Fulminant (malignant) hepatitis

Fulminant hepatitis is a special clinical form of acute hepatitis that occurs as a result of submassive or massive liver necrosis caused by an etiologic agent and is characterized by a complex of clinical and biochemical symptoms of progressive liver failure.

Malignant hepatitis is described under different names: acute liver necrosis, toxic liver dystrophy, massive or submassive liver necrosis, hepatodystrophy, acute yellow atrophy of the liver, etc. All existing names cannot be considered entirely successful, since they either reflect morphological changes (liver necrosis), or do not cover the pathogenetic essence of changes in the liver at all (toxic liver dystrophy). In foreign literature, the term "fulminant hepatitis" is used to designate such forms, that is, hepatitis with a fulminant course. In principle, such terminology does not cause objections, but the term "fulminant" or "lightning" sounds too fatal, especially considering that in recent years the disease often ends in recovery.

Clinicians are also not satisfied with terms such as “hepatodystrophy”, “liver failure”, “portal encephalopathy”, “hepatic encephalopathy”, “hepatargy”, “hepatonecrosis”, etc.

According to most clinicians, for example, viral hepatitis accompanied by massive or submassive liver necrosis and progressive liver failure is more correctly called malignant, given the severity of clinical manifestations and high mortality. The malignant form cannot be identified with the severe form of the disease. These are two qualitatively different conditions - both in clinical manifestations (in the malignant form, symptoms are observed that are absent in other forms of hepatitis) and morphological (massive, sometimes total, liver necrosis is detected only in the malignant form). On the other hand, the malignant form cannot be identified with the concept of "liver failure" or "hepatic coma". The term "malignant form" is used to designate a separate clinical form of viral hepatitis, while the concept of "liver failure" reflects a violation of liver function. It is customary to distinguish between liver failure of I, II, III degree, as well as compensated, subcompensated and decompensated forms of malignant hepatitis. In cases where liver failure is accompanied by damage to the central nervous system, it is customary to speak of hepatic coma. Consequently, hepatic coma is an extremely severe manifestation of liver failure, its final stage.

The malignant form cannot be interpreted as a complication of viral hepatitis. S. P. Botkin put forward the position that acute yellow atrophy fits well into the concept of "catarrhal jaundice" as the most severe form, the same as it in etiology and essence. According to modern concepts, in every, even the mildest, case of viral hepatitis, liver cells die, that is, there is "miniature liver atrophy". Taking this into account, the malignant form should be considered as the most severe form of viral hepatitis.

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Causes of malignant hepatitis

Among the factors capable of causing the development of a fulminant process in the liver, hepatotropic viruses are primarily distinguished - the causative agents of hepatitis A, B, C, D and E, while their share in the occurrence of malignant hepatitis is 60-70%.

Herpes viruses types 1, 2, 4, 5 and 6 can be identified as causative agents of fulminant hepatitis.

Fulminant hepatitis may occur with toxic liver damage due to poisoning with alcohol, mushrooms, industrial poisons, and drugs (antidepressants, anti-tuberculosis drugs, paracetamol, etc.). Some metabolic diseases, such as Wilson-Konovalov disease, steatohepatitis, in some cases cause fulminant hepatitis. It should be noted that, according to various authors, in 20-40% of cases the etiology of fulminant hepatitis remains unknown.

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Pathomorphology

Depending on the degree of expression and prevalence, liver necrosis in malignant hepatitis can be massive or submassive. In massive necrosis, almost all the epithelium dies or a small border of cells on the periphery of the lobules is preserved. In submassive necrosis, most hepatocytes are destroyed, mainly in the center of the lobules.

Liver necrosis may occur acutely or subacutely. In viral hepatitis, it is usually observed at the height of clinical manifestations, from the 5th to the 14th day of the disease. Less often, massive liver necrosis develops at the onset of the disease, even before the appearance of jaundice (fulminant forms), or in the late period - on the 3rd-4th week from the onset of the disease (subacute forms).

Pathological examination reveals acute necrosis of the liver, a decrease in mass by almost half, a wrinkled capsule of flabby consistency; the liver seems to spread out on the table, the tissue is easily torn. The section reveals extensive areas of ochre-yellow or dark red color due to tissue impregnation with bile and circulatory disorders (emphasized nutmeg). Histological examination reveals extensive fields of devastated, collapsed stroma with only a small border of liver epithelium preserved along the periphery of the lobules; regenerative processes are absent or insignificant. The stroma and reticuloendothelium are usually not subject to necrosis. Necrotic changes can be so great that the preparation resembles a picture of complete cadaveric autolysis of the liver.

This picture is usually observed in cases of death on the 6th-8th day of the disease. In later deaths, the liver is also reduced in size and flabby, but of a somewhat more elastic consistency and on section appears mottled due to the alternation of many small, sunken red and somewhat bulging yellow areas. Histological examination reveals extensive fields of varying degrees of prevalence of dystrophic changes in the liver parenchyma with gradual elimination of cellular detritus, up to complete devastation of the parenchyma.

In subacute necrosis, the liver is usually dense, without a significant decrease in organ mass. Microscopically, heterogeneity of morphological changes in its various areas is detected, caused by the gradual involvement of lobules in the necrotic process: along with massive and submassive necrosis, active regeneration of the remaining hepatocytes is visible in some lobules with localization of regenerating cells mainly around the portal tracts, with proliferation of connective tissue and disruption of the parenchyma architectonics. In the zones of cellular regeneration, a peculiar fine-droplet obesity of hepatocytes is observed with an increase in their size and preservation of the nucleus in the center. The processes in different parts of the liver proceed differently. In the central, especially peripheral, areas near large vessels, the development of the pathological process outpaces changes in the peripheral areas of the organ. In addition, the left lobe of the liver is usually affected more than the right. If acute liver necrosis persists for a long period of time (5-6 months or more), then a picture of postnecrotic liver cirrhosis develops.

In malignant forms of hepatitis, dystrophic changes are found not only in the liver, but also in the kidneys, spleen, brain and other organs. In patients who died from hepatic coma, varying degrees of fatty and protein dystrophy are found in the kidneys, up to widespread necrosis of the renal epithelium; in the spleen - hyperemia, reticular hyperplasia and myelosis of the pulp; in the brain - severe dystrophic changes in nerve cells, glial vessel walls with predominant localization in the cortex, subcortical-stem regions and cerebellum. In some cases, histological examination of the brain of children who died from hepatic coma reveals cellular perivascular infiltrates around the basal ganglia, in the pia mater and white subcortical matter. Circulatory disorders, stasis, perivascular edema, severe dystrophic changes in macroglia leading to their death, as well as microglia are usually observed. In some cases of subacute dystrophy, proliferative changes in macroglia are recorded. Morphological changes in the brain are usually associated with toxic effects developing in connection with the rapid decay of liver tissue.

Why does hepatitis take a malignant course in some patients?

The question is very complex. Considering that fulminant hepatitis develops almost exclusively in young children, and especially often in premature babies aged 2-6 months, it can be assumed that the determining factors are the imperfection of the immunocompetent systems and the special sensitivity of metabolic processes occurring in conditions of insufficiently differentiated liver parenchyma.

It is also necessary to take into account the fact that at the age of up to 1 year, the child experiences particularly rapid growth and an increase in liver mass, which, in turn, predetermines the intensity of metabolic processes and, consequently, their increased vulnerability.

A factor that adversely affects the course of viral hepatitis may also be the high infectivity of the pathogen. It is important to emphasize that all children who died from massive liver necrosis were diagnosed with hepatitis B or hepatitis B and D; they were infected with intravenous plasma or blood transfusions, sometimes multiple, i.e. the infection was massive.

At first glance, the absence of HBsAg in the blood serum of children with malignant hepatitis seems paradoxical. Of the 36 patients with massive liver necrosis examined by us, HBsAg was detected in 9 children. Moreover, the antigen in these patients was determined only in the first days of the disease; in subsequent studies in the precomatose and comatose periods, it was no longer determined. These data can be explained by the total destruction of the liver parenchyma, which serves as a morphological substrate for virus replication.

Apparently, in fulminant hepatitis, due to weak synthesis of HBsAg in deeply damaged hepatocytes and insufficient supply of it into the blood, instead of an excess of antigen (as occurs in mild and moderate forms), there is an excess of the corresponding antibodies (anti-HBe;, anti-HBs and anti-HBV).

Thus, our studies have allowed us to deepen our understanding of the immunopathogenesis of viral hepatitis. To a certain extent, they have allowed us to consider that a hyperimmune attack on the infected liver plays a role in the development of the malignant form of the disease. There are also grounds to regard the action of the virus and its complexes with antibodies as a determining factor in the development of massive liver necrosis. In the intimate mechanism of interaction of the virus with hepatocytes, the leading role is played by activated processes of lipid peroxidation and the action of lysosomal hydrolases.

The hypothesis we propose can serve as a basis for constructing pathogenetic therapy for severe forms of viral hepatitis and become a starting point for further in-depth study of the pathogenesis of the disease.

How does malignant hepatitis develop?

The role of hepatotropic viruses

The question of the pathogenesis of malignant forms remains difficult and poorly understood. First of all, it is not easy to answer the question of what underlies the avalanche-like uncontrolled disintegration of the liver parenchyma, what is the role of viruses and factors of autoimmune aggression in it, what are the driving mechanisms of cytolysis and autolysis.

We attempted to answer these questions based on a comprehensive study of the persistence of hepatotropic viruses, the study of lipid peroxidation, the activity of lysosomal hydrolases, and the fixation of specific antibodies and autoantibodies on liver tissue.

In HBV isolates obtained from patients with fulminant hepatitis B, multiple and unique mutations in the pre-core and core regions of the C gene, as well as in the polymerase gene, are detected significantly more often than in patients with the benign variant of the disease. In addition, with high frequency in fulminant hepatitis B, a violation of the synthesis of the full-fledged pre-82 region is noted in the HBV genome.

There is evidence of the predominant detection of the mutant HBVe-minus strain in patients with fulminant hepatitis B.

In the occurrence of a malignant form in acute viral hepatitis, in addition to mutant strains of pathogens, great importance is attached to mixed infection. For example, coinfection with hepatitis B and D viruses, as well as superinfection with the hepatitis D virus on chronic carriage of HBV or chronic hepatitis B can with high frequency lead to the formation of fulminant forms of hepatitis.

As studies have shown, in case of co-infection with hepatitis B and D, a mild form of the disease was recorded in 14%, moderate in 18%, severe in 30%, and malignant in 52% of patients.

Superinfection of hepatitis D in chronic carriers of the HBV virus in fulminant form was established in 42% of observations.

According to the general opinion of hepatologists, fulminant hepatitis develops mainly with hepatitis B and D, but there are isolated reports of the occurrence of a malignant form with hepatitis C. However, more often with fulminant hepatitis, the HCV genome is detected simultaneously with the hepatitis B virus.

Enteral hepatitis A and E can develop in a fulminant form relatively rarely.

The hepatitis E virus is associated with a high incidence of fulminant hepatitis in pregnant women in hepatitis E endemic regions, reaching 20-40%.

Hepatitis A is most dangerous for older people in terms of the possible development of a malignant form.

The mechanism of development of acute or subacute massive or submassive liver necrosis is one of the most complex and least studied in hepatology. Most modern hepatologists associate the occurrence of massive liver necrosis with cytolytic syndrome, which is commonly understood as a set of all changes in hepatocytes, reflecting histological, biochemical and humoral disorders in the liver, arising in response to damage to liver cells by aggressive factors (mainly hepatotropic viruses).

This article attempts to present the pathogenesis of liver necrosis based on the study of lipid peroxidation, the role of lysosomal proteinases, immunological status and autoimmune processes.

Lipid peroxidation and cytolysis syndrome

It is known that the primary and earliest sign of various cell damages are changes in cell membranes, and among the causes of these disorders, lipid peroxidation is one of the first.

Peroxidation occurs in any cell and in various membrane structures. This process has a chain, free-radical nature in pathological conditions. In physiological conditions, this does not occur, since there is a whole system regulating peroxidation. The stationary low level of the endogenous process is normally regulated primarily by tissue antioxidants (tocopherol, glucocorticoids, etc.), the presence of glutathione peroxidase, which decomposes lipid hydroperoxides without the formation of free radicals, and a strictly ordered cell structure. However, in various pathological conditions, when the restraining effect of antioxidants decreases or the structural organization of the cell changes, peroxidation can accelerate sharply, acquiring an "explosive", dangerous nature.

To study lipid peroxidation, a kinetic method was used to measure the chemiluminescence of blood serum, i.e., ultra-weak luminescence initiated by divalent iron ions. According to Yu. A. Vladimirov et al. (1969), such luminescence is due to the recombination of peroxide radicals, so its intensity characterizes the rate of lipid peroxidation. The activity of the latter was also estimated by the amount of the formed end product - malondialdehyde (MDA). The lipid spectrum of blood serum was studied using thin-layer chromatography on a fixed gel modified by Yu. A. Byryshkov et al. (1966); Yu. E. Veltishev et al. (1974). This technique allows identifying phospholipids, free cholesterol, mono-, di- and triglycerides, cholesterol esters, as well as NEFA. By simple addition, it is possible to calculate the level of total cholesterol and total lipids, as well as to derive the cholesterol esterification coefficient.

It turned out that in the acute period of viral hepatitis, the number of significantly elevated lipid peroxidation indices in the blood serum increases sharply and the superweak glow of the blood serum increases. The degree of expression of the detected disorders directly depends on the severity of the disease.

High rates of lipid peroxidation are also observed during the development of hepatodystrophy, in the period of acute reduction in liver size. During the development of hepatic coma, these rates in some patients show a tendency to decrease. At the same time, during the period of deep hepatic coma, the intensity of chemiluminescence dropped sharply (by 3 times compared to that in precoma), and the MDA content, after some decrease, increased again, approaching the values noted in severe forms, at the beginning of the development of liver necrosis. These shifts in the terminal phase of liver necrosis are apparently associated with the complete disintegration and devastation of the parenchyma of this organ. The processes of lipid peroxidation in viral hepatitis are enhanced against the background of significant changes in the lipid spectrum of blood serum. In the acute period, in all forms of the disease, the content of triglycerides, phospholipids, NEFA, beta-lipoproteins, free cholesterol increases with a simultaneous decrease in the cholesterol esterification coefficient.

The severity of these disorders, as well as the peroxidation indices, directly depend on the severity of the disease. If in the mild form the content of triglycerides, phospholipids, mono- and diglycerides, free cholesterol and total lipids increases by 44-62%, then in the moderate and severe forms - by 70-135% compared to the norm. The content of PEFA increases even more significantly. In the mild form their amount exceeds the normal by 2.8 times, and in the severe form - by 4.3 times. Another dependence characterizes the dynamics of cholesterol esters; in the mild form their content is within the normal range, in the severe form - below the norm by 40.2%. The level of total cholesterol does not correlate with the severity of the disease. In all forms, it increases by 16-21% mainly due to the increase in the free fraction, the content of which in the mild form increases by 1.6 times, and in the severe form - by 2.2 times against the norm. The more severe the form of the disease, the more the cholesterol esterification coefficient decreases.

With the development of massive liver necrosis, the content of beta-lipoproteins, cholesterol esters and triglycerides sharply decreases with a simultaneous moderate decrease in other lipid fractions, except for phospholipids and PEFA, whose content increases even more with the development of hepatic coma.

When comparing the indices of lipid peroxidation with the lipid spectrum of blood serum in the dynamics of the disease, a direct correlation is noted between the intensity of lipid peroxidation, on the one hand, and the content of NEFA, mono- and diglycerides, phospholipids, triglycerides, on the other, then the indices of these lipid fractions are higher, the more intense the luminescence of the blood serum and the higher the content of MDA.

Many authors also include hypoxia among the factors that enhance lipid peroxidation processes.

During hypoxia, partial disruption of the membrane structure occurs, reduced iron accumulates, and conditions are created for increased lipid peroxidation.

Studies have shown the presence of hypoxia in patients with viral hepatitis. The nature of hypoxia has not been finally established. It is assumed that there is development of circular hypoxia with local circulatory disorder in the liver and tissue hypoxia due to a decrease in the activity of oxidation-reduction processes. M.V. Melk established a direct relationship between the degree of intoxication and the severity of hypoxia.

The phenomena of hypoxia, accumulation of iron, unsaturated fatty acids and pronounced changes in the lipid spectrum create the necessary conditions for increased lipid peroxidation in viral hepatitis.

No less significant in enhancing lipid peroxidation can be the disturbances of antioxidant systems - the process suppressors. Under physiological conditions, antioxidants reduce the intensity of lipid peroxidation. Some researchers associate antioxidant properties with certain substances, such as tocopherol, steroid hormones. Others believe that antioxidant properties are inherent in the sum of lipid components, the mutual influence of which leads to a change in antioxidant properties.

It has been shown that substances rich in sulfhydryl (SH) groups can neutralize the damaging effects of lipid peroxidation products. However, this mechanism of neutralizing toxic peroxides cannot occur in viral hepatitis, since the content of sulfhydryl groups in this disease decreases sharply. Particularly low levels of SH groups in the blood serum are observed in massive liver necrosis with a fatal outcome. Consequently, increased lipid peroxidation and accumulation of toxic peroxides, which cause damage to cell membranes in viral hepatitis, are associated with a decrease in the activity of antioxidant systems.

Thus, the conducted studies allowed to establish significant disturbances in lipid metabolism in viral hepatitis, the essence of which lies in the increase in the content of NEFA, mono-, di- and triglycerides and free cholesterol in the blood serum, and increased lipid peroxidation processes. These disturbances are proportional to the severity of the pathological process in the liver. It can be assumed that as a result of the penetration of the virus into the epithelial cells of the liver and its subsequent interaction with the substrates of the cell, chain radical reactions occur, acting as initiators of lipid peroxidation - the most important components of cell membranes. The hydroxyl groups formed in this case cause the appearance of "holes" in the hydrophobic barrier of the biological membrane. First of all, the permeability of the membranes for hydrogen, potassium, sodium and calcium ions increases. The cells lose biologically active substances, including enzymes. The biological potential of the hepatocyte decreases. Lysosomal proteinases are activated, which can become the final stage of the death of the liver parenchyma.

Lysosomal proteolytic enzymes and autolysis syndrome

Lysosomes contain more than 60 hydrolytic enzymes (including cathepsins A, B, D, C), capable of breaking down biologically active compounds of all major classes and thus causing cell death. However, today the dominant idea is that lysosomes are a "bag" containing everything necessary for cell life.

Intracellular proteolysis plays an important role in immune reactions, synthesis and breakdown of physiologically active substances. For example, acid hydrolases have been shown to participate in the formation of isoforms of some enzymes, as well as hormonal substances of protein nature (thyroxine, insulin, etc.). Reactions occurring in lysosomes under physiological conditions can be characterized as limited autolysis, which is an integral part of the continuous process of cell renewal. Much data has been obtained on the role of lysosomes and lysosomal enzymes in accelerating the processes of exfoliation and lysis of functionally unsuitable cells. The energy and plastic material released in this process is used in the construction of new cellular structures. Thus, lysosomes "clear the way" for intracellular regeneration, freeing the cell from decay products. The structural isolation of acid hydrolases inside lysosomes is of great biological importance, since it provides physiological protection of intracellular proteins from the destructive action of their own enzymes. The presence of proteolysis inhibitors in the cell provides additional protection. Currently, inhibitors of cathepsins B, C, D and other proteolytic enzymes are known.

The pH of the environment, the concentration of calcium and sodium ions can play a major role. Lysosomal hydrolases are especially easily activated when the pH shifts to the acidic side, since in an acidic environment not only are hydrolases activated, but this also promotes the denaturation of protein substrates, thereby facilitating their breakdown by lysosomal enzymes. The state of lysosomal membranes is especially important for the activation of lysosomal hydrolases. With increased permeability of the latter or in the case of their rupture, contact between enzymes and substrates can be especially easy. In this case, acidic hydrolases can diffuse into the cytoplasm and cause hydrolytic breakdown of cells. It can be assumed that similar conditions are created in viral hepatitis, especially in cases accompanied by massive liver necrosis.

The conducted studies allowed to reveal very important shifts in the system of proteolytic and antiproteolytic activity of blood serum in viral hepatitis in children. The essence of these shifts is that in the acute period of the disease there is a regular increase in the activity of acid RNase, leucine aminopeptidase, cathepsins D, C and, to a lesser extent, cathepsin B. At the same time, the activity of their inhibitor - a2-macroglobulin - shows a pronounced tendency to decrease.

The noted shifts are more pronounced in severe forms of the disease than in mild ones. As clinical manifestations of the disease decrease and the functional capacity of the liver is restored, the activity of lysosomal enzymes decreases, while the activity of a2-macroglobulin increases, approaching normal values during the convalescence period, but only in mild forms of the disease.

Increased activity of lysosomal enzymes indicates a sharp increase in the permeability of lysosome membranes - "storage" of proteolytic enzymes. Conditions are created for the destructive action of enzymes on the liver parenchyma affected by the virus. However, in cases occurring without massive necrosis, the destructive action of lysosomal hydrolases is limited by the preserved structural organization of the cell and, apparently, the absence of optimal environmental conditions (pH, concentration of K+, Ca2+, Na2+, etc.), as well as the restraining effect of inhibitory systems.

In massive and submassive necrosis due to deep dystrophic processes in the liver parenchyma, the synthesis of the lysosomal proteinase inhibitor, a2-macroglobulin, is particularly sharply reduced and a shift in pH to the acidic side is noted, optimal conditions arise for the activation and release of acid hydrolases from lysosomal vacuoles. The final phase of their action may be autolysis of the liver parenchyma.

In the early stages of necrobiosis, in the "living cell" - "dead cell" period, the intensification of autolytic processes occurs both due to an increase in the "attackability" of proteins by enzymes and as a result of an increase in the activity of proteolytic enzymes. With deeper necrobiosis (mainly in the "dead cell" - "necrotic cell" period), the activity of proteolytic enzymes decreases due to their own disintegration, in addition, the ability of proteinases to affect proteins is sharply reduced, since protein coagulation occurs and stable, poorly soluble compounds can be formed. Obviously, in viral hepatitis, there are complex interactions between the processes of necrobiosis, coagulation and proteolysis. Necrobiosis and proteolysis in cells apparently develop simultaneously, reinforcing each other. In this case, proteolytic enzymes can probably change the physicochemical state of cellular structures, causing their degeneration, and this, in turn, contributes to increased proteolysis. A vicious circle is created - the hepatocyte becomes a “victim” of its own proteolytic systems.

Important conclusions follow from the analysis of the results of determination of the activity of trypsin-like proteinases in the blood,

In viral hepatitis, in the acute period of the disease, the activity of trypsin-like proteinases is lower than normal, and in severe forms of the disease, it is not determined at all. The decrease in the activity of trypsin-like proteinases can be explained by a particularly sharp increase in the content of their inhibitor in the blood serum - a 1-antitrypsin, whose activity in mild forms exceeds the norm by 0.5-2 times, and in severe forms - by 2-3 times.

As the clinical manifestations of viral hepatitis subside and liver function tests normalize, the activity of the inhibitor of trypsin-like proteinases decreases, while the activity of serum proteolytic enzymes increases, approaching the norm. Complete normalization of trypsin-like proteinases occurs by the 15th-20th day of the disease, regardless of severity, and their inhibitor - on the 25th-30th day of the disease and only in mild forms.

In patients with fulminant hepatitis in the precomatose and especially comatose period, the activity of trypsin-like proteinases begins to increase sharply, while the activity of the inhibitor rapidly decreases.

We tend to regard the increase in the activity of a1-antitrypsin in the favorable course of viral hepatitis as a protective reaction aimed at suppressing the activity of trypsin-like proteinases - trypsin, kallikrein, plasmin, etc. This position is confirmed by low activity levels of serum proteinases in mild, moderate and severe forms not accompanied by liver necrosis.

A different picture is observed in patients with massive liver necrosis, development of hepatic coma and subsequent death. In these cases, a sharp drop in inhibitor activity is accompanied by an equally sharp increase in the activity of trypsin-like proteinases in the blood, creating optimal conditions for their pathological action. It is known that an increase in the activity of trypsin-like proteinases leads to increased formation of their precursors - biologically active substances kinins (bradykinin, calidin), which sharply increase the permeability of the vascular wall, lower blood pressure and diuresis, cause pain, asthma and palpitations. There is every reason to believe that kinins activated by proteolytic enzymes in the blood play an important role in the pathogenesis of hepatic coma and especially in the genesis of hemorrhagic syndrome in viral hepatitis. Thus, as a result of increased permeability of lysosome membranes in the acute period of viral hepatitis, the activity of tissue acidic proteinases - RNase - sharply increases in the blood serum. leucine aminopeptidase (LAP), cathepsins B and C. In the case of a favorable course of viral hepatitis, the destructive action of proteinases is limited by the preserved structural organization of hepatocytes, sufficient production of a 1-antitrypsin and a2-macroglobulin and, possibly, the absence of optimal environmental conditions (pH, ion concentration, etc.).

In the malignant form, due to deep destructive processes in the liver parenchyma, disruption of the organization of subcellular structures, and a sharp decrease in the content of proteolysis inhibitors, optimal conditions are created for the release of acidic hydrolases from lysosomal vacuoles and their destructive effect on protein substrates inside hepatocytes. This is to a certain extent facilitated by a shift in pH to the acidic side, accumulation of sodium and calcium ions in hepatocytes. The final phase of the action of lysosomal hydrolases in patients with fulminant hepatitis is autolysis of the liver parenchyma with the breakdown of its own proteins into simpler substances - amino acids and peptides. Clinically, this is manifested by a decrease in the size of the liver and the mass of the liver parenchyma, a rapid increase in intoxication symptoms, and the development of hepatic coma. A decrease in the activity of lysosomal enzymes to zero following an acute reduction in the size of the liver during a period of deep hepatic coma indicates the complete destruction of the lysosomal apparatus of the hepatocyte with subsequent cessation of its functional activity.

This seems to be the main pathogenetic significance of lysosomal hydrolases in viral hepatitis, accompanied by massive or submassive liver necrosis.

The role of cellular immunity in the pathogenesis of massive liver necrosis

Cellular immune responses are known to be of significant importance in determining the course of viral hepatitis. It has been suggested that as a result of damage to liver cells by the virus and their reorganization to synthesize viral proteins, autoimmune reactions against liver cells occur, with the pathological process developing as delayed-type hypersensitivity with a predominance of cellular autoimmune reactions. The essence of the latter is that as a result of the interaction of the virus and hepatocytes, virus-induced antigens appear on the surface of the latter; T cells that recognize these new determinants destroy the infected hepatocytes. The virus is released from the cells and, in turn, infects other hepatocytes. Consequently, liver cells are freed from the virus at the cost of their own death. In addition, as a result of stimulation of T cells by damaged hepatocytes, activation of B cells occurs, which react to the surface antigens of hepatocytes, including the liver-specific lipoprotein. Synthesis of antibodies to this macrolipoprotein, considered a normal component of intact hepatocyte membranes, occurs. These antibodies, reaching the liver, bind to the surface of hepatocytes. Since the most probable mechanism leading to necrosis is complement binding, activation of K-cells is also assumed. According to these concepts, the pathological process in severe forms of viral hepatitis is caused not so much by the replication and cytotoxic effect of the virus, as by the reaction of immunocompetent cells to antigenic determinants.

H.M. Veksler et al. studied the cytotoxic function of lymphocytes on a model of regenerating hepatocytes of a cultured explant of biopsied liver tissue from patients with hepatitis B (1973). The studies revealed a distinct cytotoxic effect of lymphocytes on liver cells in 55% of patients with acute viral hepatitis and in 67% of patients with liver cirrhosis. In addition, blood serum rich in HBsAg and a purified HBsAg preparation stimulated the proliferation of cells in cultures of biopsied liver tissue and bile ducts.

Based on the results of these studies, hepatologists began to believe that the most important, if not decisive, factor in the development of massive liver necrosis is the activity of immunocompetent cells in relation to immunogenic antigenic determinants of the virus. Consequently, viral hepatitis, including its severe forms, can be considered an immunological disease caused by the reaction of immunocompetent cells. It must be assumed that in patients with massive liver necrosis, especially active full-fledged virus particles predominate in hepatocytes. According to this point of view, the main mechanism of liver necrosis development is immune cytolysis, causing death of the liver parenchyma mass. Since signs of sensitization to a liver-specific lipoprotein are found in most patients with hepatitis, the mechanism of sensitization to the liver cell membrane antigen began to be considered the main autoimmune process common to all types of the disease, and, most likely, it becomes the cause of long-term liver damage.

However, despite these data, many hepatologists are cautious in interpreting the results obtained with respect to cytotoxicity. The fact is that the phenomenon of lymphocyte cytotoxicity is a universally widespread process and should not necessarily be considered as the leading link in the pathogenesis of the disease. It is also necessary to take into account the fact that in deceased patients with fulminant massive liver necrosis, massive lymphocytic infiltration cannot be detected at autopsy and during morphological examination; at the same time, continuous fields of necrotic liver epithelium are revealed without resorption and lymphomonocytic aggression.

The results of the study showed that in the acute period of hepatitis B, both the surface HBs antigen and the E antigen, related to the inner membrane of the virus, are detected in the blood. The circulation of the E antigen is short-lived (during the first 2 weeks of the disease), and later antibodies appear - anti-HBE. In general, the components of the e-system, that is, HBeAg and anti-HBe, were detected in 33.3% of those examined. The circulation of HBsAg in the blood turned out to be longer (on average 31 days); at the same time, HBsAg titers in patients with a moderate form were higher than in patients with a mild form. Antibodies to HBsAg were not detected. In the malignant variant of hepatitis, the majority of those examined for the e-system at the very beginning of the disease showed the appearance in the blood along with HBeAg and HBsAg, but as precoma and coma develop, virus antigens are no longer detected in the blood. Against the background of the circulation of viral components, changes in the quantitative ratios of lymphocyte subpopulations are observed in the dynamics of hepatitis B. Thus, in the first and second decades of the disease, that is, at the height of the disease, the level of E-POC in all forms of the disease significantly decreases both in percentage and absolute value. In the fourth decade, with mild and moderate forms, the amount of E-POC increases to a normal value, with a severe form of the disease, the content of E-POC in this period has not yet normalized, amounting to 47.5 ± 6.2% (1354.9 ± 175.3 cells / mm ³ ). The content of B-cells reliably increases at the height of hepatitis only with a mild form and fluctuates within the normal range with moderate and severe forms. By the period of early convalescence in patients with a severe form, the content of B cells increases to 525.4±98.9 cells/mm3 ^against 383.9+33.2 cells/mm3 ^at the height of the disease (p<0.05 g). In general, the dynamics of the B cell content was characterized by small fluctuations during the cyclic course of the disease, compared with the dynamics in healthy children. The content of lymphocytes that do not have receptors for T and B cells (null cells) at the height of hepatitis exceeds the norm by more than 2 times in all forms of the disease. In the period of early convalescence, the level of null cells remains significantly elevated in mild and severe forms of the disease.

The content of T-lymphocytes, which play a regulatory role in the relationship between T-T-cells, T- and B-cells (TM- and TG-cells), depends little on the severity of the disease. A characteristic feature was a decrease in the number of TM-cells in mild and moderate forms by an average of 1.5 times against the norm, amounting to 22.7+3.1% (norm 36.8±1.2%). The fractions of TG-cells remain unchanged during the disease: the level at the height of the disease is 10.8±1.8% (norm 10.7+0.8%).

The response of lymphocytes to the universal mitogenic stimulator PHA in patients with acute cyclic course of hepatitis B remains close to normal; the number of mature T-lymphocytes at the height of the disease is 57.2±3.6% with a norm of 62.0±2%.

Specific T-cell reactivity to stimulation with HBsAg increases with recovery: the frequency of positive RTML results increases from 42% in the first two weeks of the disease to 60% in the 4th week. The average migration index is 0.75±0.05 (normal 0.99+0.03). As a result, specific sensitization to the hepatitis B surface antigen is detected in 86% of patients. During follow-up examination in the 3rd-9th month after acute hepatitis B, inhibition of leukocyte migration during in vitro stimulation with HBsAg persists in half of the convalescents.

Compared with benign forms of the disease, in malignant forms, the reactions of cellular and humoral immunity in patients have a number of distinctive features. Thus, the content of E-POC, which is quite low in precoma, is characterized by a steady decrease and during the coma period is almost 2 times lower than normal, while the number of B cells is 2 times higher than normal. The quantitative content of subpopulations of active E-POC and stable E-POC changes little both in the dynamics of the disease and in comparison with the number in healthy patients. In parallel with the decrease in the number of T cells, the number of null cells increases 3 times against the norm. In malignant hepatitis, during the period of development of massive liver necrosis and especially hepatic coma, there is a complete inability of lymphocytes to undergo blast transformation under the influence of phytohemagglutinin, staphylococcal endotoxin and HBsAg of their functional inferiority, it can be concluded that in viral hepatitis, especially in the malignant form, there is gross damage to lymphocytes.

The presented data indicate significant disturbances in the cellular link of immunity in patients with viral hepatitis, accompanied by massive liver necrosis. The nature of the detected disturbances remains unclear. They may indicate a defect in the cellular link of immunity in patients with malignant forms of viral hepatitis, but it is more likely that these changes occur as a result of damage to immunocompetent cells of the peripheral blood by toxic metabolites. In this regard, the question arises: how do degeneratively altered lymphocytes with pathologically altered membranes, incapable of blast transformation and migration, with such a sharp quantitative decrease in them, have a destructive effect on the liver parenchyma, up to its complete necrosis and lysis. That is why the hypothesis of autoimmune aggression with the participation of immunocompetent cells requires further in-depth study.

The role of autoantibodies in the pathogenesis of liver necrosis in viral hepatitis

Modern ideas about the autoimmune nature of liver damage are based on the very frequent detection of anti-organ antibodies in viral hepatitis. Many authors believe that autoantibodies are more often detected in severe forms of the disease.

However, the simple detection of anti-organ antibodies circulating in the blood does not yet determine their real role in the pathogenesis of the disease. More promising in this regard are the methods of studying immunomorphological changes directly in the liver tissue. In one of the first works on the immunopathochemical study of liver tissue in hepatitis, antibodies labeled with fluorescent dyes against human y-globulin were used. It was shown that in acute viral hepatitis, y-globulin-containing cells are constantly found in the liver tissue, located mainly in the portal tracts and sinusoids inside the lobules. According to F. Paronetto (1970), cells synthesizing y-globulins are not related to the virus; their number is interconnected with the degree of destruction of liver tissue. The results of these studies have been mainly confirmed by works of recent years, where labeled monovalent sera containing antibodies against IgA, IgG, IgM were used.

To establish the role of autoaggression in the development of massive liver necrosis in children, histochemical and immunofluorescent studies of liver tissue from 12 children who died with hepatic coma were performed (8 of them had massive liver necrosis, 2 had submassive necrosis, and 2 had subacute active giant cell cholestatic hepatitis). In addition to the generally accepted methods of morphological and histochemical studies, a direct version of the Coons method was used.

Humoral immunity factors (immunoglobulins and autoantibodies) were studied in 153 patients with viral hepatitis. Severe form of the disease was in 12, moderate - in 48, mild - in 80; 13 children suffered from viral hepatitis of latent or anicteric form.

Determination of circulating anti-organ antibodies was carried out repeatedly in the dynamics of the disease. In the same sera, the level of IgA and IgM was studied.

Organ antibodies to the liver and smooth muscles of the intestine were determined in the PGA reaction, according to Boyden, the content of immunoglobulins - by the method of simple radial diffusion in agar. Statistical processing of the results was carried out using a multichannel system for single and multiple serological reactions, taking into account negative results.

The statistical processing method we used is based on the logarithmically normal distribution of antibody titers; the ordinal numbers of dilutions in a series of test tubes are distributed according to the normal law. Averaging over the series was carried out after establishing the position of the test tube with the 2+ reaction assessment in each row and taking into account the negative results, due to which the entire material was involved in the processing.

The reliability of the difference between the height of antibody titers in different groups of patients was calculated using the Student criterion. The correlation between the titers of anti-tissue antibodies and the content of immunoglobulins in the sera was determined on a computer using a standard program.

The results of the studies showed that in healthy individuals, anti-organ antibodies in a titer of 1:16 and higher are rarely detected; antibodies to liver tissue were detected in 2 of 20 subjects, antibodies to kidney tissue in 2 subjects, and antibodies to intestinal smooth muscles in 1 subject. Of the patients with viral hepatitis, antibodies to liver tissue in a diagnostic titer (1:16) and higher were detected in 101 (66%) of 153 subjects, antibodies to kidney tissue in 13 (21.7%) of 60 subjects, and antibodies to intestinal smooth muscles in 39 (26.4%) of 144 subjects. Antibodies to liver tissue in patients with moderate and mild forms of the disease occurred with approximately the same frequency (in 36 of 48 and 52 of 80, respectively), and significantly less frequently in patients with severe forms (in 4 of 12).

In the cyclic course of viral hepatitis, the curve of antihepatic antibody titers in mild and moderate forms of the disease had a pronounced rise in the period of decline in clinical and biochemical manifestations of the disease. The curve of smooth muscle antibody titers repeated the previous curve, but at a lower level. The figure shows that with increasing severity of the disease, the titers of organ antibodies significantly decrease, and the lowest titers of antibodies were in the severe form of viral hepatitis. In patients with a malignant form, the titers of antibodies to liver tissue were especially low, and in the period of deep hepatic coma, autoantibodies were not detected.

The following results were obtained during a simultaneous study of the level of immunoglobulins in blood serum.

In severe forms of the disease, at the height of clinical manifestations, a moderate increase (1.5-1.8 times compared to the norm) in the concentration of immunoglobulins of all classes was noted, with the content of IgM equal to 1.72±0.15 g/l - 13.87±0.77 g/l, IgA - 1.35±0.12 g/l. In the period of early convalescence, a decrease in the level of IgM was statistically significant. The elevated concentration of IgA and IgG remained.

In patients with the malignant form, during the period of deep hepatic coma, the immunoglobulin content tended to decrease and averaged 1.58 versus 2.25 g/l in the precomatose period.

The results of the correlation analysis of the titers of anti-liver antibodies and immunoglobulins made it possible to establish a high correlation between liver antibodies and IgM (correlation coefficients of 0.9 and 0.8).

Since autoantibodies (anti-tissue, antibodies to cell components, rheumatoid factor, etc.) are detected in viral hepatitis, the total pool of immunoglobulins may also include antibodies to the host's tissues and cells. It is also known that in acute viral hepatitis, the antibodies to smooth muscles that form are IgM antibodies, so it is possible that the lower IgM level in patients with hepatitis B is explained by the low content of anti-organ antibodies in the blood serum. In patients with the malignant form, in whom autoantibodies were not detected or were determined in low titers, the content decreased with the development of deep hepatic coma.

Thus, the research data confirm the possibility of autoimmune reactions in viral hepatitis in children. The participation of autoantibodies in the pathogenesis of liver necrosis is indirectly confirmed by a decrease in the titer of circulating autoantibodies in more severe forms of the disease, especially in patients with a malignant form. Apparently, the depth of liver damage in viral hepatitis correlates with the degree of antibody fixation on the organ. Higher titers of liver and smooth muscle antibodies in mild forms of viral hepatitis may reflect a low degree of their fixation.

Studies conducted using the fluorescent antibody method also indicate the involvement of the liver in the immunopathological process in viral hepatitis. All patients who died from massive and submassive liver necrosis had immunoglobulin - cell content - in the liver tissue, spleen and lymph nodes. These cells were located both individually and in groups around the remaining hepatocytes, as well as in the central and intermediary zones emptied of liver cells. It is characteristic that the cells containing IgA, IgG and IgM were approximately equal in number. Groups of luminous hepatocytes with immunoglobulins fixed on their surface were also detected.

Based on the literature data indicating that the liver in the postnatal period under normal conditions does not participate in immunogenesis and does not contain plasma cells and does not produce immunoglobulins, it can be considered that in the malignant form the liver is included in the immunopathological process and that the specific luminescence of hepatocyte groups is apparently due to the formation of antigen-antibody complexes. It is known that complement or some of its components, when fixed on the antigen-antibody complex, cause a number of pathological processes that contribute to necrosis (intravascular coagulation of blood, aggregation of leukocytes with disruption of the integrity of their membranes and subsequent release of hydrolytic enzymes of lysosomes, histamine release, etc.). The possibility of a direct damaging effect of fixed antibodies on hepatocytes is also possible.

Thus, a comprehensive study of immunological processes in patients with viral hepatitis suggests that in response to numerous antigens that arise during autolytic decay, anti-organ antibodies, most likely IgM, accumulate in the blood serum of patients. Since the titer of anti-organ antibodies decreases as the severity of the disease increases, and antigen-antibody complexes are found in liver sections treated with monovalent anti-IgM, IgA, and Ig-fluorescent serums, it can be assumed that autoantibodies are fixed to liver tissue in viral hepatitis. This process is especially intense in severe forms of the disease. Fixed autoantibodies are capable of deepening the pathological process in the liver. This is probably where the role of organ antibodies in the pathogenesis of liver necrosis in viral hepatitis is manifested.

Hypothesis of the pathogenesis of massive liver necrosis in viral hepatitis

The results of a comprehensive study of the processes of lipid peroxidation, marker, lysosomal hydrolases in combination with their inhibitors, immune status and autoimmune shifts allow us to present the pathogenesis of liver necrosis as follows.

Hepatitis viruses, due to their tropism for liver epithelial cells, penetrate into the hepatocyte, where, as a result of interaction with biological macromolecules (possibly with components of the endoplasmic reticulum membranes capable of participating in detoxification processes, by analogy with other damaging agents, as was shown in relation to carbon tetrachloride), free radicals are formed, which act as initiators of lipid peroxidation of cell membranes. A sharp increase in lipid peroxidation leads to a change in the structural organization of the lipid components of the 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. It becomes possible for biologically active substances to move along a concentration gradient. Since the concentration of enzymes inside cells is tens and even several thousand times higher than that in the extracellular space, the activity of enzymes with cytoplasmic, mitochondrial, lysosomal and other functions increases in the blood serum. localization, which indirectly indicates a decrease in their concentration in intracellular structures, and, consequently, a reduced bioenergetic regime of chemical transformations. The replacement of intracellular potassium with sodium and calcium ions increases breakdowns in oxidative phosphorylation and promotes the development of intracellular acidosis (accumulation of H-ions).

The changed reaction of the environment in hepatocytes and the disruption of the structural organization of subcellular membranes lead to the activation and release of acid hydrolases (RNAse, DNAse, cathepsins, etc.) from lysosomal vacuoles. This is to a certain extent facilitated by a decrease in the activity of proteinase inhibitors - a2-macroglobulin and a1-antitrypsin. The action of proteolytic enzymes ultimately leads to the disintegration of liver cells with the release of protein components. They can act as autoantigens and, along with the hepatotropic virus, stimulate the formation of specific antihepatic antibodies capable of attacking the liver parenchyma. This can become the final stage in the occurrence of irreversible changes in the liver parenchyma. The issue of sensitization of T and B lymphocytes and their participation in the pathogenesis of massive liver necrosis requires additional study.

Lipid peroxidation products, which have now been proven to control the permeability of cell membranes, trigger the pathological process. Research results have shown a sharp increase in peroxidation processes from the first days of viral hepatitis.

The hypothesis about the role of lipid peroxidation and cell death in general was put forward and substantiated by Yu. A. Vladimirov and A. I. Archakov (1972). According to this hypothesis, under conditions of sufficient oxygen access, any type of tissue damage at some stage includes chain radical oxidation of lipids, and this damages the cell due to a sharp violation of the permeability of cell membranes and the inactivation of vital enzymes and processes. Among the consequences of excessive formation of lipid peroxides, according to the authors, the accumulation of Ca2+ in cells, early uncoupling of oxidative phosphorylation, and activation of lysosomal hydrolases may be of significant importance.

Studies have shown that in viral hepatitis there is a sharp increase in the activity of acid hydrolases and a natural movement of electrolytes along the concentration gradient is observed.

In the proposed hypothesis of the pathogenesis of liver necrosis, the immediate cause of hepatocyte death at the early stages of the disease is the dissociated reactions of oxidative phosphorylation. This process occurs with the participation of lysosomal hydrolases and is most likely limited in nature at the initial stage with autolytic disintegration of individual hepatocytes and the release of antigen complexes. However, later the process acquires an avalanche character. There are several reasons for such a mechanism of development of the process.

Firstly, lipid peroxidation by its nature has a chain avalanche character, so that at the height of the disease a sufficient amount of toxic peroxide products accumulates. They cause polymerization of proteins, destroy sulfhydryl groups of enzymes, disrupt the structural organization of cell membranes, which ultimately leads to total uncoupling of oxidative phosphorylation. Secondly, at the height of the disease, a particularly high activity of lysosomal hydrolases is noted: their pathological action is facilitated by complete structural disorganization of the cell and a sharp drop in the activity of proteolysis inhibitors. And, finally, by this period, sufficiently high titers of antihepatic antibodies accumulate in the blood, affecting the liver parenchyma.

The development of massive liver necrosis is preceded by intensive virus production, as evidenced by the presence of HBsAg and HBeAg in the blood at the earliest stages of the development of the malignant form of hepatitis. At the same time, the number of T-lymphocytes steadily decreases with a clear increase in the content of B-cells and a release of high concentrations of immunoglobulins, mainly IgM, into the bloodstream is noted. These data correlate well with the data that many patients with malignant hepatitis B have excess anti-HBg-IgM, while in the favorable course of the disease, anti-HBe are extremely rarely detected in the acute period.

Insufficient and short-term detection of HBV antigens in the blood in fulminant hepatitis is difficult to explain by a sudden cessation of their production; most likely, they are produced in sufficient quantities, but are blocked in the blood and liver by excess antibodies, as indicated by the detection of HBsAg-anti-HBs complexes in the blood, a drop in humoral autoantibody titers, and fixation of immunoglobulins on hepatocytes in those who died from massive liver necrosis. It can be thought that as a result of massive invasion of the infectious agent (usually in patients who received transfusions of blood and its components), a strong immune reaction of the IgM type occurs in the body, which depends little on the influence of T cells and leads to blocking of the virus in situ, and, consequently, to the death of the infected cell. Since there is a massive invasion of the virus, massive destruction of the epithelial tissue also occurs due to the mechanisms presented in the diagram.

A decrease in the number of T cells, especially in patients in a coma, as well as paresis of the functional capacity of lymphocytes (rosette formation in the RBTL and RTML toasts, lack of redistribution in the subpotgulations of T lymphocytes; and an increase in the permeability of lymphocyte membranes become secondary phenomena due to the toxic effect of metabolites and radicals of incomplete intermediate metabolism on immunocompetent cells.

In conclusion, it should be emphasized that the above hypothesis on the pathogenesis of severe forms of the disease can be extended to cases of viral hepatitis with a favorable course, with the only peculiarity being that all links of pathogenesis are realized at a qualitatively different level. Unlike the malignant form, with a favorable course of viral hepatitis, the processes of lipid peroxidation are not enhanced so significantly: the activation of acid hydrolases leads only to limited autolysis with an insignificant release of the antigen complex, therefore, without massive autoaggression. That is, all links of pathogenesis with a favorable outcome are realized within the framework of the preserved structural organization of the liver parenchyma and the adequacy of the defense systems, and therefore the process does not have such a destructive force as in fulminant hepatitis.

Symptoms of malignant hepatitis

Clinical symptoms of malignant hepatitis depend on the prevalence of massive liver necrosis, the rate of its development, and the stage of the pathological process. It is customary to distinguish between the initial period of the disease, or the period of precursors, the moment of development of massive liver necrosis (which usually corresponds to the state of precoma), and the period of rapidly progressing decompensation of liver functions, clinically manifested by coma I and coma II.

The disease often begins acutely - the body temperature rises to 38-39 °C, lethargy, adynamia, sometimes drowsiness appear, followed by attacks of anxiety or motor agitation. Dyspeptic disorders are expressed: nausea, vomiting (often repeated), sometimes diarrhea. However, not all of these symptoms appear on the first day of the disease. Among the patients we observed, acute onset was observed in almost 70%, repeated vomiting was noted in half, anxiety with attacks of drowsiness - in 40%, diarrhea - in 15% of patients. In some cases, at the beginning of the disease, symptoms of intoxication were completely absent, and the onset of the disease was considered the appearance of jaundice. The duration of the pre-icteric period in the malignant form is short: up to 3 days - in 50%, up to 5 days - in 75% of patients.

With the appearance of jaundice, the condition of patients quickly worsens: symptoms of intoxication increase, vomiting becomes frequent and with an admixture of blood. Jaundice is accompanied by a rapidly progressing hemorrhagic syndrome, the size of the liver decreases, symptoms of cardiovascular failure appear.

Neuropsychiatric disorders. The main and earliest clinical sign of the developing malignant form in young children is psychomotor agitation, which is characterized by severe anxiety, causeless crying, and screaming. The attacks last for hours and usually occur at night. The child rushes about, asks to be picked up, looks for the mother's breast, tries to suck greedily, but then immediately refuses the breast with a cry, kicks his legs, and turns his head. The cause of this agitation is most likely a lesion of the subcortical centers, which manifests itself in the early stages of the disease by disinhibition of the subcortical and basal ganglia. As liver failure develops and deepens and hepatic coma develops, an inhibitory process occurs, spreading to the subcortical nodes, the brain stem, and the cerebral cortex.

Frequency of clinical symptoms in different periods of malignant viral hepatitis (%)

Clinical symptom	Period
	Onset of the disease	Precoma	Coma
Lethargy	100	100	100
Decreased appetite, anssheksia	42.2	100	100
Repeated or multiple vomiting	44.4	66.6	97.7
Vomiting with blood	17.7	66.6	86.6
Anxiety	64.4	86.6	95.5
Sleep inversion	26.6	42.2	64.4
Screams	26.6	44.4	66.6
Convulsive syndrome	22,22	53.3	84.6
Increased body temperature	48.8	31.3	46.6
Tachycardia	45.4	81.5	85.2
Toxic Breath	13 3	55.5	86.6
Hemorrhagic rashes	40	62.2	66.6
Pasty tissue	17.7	33.3	41.5
Bloating	26.6	64.4	91.5
Ascites	-	4.4	8.8
Liver odor	-	28.8	40.0
Empty hypochondrium symptom	-	6.8	60.4
Anuria	-	_	31.1
Melena	-	-	15.5
Pulmonary edema	-	-	13.5

In older children and adults, symptoms indicating CNS damage include mental instability, irritability, and disorientation in time and space. Older children may complain of bouts of melancholy, memory lapses, and handwriting disorders. Further progression of the listed symptoms may be accompanied by acute psychosis and delirious state with motor agitation, delirium, and hallucinations. In the final stage of the disease, a state of agitation and convulsions are observed.

According to research data, in children in the first months of life, changes in the central nervous system were characterized by the appearance of symptoms such as anxiety, screaming, drowsiness, chin trembling, tonic-clonic seizures, and in advanced cases, a decrease in tendon reflexes, impaired consciousness, and often the appearance of various pathological reflexes (proboscis, Babinski's symptom, clonus of the feet) were noted.

The "flapping" tremor characteristic of the malignant form in adults, which many authors attribute to crucial importance for the diagnosis of impending hepatic coma, is not observed in young children. They usually have involuntary chaotic twitching of the fingers, less often of the hands. Many of the listed symptoms indicating damage to the central nervous system appear even before the onset of a pre-comatose state, but most often and most fully are expressed in the comatose period.

Vomiting is a characteristic symptom of malignant hepatitis. If vomiting occurs in the pre-icteric period in mild forms of viral hepatitis, then in patients with the malignant form it is repeated throughout the disease. In addition, frequent regurgitation is constantly observed in young children. At the onset of the disease, vomiting usually occurs after eating, drinking or taking medications, then appears spontaneously, often taking on the color of coffee grounds. Blood in the vomit is observed only in patients with the malignant form. This symptom indicates the occurrence of severe disorders in the blood coagulation system. The admixture of blood at first may be insignificant, dark brown coloring is observed only in individual portions of vomit, so this important symptom is sometimes not recorded. With profuse gastric and intestinal bleeding, which usually occurs at the height of clinical manifestations of the malignant form, the vomit is colored more intensely and acquires a dark brown color. Dark tarry feces also appear. Among the children we observed, repeated vomiting was observed in all, vomiting with blood in 77%, and tarry stools (melena) in 15%.

In addition, nosebleeds, minor hemorrhages, and even ecchymosis on the skin of the neck, trunk, and less commonly on the extremities were noted.

There may be hemorrhages in the mucous membrane of the oropharynx and uterine bleeding. The hemorrhagic syndrome is based on a sharp disruption of the synthesis of blood coagulation factors in the liver and toxic damage to blood vessels. Much importance is attached to consumption coagulopathy (intravascular blood coagulation), which occurs against the background of increased activity of procoagulation factors. It is believed that the coagulopathy process is carried out mainly by thromboplastin released from necrotic hepatocytes and, possibly, by the effect of the virus on endothelial cells and platelets.

Hemorrhagic syndrome can be considered a typical sign of the malignant form of hepatitis B. According to research data, hemorrhagic rashes on the skin and visible mucous membranes were present in 66.6% of patients, and during morphological examination, hemorrhages in the internal organs were detected in all cases with a legal outcome: more often - under the pleura, in the epicardium, brain matter, lungs, liver, stomach and intestines, less often - in the kidneys, spleen, thymus, sometimes in the adrenal glands, pancreas, heart muscle and mesentery.

Liver odor (Peach's foetor) can also be considered a pathognomonic sign of the malignant form of the disease. It usually resembles the smell of fresh raw liver. It is best detected by the patient's breath, but urine, vomit, and dirty linen have approximately the same smell. It is assumed that this sign is caused by a disorder of methionine metabolism, as a result of which methyl mercaptan accumulates in the blood, producing a characteristic odor. The appearance of the odor almost always indicates severe liver damage, but it does not occur in all cases of malignant forms of hepatitis. This symptom is observed in only a third of patients.

Fever usually occurs in the terminal period of malignant forms, but sometimes appears at the moment of acute reduction in liver size, which allows us to think about the connection between the increase in body temperature and the disintegration of the liver parenchyma. In the patients with the malignant form of the disease that we observed, fever was noted in 46.6% of cases. Body temperature reached 40 °C and higher. In the terminal period, fever was persistent and did not respond to antipyretic drugs. It can be considered that hyperthermia in these patients was a consequence of severe damage to the diencephalic region with a violation of the function of the thermoregulatory center.

In some patients, the disease may occur at normal body temperature. Sometimes the appearance of fever is associated with the layering of an intercurrent disease - acute respiratory disease, pneumonia, etc.

By its nature, fever in the malignant form has no specific features. Most often, body temperature increases gradually or stepwise. There are cases in which it quickly rises to high values.

Pain syndrome can be attributed to early signs of developing malignant form of the disease. Adults usually complain of dull, aching pain in the right hypochondrium. Sometimes sharp pains occur, which in some cases can resemble an attack of gallstone disease or acute appendicitis. The appearance of pain in young children is primarily indicated by sharp anxiety and periodic screams, when trying to palpate the liver, motor restlessness occurs and the scream intensifies.

The causes of pain are most likely necrosis and autolytic decay of the liver parenchyma. Less significant, apparently, is the damage to the bile ducts, capsule and pancreas.

Acute reduction in liver size is one of the most characteristic signs of the developing malignant form. In deceased patients, a decrease in organ mass by 1.5-2 or even 3 times is detected. It is important to pay attention to the rate of decrease in liver size and its consistency. At the earliest stages of the disease, the liver is still usually enlarged, but its consistency becomes less dense, even doughy. Then, a rapid decrease in the liver begins, and its rate reflects the dynamics of the development of massive necrosis of the liver parenchyma, its decay and autolysis. In cases of acute malignant form, the liver size usually decreases quite quickly, literally within 12-24 hours, with a hollow thunderclap course of the disease - gradually, in spurts, with each subsequent decrease in the organ accompanied by an increase in intoxication symptoms. Sometimes, with an acute course of the disease, the decrease in liver size is not so fast - within 2-3 days; in some cases, with a lightning-fast course, it is not possible to detect this process, since already upon admission the liver size is small (its edge is palpated at the costal arch and has a doughy consistency). A decrease in the liver size is usually also noted in cases of hepatic coma in chronic hepatitis. This circumstance must be taken into account when diagnosing malignant forms.

Jaundice, when the malignant form of the disease occurs, quickly increases and reaches its maximum expression in the comatose period. However, malignant forms also occur with relatively weak icterus. This usually happens with a fulminant course of the disease, when massive necrosis occurs in the very initial, pre-icteric period of the disease, but sometimes weak jaundice occurs in the subacute course of malignant forms. True, in such patients, at the very beginning of the disease, jaundice is pronounced, then, before the onset of coma, it begins to decrease and may already be weak in the comatose period. In rare cases, with malignant forms, a recurrent nature of jaundice may also be noted.

Assessing jaundice as an indicator of severity, it is necessary to emphasize that in children of the first year of life, the average bilirubin content in the blood with malignant forms is reliably lower than in older children with similar forms of the disease. Thus, according to our data, in young children this indicator at the height of the malignant form was within 137-222 μmol/l, while in older children with the same forms it was higher than 250 μmol/l.

Changes in the cardiovascular system are observed in all patients with the malignant form of the disease. They are usually characterized by the appearance of tachycardia and a decrease in blood pressure - less often systolic, more often diastolic. In the comatose period, there may be a drop in cardiovascular activity by the type of collapse. At the height of clinical manifestations, a violation of the pulse rhythm in the form of extrasystole in combination with tachycardia is sometimes observed. It is believed that the premature appearance of the second tone due to accelerated emptying of the heart ("woodpecker knock") is typical for malignant forms. This phenomenon appears as a result of gross violations of the contractile process in the heart muscle.

As the malignant form progresses in its terminal stage, changes in the cardiovascular system are often accompanied by symptoms of cardiopulmonary insufficiency, as evidenced by increasing pallor, cyanosis, and pulmonary edema.

Changes in the cardiovascular system in patients with malignant forms, on the one hand, can be explained by extracardiac influences due to damage to the central nervous system (midbrain and medulla oblongata), as well as the autonomic nervous system; and on the other hand, by the development of the so-called hepatocardial syndrome in liver failure due to metabolic disorders in the myocardium (energy-dynamic cardiac failure caused by ATP metabolism disorders).

However, regardless of the mechanism of damage to the cardiovascular system, in practical terms it is important to know that the appearance of tachycardia in viral hepatitis is a prognostically unfavorable sign.

Electrocardiographic changes in the malignant form are expressed in flattening and reduction of the T wave, prolongation of the QT interval, and often in a decrease in the ST interval.

Pathological changes in the heart are characterized by dilation of its cavities and gross dystrophic processes in the myocardium.

Changes in the respiratory system in patients with the malignant form include dyspnea (toxic noisy breathing); as the comatose state deepens, breathing becomes intermittent, like Kussmaul or Cheyne-Stokes. In the terminal stage, breathing can become much slower. Pulmonary edema appears and progresses rapidly. In such patients, a large number of different-sized moist rales are heard, foamy fluid is released from the mouth and nose, sometimes with an admixture of blood (hemorrhagic pulmonary edema).

For diagnostics, it is especially important that changes in the respiratory system in patients with a malignant form in the form of toxic dyspnea often appear in the earliest stages of liver necrosis.

Changes in the kidneys are observed in all patients with the malignant form. The daily amount of urine excreted is significantly reduced already in the early stages of the disease, which has diagnostic significance. Sometimes, as the process progresses, anuria may occur. In these cases, the disease usually has a poor prognosis. And, conversely, an increase in diuresis, especially polyuria, can be considered a favorable prognostic sign, a kind of crisis, after which a gradual recovery begins.

Along with a decrease in diuresis, in the malignant form, a moderate increase in the residual nitrogen content with a simultaneous decrease in the content of inulin and creatinine, progression of hyponatremia and hypokalemia, a decrease in renal plasma flow and especially glomerular filtration can be observed. These changes can be interpreted as hepatorenal syndrome. Great importance in the disruption of the functional state of the kidneys is given to hormonal regulation, in particular the renin-angiotensin-aldosterone system. According to research data, in patients with a malignant form, the synthesis, breakdown and inactivation of some hormones are sharply disrupted.

On the part of the adrenal cortex, a pronounced promineralocorticoid orientation with signs of hyperaldosteronism is noted. The accumulation of aldosterone in the blood leads to the retention of sodium and potassium, which results in increased reabsorption of water in the kidneys, which causes its retention in the body. Clinically, this is manifested by tissue pastosity and even ascites. However, we observed edematous-ascitic syndrome exclusively in the subacute course of the malignant form. In cases with an acute course of the disease, renal dysfunction was also sharply expressed, but edematous-ascitic syndrome did not occur.

It must be assumed that renal dysfunction in patients with malignant forms is caused by many factors. Among them, an important place belongs to morphological changes in the renal parenchyma, which are apparently caused by both immunopathological reactions initiated by the virus itself and the toxic effect of many products of impaired metabolism. Functional (mainly extrarenal) disorders associated with the accumulation of aldosterone and pituitary antidiuretic hormone in the blood are also important. Metabolic acidosis and disturbances of water-electrolyte balance, as well as rapidly progressing hypoproteinemia, play an important role.

Thus, in patients with a malignant form, the most constant clinical symptoms are psychomotor agitation, repeated vomiting with blood, tachycardia, toxic breath, abdominal distension, severe hemorrhagic syndrome, increased body temperature and decreased diuresis. It is important to emphasize that symptoms such as coffee-ground vomiting, sleep inversion, convulsive syndrome, hyperthermia, tachycardia, toxic breath, liver odor, and decreased liver size are observed only in malignant forms of the disease. Following these symptoms or simultaneously with them, there is a clouding of consciousness with a characteristic clinical picture of hepatic coma.

Diagnosis of malignant hepatitis

For early diagnosis of the malignant form, the rate of jaundice development and the level of bilirubin in the blood serum are important. In the malignant form, the bilirubin content in the blood increases very quickly and reaches its maximum values already on the 3rd-5th day from the onset of jaundice. Of particular importance is the rapid increase in the level of unconjugated bilirubin in the blood serum. As a result, the ratio of the amount of free bilirubin to the content of the conjugated fraction approaches one, sometimes it is greater than one, while in patients with a severe form without the development of massive liver necrosis, this indicator is always less than one. However, its value has prognostic significance only in cases of high total bilirubin content in the blood serum; in this case, it is necessary to take into account the severity of the clinical picture.

The malignant form is also characterized by bilirubin-enzyme dissociation - with a high content of bilirubin in the blood serum, a decrease in the activity of cytoplasmic, mitochondrial, lysosomal and other enzymes is noted. This process is associated with the disintegration of the liver parenchyma, and therefore, by determining the activity of enzymes with different subcellular localization, it is possible to establish not only the site of primary damage to the hepatocyte structure, but also the stage from which cell function disorders become irreversible.

According to research data, the activity of all cytoplasmic, mitochondrial and lysosomal enzymes is highest at the onset of the malignant form of the disease, later, as the symptoms of intoxication increase and the liver shrinks, their activity quickly decreases. At the same time, the dynamics of the decrease in activity varies significantly in the groups of enzymes reflecting the state of various subcellular structures. The essence of this difference is that the activity of lysosomal enzymes falls especially quickly as the liver shrinks and is not determined at all during deep hepatic coma, while the activity of mitochondrial and cytoplasmic enzymes decreases more slowly, and even immediately before death, increased activity of these enzymes is determined in the blood serum. Our data allow us to believe that the death of hepatocytes in malignant forms occurs due to the depletion of the lysosome enzyme systems, later the mitochondrial enzyme systems are completely disorganized, the functional capacity of the cytoplasmic matrix is preserved the longest.

Lipidogram indicators are also highly informative. In patients with the malignant form, the content of beta-lipoproteins, triglycerides, free and ether-bound cholesterol is sharply reduced. The cholesterol esterification coefficient decreases. Beta-lipoproteins are especially indicative, the content of which begins to decrease already at the earliest stages of massive liver necrosis, when clinical manifestations and normal biochemical indicators do not yet indicate the particular severity of liver damage.

Changes in peripheral blood may be of auxiliary importance for the diagnosis of malignant hepatitis. In malignant forms, moderate microcytic anemia is often observed already at early stages, and a clear tendency towards a decrease in the amount of hemoglobin and platelets is observed. Leukocytosis is more often observed in white blood, more pronounced in the precomatose period; neutrophilia with a shift to band cells (sometimes to young forms and myelocytes), lymphopenia and eosinopenia are characteristic; ESR is usually reduced.

For early diagnostics of malignant forms, detection of antibodies against the surface antigen - anti-HBs - in free circulation is also important. According to research data, anti-HBs were often detected already at the early stages of malignant forms, whereas in the benign course of the disease they were detected no earlier than 2-3 months after the onset of hepatitis.

[ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ]

Treatment of malignant forms of viral hepatitis and hepatic coma

Patients with fulminant hepatitis and hepatic coma should be treated in the intensive care unit of an infectious diseases clinic or in a specialized hepatology center.

The protein content of the patients' diet is significantly limited to 0.5 g/kg per day, with a subsequent increase to 1.5 g/kg as the condition improves. With the development of hepatic coma, proteins and fats are completely excluded from the diet. After the patient comes out of the comatose state, the protein content in the daily diet is gradually increased to 20 g, and then to 40-50 g, mainly due to dairy products. The energy value of the daily diet is 900-1200 kcal. Fruit and vegetable juices, rosehip decoction, kissels, jelly, honey, slimy soups, strained cottage cheese, unsalted butter are recommended. The patient should be fed every 2 hours; food is given in a strained form.

To ensure the body's energy needs during coma, parenteral administration of a 10% glucose solution is performed. If the act of swallowing is maintained, the patient is prescribed a 20-40% glucose solution, fruit and vegetable juices for drinking.

For enteral nutrition, compositions containing arginine, purine nucleotides, omega-3 fatty acids are used. Enteral nutrition helps maintain the protective barrier of the intestinal mucosa, which prevents the translocation of pathogenic microbes into the vascular bed.

Decontamination of the intestines is carried out. For this purpose, patients are given high cleansing enemas, repeated gastric lavage, and enteral antibacterial drugs are prescribed: semi-synthetic penicillins, aminoglycosides, metronidazole, etc. Decontamination of the intestines in patients with fulminant hepatitis reduces the frequency of infectious complications to 20%.

There is no etiotropic therapy for fulminant viral hepatitis. The use of recombinant interferon-alpha preparations in the immunopathogenesis of acute submassive and massive liver necrosis is ineffective.

Detoxification is the first priority in the treatment of patients with hepatic encephalopathy and coma. In this case, parenteral administration of low-concentration glucose solutions and polyionic crystalloid solutions is combined. Combinations of hemodesis, glucose solution and polyionic crystalloid solutions are effective. Taking into account the microcirculatory disorders developing during acute massive liver necrosis, which create conditions for the development of erythrocyte "sludge", subsequent disseminated thrombosis and increased autolysis, the administration of a solution of low-molecular dxstran - rheopodiglucin is added to the therapy of patients with hepatic coma. According to A. A. Mikhailenko and V. I. Pokrovsky (1997), the inclusion of rheopodiglucin in the treatment program for patients with hepatic coma contributed to the recovery from coma in 4 out of 5 treated patients, compared with 3 out of 14 who did not receive this drug.

The fight against cerebral edema is carried out with the help of intravenous administration of a 20% solution of mannitol - its administration to patients with hepatic coma increased the proportion of surviving patients from 5.9 to 47.1%.

Taking into account water-electrolyte disturbances in fulminant deficiency, it is necessary to monitor potassium levels and correct hypokalemia.

It is important to remember that infusion therapy in patients with malignant hepatitis should be carried out with strict control of diuresis, since excessive fluid administration becomes one of the causes of cerebral edema that occurs with comatogenic liver failure.

Due to the decline in the liver's detoxifying function, it must be compensated with medications. One of them is the domestic drug Reamberin. This is a fourth-generation infusion drug - a balanced isotonic detoxifying infusion solution based on succinic acid. It has antihypoxic and antioxidant effects. Reamberin activates the antioxidant enzyme system and inhibits lipid peroxidation processes in ischemic organs, exerting a membrane-stabilizing effect on the cells of the brain, liver, and kidneys; in addition, it has a moderate diuretic effect.

One of the controversial aspects of intensive care in comatose states is the use of glucocorticoids. Since the publication of the work of H Ducci and K Catz in 1952, the prescription of glucocorticoids for comatogenic liver failure has become mandatory. Many researchers note the high risk of developing side effects of glucocorticoids - stimulation of protein catabolism with increasing azotemia, the development of septic complications and gastrointestinal ulcers.

K. Mayer (2000) believes that glucocorticoids are contraindicated in fulminant hepatitis.

According to clinical observations, in pediatric practice, the administration of glucocorticoids to patients with malignant viral hepatitis, especially before the development of coma, gives a positive result and promotes the survival of patients. It is advisable to conduct a short (7-10-day) course of hormonal therapy, with the maximum dose of glucocorticoids prescribed on the 1st-2nd day, followed by a significant reduction in the dose of the drug over 4-7 days.

Taking into account the pathogenetic role of proteolytic enzymes in the development of autolysis in fulminant hepatitis, proteolysis inhibitors are included in the therapy of malignant forms of viral hepatitis: aprotinin (trasylol, gordox, contrikal) in a dosage regimen appropriate for age.

One of the methods of treating hepatic coma is anesthetic protection of the central nervous system, based on the use of sodium oxybutyrate. This drug not only relieves psychomotor agitation, but also slows the rate of progression of the comatose state. The basis of anesthetic protection of the central nervous system is probably the rupture of the vicious circle of pathological impulses from the center to the periphery by the anesthetic, developing in comatogenic liver failure.

In comatose states, hemostasis is corrected using heparin, fibrinogen, aminocaproic acid, and transfusion of fresh frozen plasma. The mechanism of therapeutic action of plasma is associated with the detoxifying effect, correction of plasma protein deficiency, which helps ensure the transport, oncotic function of the blood and normalization of metabolic processes. Concentrated solutions of albumin and protein (a complex of all protein fractions of plasma) can also be used. In their hemodynamic effect, they are superior to native plasma, which makes their use preferable in the correction of hemodynamic disorders, cerebral and pulmonary edema.

Extracorporeal detoxification methods such as dialysis and sorbent hemoperfusion (hemosorption) have been used to treat patients with fulminant liver failure. These methods significantly reduce the manifestations of encephalopathy in chronic liver diseases, but they are ineffective in patients with fulminant hepatitis.

The use of high-volume plasmapheresis with replacement of 1 l/h of plasma for 3 days improves hemodynamic parameters and cerebral blood flow, reduces manifestations of encephalopathy, serum bilirubin levels and normalizes prothrombin time in patients with fulminant liver failure. However, no reduction in mortality is observed.

Artificial liver for malignant hepatitis

Human hepatoblastoma cells and porcine hepatocytes are used as artificial livers. Plasma or blood from a patient with fulminant liver failure is passed through a network of thin, permeable capillary tubes placed in a chamber containing a hepatocyte culture. The purpose of using an artificial liver is to create conditions for restoring the patient's liver function or replacing it in preparation for a donor organ transplant.

The use of artificial liver has only recently begun, and many technical aspects and parameters need to be worked out. It is reported that when using a system with pig hepatocytes in patients with fulminant liver failure, a decrease in intracranial pressure and the stage of encephalopathy is noted.

It remains to be seen whether it is possible to restore the patient's liver function with the help of an artificial liver or whether it will only be a palliative method to gain time for the preparation and implementation of a liver transplant.

[ 17 ], [ 18 ], [ 19 ], [ 20 ], [ 21 ], [ 22 ]

Liver transplantation for fulminant hepatitis

Liver transplantation is performed in patients with fulminant hepatitis with developing coma who have not responded to therapeutic treatment. The purpose of transplantation is temporary replacement of the patient's liver functions during the period of recovery and regeneration of the organ.

The first liver transplant operation was performed by T. Starzl in 1963. Currently, liver transplants are regularly performed in many specialized medical centers abroad and in our country.

In almost all cases, we are talking about orthotopic transplantation, that is, transplanting a donor liver into the place of the recipient’s removed liver.

Heterotopic liver transplantation, in which the donor liver is placed in the left iliac fossa as an additional organ, is currently used only in some centers for the treatment of fulminant liver failure.

Indications for liver transplantation, contraindications, criteria for the urgency of the operation, and criteria for selecting donors for liver donation have been developed. After completion of the liver transplantation operation, the patient is admitted to the ward of the surgical transplant department, where the average length of stay in the uncomplicated postoperative period is 3 weeks. After discharge from the surgical department, the patient is transferred to outpatient observation of a therapist-hepatologist.

The basis of therapy in the post-transplant period is adequate immunosuppression, which prevents rejection of the transplanted liver.

According to S.V. Gauthier et al. (2007), since the first liver transplant in Russia (February 14, 1990), more than 200 such operations have been performed, including 123 children aged 6 months to 17 years. Several liver transplant operations were performed on an emergency basis in patients with fulminant viral hepatitis. The authors note a high survival rate of patients after liver transplantation, reaching 96.8%.

It should be emphasized that liver transplantation is a technically complex extensive surgical intervention, which is the only real possibility of saving the life of a patient with fulminant liver failure in the absence of the patient's body's response to therapeutic measures.

The use of hepatoprotective drugs containing phospholipids in the complex treatment of patients with malignant viral hepatitis seems promising. It is necessary that these drugs have high bioavailability, i.e. be prepared using nanotechnology. An example of such a drug is nanophospholip, created in the laboratory of nanomedicines of the V.N. Orekhovich Research Institute of Biomedical Chemistry. In nanophospholip, phospholipid molecules are in the smallest granules measuring 20 nm, while all existing analogs of the drug (for example, Essentiale) consist of macro-sized particles that are several orders of magnitude larger. It is possible to consider the use of nanophospholip as a "membrane glue" to strengthen cell membranes and prevent endotoxemia at the cellular level in fulminant hepatitis pathogenetically justified.