Fulminant (malignant) hepatitis

Fulminant hepatitis is a special clinical form of acute hepatitis, resulting from submissive or massive liver necrosis caused by an etiological agent and characterized by a complex of clinical and biochemical symptoms of progressive hepatic insufficiency.

Malignant form of hepatitis is described under different names: acute liver necrosis, toxic liver dystrophy, massive or submissive liver necrosis, hepatodystrophy, acute yellow atrophy of the liver, etc. All existing names can not be considered quite successful, since they either reflect morphological changes (necrosis of the liver) , or at all do not cover the pathogenetic essence of changes in the liver (toxic dystrophy of the liver). In foreign literature, the term "fulminant hepatitis", that is, hepatitis with fulminant course, is used to designate such forms. Fundamentally, this terminology is not objectionable, but the term "fulminant", or "fulminant," sounds too fatally, especially if we consider that in recent years, the disease often ends in recovery.

Do not satisfy clinicians and such terms as "hepatodystrophy", "liver failure", "portal encephalopathy", "hepatic encephalopathy", "hepatargia," hepatonecrosis, and others.

In the opinion of most clinicians, for example, viral hepatitis, accompanied by massive or submissive liver necrosis and progressive liver failure, is more correctly called malignant, given the severity of clinical manifestations and high mortality. Malignant form can not be identified with a severe form of the disease. These are two qualitatively different states - both in clinical manifestations (with malignant form, symptoms that are absent in other forms of hepatitis) and morphological (massive, sometimes total, liver necrosis is found only in malignant form). On the other hand, the malignant form can not be identified with the concept of "liver failure" or "hepatic coma". The term "malignant form" serves to refer to a separate clinical form of viral hepatitis, whereas the concept of "liver failure" reflects a violation of liver function. It is accepted to distinguish between hepatic insufficiency of I, II, III degrees, as well as compensated, subcompensated and decompensated forms of malignant hepatitis. In those cases when hepatic failure is accompanied by CNS damage, it is customary to talk about a hepatic coma. Consequently, the hepatic coma is an extremely severe manifestation of hepatic insufficiency, its final stage.

Malignant form can not be interpreted as a complication of viral hepatitis. Still S.P. Botkin put forward the proposition that acute yellow atrophy fits into the concept of "catarrhal jaundice" as the most severe form, unified with it in etiology and essence. According to modern ideas, in every, even the easiest, case of viral hepatitis, hepatic cells die, that is, there is "liver atrophy in miniature." In view of this, 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 that can determine the development of fulminant process in the liver, primarily hepatotropic viruses - pathogens of hepatitis A, B, C, D and E, are distinguished, and their share in the occurrence of malignant hepatitis is 60-70%.

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

Fulminant hepatitis can occur with toxic liver damage due to poisoning with alcohol, fungi, industrial poisons, as well as drugs (antidepressants, antituberculosis drugs, paracetamol, etc.). Some metabolic diseases "such as Wilson-Konovalov's disease, steatohepatitis, in some cases become the cause of fulminant hepatitis. It should be noted that, according to various authors, in 20-40% of cases the etiology of fulminate hepatitis remains unsettled.

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Pathomorphology

In terms of severity and prevalence, liver necrosis in malignant forms of hepatitis can be massive or submissive. With massive necrosis, almost all the epithelium perishes or an insignificant rim of cells is left around the periphery of the lobules. With submissive necrosis, the majority of hepatocytes are destroyed. Mainly in the center of the lobules.

Necrosis of the liver can be acute or subacute. With 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 necrosis of the liver develops at the onset of the disease, even before the appearance of jaundice (lightning-fast forms), or in the late period - on the 3-4th week from the onset of the disease (subacute forms).

When pathoanatomical investigation revealed acute necrosis of the liver, a decrease in mass almost twice, a wrinkled capsule of flabby consistency is noted; the liver seems to blur on the table, the fabric easily tears. On a section, extensive areas of ocher-yellow or dark red color are determined by impregnating the tissue with bile and disturbing blood circulation (underlined muscat). Histological examination reveals extensive fields of the devastated, asleep stroma with the preservation of only a small margin of the hepatic epithelium along the periphery of the lobes; regenerative processes are absent or insignificant. Stroma and reticuloendothelium usually do not undergo necrosis. Necrotic changes are so great that the drug resembles a picture of complete cadaveric autolysis of the liver.

Such a picture is usually observed in cases of lethal outcome on the 6th-8th day of the disease. At a later onset of death, the liver is also reduced in size and flabby, but somewhat more elastic in consistency and is shown mottled by the alternation of many small, sinking reds and a few bulging yellow patches. In histological study, extensive fields of varying degrees of prevalence of dystrophic changes in the hepatic parenchyma with gradual elimination of cellular detritus are determined, up to the complete devastation of the parenchyma.

With subacute necrosis, the liver is usually dense, without a significant decrease in the weight of the organ. The inhomogeneity of the morphological changes in its various parts is determined microscopically, due to the gradual involvement of the lobules into the necrotic process: along with massive and submissive necrosis, active regeneration of the remaining hepatocytes with localization of regenerating cells predominantly around the portal tracts, with proliferation of connective tissue and violation of the paronetic architecture . In the areas of cellular regeneration, there is a peculiar small droplet obesity of hepatocytes 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 central, especially prigiljusth, sites near to large vessels development of pathological process outstrips changes in peripheral sites of an organ. In addition, the left lobe of the liver is usually more affected by the right. If acute liver necrosis is prolonged for a long time (5-6 months or more), then the picture of postnecrotic 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, kidneys show varying degrees of fat and protein dystrophy, up to the widespread necrosis of the renal epithelium; in the spleen - hyperemia, reticular hyperplasia and pulpal myelosis: in the brain - severe dystrophic changes of nerve cells, walls of glia vessels with predominant localization in the cortex, subcortical-stem divisions and the 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 soft dura mater and white subcortical substance. Usually there are circulatory disorders, stasis, perivascular edema, severe dystrophic changes in macroglia leading to its death, as well as microglia. In 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 dissolution of the hepatic tissue.

Why does individual hepatitis take a malignant course?

The question is very complicated. Given that fulminant hepatitis develops almost exclusively in young children, and especially often in premature infants at the age of 2-6 months, it can be assumed that the imperfections of immunocompetent systems and the special sensitivity of metabolic processes under conditions of insufficiently differentiated hepatic parenchyma become the determining factors

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

Factor adversely affecting the course of viral hepatitis, can also be high infectiousness of the pathogen. It is important to emphasize that all children who died from massive liver necrosis are diagnosed with hepatitis B or hepatitis B and D; infection in them occurred with intravenous transfusion of plasma or blood, sometimes multiple, that is, the infection was massive.

Paradoxical at first glance seems to be the absence of HBsAg in the serum of children with malignant forms of hepatitis. Of the 36 patients examined with massive liver necrosis, HBsAg was detected in 9 children. And the antigen in these patients was determined only for the first time days of illness; during subsequent studies in precomatous and comatose periods was no longer determined. These data can be explained by the total destruction of the hepatic parenchyma, which serves as a morphological substratum for viral replication.

Apparently, with fulminant hepatitis, due to the weak synthesis of HBsAg in deeply damaged hepatocytes and its inadequate intake into the blood instead of excess antigen (as is the case with light and medium-heavy forms), there is an excess of 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. They to a certain extent allowed us to believe that the 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 effect 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 activated processes of lipid peroxidation and the action of lysosomal hydrolases are of great importance.

The hypothesis suggested by us can serve as a basis for constructing pathogenetic therapy of severe forms of viral hepatitis and to 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 pathogenesis of malignant forms remains difficult and poorly understood. First of all, it is difficult to answer the question what is behind the avalanche uncontrolled decay of the hepatic parenchyma, what is the role of viruses and factors of autoimmune aggression in it, what are the driving mechanisms of cytolysis and autolysis.

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

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

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

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

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

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

According to the general opinion of hepatologists, fulminant hepatitis develops predominantly with hepatitis B and D, but there are isolated reports of the occurrence of malignant form and with hepatitis C. Still more often with fulminant hepatitis, the HCC gene is detected simultaneously with the hepatitis B virus.

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

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

Hepatitis A in terms of the possible development of malignant form is most dangerous for the elderly.

The mechanism of development of acute or subacute massive or submissive liver necrosis is one of the most complex and least studied in hepatology. Most modern hepatologists, the emergence of massive liver necrosis is associated with cytolytic syndrome, which is understood as the totality of all changes in hepatocytes, reflecting histological, biochemical and humoral disorders in the liver that arise in response to damage to hepatic cells by aggressive factors (primarily hepatotropic viruses).

In this satchel, an attempt is made to present the pathogenesis of liver necrosis based on the study of lipid peroxidation, the role of lysosomal proteinases, immunological status and autoimmune processes.

Peroxide oxidation of lipids and cytolysis syndrome

It is known that the primary and the earliest sign of various cellular injuries are changes in cell membranes, and among the causes that cause these disorders, one of the first places is peroxide oxidation of lipids.

Peroxide oxidation occurs in any cell and in various membrane structures. This process is of a chain, free radical nature in pathological conditions. Under physiological conditions, this does not happen, since there is an entire system that regulates peroxidation. The stably low level of the endogenous process is normally regulated primarily by tissue antioxidants (tocopherol, glucocorticoids, etc.), the presence of glutathione peroxidase, decomposing lipid hydroperoxide without the formation of free radicals, a strictly ordered cell structure. However, with various pathological conditions, when the inhibiting effect of antioxidants decreases or the structural organization of the cell changes, peroxide oxidation can be accelerated dramatically, becoming "explosive", dangerous.

For the study of lipid peroxidation, a kinetic method was used to measure the chemiluminescence of blood serum, that is, an ultraweak luminescence initiated by ferrous ions. In the opinion of Yu.A. Vladimirov et al. (1969), this emission is due to the recombination of peroxide radicals, and therefore its intensity characterizes the rate of the process of lipid peroxidation. The latter was also evaluated according to the amount of the final product, malonic dialdehyde (MDA). The lipid spectrum of blood serum was examined by thin layer chromatography on a fixed gel in Yu.A. Boryshkova et al (1966); Yu.E. Veltisheva ssoavt. (1974). This technique makes it possible to identify phospholipids, free cholesterol, mono-, di- and triglycerides of cholesterol esters, as well as NLC. With a simple addition, you can calculate the level of total cholesterol and total lipids, and also derive the cholesterol esterification factor.

It turned out that in the acute period of viral hepatitis in the blood serum, the number of significantly increased lipid peroxidation rates sharply increases and superweak luminescence of blood serum increases. The degree of severity of the revealed disorders directly depends on the severity of the disease.

High levels of lipid peroxidation are also observed during the development of hepatodystrophy, in the period of acute reduction in liver size. With the development of hepatic coma, these indicators in some patients show a downward trend. At the same time, in the period of deep hepatic coma the intensity of chemiluminescence fell sharply (3 times as compared with that of precoma), and the MDA content increased after a certain decrease, approaching the values noted in severe forms, at the beginning of the development of liver necrosis. These changes in the terminal phase of liver necrosis are connected, apparently, with the complete decay and devastation of the parenchyma of this organ. The processes of lipid peroxidation in viral hepatitis intensify against the background of significant changes in the lipid spectrum of blood serum. In the acute period with all forms of the disease, the content of triglycerides, phospholipids, NEFLC, beta-lipoproteins, free cholesterol increases, while the cholesterol esterification coefficient decreases.

The degree of severity of these disorders, as well as the parameters of peroxidation, is directly related to the severity of the disease. If in a light form the content of triglycerides, phospholipids, mono- and diglitterides, free cholesterol and total lipids increases by 44-62%, then for medium and heavy forms - by 70-135% compared with the norm. Even more significantly increases the content of PEGC. With a mild form, their amount exceeds the normal by 2.8 times, and in the case of a severe form, 4.3 times. A different relationship characterizes the dynamics of cholesterol esters; with a mild form, their content is within the norm, with a severe - 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 growth of the free fraction, whose content in mild form increases 1.6 times, and in severe form - 2.2 times against the norm. The esterification coefficient of cholesterol decreases the more, the heavier the form of the disease.

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 PEGC, whose content with the development of the hepatic coma increases even more.

When comparing the indices of lipid peroxidation with the serum lipid spectrum in the dynamics of the disease, a direct correlation between the intensity of lipid peroxidation, on the one hand, and the content of NEF, mono- and diglycerides, phospholipids, triglycerides on the other, the network of these lipid fractions the higher the intensity of the blood serum and the higher the MDA content.

To the factors that enhance the processes of lipid peroxidation, many authors attribute the phenomena of hypoxia.

Under hypoxia, a partial disturbance of the membrane structure occurs, the reduced iron accumulates, and conditions are created to increase lipid peroxidation.

Studies have shown the presence of hypoxia in patients with viral hepatitis. The nature of hypoxia is not definitively established. It is suggested that the development of circular hypoxia with local circulatory disorders in the liver and tissue hypoxia is associated with a fall 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, the accumulation of iron, unsaturated fatty acids and pronounced changes in the lipid spectrum create the necessary conditions for enhancing lipid peroxidation in viral hepatitis.

No less significant in the enhancement of lipid peroxidation may be a violation of antioxidant systems - the absorbers of the process. Under physiological conditions, antioxidants reduce the intensity of lipid peroxidation. Some researchers associate antioxidant properties with certain substances, for example with tocopherol, steroid hormones. Others believe that the antioxidant properties are inherent in the sum of lipid components, the mutual influence of which leads to a change in the antioxidant properties.

It has been shown that substances rich in sulfhydryl (SH) groups can dampen the damaging effect of lipid peroxidation products. However, this mechanism of neutralization of toxic peroxides can not occur in viral hepatitis, since the content of sulfhydryl groups in this disease is sharply reduced. A particularly low level of SH groups in the blood serum is observed with massive necrosis of the liver with a lethal outcome. Consequently, the enhancement of lipid peroxidation and accumulation of toxic peroxides that cause damage to cell membranes in viral hepatitis are associated with a decrease in the activity of antioxidant systems.

Thus, the conducted studies made it possible to establish significant violations in lipid metabolism in viral hepatitis, the essence of which is an increase in the serum content of NEFLC, mono- and triglycerides and free cholesterol, and enhancement of lipid peroxidation processes. These disorders 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 substrate of the cell, radical radical reactions appear that act as initiators of lipid peroxidation, the most important components of cell membranes. The resulting hydroxyl groups cause the appearance of "holes" in the hydrophobic barrier of the biological membrane. First of all, the permeability of membranes for ions of hydrogen, potassium, sodium and calcium increases. Cells lose biologically active substances, including enzymes. The biological potential of the hepatocyte falls. Lysosomal proteinases are activated, which may become the final stage of death of the hepatic parenchyma.

Lysosomal proteolytic enzymes and autolysis syndrome

Lysosomes contain more than 60 hydrolytic enzymes (including cathepsins A, B, D, C) capable of cleaving the biologically active compounds of all the main classes and thus serving as the cause of cell death. However, today the idea of lysosomes dominates as a "bag" containing everything necessary for cell life.

Intracellular proteolysis plays an important role in the reactions of immunity, synthesis and disintegration of physiologically active substances. It is shown, for example, the participation of acid hydrolases in the formation of isoforms of certain enzymes, as well as hormonal substances of protein nature (thyroxine, insulin, etc.). The 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. Many data have been obtained on the role of lysosomes and lysosomal enzymes in accelerating the processes of sloughing and lysis of functionally unsuitable cells. The energy and plastic material released at the same time is used in the construction of new cellular structures. Thus, the lysosomes "clear the way" for intracellular regeneration, freeing the cell from the decay products. Structural isolation of acid hydrolases inside lysosomes is of great biological importance, since it provides physiological protection of intracellular proteins against the destructive effect of their own enzymes. An additional protection is the presence in the cell of inhibitors of proteolysis. At present, inhibitors of cathepsins B, C, D and other proteolytic enzymes are known.

A great role can be played by the pH of the medium, the concentration of calcium and sodium ions. Lysosomal hydrolases are particularly easily activated when the pH is shifted to the acidic side, as hydrolases are activated not only in the acid medium, but this also contributes to the denaturation of protein substrates, thereby facilitating their cleavage by lysosome enzymes. Particularly important for the activation of lysosomal hydrolases is the state of lysosomal membranes. With increased permeability of the latter or in the case of their rupture, it is especially easy to contact the enzymes with substrates. In this case, acid hydrolases can diffuse into the cytoplasm and cause hydrolytic decay of cells. It can be assumed that similar conditions are created in viral hepatitis, especially in cases accompanied by massive necrosis of the liver

The conducted researches made it possible 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 lies in the fact that in the acute period of the disease there is a regular increase in the activity of acidic RNAase, leucine aminopeptidase, cathepsins D, C and to a lesser extent cathepsin B. The activity of their inhibitor, a2-macroglobulin, shows a pronounced downward trend.

The noted shifts are more pronounced in severe forms of the disease than in the lungs. As the 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 the normal values in the period of convalescence, but only in mild forms of the disease.

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

With massive and submissive necrosis due to deep dystrophic processes in the liver parenchyma, the synthesis of the inhibitor of lysosomal proteinases - a2-macroglobulin is particularly sharply reduced and a shift of the pH is observed in the acidic side, optimal conditions for the activation and release of acid hydrolases from lysosomal vacuoles arise. The final phase of their action may be autolysis of the hepatic 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 period of the "dead cell" - "necrotic cell"), the activity of proteolytic enzymes decreases due to their own disintegration, in addition, the possibility of influencing protein proteins sharply decreases, as proteins coagulate and persistent , sparingly soluble compounds. It is obvious that in viral hepatitis, there are complex interactions between the processes of necrobiosis, coagulation and proteolysis. Necrobiosis and proteolysis in cells seem to develop simultaneously, strengthening each other. In this case, proteolytic enzymes, probably, can change the physicochemical state of cellular structures, causing their degeneration, and this, in turn, contributes to the enhancement of proteolysis. A closed krut is created - the hepatocyte becomes a "victim" of its own proteolytic systems.

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

With viral hepatitis in the acute period of the disease, the activity of trypsin-like proteinases is lower than normal, and in severe cases 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 light forms exceeds the norm by a factor of 0.5-2, and in heavy forms, by 2-3 times.

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

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

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

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

In malignant form, due to profound destructive processes in the liver parenchyma, disruption of the organization of subcellular structures, a sharp decrease in the content of proteolysis inhibitors, optimal conditions are created for the release of acid hydrolases from lysosomal vacuoles and their destructive effect on protein substrates within hepatocytes. This is, to a certain extent, promoted by the shift of the pH to the acidic side, the accumulation of sodium and calcium ions in the hepatocytes. The final phase of the action of lysosomal hydrolases in patients with fulminant hepatitis becomes autolysis of the hepatic 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 mass of the hepatic parenchyma, a rapid increase in the symptoms of intoxication, the development of the hepatic coma. Reduction of the activity of lysosomal enzymes to zero after acute reduction in liver size in the period of deep hepatic coma indicates complete destruction of the lysosomal apparatus of the hepatocyte with subsequent termination of its functional activity.

This is the main pathogenetic significance of lysosomal hydrolases in viral hepatitis accompanied by massive or submissive liver necrosis.

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

Cellular immune responses are known to be essential in determining the nature of the course of viral hepatitis. It is suggested that as a result of the defeat of the hepatocyte virus and the rearrangement of the latter to the synthesis of viral proteins, autoimmune reactions against hepatic cells occur, with the pathological process developing as a delayed type hypersensitivity with a predominance of cellular autoimmune reactions. The essence of the latter lies in the fact that, due to 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 infected hepatocytes. The virus is released from the cells and, in turn, infects other hepatocytes. Consequently, the hepatic cells are released 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 reacting to the surface antigens of hepatocytes, including liver-specific lipoprotein, occurs. There is a synthesis of antibodies to this macrolipoprotein, which is considered a normal component of membranes of intact hepatocytes. These antibodies, reaching the liver, bind to the surface of the hepatocytes. Since the most likely mechanism leading to necrosis is complement fixation, activation of K cells is also assumed. According to these ideas, the pathological process in severe forms of viral hepatitis is caused not so much by the replication and cytotoxic action of the virus as by the response of immunocompetent cells to antigenic determinants.

H.M. Wexler et al. The cytotoxic function of lymphocytes on the model of regenerating hepatocytes of a cultured explant of biopsy liver tissue of patients with hepatitis B was studied (1973). The studies made it possible to detect the distinct cytotoxic effect of lymphocytes on liver cells in 55% of patients with acute viral hepatitis and in 67% of patients with cirrhosis. Along with this, blood serum, rich in HBsAg, and purified HBsAg preparation stimulated the proliferation of cells of biopsy tissue cultures of the liver and bile ducts.

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

However, despite these data, many hepatologists show restraint in interpreting the results obtained with regard to cytotoxicity. The fact is that the phenomenon of cytotoxicity of lymphocytes is a universally widespread process and need not be considered as a leading link in the pathogenesis of the disease. We must also take into account the fact that in dead patients with fulminant course of massive necrosis of the liver at the dissection and in the morphological investigation, massive lymphocytic infiltration can not be detected; At the same time, solid fields of necrotized hepatic epithelium are revealed without the phenomena of 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 envelope 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 - anti-HBE. In general, the components of the e-system, that is, HBeAg and anti-HBe, were found in 33.3% of the examined. Circulation of HBsAg in the blood was longer (an average of 31 days); while titres HBsAg in patients with moderate-to-severe form were higher than in patients with mild form. Antibodies to HBsAg were not detected. In the malignant variant of hepatitis, the majority of those surveyed on the e-system at the very beginning of the disease had an appearance in the blood along with HBeAg and HBsAg, but as the precoma and coma develop, the virus antigens in the blood are no longer detected. Against the background of the circulation of viral components in the dynamics of hepatitis B, changes in the quantitative ratios of the subpopulations of lymphocytes are observed. So, in the first and second decades of the disease, that is, at the height of the disease, the level of E-ROC in all forms of the disease is significantly reduced in both percentage and absolute value. In the fourth decade with a mild and moderate form, the amount of E-ROC increases to normal, with a severe form of the disease the E-ROC content does not yet normalize during this period, amounting to 47.5 ± 6.2% (1354.9 ± 175.3 cells / mm ³ ). The content of B cells significantly increases in the midst of hepatitis only in mild forms and fluctuates within normal limits for moderate to severe forms. To the period of early convalescence in patients with severe form, the content of B cells increases to 525.4 ± 98.9 cells / mm ³ against 383.9 + 33.2 cells / mm ³ at the height of the disease (p <0.05 g. In general, the dynamics of B-cell content was characterized by small fluctuations in the cyclic course of the disease, in comparison with the dynamics in healthy children.The content of lymphocytes lacking T- and B-cell receptors (zero cells) exceeds the norm in the midst of hepatitis by more than 2 times for all forms of the disease. In the period of early convalescence, the level of zero cells remains significantly higher with mild and severe forms of the disease.

The content of T-lymphocytes, which have a regulating role in the relationship of T-T cells, T- and B-cells (TM and TG cells), depends little on the severity of the disease. Typical was a decrease in the number of TM cells in light and medium-heavy forms, an average of 1.5 times against the norm, which was 22.7 + 3.1% (norm 36.8 ± 1.2%). The TG-cell fraction remains 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 of PHA in patients with acute cyclic course of hepatitis B remains close to normal; the number of mature T-lymphocytes is 57.2 ± 3.6% at the peak of the disease at a norm of 62.0 ± 2%.

The specific reactivity of T cells 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 value of the migration index is 0.75 ± 0.05 (norm 0.99 + 0.03). As a result, specific sensitization to the surface antigen of hepatitis B is detected in 86% of patients. At follow-up examination at the 3rd-9th month after acute hepatitis B, inhibition of leukocyte migration during in vitro stimulation of HBsAg persists in half of the convalescents.

Compared with benign forms of the disease in malignant forms of the reaction of cellular and humoral immunity in patients have a number of distinctive features. Thus, the content of E-POK., Is quite low in the precom. Characterized by a steady decline and in the period of coma 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-POK and stable E-ROC varies 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. With malignant hepatitis in the period of massive hepatic necrosis and especially hepatic coma, complete incapacity of lymphocytes to blast transformation due to phytohemagglutinin, staphylococcal endotoxin and HBsAg of their functional inferiority is noted, it can be concluded that in viral hepatitis, especially in malignant form, there is gross damage of lymphocytes.

The presented data testify to significant disorders in the cell link of immunity in patients with viral hepatitis accompanied by massive necrosis of the liver. The nature of the violations revealed remains unclear. They may indicate the defectiveness of the cellular immunity in patients with malignant forms of viral hepatitis, but it is more likely that these changes result from the defeat of immunocompetent cells of the peripheral blood by toxic metabolites. In this connection, the question arises: how can degenerate altered lymphocytes, with pathologically altered membranes not capable of blast transformation and migration, with such a sharp decrease in their quantitative decrease have a destructive effect on the parenchyma of the liver, up to complete necrosis and lysis. That is why the hypothesis of autoimmune aggression involving 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- body antibodies in viral hepatitis. Many authors believe that autoantibodies are more often found 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 respect are the methods of studying immunomorphological changes directly in the liver tissue. In one of the first works on immunopathochemical examination of liver tissue in hepatitis, fluorescent dye-labeled antibodies against human y-globulin were used. It was shown that with acute viral hepatitis in the liver tissue, y-globulin-containing cells are constantly found, located mainly in the portal tracts and sinusoids within the lobules. According to F, Paronetto (1970), cells that synthesize y-globulins are not related to the virus; their number is interrelated with the degree of destruction of the hepatic tissue. The results of these studies were largely confirmed by recent studies using labeled monovalent sera containing antibodies against IgA, IgG, IgM.

In order to establish the role of autoagression in the development of massive liver necrosis, histochemical and immunofluorescence studies of liver tissue of 12 children who died during hepatic coma phenomena were carried out in children (8 of them had massive liver necrosis, 2 had submissive necrosis, 2 had subacute active giant cell Cholestatic hepatitis ). In addition to the generally accepted methods of morphological and histochemical research, a direct version of the Koons 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 were affected by viral hepatitis with an erased or anemia-free form.

The determination of circulating anti-organ antibodies was carried out repeatedly in the course of the disease. In the same serums, the IgA and IgM levels were examined.

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

The statistical treatment method used by us is based on the logarithmically normal distribution of antibody titers; The serial numbers of the dilutions in the row of tubes are distributed according to the normal law. Averaging over the series was carried out after establishing the position of the tube with the evaluation of the reaction of 2+ in each row and taking into account the negative results, thanks to which all the material participated in the treatment.

The reliability of the difference between the height of antibody titers in different patient groups was calculated by the Student's test. The correlation between the titers of anti-tumor antibodies and the content of immunoglobulins in whey was determined on a computer by the standard program.

The results of the studies showed that in healthy people, anti-organ antibodies in a titer of 1:16 and higher are rarely found; In 2 out of 20 examined, antibodies to liver tissue were detected, in 2 - to kidney tissue and in 1 - to smooth muscles of the intestine. From patients with hepatitis virus, antibodies to liver tissue in diagnostic titer (1:16) and above were found in 101 (66%) of 153 patients examined, 13 of them (21.7%) out of 60 and smooth muscle of the intestine - in 39 (26.4%) of the 144 examined. Antibodies to liver tissue in patients with moderate and mild forms of the disease were encountered approximately at the same frequency (in 36 of 48 and in 52 of 80, respectively), in patients with severe forms - much less (in 4 of 12).

With cyclic flow of viral hepatitis, the curve of titers of pro-hepatic antibodies in light and moderate forms of the disease had a marked increase in the period of clinical and biochemical manifestations of the disease. The curve of titers of smooth muscle antibodies 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, with the lowest antibody titers were in severe form of viral hepatitis. In patients with malignant form, titres of antibodies to liver tissue were especially low, and no autoantibodies were detected in the period of deep hepatic coma.

When the level of immunoglobulins in the blood serum was simultaneously examined, the following results were obtained.

In case of severe forms of the disease, a moderate increase (in 1.5-1.8 times compared to the norm) in the concentration of immunoglobulins of all classes was noted at the height of clinical manifestations, while the IgM content was 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 IgM level was statistically significant. An increased concentration of IgA and IgG persisted.

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

The results of the correlation analysis of the titers of anti-hepatitis antibodies and immunoglobulins allowed to establish a high correlation between hepatic antibodies and IgM (correlation coefficients 0.9 and 0.8).

Since autoantibodies are detected in viral hepatitis (anti-tissue, antibodies to cell components, rheumatoid factor, etc.), the total pool of immunoglobulins can constitute antibodies to the tissues and cells of the host. It is also known that in acute viral hepatitis, the antibodies to smooth muscle that are formed are IgM antibodies, so it is possible that the lower IgM level in patients with hepatitis B is due to the small serum content of anti-body antibodies. In patients with malignant form, in which autoantibodies were not detected or were detected in low titers, the content decreased with the development of deep hepatic coma.

Thus, the data of the studies confirm the possibility of autoimmune reactions in viral hepatitis in children. The involvement 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 malignant form. Apparently, the depth of liver damage in viral hepatitis correlates with the degree of antibody fixation on the organ. Higher tigers of hepatic and smooth muscle antibodies in mild forms of viral hepatitis may reflect a low degree of their fixation.

Studies carried out using the method of fluorescent antibodies also indicate the inclusion of the liver in viral hepatitis in the immunopathological process. In all patients who died from massive and submaxive liver necrosis, immunoglobulin-cell content was detected in the liver, spleen and lymph nodes. These cells were located both singly and in groups around the surviving hepatocytes, as well as in the central and in-ambulatory zones devastated from the hepatic cells. It is characteristic that the cells containing IgA, IgG and IgM were approximately equal. Groups of luminous hepatocytes with immunoglobulins fixed on their surface were also identified.

Based on 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 glow of groups hepatocytes, 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 promote necrosis (intravascular coagulation of blood, aggregation of leukocytes with violation of integrity of their membranes and subsequent release of hydrolytic lysosome enzymes, release of histamine, etc.), Ne The possibility of a direct damaging effect of fixed antibodies on hepatocytes is also excluded.

Thus, a comprehensive study of immunological processes in patients with viral hepatitis suggests that, in response to the numerous antigens that occur during autolytic decay, anti-organ antibodies accumulate in the serum of patients, most likely IgM. Since the titer of anti-body antibodies decreases with increasing severity of the disease, and antigen-antibody complexes are found in liver sections treated with monovalent anti-IgM, IgA and Ig fluorescent sera, it can be considered that autoantibodies are fixed on liver tissue in viral hepatitis. This process is especially intense in severe forms of the disease. Fixed autoantigels are able to deepen the pathological process in the liver. This is probably the role of organ antibodies in the pathogenesis of liver necrosis in viral hepatitis.

Hypothesis of the pathogenesis of massive liver necrosis in viral hepatitis

The results of a complex 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 in the following way.

Viruses of hepatitis due to tropicity to liver epithelial cells penetrate into the hepatocyte, where, as a result of interaction with biological macromolecules (possibly with components of membranes of the endoplasmic reticulum, capable of taking part in detoxification processes, by analogy with other damaging agents, as it was shown with respect to tetrachloride carbon, free radicals are formed that act as initiators of lipid peroxidation of cell membrane lipids. Pidov leads to a change in the structural organization of the lipid components of membranes due to the formation of hydroperoxide groups, which causes the appearance of "holes" in the hydrophobic barrier of biological membranes and, consequently, the increase in their permeability.The movement of biologically active substances along the concentration gradient becomes possible.As the concentration of enzymes within cells in tens and even a thousand times greater than that in the extracellular space, the activity of enzymes with cytoplasmic activity in the serum increases, hondrialnoy, and other lysosomal localization, which indirectly indicates the decrease in their concentration in the intracellular structures and, consequently, to reduced bioenergetic treatment chemical transformations. Replacement of intracellular potassium ions with sodium and calcium enhances the breakdown 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 activation and exit of lysosomal vacuoles of acid hydrolases (RNAase, DNAase, cathepsin, etc.). This is, to a certain extent, facilitated by a decrease in the activity of proteinase-a2-macroglobulin and a1-antitrypsin inhibitors. The action of proteolytic enzymes ultimately leads to the disintegration of the hepatic cells with the release of protein components. They can act as autoantigens and, along with the hepatotropic virus, stimulate the formation of specific anti-hepatic antibodies capable of attacking the liver parenchyma. This may be the final stage in the occurrence of irreversible changes in the liver parenchyma. The question of the sensitization of T and B lymphocytes and their participation in the pathogenesis of massive liver necrosis requires further study.

The products of lipid peroxidation, which control, as now proven, the permeability of cell membranes, trigger the pathological process. The results of the studies showed a sharp increase in the processes of peroxidation from the first days of the disease to viral hepatitis.

A hypothesis about the role of lipid peroxidation and cell death 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 involves chain radical lipid oxidation, 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, in the opinion of the authors, the accumulation of Ca2 + in cells, the early dissociation of oxidative phosphorylation, and the activation of lysosomal hydrolases may be of considerable importance.

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

In the proposed hypothesis of the pathogenesis of liver necrosis as a direct cause of death of hepatocytes in the early stages of the disease, isolated reactions of oxidative phosphorylation act. This process involves the participation of lysosomal hydrolases and is likely to be limited at the initial stage with the autolytic decay of individual hepatocytes and the release of antigenic complexes. However, in the future, the process becomes avalanche. There are several reasons for this mechanism of development of the process.

First, peroxide oxidation of lipids 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 the polymerization of proteins, destroy the sulfhydryl groups of enzymes, disrupt the structural organization of cell membranes, which ultimately leads to total dissociation of oxidative phosphorylation. Secondly, at the height of the disease, the activity of lysosomal hydrolases is particularly high: their pathological effect is facilitated by complete structural disorganization of the cell and a sharp drop in the activity of proteolysis inhibitors. And, finally, in the blood to this period, sufficiently high titres of anti-hepatic antibodies, which damage the liver parenchyma, accumulate.

The emergence of massive liver necrosis is preceded by intensive production of the virus, 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 is steadily decreasing with an apparent increase in the B-cell content and the discharge into the blood stream in a high concentration of immunoglobulins, predominantly IgM. These data correlate well with the data that in many patients with malignant course of hepatitis B excess anti-HBg-IgM is found in excess, while in the favorable course of the anti-HBe disease in an acute period are extremely rare.

Insufficient and short-term detection of HBV antigens in the blood during fulminant hepatitis is difficult to explain by the sudden cessation of their production; most likely, they are produced in abundance, but are found in the blood and liver blocked by an excess of antibodies, as indicated by the detection of HBsAg-anti-HBs in the blood, the titres of humoral autoantibodies, and the fixation of immunoglobulins on hepatocytes in those killed by massive necrosis of the liver. It can be thought that as a result of massive infectious infection (usually in patients who received blood and its transfusion transfusions), an immune response to the type of IgM response arises in the body, which depends little on the effect of T cells and results in blocking 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 epithelial tissue also occurs due to the mechanisms presented in the diagram.

The decrease in the number of T cells, especially in patients with coma, as well as the paresis of the functional capacity of lymphocytes (rosette formation in RBTL and RTML toasts, the lack of redistribution in the subpotulation of T lymphocytes, and the increase in the permeability of lymphocyte membranes become secondary phenomena due to toxic effects on the immunocompetent cells of metabolites and radicals of incomplete interchange.

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, it is only a feature that all links of pathogenesis are realized at a qualitatively different level. Unlike the malignant form, with a favorable course of viral hepatitis, lipid peroxidation processes are not significantly enhanced: the activation of acid hydrolases only leads to limited autolysis with an unimportant release of the antigenic complex, hence without massive autoaggression. That is, all links of pathogenesis with a favorable outcome are carried out within the framework of the continuing structural organization of the liver parenchyma and the adequacy of the defense systems, and therefore the process does not have such destructive power as fulminant hepatitis.

Symptoms of Malignant Hepatitis

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

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

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

Neuropsychiatric disorders. The main and the earliest clinical sign of developing malignant form in young children is psychomotor agitation, in which there is a sharp concern, uncaused crying, screaming. Attacks last for hours, usually occur at night. The child rushes, asks for his hands, looks for the mother's breast, tries to suck with greed, but immediately with a cry refuses his chest, knocks, turns his head. The cause of this arousal is most likely the defeat of the subcortical centers, manifested in the early stages of the disease by the disinhibition of the subcortical and basal ganglia. As the development and deepening of liver failure and the development of the hepatic coma, a braking process develops, spreading to the subcortical nodes, the brain stem and the cerebral cortex.

The frequency of clinical symptoms at different periods of the malignant form of viral hepatitis (%)

Clinical symptom	Period
	Onset of disease	Precombat	Coma
Lethargy	100	100	100
Impairment of appetite, Anshexia	42.2	100	100
Repeated or repeated vomiting	44.4	66.6	97.7
Vomiting with an admixture of blood	17.7	66.6	86.6
Anxiety	64.4	86.6	95.5
Inversion of sleep	26.6	42.2	64.4
Screaming	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 breathing	13 3	55.5	86.6
Hemorrhagic eruptions	40	62.2	66.6
Pulverizing tissues	17.7	33.3	41.5
Bloating	26.6	64.4	91.5
Ascites	-	4.4	8.8
Liver odor	-	28.8	40.0
Symptom of empty hypochondrium	-	6.8	60.4
Anuria	-	_	31.1
Melena	-	-	15.5
Pulmonary edema	-	-	13.5

In older children and adults, among the symptoms indicative of CNS involvement, one should note the instability of the psyche, irritability, disorientation in time and space. Older children can complain of bouts of longing, memory dips, handwriting disorder. Further progression of these symptoms can be accompanied by acute psychosis and delirious state with motor excitement, delirium, hallucinations. In the final stage of the disease, a state of arousal and convulsions are observed.

According to the research, in the children of the first months of life, changes in the central nervous system were characterized by the appearance of symptoms such as anxiety, screaming, drowsiness, chin jerking, tonic-clonic convulsions, and in far-reaching cases, decrease tendon reflexes, impaired consciousness and often - pathological reflexes (proboscis, Babinsky symptom, clonus stop).

Characteristic for the malignant form in adults of the "flapping tremor", which many authors attach to the crucial for the diagnosis of impending hepatic coma, in young children is not observed. They usually have involuntary chaotic twitching of the fingers, less often brushes. Many of these symptoms, indicating the defeat of the central nervous system, appear even before the appearance of the precomatous state, but most often and most fully occur in the comatose period.

Vomiting is a characteristic sign of a malignant form of hepatitis. If in viral forms of viral hepatitis vomiting occurs in the pre-zheltushnom period, then in patients with malignant form, it is repeated, throughout the disease. In young children, in addition to this, there are frequent frequent regurgitations. At the beginning of the disease, vomiting usually occurs after ingestion of food, water or medicine, then appears spontaneously, often takes the color of the coffee grounds. The admixture of blood in vomit masses is observed only in patients with malignant form. This symptom indicates the occurrence of severe disorders in the blood coagulation system. An admixture of blood may initially be insignificant, a dark brown color is noted only in individual portions of the vomiting, so this important symptom is sometimes not recorded. With abundant gastric and intestinal hemorrhage, usually occurring at the height of clinical manifestations of malignant form, vomit stains become more intense and acquire a dark-brown color. Also appear dark tar-like stool. Among the children we observed, repeated vomiting was noted in all, vomiting with an admixture of blood - in 77%, tarry stool (melena) - in 15%.

In addition, there were nasal bleeding, minor hemorrhages and even ecchymoses on the skin of the neck, trunk, less often on the limbs.

There may be hemorrhages in the mucous membrane of the oropharyngeal cavity and uterine bleeding. At the heart of hemorrhagic syndrome lie a sharp violation of the synthesis in the liver of coagulation factors and toxic damage to blood vessels. Great importance is attached to the coagulopathy of consumption (intravascular coagulation), proceeding against the background of increased activity of factors of procoagulation. It is believed that the process of coagulopathy is mainly carried out by thromboplastin released from necrotic hepatocytes and, possibly, by the action of the virus on endothelial cells and thrombocytes.

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

Hepatic smell (foetor Peach) can also be considered a pathognomonic sign of a malignant form of the disease. Usually it resembles the smell of fresh raw liver. It is best to catch when the patient breathes, but about the same smell as urine, vomit, contaminated laundry. It is assumed that this sign is due to a violation of methionine metabolism, as a result of which methyl mercaptan accumulating in the blood gives a characteristic odor. The appearance of a smell almost always indicates a severe liver damage, but it does not happen in all cases of malignant forms of hepatitis. This symptom is observed only in a third of patients.

Fever usually occurs in the terminal period of malignant forms, but sometimes appears at the time of acute reduction in liver size, which allows us to think about the relationship between a rise in body temperature and the disintegration of the hepatic parenchyma. In our patients with malignant disease, fever was noted in 46.6% of cases. Body temperature reached 40 ° C and above. In the terminal period, the fever was persistent and did not respond to antipyretic agents. We can assume that the hyperthermia in these patients was the result of severe damage to the diencephalic region with a violation of the function of the thermoregulatory center.

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

By its nature, fever in malignant form does not have specific features. Most often, the body temperature rises gradually or stepwise. There are cases in which it quickly rises to high values.

Pain syndrome can be attributed to the early signs of developing malignant disease. Adults usually complain of dull, aching pain in the right hypochondrium. Sometimes there are sharp pains that may in some cases resemble an attack of cholelithiasis or acute appendicitis. The appearance of pain in young children is first and foremost evidence of acute anxiety and periodic screaming, when trying to palpate the liver there is motor anxiety and a cry increases.

The causes of pain, most likely, are necrosis and autolytic decay of the hepatic parenchyma. Less important, apparently, is the defeat of the biliary tract, capsule and pancreas.

Acute reduction in liver size is one of the most characteristic signs of a developing malignant form. In the deceased, a decrease in the weight of the organ is found to be 1.5-2 or even 3 times. It is important to pay attention to the rate of reduction in liver size and its consistency. At the earliest stages of the development of the disease, the liver is still usually enlarged, but it becomes less dense, even a testicle, in consistency. Further, a rapid decrease in the liver begins, and its rate reflects the dynamics of the development of massive necrosis of the hepatic parenchyma, its decay and autolysis. In cases of acute malignant form, the liver usually shrinks quite quickly, literally within 12-24 hours, with a hollow thunder of the course of the disease - gradually, jerky, with each subsequent decrease in the organ accompanied by an increase in the symptoms of intoxication. Sometimes, in acute disease, the decrease in liver size is not so fast - within 2-3 days; in some cases with lightning flow, this process can not be detected, since already at the admission the dimensions of the liver are small (its edge is palpable at the costal arch and has a testic consistency). Reduction of liver size is usually noted in cases of hepatic coma in chronic hepatitis. This circumstance must be taken into account in the diagnosis of malignant forms.

Jaundice in the occurrence of malignant form of the disease is rapidly increasing and reaches a maximum in the comatose period. However, malignant forms also occur with relatively poorly expressed icterism. Usually this happens with the lightning-fast course of the disease, when massive necrosis occurs in the very initial, pre-jaundiced period of the disease, but sometimes mild jaundice can occur in subacute and malignant forms. However, in such patients at the very beginning of the disease jaundice is clearly pronounced, then, before the onset of coma, begins to decrease and in the comatose period may be already weak. In rare cases, with malignant forms, the recurrent nature of jaundice can also be noted.

Assessing jaundice as an indicator of severity, it must be emphasized that in children of the first year of life the average bilirubin content in the blood in malignant forms is significantly less than in older children with similar forms of the disease. So, according to our data, in young children this indicator was at the height of malignant form within the limits of 137-222 μmol / l, while in older children it was above 250 μmol / l with the same forms.

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

With the progression of the malignant form in its terminal stage, changes in the cardiovascular system are often accompanied by cardiopulmonary failure, as evidenced by the growing pallor, cyanosis, pulmonary edema.

Changes in the cardiovascular system in patients with malignant forms, on the one hand, can be explained by extracardiac effect in connection with. Defeat of the central nervous system (middle and oblong brain), as well as the autonomic nervous system; and on the other hand, the development of hepatocardial syndrome in hepatic insufficiency due to metabolic disturbances in the myocardium (energy-dynamic heart failure caused by a violation of ATP metabolism).

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

Electrocardiographic changes in malignant form are expressed in flattening and lowering of the T wave, elongation of the QT inte- grated, and often in the omission of the ST interval.

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

Changes in the side of the respiratory organs in patients with malignant form consist in the appearance of dyspnea (toxic noisy breathing); As the coma deepens, the breathing becomes intermittent, like Kussmaul or Cheyne-Stokes. In the terminal stage, breathing can be sharply reduced. Appears and rapidly progresses pulmonary edema. In such patients, a large number of differently-moist, wet rales are listened, a frothy liquid is discharged from the mouth and nose, sometimes with an admixture of blood (hemorrhagic pulmonary edema).

For diagnostics it is especially important that changes on the part of the respiratory organs in patients with malignant form in the form of toxic dyspnea often appear at the earliest stages of the development of liver necrosis.

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

Along with a decrease in diuresis, malignant form can be accompanied by a moderate increase in the content of residual nitrogen with a simultaneous decrease in inulin and creatinine, the progression of hyponatremia and hypokalemia. Decreased renal plasmotok and, especially, glomerular filtration. These changes can be interpreted as a hepatorenal syndrome. Great importance in the violation of the functional state of the kidneys is given hormonal regulation, in particular the renin-angiotensin-aldosterone system. According to the research, in patients with malignant form, the synthesis, cleavage and inactivation of certain hormones are severely impaired.

From the side of the adrenal cortex, 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 an increase in the reabsorption of water in the kidneys, which causes its retention in the body. Clinically, this is manifested by the pastosity of the tissues and even ascites. However, edematous-ascitic syndrome, we observed only in the subacute course of the malignant form. In cases with acute course of the disease, renal dysfunction was also pronounced, but there was no edematous-ascitic syndrome.

It should be assumed that violations of kidney function in patients with malignant forms are due to many factors. Among them, an important role belongs to the morphological changes in the parenchyma of the nights, which, apparently, are caused both by immunopathological reactions initiated by the virus itself and by the toxic influence of many products of disturbed metabolism. Important and functional (mostly extrarenal) disorders associated with the accumulation in the blood of aldosterone and antidiuretic hormone of the pituitary gland. An important role is played by metabolic acidosis and disturbances of water-electrolyte equilibrium, as well as rapidly progressing hypoproteinemia.

Thus, in patients with a malignant form of clinical symptoms, the most constant - psychomotor agitation, repeated vomiting with a blood admixture, tachycardia, toxic respiration, bloating, severe hemorrhagic syndrome, fever and diuresis It is important to emphasize that symptoms such as vomiting of the type coffee invasion, sleep inversion, convulsive syndrome, hyperthermia, tachycardia, toxic respiration, hepatic odor, decrease in liver size, are observed only in malignant forms of the disease. Following these symptoms or simultaneously with them comes the blackout of consciousness with a characteristic clinical picture of the hepatic coma.

Diagnosis of malignant hepatitis

For the early diagnosis of malignant form, the rate of jaundice build-up and the serum level of bilirubin are important. With malignant form, the content of bilirubin in the blood increases very quickly and reaches its maximum values already on the 3-5th day from the onset of jaundice. Of particular importance is the rapid increase in serum levels of non-conjugated bilirubin. As a result, the ratio of the amount of free bilirubin to the content of the conjugated fraction approaches unity, sometimes more than one, while in patients with severe form without the development of massive liver necrosis this index is always less than unity. However, its magnitude is of prognostic value only in cases of high content of total bilirubin in the blood serum; and the severity of the clinical picture must be taken into account.

For malignant forms, bilirubin-enzyme dissociation is also characteristic - with a high content of bilirubin in the blood serum, there is a decrease in the activity of cytoplasmic, mitochondrial, lysosomal and other enzymes. This process is associated with the disintegration of the hepatic parenchyma, and therefore, by determining the activity of enzymes with various subcellular localization, it is possible to establish not only the place of primary damage to the hepatocyte structure, but also the stage from which the cell function disturbances become irreversible.

According to the research data, the activity of all cytoplasmic, mitochondrial and lysosomal enzymes is the highest at the onset of malignant disease, then, as the symptoms of intoxication and liver size decrease increase, their activity rapidly decreases. At the same time, the dynamics of the fall in activity is significantly different in the groups of enzymes that reflect the state of various subcellular structures. The essence of this difference is that the activity of lysosomal enzymes diminishes with a particularly rapid decrease and in the period of deep hepatic coma is not determined at all, while the activity of mitochondrial and cytoplasmic enzymes decreases more slowly, and even immediately before the onset of death in serum is determined increased activity of these enzymes. Our data suggest that the death of hepatocytes in malignant forms occurs due to the depletion of enzyme systems by lysosomes, later the enzymatic systems of the mitochondria completely disorganized, the functional capacity of the cytoplasmic matrix is retained for the longest time.

Highly informative and lipidogram indices. In patients with malignant form, the content of beta-lipoproteins, triglycerides, free and ester-bound cholesterol is sharply reduced. The esterification ratio of cholesterol decreases. Particularly indicative are beta-lipoproteins, the content of which begins to decrease already at the earliest stages of the development of massive liver necrosis, when clinical manifestations and usual biochemical indicators do not yet indicate the special severity of liver damage.

An auxiliary value for the diagnosis of malignant forms of hepatitis may have changes in the peripheral blood. At malignant forms already at early stages often there is a moderate anemia of microcyptic character, the accurate tendency of decrease in quantity of a hemoglobin and thrombocytes is traced. From the side of white blood more often leukocytosis is noted, more pronounced in the precomatosis period; characterized by neutrophilia with a stab-shift (sometimes to young forms and myelocytes), lymphopenia and eosinopenia; ESR, as a rule, is reduced.

For early diagnosis of malignant forms, the detection of free antibodies against the surface antigen, anti-HBs, is also important. According to the research, anti-HBs were often detected already in the early stages of malignant forms, whereas in benign 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 the Infectious Diseases Clinic or in a specialized hepatology center.

In the diet of patients, the protein content is significantly limited - up to 0.5 g / kg per day, followed by an increase as the condition improves to 1.5 g / kg. With the development of the hepatic coma, proteins and fats are completely excluded from the diet. After the patient leaves the comatose state, the protein content in the diets is gradually increased to 20 g, and further to 40-50 g, mainly due to dairy products. The energy value of a daily diet is 900-1200 kcal. Fruit and vegetable juices, broth of wild rose, jelly, jelly, honey, mucous soups, wiped cottage cheese, creamy unsalted butter are recommended. Feed the patient every 2 hours; food is given in a grated kind.

Day providing the energy needs of the body for coma is parenteral administration of 10% glucose solution. While maintaining the act of swallowing, the patient is prescribed 20-40% glucose solution, fruit and vegetable juices for drinking.

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

Decontamination of the intestine is carried out. For this purpose, patients are given high cleansing enemas, repeated gastric lavage, and enterally antibacterial drugs: semisynthetic penicillins, aminoglycosides, metronidazole, etc. Decontamination of the intestine in patients with fulminant hepatitis reduces the incidence of infectious complications to 20%.

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

Detoxification is in the first place in the treatment of patients with hepatic encephalopathy and coma. In this case, parenteral administration of low-concentration solutions of glucose and polyionic crystalloid solutions is combined. Effective combinations of hemodesy, glucose solution and polyionic crystalloid solutions. Given the development of microcirculatory disorders in acute massive necrosis of the liver, which create conditions for the development of "sludge" of erythrocytes, subsequent disseminated thrombosis and increased autolysis, the administration of a solution of low molecular weight dscstrane - rheopodiglyukin - is added to the therapy of patients with hepatic coma. According to AA Mikhaylenko and V.I. Pokrovsky (1997), the inclusion in the treatment program for patients with hepatic coma rheopodiglyukin contributed to the withdrawal from coma 4 of the 5 treated patients, compared with 3 of 14 who did not receive this drug.

The fight with brain edema is carried out by intravenous injection of 20% mannitol solution - its appointment to patients with hepatic coma increased the proportion of surviving patients from 5.9 to 47.1%.

Taking into account water-electrogrolith disorders in fulminant insufficiency, it is necessary to control the potassium level and correct hypokalemia.

It should be remembered that infusion therapy in patients with malignant form of hepatitis should be carried out under strict control of diuresis, since excessive fluid intake becomes one of the causes of cerebral edema that occurs with comatogenic hepatic insufficiency.

In connection with the fall of the detoxification function of the liver, it must be compensated with medications. One of them is the domestic drug reamberin. This IV infusion drug is a balanced isotonic detoxifying infusion solution based on succinic acid. It has antihypoxic and antioxidant effects. Reamberin activates the antioxidant system of enzymes and inhibits the processes of lipid peroxidation in ischemic organs, providing a membrane-stabilizing effect on cells of the brain, liver, and kidneys; in addition, it has a moderate diuretic effect.

One of the debatable moments of intensive therapy for comatose conditions is the use of glucocorticoids. Since the publication of the work of H Ducci and k. Catz in 1952, the appointment of glucocorticoids in comatogenic hepatic failure became mandatory. Many researchers note a high risk of side effects of glucocorticoids - the stimulation of protein catabolism with the growth of azotemia, the development of septic complications and gastrointestinal ulcers.

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

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

Taking into account the pathogenetic role of proteolytic enzymes in the development of autolysis in fulminant hepatitis, malignant forms of viral hepatitis include proteolysis inhibitors: aprotinin (trasilol, gordoks, contrikal) in the dosage regimen corresponding to age.

One of the methods of therapy for hepatic coma is anesthesia of the central nervous system, based on the use of sodium oxybutyrate. This drug not only removes psychomotor agitation, but also slows the rate of progression of the coma. At the heart of anesthetic protection of the central nervous system, it is likely that an anesthetic breaks the vicious circle of pathological impulses from the center to the periphery, which develops with comatogenic hepatic insufficiency.

In comatose states, hemostasis is corrected with heparin, fibrinogen, aminocaproic acid, as well as transfusion of freshly frozen plasma. The mechanism of therapeutic action of plasma is associated with detoxification effect, correction of deficiency of plasma proteins, which contributes to the provision of transport, oncotic function of blood and normalization of metabolic processes. You can also use concentrated solutions of albumin and protein (a complex of all protein fractions of plasma). By their hemodynamic effect, they exceed the native plasma, which makes their use preferable in the correction of hemodynamic disorders, cerebral edema, pulmonary edema.

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

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

Artificial liver with malignant hepatitis

As an artificial liver, human hepatoblastoma cells and pig hepatocytes are used. The plasma or blood of a patient with fulminant hepatic insufficiency is passed through a network of thin permeable capillary tubes placed in a chamber containing a culture of hepatocytes. The purpose of using an artificial liver is to create conditions for restoring the functions of the patient's liver or replacing it when preparing a donor organ transplant.

The use of artificial liver has been started recently, 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 hepatic insufficiency, there is a decrease in intracranial pressure and the stage of encephalopathy.

It is to be determined whether an artificial liver can be used to restore the liver function of the patient or it will be only a palliative method that will allow time to prepare and conduct liver transplantation.

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

Liver transplantation with fulminant hepatitis

Liver transplantation is performed in patients with fulminant hepatitis with developing coma that did not respond to therapeutic treatment. The purpose of transplantation is temporary replacement of the patient's liver functions for the period of organ regeneration and regeneration.

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

Practically in all cases, we are talking about orthotopic transplantation, that is, donor liver transplantation to the site of the recipient's distant liver.

Heterotopic liver transplantation, in which the donor liver is placed in the left ileal fossa as an additional organ, is currently used only in some centers to treat fulminant liver failure.

Developed indications for liver transplantation, contraindications, criteria for the urgency of the operation, the criteria for selecting donors for taking the liver. After the liver transplantation is completed, the patient enters the surgical transplantation ward, where the average stay in the uncomplicated postoperative period is 3 weeks. After discharge from the surgical department, the patient goes over to an outpatient observation of the hepatology therapist.

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

According to S.V. Gaultier et al. (2007), more than 200 such operations have been performed since the first liver transplantation in Russia (February 14, 1990), including 123 children aged 6 months to 17 years. Several liver transplantation operations were performed urgently 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 technically complex extensive surgical intervention, which is the only real possibility of saving a patient's life with fulminant hepatic insufficiency in the absence of a patient's response to therapeutic measures.

The use of hepatoprotective preparations containing phospholipids appears promising in the complex treatment of patients with malignant viral hepatitis. It is necessary that these drugs have high bioavailability, that is, they were prepared on the basis of nanotechnology. An example of such a drug is nanophospholip, created in the laboratory of nano-drugs of the Research Institute of Biomedical Chemistry. V.N. Orekhovich. In a nanophospholip, phospholipid molecules are in minute granules of 20 nm in size, while all existing analogs of the preparation (for example, essentials) consist of macro-sized particles that are several orders of magnitude larger. It can be considered pathogenetically justified the appointment of a nanophospholip as a "membrane glue" to strengthen cell membranes and prevent endotoxemia at the cellular level in fulminant hepatitis.