perspective such a definition cannot be considered completely correct, metabolic disorders play an important role in the pathogenesis of the disease.

In hepatitis A, all types of metabolism (protein, fat, carbohydrate, pigment, etc.) are disrupted. The biochemical basis of these processes is the release of intracellular enzymes and their transfer from hepatocytes to the blood. Initially, the cells are left by enzymes of cytoplasmic localization (ALT, AST, F-1-FA, sorbitol dehydrogenase, etc.), then mitochondrial (glutamate dehydrogenase, urocaninase, malate dehydrogenase, etc.) and lysosomal localization (cathepsins D, C, leucine aminoneptidase, etc.). The loss of enzymes by hepatocytes, 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 underlies the progressive metabolic disorder. The synthesis of albumin, blood clotting factors, vitamins is reduced, the metabolism of microelements, hormones, carbohydrates, fats, etc. is disrupted. Consequently, metabolic disorders in viral hepatitis always occur secondarily, following a massive loss of liver-cell enzymes.

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

In the mechanism of development of the pathological process, an important role is also played by disturbances in pigment metabolism. It is known that the liver is the most important organ that carries out the transformation of bilirubin, as a result of which the pigment loses its toxic properties and is excreted from the body. Under physiological conditions, bilirubin is formed in the reticuloendothelial network from hemoglobin released during hemolysis of erythrocytes.

In viral hepatitis, pigment metabolism disorders occur primarily at the level of excretion of bound bilirubin by hepatocytes. At the same time, the functions of capture and conjugation of free bilirubin are practically not affected at the early stages of the disease. The main cause of bilirubin excretion disorders should be considered to be damage to enzyme systems and a decrease in the energy potential of hepatocytes. The bound bilirubin formed during metabolic transformations ultimately enters not the bile capillary, but directly into the blood (paracholia). Other mechanisms, such as mechanical obstruction due to the formation of bile clots or compression of the bile ducts, are not significant in hepatitis A. The only exception is cholestatic forms of the disease, in which mechanical factors can acquire significance in the pathogenesis of long-term jaundice.

Pathomorphology of hepatitis A

The morphology of hepatitis A has been studied based on data from intravital liver puncture biopsies. Changes are observed in all tissue components of the liver - parenchyma, connective tissue stroma, reticuloendothelium, biliary tract. The degree of organ damage may vary from minor dystrophic and isolated necrotic changes in the epithelial tissue of the liver lobule in mild forms to more pronounced focal necrosis of the liver parenchyma in moderate and severe forms. There is no widespread necrosis of the liver parenchyma and, especially, massive liver necrosis in hepatitis A.

Based on the nature of morphological changes, one can distinguish between acute and protracted forms of the disease.

In the acute cyclic form, diffuse damage to hepatocytes, endothelial and mesenchymal elements is detected in the liver. A diversity of microscopic changes is noted due to discomplexation of the beam structure and different nature of damage to hepatocytes, their significant polymorphism: along with widespread dystrophic changes, there are also pronounced regeneration processes. The presence of necrotic hepatocytes scattered over the lobule is characteristic, as well as the presence of individual liver cells with homogenized acidophilic cytoplasm with a pycnotic nucleus (eosinophilic body). Obesity of liver cells is not noted. Only necrotic cells lose glycogen.

Changes in the mesenchymal elements inside the lobule are expressed in the proliferation of stellate reticuloendotheliocytes (Kupffer cells) with their transformation into macrophages found in the lumen of the capillaries. The cytoplasm of these cells is basophilic, contains bile pigment and lipofuscin. Small lymphohistiocytic clusters are noted in place of necrotic hepatocytes scattered throughout the lobule. The capillaries in the center of the lobules are dilated. The stroma is without visible changes. In the portal tract, proliferation of lymphohistiocytic elements with an admixture of plasma cells, eosinophils and neutrophils is noted.

Morphological changes in the liver are cyclical. By the end of the 1st - beginning of the 2nd week of the disease in the portal tracts and around the hepatic veins against the background of edema of connective tissue structures there is already a loose abundant infiltrate. At the height of the disease (2-3rd week 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 liver cells. In more severe cases, fields of "enlightened" (balloon) cells predominate and numerous mummified cells (Kounsilman bodies) are detected. Small focal or even focal necrosis may be detected, scattered throughout the entire lobule,

In hepatitis A, unlike hepatitis B, inflammatory-dystrophic and proliferative changes are localized along the periphery of the lobules, spreading to the center, into the parenchyma, in the form of a thin mesh and tracks. In the peripheral zones of the lobules, the appearance of multinucleated cells with a tendency to form symplast-like structures is possible: an increase in the number of plasma cells is characteristic

Bile thrombi may appear in the bile capillaries, traces of some coarsening and collagenization of the reticular framework are possible, but small necroses with regenerates of multinucleated cells and proliferation of false bile ducts may still remain along the periphery of the lobules, which should be regarded as manifestations of regeneration of the liver parenchyma.

During the 4th week, necrotic-dystrophic changes in the parenchyma disappear, mesenchymal infiltration decreases significantly. Cytoplasmic "clearings" (balloon dystrophy) completely disappear.

In former foci of necrosis, rarefaction zones are visible - "flaws" of the parenchyma. Regeneration and restoration phenomena predominate.

According to most morphologists, by the end of the 5th-6th week of the disease, all inflammatory phenomena disappear, and by the end of the 2nd-3rd month, the pathological process in the liver with hepatitis A in the vast majority of cases is completely completed. The structure and function of the liver are restored.

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

Extrahepatic changes in hepatitis A include enlargement of the portal lymph nodes and spleen with reticular hyperplasia of the stroma and myelosis of the splenic pulp. Reactive changes in the reticuloendothelial system of the pancreas, kidneys and other organs are also possible. Changes in the central nervous system have also been described.

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 detected in the central nervous system.

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

It is believed that changes in the central nervous system in viral hepatitis are similar to hepatocerebral syndrome in hepatolenticular degeneration.