Cirrhosis of the liver

Liver cirrhosis is a chronic polyetiological diffuse progressive liver disease characterized by a significant decrease in the number of functioning hepatocytes, increasing fibrosis, restructuring of the normal structure of the parenchyma and vascular system of the liver, the appearance of regeneration nodes and the subsequent development of liver failure and portal hypertension.

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Epidemiology

Mortality from liver cirrhosis varies from 14 to 30 cases per 100,000 population in different countries.

Due to the irreversibility of liver cirrhosis, the main criterion for assessing its prevalence among the population is not so much morbidity as mortality rates. In Western Europe and the United States, the frequency, according to autopsy data, fluctuates between 3-9%.

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Causes liver cirrhosis

Liver cirrhosis is a progressive fibrosis resulting in diffuse disorganization of the normal liver structure, characterized by the formation of regenerative nodules surrounded by dense fibrous tissue. Symptoms often do not appear for many years and are often nonspecific (loss of appetite, even anorexia, fatigue, and weight loss). Terminal symptoms include portal hypertension, ascites, and liver failure. Diagnosis often requires liver biopsy. Treatment is generally symptomatic.

Liver cirrhosis is one of the leading causes of death worldwide. The causes of this disease are the same as those of fibrosis. In developed countries, most cases are due to chronic alcohol abuse or chronic viral hepatitis. In many parts of Asia and Africa, liver cirrhosis develops against the background of chronic infectious hepatitis B. Diagnosis of this disease of unclear etiology is becoming less common, as many causes have been discovered (for example, chronic hepatitis C, steatohepatitis).

Fibrosis is not a synonym for cirrhosis. For example, congenital liver fibrosis does not lead to cirrhosis; the latter also does not occur with zone 3 fibrosis in heart failure, zone 1 fibrosis characteristic of bile duct obstruction, or interlobular fibrosis observed in granulomatous liver disease.

The formation of nodules without fibrosis, which is observed in partial nodular transformation of the liver, is also not cirrhosis.

According to pathological criteria, liver cirrhosis is an irreversible diffuse process characterized by a pronounced fibrosing reaction, restructuring of the normal architecture of the liver, nodular transformation and intrahepatic vascular anastomoses.

Viral hepatitis

Viral hepatitis is the cause of the development of viral liver cirrhosis in 10-23.5% of cases. According to the figurative expression of E. M. Tareev, viral hepatitis plays the same role in the development of liver cirrhosis as rheumatism plays in the development of heart defects.

Chronic hepatitis B, chronic hepatitis C, chronic hepatitis D and, probably, chronic hepatitis G can result in liver cirrhosis. In 30% of cases (and according to some data - in 50%), chronic active viral hepatitis evolves into liver cirrhosis. Among chronic HBsAg carriers, liver cirrhosis develops in 10% of cases, and according to morphological examination of biopsies - in 20-60% of cases. Chronic hepatitis B transforms into liver cirrhosis in 2.3% of cases.

Liver cirrhosis develops in 20-25% of patients with chronic hepatitis C, and with histological control of biopsies - in 50%.

The most cirrhotic is HCV genotype 1b. HCV cirrhosis of the liver remains compensated for many years and is not recognized.

The main feature of chronic hepatitis D is its high cirrhosis potential. Liver cirrhosis develops in 13-14% of patients with chronic hepatitis D, and at an earlier stage than with other viral hepatitis, sometimes over the course of only a few months.

There is a point of view that cirrhosis of the liver of viral etiology is characterized by a faster rate of progression and, consequently, a shorter life expectancy. In viral cirrhosis, the mortality rate is 70% already 5 years after diagnosis, and in alcoholic cirrhosis (provided that alcohol intake is completely stopped) - 30%.

Autoimmune hepatitis

Autoimmune hepatitis is characterized by a severe course, the frequency of its transition to liver cirrhosis is higher, and the prognosis is much more serious than with viral hepatitis.

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Chronic alcohol abuse

Chronic alcohol intoxication is the cause of liver cirrhosis in 50% of cases. The disease usually develops 10-15 years after the onset of alcohol abuse. According to Thaler, liver cirrhosis develops in men with daily consumption of 60 g of alcohol, in women - 20 g during the specified period.

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Genetically determined metabolic disorders

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α1-antitrypsin deficiency

A1-antitrypsin is a glycoprotein synthesized in the liver. It inhibits trypsin, elastase, collagenase, chymotrypsin, and plasmin. There are 24 alleles of the a1-antitrypsin gene that are inherited codominantly. Liver cirrhosis is found in more than half of patients with homozygous a1-antitrypsin deficiency. The concentration of a1-antitrypsin and a2-globulin in the blood of patients is reduced, while there are deposits of a1-antitrypsin in the liver and antibodies to it are formed. It is assumed that a1-antitrypsin deposits are due to previous necrosis of hepatocytes. Deficiency of a1-antitrypsin in the blood and its deposits in hepatocytes cause hypersensitivity of the liver to the damaging effects of alcohol and other hepatotropic toxins, and disrupt the synthesis and transportation of proteins. Most often, primary biliary cirrhosis of the liver develops with a1-antitrypsin deficiency.

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Galactose-1-phosphate uridyltransferase deficiency

Congenital deficiency of galactose-1-phosphate uridyltransferase leads to the development of galactosemia. In this case, early childhood cirrhosis of the liver is formed. The mechanism of development of this cirrhosis is unknown.

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Glycogen storage diseases

Congenital deficiency of the enzyme amylo-1,6-glycosidase leads to the development of glycogen storage diseases and liver cirrhosis.

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Hemochromatosis and hepatocerebral dystrophy (Wilson-Konovalov disease)

These diseases are genetically determined and lead to the development of liver cirrhosis.

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Chemical toxic substances and drugs

Liver cirrhosis can develop under the influence of the following toxic substances:

• industrial poisons (carbon tetrachloride, dimethylnitrosamine, chloroform, benzene, nitro and amino compounds, etc.);
• heavy metal salts (chronic mercury intoxication, etc.);
• mushroom poisons (phalloidin, phalloin, beta-amanitin) cause massive liver necrosis with subsequent formation of cirrhosis;
• aflatoxins (found in overwintered grain, corn, rice).

In addition, some medications, when used over a long period of time, can cause the development of liver cirrhosis:

• methyldopa;
• isoniazid;
• para-aminosalicylic acid (PAS);
• ipraside;
• preparations containing arsenic;
• inderal in high doses;
• cytostatics (in particular, methotrexate);
• steroid anabolic drugs and androgens.

Androgens, anabolic steroids, major tranquilizers can cause biliary cirrhosis. The other above-mentioned drugs can lead to the development of postnecrotic cirrhosis of the liver as a result of acute drug-induced hepatitis with submassive or small focal necrosis.

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Obstruction of extrahepatic and intrahepatic bile ducts

Intrahepatic biliary obstruction of autoimmune genesis leads to the development of primary biliary cirrhosis. Secondary biliary cirrhosis develops as a result of long-term obstruction of bile outflow at the level of large intrahepatic and extrahepatic bile ducts (cholelithiasis, inflammatory and cicatricial diseases of the digestive organs, narrowing of the bile ducts; tumors of the hepatopancreatoduodenal zone; congenital malformations of the extrahepatic bile ducts, cystic dilation of the intrahepatic bile ducts - Caroli syndrome ). The most favorable background for the development of cirrhosis is incomplete obstruction of the bile duct. Liver cirrhosis develops 3-18 months after obstruction.

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Long-term venous congestion in the liver

Long-term venous congestion in the liver contributes to the development of liver cirrhosis. Most often, venous congestion is caused by heart failure (especially with tricuspid insufficiency), less often by constrictive pericarditis and endophlebitis of the hepatic veins (Budd-Chiari disease).

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Combined influence of etiological factors

About 50% of all liver cirrhoses develop under the influence of several etiologic factors. The most common are active viral hepatitis B and alcohol abuse, congestive heart failure and chronic alcoholism. Other combinations of etiologic factors are also possible.

Rendu-Osler disease

Rendu-Osler disease (hereditary hemorrhagic telangiectasia) is a rare cause of liver cirrhosis, which is considered a specific manifestation of this disease and develops, probably, as a result of congenital inferiority of the vascular system of the liver and in connection with the development of arteriovenous aneurysms.

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Cryptogenic liver cirrhosis

Liver cirrhosis of unknown etiology (cryptogenic) develops in 12-40% of cases. Cryptogenic cirrhosis includes primary biliary cirrhosis, liver cirrhosis in children aged 6 months to 5 years in India, etc.

Other factors may also cause liver cirrhosis:

• Malnutrition.
• Infections. Malaria plasmodia do not cause cirrhosis. Cirrhosis in malaria is probably due to malnutrition or viral hepatitis.
• Syphilis can cause cirrhosis only in newborns.
• In schistosomiasis, the parasite eggs cause fibrous tissue to grow in the portal areas. In some countries, the true cause of liver cirrhosis when combined with schistosomiasis may be another disease, such as viral hepatitis C.
• Granulomatosis. Focal granulomas, such as those seen in brucellosis, tuberculosis, and sarcoidosis, resolve with the development of fibrosis, but no regenerative nodes are present.
• Cryptogenic cirrhosis is a collective term for cirrhosis of unknown etiology. Its incidence varies across countries; in the UK, cryptogenic cirrhosis accounts for 5-10% of all cases of liver cirrhosis, while in countries with a higher prevalence of alcoholism, such as France or industrial areas of the USA, its incidence is even lower. The diagnosis of cryptogenic cirrhosis will become less common as specific diagnostic tests become available. The development of methods for detecting HBsAg and antibodies to the hepatitis C virus has made it possible to establish that many cases of cirrhosis previously considered cryptogenic are caused by viral hepatitis. The detection of antibodies to mitochondria and smooth muscles, as well as a more thorough analysis of histological changes in the liver, make it possible to attribute some cases of cryptogenic cirrhosis to autoimmune chronic hepatitis and PBC. In some patients, cryptogenic liver cirrhosis may be explained by alcoholism, which they deny or have forgotten about over the years. However, in some patients, cirrhosis must be recognized as cryptogenic.

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Pathogenesis

There are individual differences in the rate of fibrosis progression with transformation into cirrhosis, the morphological picture of cirrhosis, despite the same damaging factor. The reasons for such differences are unknown.

In response to injury, growth regulators induce hepatocellular hyperplasia (development of regenerative nodes) and arterial growth (angiogenesis). Among the growth regulators, cytokines and liver growth factors (e.g., epithelial growth factor, hepatocyte growth factor, transforming growth factor alpha, tumor necrosis factor) are distinguished. Insulin, glucagon, and intrahepatic blood flow characteristics are also determinants of node formation.

Angiogenesis results in the formation of new vessels within the fibrous tissue surrounding the nodes; these intervascular "bridges" connect the hepatic artery and portal vein vessels to the hepatic venules, restoring intrahepatic blood flow. These vascular connections provide a relatively low-volume, high-pressure venous return that is unable to accommodate such a large volume of blood, thereby increasing portal venous pressure. These changes in blood flow within the nodes, along with compression of the hepatic venules and regenerative nodes, contribute to the development of portal hypertension.

Liver cirrhosis may cause right-to-left intrapulmonary shunting and ventilation/perfusion failure, resulting in hypoxia. Progressive loss of liver function leads to liver failure and ascites. Hepatocellular carcinoma frequently complicates liver cirrhosis, especially cirrhosis due to chronic viral hepatitis B and C, hemochromatosis, alcoholic liver disease, alpha1-antitrypsin deficiency, and glycogen storage disease.

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Histopathology

In this disease, both nodular regeneration and fibrosis occur simultaneously. Completely unformed liver nodules, nodules without fibrosis (nodular regenerative hyperplasia), and congenital fibrosis (i.e., widespread fibrosis without regenerative nodules) are not true cirrhosis. The disease may be micronodular or macronodular. The micronodular variant is characterized by uniformly small nodules (< 3 mm in diameter) and thick, regular bundles of connective tissue. As a rule, the nodules lack lobular structure; the terminal (central) hepatic venules and portal triads are disorganized. Over time, a macronodular variant often develops, in which the nodules are of varying size (from 3 mm to 5 cm in diameter) and contain some fairly normal lobular structure of the portal triads and central venules. Broad fibrous bundles of varying thickness surround the large nodules. Destruction of the normal liver architecture suggests a concentration of portal triads within fibrous cords. The mixed variant (incomplete intermediate liver cirrhosis) combines elements of the micronodular and macronodular variants.

The pathogenesis of liver cirrhosis is determined by etiological features, as well as the mechanism of self-progression of cirrhosis, common to all forms of this disease.

Viral cirrhosis of the liver develops as a result of persistent viral infection and the resulting immune-inflammatory process, the cytopathic (hepatotoxic) effect of the hepatitis D virus and hepatitis C virus, and the development of autoimmune reactions.

In the development of autoimmune cirrhosis of the liver, the main role is played by autoimmune reactions, causing a pronounced immune-inflammatory process with necrosis of liver tissue.

In the pathogenesis of alcoholic liver cirrhosis, the leading roles are played by damage to hepatocytes by alcohol and its metabolic product acetaldehyde, the development of an autoimmune inflammatory process (in response to the deposition of alcoholic hyaline in the liver), and stimulation of fibrosis in the liver under the influence of alcohol.

In the origin of cardiac (congestive) cirrhosis of the liver, the following are important: a decrease in cardiac output, venous retrograde congestion, a decrease in the perfusion pressure of blood entering the liver, the development of hepatocyte hypoxia, which leads to atrophy and necrosis of hepatocytes, primarily in the central part of the liver lobules.

In all cases of liver cirrhosis, the central mechanism in the pathogenesis is the self-progression of cirrhosis and stimulation of the formation of connective tissue.

The mechanism of self-progression of liver cirrhosis is as follows. The trigger factor in the morphogenesis of cirrhosis is the death of the liver parenchyma. In postnecrotic liver cirrhosis, massive or submassive necrosis of the parenchyma occurs. At the site of dead hepatocytes, the reticulin skeleton collapses, an organic scar is formed. The vessels of the portal tract approach the central vein. Conditions are created for the transition of blood from the hepatic artery and portal vein to the central vein, bypassing the sinusoids of the adjacent undamaged areas of the liver. Under normal conditions, the portal vein and hepatic artery give their blood through the terminal plate to the sinusoids located between the beams of hepatocytes in the lobule, and then the blood enters the sinusoids into the central (hepatic) vein.

Blood flow bypassing the sinusoids of undamaged areas of the liver leads to their ischemia and then necrosis. During necrosis, substances stimulating liver regeneration are released, regeneration nodes develop, which compress the vessels and contribute to further disruption of blood flow in the liver

The breakdown products of hepatocytes stimulate an inflammatory reaction, inflammatory infiltrates are formed, which spread from the portal fields to the central parts of the lobules and contribute to the development of postsinusoidal block.

The inflammatory process in liver cirrhosis is characterized by intense fibrosis. Connective tissue septa are formed. They contain vascular anastomoses, connect the central veins and portal tracts, the lobule is fragmented into pseudolobules. In pseudolobules, the relationship of the portal vessels and the central vein is changed, in the center of the pseudolobules, the central vein is not found, and there are no portal triads along the periphery. Pseudolobules are surrounded by connective tissue septa containing vessels connecting the central veins with the branches of the hepatic vein (intrahepatic portocaval shunts). Blood enters directly into the hepatic vein system, bypassing the parenchyma of the pseudolobules, this causes ischemia and necrosis. This is also facilitated by mechanical compression of the venous vessels of the liver by connective tissue.

The regeneration nodes have their own newly formed portal tract, anastomoses develop between the portal vein and the hepatic artery and hepatic vein.

In the pathogenesis of all types of liver cirrhosis, the activation of lipid peroxidation, the formation of free radicals and peroxides, which damage hepatocytes and contribute to their necrosis, is also of great importance.

In recent years, there have been reports of the role of keillons in the pathogenesis of liver cirrhosis. Keillons are tissue-specific but non-species-specific mitotic inhibitors that control tissue growth by suppressing cell division. They are found in cells of all tissues. Keillons are peptides or glycopeptides, and their action is carried out by the principle of negative feedback. There are two types of keillons:

• Type I chalones prevent the transition of cells preparing to divide from the G phase of the cell cycle to the S phase;
• Type II chalones block the transition of cells from the G2 phase to mitosis.

Scientific studies have established that the liver extract of patients with active liver cirrhosis not only does not have an inhibitory effect, but even causes significant stimulation of the mitotic activity of hepatocytes in the regenerating liver. This suggests that chalones promote the development of regeneration nodes in liver cirrhosis.

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Development of liver cirrhosis

Necrosis causes certain changes in the liver; the most important of these are the collapse of the liver lobules, the diffuse formation of fibrous septa, and the appearance of regenerative nodes. Regardless of the etiology of necrosis, the histological picture when examining the liver is always the same. The necrosis itself may no longer be detected at autopsy.

Fibrosis develops after hepatocyte necrosis. Thus, after portal hepatitis, portoportal fibrous septa appear in zone 1. Confluent necrosis in zone 3 leads to the development of portocentral fibrosis. Focal fibrosis develops after focal necrosis. Regeneration nodes are formed in areas of cell death, which disrupt the normal architecture of the liver and lead to the development of cirrhosis.

Sinusoids are preserved along the periphery of the regeneration nodes in the area of the portocentral septa. Blood supply from the portal vein to the functioning liver tissue, in particular the central part of the nodes (zone 3), is disrupted, which can contribute to the progression of cirrhosis even after its cause has been eliminated. A pathological collagen matrix is formed in the Disse space, preventing normal metabolism between the blood of the sinusoids and hepatocytes.

Fibroblasts appear around dead hepatocytes and proliferating ductules. Fibrosis (collagenization) is initially reversible, but after the formation of septa in zone 1 and in the lobules that do not contain cells, it becomes irreversible. The localization of fibrous septa depends on the cause of cirrhosis. For example, in hemochromatosis, iron deposition causes fibrosis of the portal zone, while in alcoholism, fibrosis of zone 3 predominates.

Normally, the liver connective tissue matrix contains collagen type IV, laminin, heparan sulfate, proteoglycan, and fibronectin. All of these are found in the basement membrane. Liver damage results in an increase in the extracellular matrix, which contains collagen types I and III, which form fibrils, as well as proteoglycans, fibronectin, hyaluronic acid, and other matrix glycoconjugates.

The formation of a fibrous scar is the result of the prevalence of extracellular matrix formation processes over its destruction. These are complex and multicomponent processes.

Perhaps in the future, a better understanding of them will allow the development of new methods of treatment. Fibrosis in the early stages of development is a reversible process; cirrhosis of the liver, which is characterized by cross-links between collagen fibers and regeneration nodes, is irreversible.

The hepatic stellate cell (also called an lipocyte, fat-storing cell, Ito cell, or pericyte) is a key player in fibrogenesis. It is located in the Disse space between endothelial cells and the sinusoid-facing surface of hepatocytes. Similar perivascular cells are found in the kidneys and other tissues. At rest, the hepatic stellate cells contain fat droplets containing vitamin A; they contain the body's major retinoid reserves. The cells express desmin, a filament-forming protein found in muscle tissue.

Liver damage activates stellate cells. They proliferate and enlarge, fat droplets containing retinoids disappear from them, the rough endoplasmic reticulum increases, and a specific smooth muscle protein, a-actin, appears. The number of receptors for cytokines that stimulate proliferation and fibrogenesis increases. At present, the factors activating stellate cells have been poorly studied. Perhaps, transforming growth factor-beta (TGF-beta), secreted by Kupffer cells, is of some importance. In addition, stellate cell activation factors can also be secreted by hepatocytes, thrombocytes, and lymphocytes.

Cytokines acting on activated cells can induce proliferation (eg, platelet-derived growth factor) and stimulate fibrogenesis (eg, TGF-beta). A number of other growth factors and cytokines also act on stellate cells, including fibroblast growth factor, interleukin-1 (IL-1), epidermal growth factor (EGF), and tumor necrosis factor-α (TNF-α). Some of these are secreted by Kupffer cells as well as by stellate cells themselves, providing autocrine regulation. In addition, stellate cells are influenced by acetaldehyde, which is formed during alcohol metabolism, and by lipid peroxidation products formed as a result of the damaging effects of alcohol or excess iron. Thrombin stimulates stellate cell proliferation. Damage to the extracellular matrix by stellate cells promotes their activation.

Activated stellate cells (myofibroblasts) acquire smooth muscle cell-like properties and are capable of contraction. They synthesize endothelin-1, which can cause their contraction. Thus, these cells can also participate in the regulation of blood flow.

Another leading factor in the formation of fibrous tissue is the destruction of matrix proteins. It is provided by a number of enzymes called metalloproteinases. There are 3 main groups of these enzymes: collagenases, gelatinases and stromelysins. Collagenases destroy interstitial collagen (types I, II and III), gelatinases - collagen of the basement membranes (type IV) and gelatin. Stromelysins are able to destroy many other proteins, including proteoglycans, laminin, gelatins and fibronectin. These enzymes are synthesized mainly in Kupffer cells and in activated stellate cells. The activity of metalloproteinases is suppressed by tissue inhibitors of metalloproteinases (TIMPs). Activated stellate cells secrete TIMP-1 and therefore play a major role not only in the synthesis of fibrous tissue, but also in the destruction of the matrix. It has been established that in alcoholic liver disease at the precirrhotic and cirrhotic stages, the TIMP content in the blood increases.

After liver damage, early changes in the matrix in the Disse space become very important - deposition of collagen types I, III and V, which make up the fibrils, and fibronectin. Sinusoids turn into capillaries ("capillarization"), endothelial fenestrae disappear, which disrupts the metabolism between hepatocytes and blood. The experiment showed that stenosis of sinusoids increases vascular resistance in the liver and causes portal hypertension. Progression of fibrosis disrupts the liver architecture and causes the development of cirrhosis and portal hypertension.

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Cytokines and growth factors in the liver

In addition to their involvement in fibrogenesis, cytokines perform many other functions. These proteins act like hormones, coordinating cell differentiation and maintaining or restoring normal homeostasis. They provide not only intrahepatic intercellular interactions, but also the connection of the liver with other organs. Cytokines participate in the regulation of the metabolism of amino acids, proteins, carbohydrates, lipids, and minerals. They also interact with such classical hormones as glucocorticoids. Since many cytokines, in addition to specific proinflammatory effects, act like growth factors, attempts to separate cytokines and growth factors seem somewhat artificial.

In the liver, primarily in Kupffer cells, proinflammatory cytokines such as TNF-a, IL-1, and IL-6 are produced. In addition, blood cytokines are inactivated in the liver, which weakens their systemic action. It is possible that the disruption of this inactivation in cirrhosis is the cause of some of the immune disorders observed in this condition.

Cytokines are formed with the participation of monocytes and macrophages activated by endotoxin released in the intestine. Endotoxemia in cirrhosis is caused by increased permeability of the intestinal wall and suppression of the activity of Kupffer cells, which, absorbing endotoxin, neutralize and remove it. This leads to the production of excess monokines.

Cytokines are responsible for some of the systemic manifestations of cirrhosis, such as fever and anorexia. TNF-a, IL-1, and interferon-a increase fatty acid synthesis, resulting in fatty liver disease.

Cytokines suppress liver regeneration. Under the influence of IL-6, IL-1 and TNF-a, the liver begins to synthesize acute phase proteins, including C-reactive protein, A-amyloid, haptoglobin, complement factor B and alpha1-antitrypsin.

The liver is known to have an unusually high capacity for regeneration even after significant damage, such as viral hepatitis or as a result of its resection. Regeneration begins with the interaction of growth factors with specific receptors of cell membranes.

Hepatocyte growth factor is the most powerful stimulator of DNA synthesis by mature hepatocytes, initiating liver regeneration after injury. However, it can be synthesized not only by liver cells (including stellate cells), but also by cells of other tissues, as well as tumor cells. Its synthesis is regulated by many factors, including IL-1a, IL-1beta, TGF-beta, and glucocorticoids. Under the influence of TGF, the growth of other types of cells, such as melanocytes and hematopoietic cells, is also enhanced.

Epidermal growth factor (EGF) is formed in hepatocytes during regeneration. There are a large number of EGF receptors on the hepatocyte membrane; in addition, receptors are present in the hepatocyte nucleus. EGF is most actively absorbed in zone 1, where regeneration occurs especially intensively.

Transforming growth factor a. (TGF-alpha) has a chain region comprising 30-40% of the length of its molecule that is homologous to EGF and can bind to EGF receptors, stimulating hepatocyte proliferation.

Transforming growth factor beta1 (TGF-beta1) is probably the main inhibitor of hepatocyte proliferation; during liver regeneration, it is secreted in large quantities by non-parenchymatous cells. In experiments on cell cultures, TGF-beta1 exerted both stimulatory and inhibitory effects, which depended on the nature of the cells and their culture conditions.

The absorption of amino acids by hepatocyte culture increases under the influence of EGF, and decreases under the influence of TGF-beta.

The influence of all growth factors and cytokines is realized only in interaction with each other; the mechanism of this interaction is complex, and the volume of information about it is growing rapidly.

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Monitoring fibrogenesis

Specific proteins and metabolic products participate in connective tissue metabolism, the content of which can be determined when they enter the plasma. Unfortunately, the data obtained in this way reflect the activity of fibrogenesis in the body as a whole, and not in the liver.

During the synthesis of type III collagen fibrils from the procollagen molecule, the amino-terminal peptide of type III procollagen (P-III-P) is released. Its content in serum has no diagnostic value, but allows monitoring of fibrogenesis in the liver, in particular in patients with alcoholism. In chronic liver diseases, primary biliary cirrhosis (PBC) and hemochromatosis, an elevated level of P-III-P may reflect inflammation and necrosis rather than fibrosis. The level of this peptide is elevated in children, pregnant women and patients with renal failure.

Other substances have also been studied: propeptide of procollagen type IV, laminin, undulin, hyaluronic acid, TIMP-1 and integrin-beta 1. In general, these factors are of scientific interest and have no clinical significance. In the diagnosis of liver fibrosis and cirrhosis, serological studies cannot replace liver biopsy.

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Pathogenesis of portal hypertension

Portal hypertension is the most important syndrome of liver cirrhosis and has a complex genesis.

The following main mechanisms are important in the development of portal hypertension:

• postsinusoidal block of blood flow in the liver (compression of the branches of the portal vein by nodes of regenerating hepatocytes or growths of fibrous tissue);
• perisinusoidal fibrosis;
• the presence of arteriovenous anastomoses in the intralobular connective tissue septa (transfer of hepatic arterial pressure to the portal vein);
• portal infiltration and fibrosis;
• increasing blood flow to the liver.

The first three of these factors lead to an increase in intra-sinusoidal pressure and contribute to the development of ascites and liver failure.

The last two mechanisms of portal hypertension are responsible for the increase in presinusoidal pressure and the development of extrahepatic manifestations of portal hypertension.

As a result of portal hypertension, the most important clinical manifestations of liver cirrhosis develop - portocaval anastomoses, ascites, splenomegaly.

A significant consequence of the development of portocaval anastomoses and bypassing the liver parenchyma is its partial functional shutdown. In turn, this contributes to the development of bacteremia (the result of shutdown of the liver's reticulohistiocytic system, intestinal dysbacteriosis and dysfunction), endotoxinemia; insufficient inactivation of aldosterone, estrogens, histamine; decreased supply of hepatotropic substances ( insulin, glucagon ) to the liver and dysfunction of hepatocytes.

The most serious and prognostically unfavorable consequence of portocaval shunting is exogenous (portocaval) coma.

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Pathogenesis of hepatocellular insufficiency

Along with portal hypertension, hepatocellular insufficiency syndrome is the most important manifestation of liver cirrhosis and is caused by the following reasons:

• continuing action of the primary pathogenic (etiological) factor and autoimmune processes;
• hemodynamic disorders in the liver (blood drainage from the liver through portocaval anastomoses, intrahepatic blood shunting and decreased blood supply to the liver parenchyma, impaired intralobular microcirculation).

As a result of the above factors, the mass of functioning hepatocytes and their functional activity decrease, which leads to the development of hepatocellular insufficiency, the most severe manifestation of which is hepatic coma.

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Symptoms liver cirrhosis

Liver cirrhosis may be asymptomatic for many years. Often, the first symptoms of liver cirrhosis are atypical (general weakness, anorexia, malaise, and weight loss). The liver is usually palpable and firm, with a blunt edge, but sometimes it is small and difficult to palpate. Nodes are usually not palpable.

As a rule, malnutrition together with anorexia and poor diet, insufficient secretion of bile cause malabsorption of fats and fat-soluble vitamins. Usually, patients with cirrhosis due to alcoholic liver disease have pancreatic enzyme deficiency, which contributes to malabsorption.

If cholestasis is present (eg, in primary biliary cirrhosis), jaundice, pruritus, and xanthelasma may occur. Portal hypertension is complicated by gastrointestinal bleeding from esophageal and gastric varices, gastropathy, or varicose hemorrhoids; splenomegaly and hypersplenism; portosystemic encephalopathy and ascites. In the terminal stage of the disease, liver failure may develop, leading to coagulopathy, possibly hepatorenal syndrome, and the development of jaundice and hepatic encephalopathy.

Other clinical features may indicate chronic liver disease or chronic alcohol abuse, but are not characteristic of liver cirrhosis: muscle wasting, palmar erythema, parotid gland enlargement, white nails, Dupuytren's contracture, spider angiomas (normal < 10), gynecomastia, axillary hair loss, testicular atrophy, and peripheral neuropathy.

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Forms

The International Classification of Chronic Diffuse Liver Diseases (World Association for the Study of Liver Diseases, Acapulco, 1974; WHO, 1978) distinguishes the following morphological forms of liver cirrhosis: micronodular, macronodular, mixed (macro-micronodular) and incomplete septal.

The main criterion for dividing cirrhoses is the size of the nodules.

In micronodular cirrhosis, the liver surface is represented by small nodes, about 1-3 mm in diameter, regularly located and having almost the same size, separated by a thin (about 2 mm wide) regular network of scar tissue. Microscopically, the presence of thin, approximately equal width connective tissue septa is characteristic, cutting the liver lobule into separate pseudolobules, pseudolobules of approximately equal size, as a rule, do not contain portal tracts and hepatic veins.

The liver in micronodular cirrhosis is not greatly enlarged or has normal dimensions. This form of cirrhosis is most typical for chronic alcoholism, obstruction of the bile ducts, hemochromatosis, and prolonged venous congestion in the liver.

In macronodular cirrhosis, the liver is usually sharply deformed. Its surface is represented by irregularly located nodes of different sizes (significantly more than 3 mm, sometimes up to 5 cm in diameter), which are separated by irregular, different width strands of connective tissue. Microscopically, macronodular cirrhosis of the liver is characterized by pseudolobules of different sizes; an irregular network of connective tissue in the form of strands of different widths, often containing three or more closely spaced portal triads and central veins.

Mixed macro-micronodular cirrhosis of the liver combines features of micro- and macronodular cirrhosis and in most cases represents an intermediate stage of the transition from micronodular cirrhosis to macronodular cirrhosis.

Usually, with a mixed form, the number of small and large nodes is almost equal.

Incomplete septal cirrhosis is characterized by the presence of connective tissue septa that dissect the parenchyma and often end blindly, without connecting the portal field to the central vein. Regeneration is present, but it is diffuse rather than nodular. Histologically, this is manifested as bilayered liver plates and pseudoductular proliferation of hepatocytes ("rosette formation").

In addition, microscopically, monolobular, multilobular and monomultilobular forms of liver cirrhosis are distinguished.

Typically, micronodular cirrhosis of the liver is monolobular (micronodular nodules consist of part of one lobule); macronodular is multilobular (false lobules include the remnants of many lobules); macromicronodular is monomultilobular (the number of mono- and multilobular lobules is approximately equal).

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Classification of liver cirrhosis

There is no single classification of liver cirrhosis. Most specialists consider it appropriate to classify liver cirrhosis depending on the etiology, morphological characteristics, stage of portal hypertension and hepatocellular insufficiency, activity of the inflammatory process, and course variant.

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Diagnostics liver cirrhosis

Liver cirrhosis is diagnosed when multiple nodes are detected in the liver in combination with fibrosis. This can be done by direct visualization, for example, by laparotomy or laparoscopy. However, it is not advisable to perform laparotomy specifically for the diagnosis of cirrhosis, since it can cause liver failure even with compensated liver function.

During laparoscopy, nodules are visible on the surface of the liver, which can be subjected to targeted biopsy.

Scintigraphy reveals decreased radiopharmaceutical absorption, uneven distribution, and absorption by the spleen and bone marrow. Nodes are not visualized.

In ultrasound examination (ultrasound of the liver), signs of cirrhosis are uneven density of liver tissue and areas of increased echogenicity. The caudate lobe is enlarged. However, ultrasound data do not allow diagnosing cirrhosis until ascites appears. Regeneration nodes may resemble focal liver lesions. Dynamic observation or determination of the alpha-fetoprotein level is necessary to exclude their malignant nature.

Diagnosis of cirrhosis and its complications using computed tomography (CT) is cost-effective. Abdominal CT allows assessing the liver size and revealing the unevenness of its surface caused by nodes. CT scans cannot distinguish regenerative nodes from the rest of the liver tissue. CT scans can detect fatty infiltration, increased liver tissue density caused by iron deposition, and space-occupying lesions. After intravenous administration of a contrast agent, the portal and hepatic veins are visualized, as well as collateral vessels and an enlarged spleen - reliable signs of portal hypertension. Detection of large collateral vessels, which are usually located around the spleen or esophagus, serves as additional information to the clinical signs of chronic portosystemic encephalopathy. Ascites may be detected. If there are stones in the gallbladder or common bile duct, their shadows can be seen on CT scans. CT scans are an effective method for monitoring the course of cirrhosis. CT-guided targeted liver biopsy can be performed with minimal risk.

Diagnosis of cirrhosis from biopsy may be difficult. Reticulin and collagen staining may reveal a rim of fibrous tissue around the nodules.

The absence of portal tracts, disruption of the vascular pattern, detection of branches of the hepatic artery not accompanied by branches of the portal vein, the presence of nodes with fibrous septa, heterogeneity of the size and appearance of hepatocytes in different areas, and thickening of the hepatic beams are of diagnostic significance.

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Liver function assessment

Liver failure is manifested by jaundice, ascites, encephalopathy, lowserum albumin levels, and prothrombin deficiency that cannot be corrected by vitamin K administration.

Portal hypertension is diagnosed on the basis of splenomegaly and varicose veins of the esophagus, as well as increased pressure in the portal vein, which can be detected by modern research methods.

Dynamic monitoring of the clinical and histological picture, as well as biochemical indicators of liver function, allows us to assess the course of cirrhosis, which can be progressive, regressive or stable.

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Examples of formulation of diagnosis for liver cirrhosis

The diagnosis for each patient should be formulated with an indication of the etiology, morphological changes and liver function. Examples of detailed clinical diagnoses are given below.

1. Large-nodular progressive cirrhosis resulting from hepatitis B with hepatocellular insufficiency and portal hypertension.
2. Small-nodular regressive alcoholic cirrhosis with hepatocellular insufficiency and minimal signs of portal hypertension.
3. Mixed small- and large-nodular progressive cirrhosis due to biliary stricture with mild hepatocellular insufficiency and portal hypertension.

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Laboratory and instrumental data in liver cirrhosis

1. Complete blood count: anemia (usually with decompensated liver cirrhosis), with the development of hypersplenism syndrome - pancytopenia; during the period of exacerbation of cirrhosis - leukocytosis (a shift in the leukocyte formula to the left is possible), increased ESR.
2. General urine analysis: in the active phase of the disease, as well as with the development of hepatorenal syndrome - proteinuria, cylindruria, microhematuria.
3. Blood biochemistry: changes are more pronounced in the active and decompensated phases of liver cirrhosis, as well as with the development of hepatocellular insufficiency. Hyperbilirubinemia with an increase in both conjugated and unconjugated fractions of bilirubin; hypoalbuminemia, hyper alpha2- and y-globulinemia; high thymol and low sublimate test values; hypoprothrombinemia; decreased urea and cholesterol levels; high activity of alanine aminotransferase, y-glutamyl transpeptidase and organ-specific liver enzymes: fructose-1-phosphate aldolase, arginase, nucleotidase, ornithine carbamoyltransferase; with active liver cirrhosis, biochemical manifestations of the inflammatory process are pronounced - the content of haptoglobin, fibrin, sialic acids, seromucoid in the blood increases; the content of procollagen-III peptide, a precursor of collagen, is increased, which indicates the severity of connective tissue formation in the liver (normally, the content of aminoterminal procollagen-III peptide ranges from 5 to 12 ng/ml).
4. Immunological blood test: decreased quantity and activity of T-lymphocyte suppressors, increased immunoglobulin levels, hypersensitivity of T-lymphocytes to liver-specific lipoprotein. These changes are more pronounced in the active phase of liver cirrhosis.
5. Ultrasound of the liver: in the early stages of liver cirrhosis, hepatomegaly is detected, the liver parenchyma is homogeneous, sometimes hyperechoic. As the disease progresses, with micronodular liver cirrhosis, a homogeneous increase in the echogenicity of the parenchyma appears. With macronodular cirrhosis, the liver parenchyma is heterogeneous, regeneration nodes of increased density are detected, usually less than 2 cm in diameter, irregularity of the liver contours is possible due to regeneration nodes. A. I. Shatikhin and I. V. Makolkin (1983) suggest that echo inclusions up to 1 cm in diameter be designated as small-focal, and more than 1 cm - as large-focal acoustic heterogeneity. In this case, small-focal infertility more often corresponds to micronodular cirrhosis of the liver, large-focal - to macronodular cirrhosis, and the presence of heterogeneity of both sizes - to mixed macro-micronodular cirrhosis of the liver. As fibrosis progresses, the size of the right lobe of the liver decreases, and the left and caudate lobes increase. In the terminal stage of cirrhosis, the liver can be significantly reduced in size. An enlarged spleen and manifestations of portal hypertension are also detected.
6. Laparoscopy. Macronodular cirrhosis of the liver has the following characteristic picture - large (more than 3 mm in diameter) nodes of round or irregular shape are determined; deep cicatricial connective tissue grayish-white retractions between the nodes; newly formed nodes are bright red, and those formed earlier are brownish. Micronodular cirrhosis of the liver is characterized by minor deformation of the liver. The liver has a bright red or grayish-pink color, nodules no more than 0.3 cm in diameter are determined. In some cases, regeneration nodules are not visible, only thickening of the liver capsule is noted.
7. Liver biopsy. Micronodular liver cirrhosis is characterized by thin, equal-width connective tissue septa that dissect the liver lobule into separate pseudolobules of approximately equal size. Pseudolobules only occasionally contain portal tracts and hepatic veins. Each lobule or most of them are involved in the process. Regeneration nodules do not exceed 3 mm. Macronodular liver cirrhosis is characterized by pseudolobules of varying size, an irregular network of connective tissue in the form of strands of varying width, which often contain closely spaced portal triads and central veins. Mixed macromicronodular liver cirrhosis combines features of micro- and macronodular cirrhosis.

Incomplete septal cirrhosis is characterized by the following manifestations:

• connective tissue septa that dissect the parenchyma (often ending blindly, without connecting the portal field with the central vein);
• regenerative nodules are not visible;
• regeneration becomes diffuse in nature and manifests itself in the form of double-row liver plates and pseudoductular proliferation of hepatocytes.

7. Radioisotope scanning reveals hepatomegaly, diffuse changes in the liver, splenomegaly. Radioisotope hepatography reveals a decrease in the secretory-excretory function of the liver.
8. In viral cirrhosis of the liver, markers of hepatitis B, C, and D viruses are detected in the blood serum.
9. FEGDS and X-ray examination of the esophagus and stomach reveal varicose veins of the esophagus and stomach, chronic gastritis, and in some patients, stomach ulcers or duodenal ulcers.

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Clinical and morphological relationships

1. Nutritional characteristics. In cirrhosis, fat reserves and muscle mass often decrease, especially in alcoholics and in patients belonging to Child's group C. Muscle atrophy is caused by a decrease in protein synthesis in the muscles, associated with a violation of protein metabolism in the body as a whole. As the disease progresses, the body's energy expenditure at rest increases. This pattern persists even after liver transplantation if the patient has poor nutrition.

Patients with liver cirrhosis may have impaired taste and smell. Insufficient attention paid by patients (especially those suffering from alcoholism) to the condition of the oral cavity and its hygiene leads to frequent damage to the teeth and periodontium, although liver cirrhosis itself does not predispose to such diseases.

2. Eye symptoms: Patients with liver cirrhosis have a higher incidence of eyelid retraction and upper eyelid lag compared to the general population.

There are no signs of thyroid disease. The level of free thyroxine in the serum is normal.

3. Enlargement of the parotid salivary glands and Dupuytren's contracture may also occur in alcoholic cirrhosis.
4. Clubbing and hypertrophic osteoarthropathy may complicate cirrhosis, especially biliary cirrhosis. They may be caused by platelet clots that easily pass through pulmonary arteriovenous shunts into the peripheral circulation and clog capillaries, releasing platelet-derived growth factor.
5. Muscle cramps develop significantly more frequently in cirrhosis than in people with a healthy liver. Their frequency correlates with the presence of ascites, low mean arterial pressure, and plasma renin activity. Muscle cramps are often successfully treated with oral quinine sulfate. An increase in the effective circulating blood volume can be achieved by weekly transfusions of human albumin.
6. Steatorrhea is common even in the absence of pancreatitis or alcoholism. It may be caused by decreased secretion of bile acids by the liver.
7. Splenomegaly and dilated venous collaterals in the anterior abdominal wall usually indicate the presence of portal hypertension.
8. Abdominal wall hernias with ascites are common. They should not be treated radically unless they are life-threatening or if ascites is not sufficiently compensated.
9. Gastrointestinal symptoms. Varicose veins are detected on endoscopy. In a study of 324 patients with liver cirrhosis, peptic ulcers were found in 11%. Ulcers developed even more frequently in HBsAg carriers. In 70% of cases, they were asymptomatic. Ulcers developed more often in the duodenum than in the stomach, healed more slowly, and recurred more often than in patients without cirrhosis.

Dysbacteriosis of the small intestine in alcoholic cirrhosis develops in 30% of cases, more often in the presence than in the absence of ascites (37% versus 5%).

10. Primary liver cancer is a common complication of all forms of cirrhosis, with the exception of biliary and cardiogenic cirrhosis. It is believed that metastases of tumors to the liver are rare, since extrahepatic tumors rarely develop in cirrhosis. However, when comparing the frequency of metastatic liver tumors in patients with and without cirrhosis, it was found that the presence of cirrhosis does not affect it.
11. Gallstones. Ultrasound examination of patients with chronic liver disease revealed gallstones (usually pigmented) in 18.59% of men and 31.2% of women, which is 4-5 times more common than in the population. The presence of stones does not affect survival. A low ratio of bile acids to unconjugated bilirubin and a very high level of monoconjugated bilirubin in bile predispose to the development of pigment stones. In uncomplicated gallstone disease, surgical treatment should be avoided, since the risk of surgery is very high.
12. Chronic recurrent pancreatitis and pancreatic calcification are common in alcoholic liver disease.
13. Cardiovascular system damage. In patients with liver cirrhosis, atherosclerosis of the coronary arteries and aorta develops less frequently than in the general population. Myocardial infarction occurs almost 4 times less frequently in autopsy patients with liver cirrhosis than in individuals without cirrhosis. In liver cirrhosis, cardiac output and heart rate increase, while total peripheral vascular resistance and arterial pressure decrease. During an exercise test, the maximum values of heart rate and cardiac output do not reach the expected values, and signs of autonomic nervous system dysfunction are noted. Due to decreased vascular tone, the response of the circulatory system and kidneys to an increase in circulating blood volume is insufficiently expressed. This is partly due to a decrease in sensitivity to catecholamines and an increase in the synthesis of nitric oxide in the vascular wall. In patients with liver cirrhosis, belonging to Child's group C, the content of nitric oxide in exhaled air is 2 times higher than in healthy people.
14. Kidney damage. In all forms of liver cirrhosis, blood circulation in the kidneys is impaired. In particular, the blood supply to the cortex is impaired, which contributes to the development of hepatorenal syndrome. Arterial hypotension and shock observed in the terminal stage of cirrhosis cause acute renal failure.

In the glomeruli, there is a thickening of the mesangium and, to a lesser extent, the capillary walls (cirrhotic glomerulosclerosis). IgA deposits are often found in the mesangium, especially in alcoholism. These changes usually occur latently, but can sometimes be accompanied by a proliferative reaction and clinical manifestations of glomerular failure. Cryoglobulinemia and membranoproliferative glomerulonephritis develop against the background of chronic hepatitis C.

15. Infectious complications. In liver cirrhosis, the phagocytic activity of the cells of the reticuloendothelial system decreases, which is partly due to portosystemic shunting of blood. As a result, bacterial infections (usually caused by intestinal microflora) often develop. These complications are observed annually in 4.5% of patients with liver cirrhosis.

Septicemia is often observed in the terminal stage of cirrhosis; it should be excluded in all cases of fever and deterioration of the patient's condition. Septicemia often cannot be diagnosed in a timely manner. The possibility of spontaneous bacterial peritonitis should not be forgotten. A sensitive indicator of infection during hospitalization of patients with decompensated cirrhosis can be the level of IL-6 in plasma (more than 200 pg/ml).

The incidence of tuberculosis in patients with liver cirrhosis has decreased, but tuberculous peritonitis still occurs and often remains unrecognized. It has also been noted that respiratory tract infections in patients with liver cirrhosis have become milder.

16. Drug metabolism. Liver biopsy reveals decreased drug metabolism due to a decrease in the number of functioning hepatocytes. The metabolic activity of the remaining hepatocytes is not reduced.

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Histocompatibility antigens (HLA)

The HLA-B8 antigen is detected in 60% of patients with chronic hepatitis who do not have HBsAg. These are usually women under 40 years of age, for whom corticosteroid therapy allows achieving remission. Serological testing reveals non-specific antibodies and a high level of y-globulins. In HBsAg-positive chronic hepatitis, the HLA-B8 antigen is detected with a frequency characteristic of the general population. Even more often, in patients with HBsAg-negative chronic hepatitis, the Dw3 antigen of class II of the HLA system is found.

In alcoholic liver disease, there are differences in the frequency of detection of HLA antigens depending on the region.

A link has been established between idiopathic hemochromatosis and the A3, B7, and B14 antigens of the HLA system. The presence of a genetic link with the A and B HLA antigens makes it possible to identify a high risk of the disease in the patient's brothers and sisters.

Data on the association of primary biliary cirrhosis of the liver with class II antigens of the HLA system are contradictory.

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Hyperglobulinemia

Chronic liver disease is accompanied by an increase in the level of globulins, especially y-globulins, in the serum. Electrophoresis usually reveals a polyclonal nature of hyper-y-globulinemia, although in rare cases it may be monoclonal. The increase in the level of y-globulins is partly explained by an increase in the level of tissue autoantibodies, for example, to smooth muscles. The main reason is the disruption of the clearance of intestinal antigens by the affected liver. In cirrhosis of the liver, the level of antibodies to antigens produced in the gastrointestinal tract, especially to Escherichia coli antigens, increases in the serum. These antigens bypass the liver, passing through portosystemic anastomoses or through intrahepatic shunts formed around nodes in the liver. Entering the systemic circulation, they stimulate the production of antibodies, especially in the spleen. Systemic endotoxemia can develop similarly. In addition, IgA and their complexes with antigens can enter the systemic circulation. In chronic liver diseases, the activity of T-suppressors, which suppress B-lymphocytes, decreases, which contributes to an increase in the production of antibodies.

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Diagnostic value of liver biopsy

Puncture biopsy can play a key role in establishing the etiology of liver cirrhosis and determining its activity. If there are contraindications to biopsy (for example, ascites or blood clotting disorder), it should be performed through the jugular vein. To assess the progression of the disease, it is advisable to perform a dynamic biopsy.

To obtain sufficiently large samples of liver tissue and to avoid damage to other organs (especially the gallbladder) in liver cirrhosis, targeted biopsy with a sharp needle under visual control during ultrasound or CT is indicated.

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Treatment liver cirrhosis

In general, treatment of liver cirrhosis is symptomatic and consists of eliminating damaging agents, therapeutic nutrition (including additional vitamins), and treating the main manifestations and complications. Alcohol and hepatotoxic drugs should be avoided. Doses of drugs metabolized in the liver should be reduced.

Patients with esophageal and gastric varices require appropriate treatment to prevent bleeding. A positive treatment outcome may subsequently slow down the progression of liver fibrosis. Liver transplantation should be performed in end-stage liver failure in appropriate candidates.

Some sick people continue to abuse alcohol. Physicians should be prepared for the development of withdrawal syndrome during hospitalization.

Compensated liver cirrhosis requires dynamic monitoring for timely detection of liver cell failure. Treatment of liver cirrhosis is effective only if a balanced diet is followed and alcohol consumption is abstained.

If the patient is not exhausted, it is enough to take 1 g of protein per 1 kg of body weight. Methionine or various hepatoprotectors should not be prescribed additionally. Refusal of butter and other fats, eggs, coffee and chocolate has no therapeutic value.

In stable cirrhosis, there is no need to recommend additional intake of branched-chain amino acids. In severe dystrophy, it is useful to supplement the usual diet with frequent, unscheduled intake of small portions of food. Complete enteral nutrition for 3 weeks is accompanied by an increase in the albumin level and an improvement in the prognostic index determined by the Child criteria system.

In the development of hepatocellular insufficiency, accompanied by edema and ascites, it is recommended to limit sodium intake with food and prescribe diuretics; if encephalopathy occurs, it is necessary to limit protein intake and prescribe lactulose or lactitol.

Portal hypertension may require special therapy.

Drugs for the prevention of liver fibrosis

One of the goals of treating liver cirrhosis is to block collagen synthesis.

Secretion of procollagen requires polymerization of microtubules. This process can be blocked by drugs that disrupt microtubule complexes, such as colchicine. Colchicine at a dose of 1 mg/day for 5 days a week has been shown to increase survival. However, in this study, patients treated with colchicine initially had higher serum albumin levels than the control group; in addition, patients were less compliant with treatment, and many were lost to follow-up at long-term follow-up. The study is insufficiently conclusive to recommend long-term use of colchicine in cirrhosis. The drug is, however, relatively safe, with diarrhea being its only reported side effect.

Corticosteroids, along with their anti-inflammatory action, inhibit propyl hydroxylase. They suppress collagen synthesis, but also inhibit procollagenase. They are used in autoimmune chronic hepatitis.

A number of drugs have been proposed for the treatment of liver fibrosis, such as γ-interferon and other propyl hydroxylase inhibitors, such as HOE 077. Clinical studies of their effectiveness have not been conducted.

The appearance of drugs that activate extracellular proteases and ensure the decomposition of collagen is expected. In the future, the newest treatment for liver cirrhosis may be developed - gene therapy, which allows for direct blocking of the synthesis of connective tissue proteins.

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Surgical treatment of liver cirrhosis

In liver cirrhosis, any surgery is accompanied by a high risk of complications and death. The operative mortality rate in cirrhosis without bleeding is 30%, and 30% of surviving patients develop complications. In groups of patients A, B and C according to Child, the operative mortality rate is 10, 31 and 76%, respectively. The prognosis is especially unfavorable after operations on the bile ducts, for peptic ulcer disease and after colon resection. Unfavorable prognostic factors include low serum albumin levels, concomitant infections and an increase in prothrombin time.

If a patient is scheduled for a liver transplant, they should not have upper gastrointestinal surgery, as this makes the transplant more difficult.

Successful segmental resections of small hepatocellular carcinomas that form in the liver during cirrhosis are described.

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Clinical guidelines for the management of liver cirrhosis

Management of liver cirrhosis involves many aspects, and the treatment plan should be tailored to the individual patient, taking into account the severity of cirrhosis, its causes, and associated factors. Below are general clinical guidelines for the management of liver cirrhosis:

1. Treatment of the underlying disease:

   • If cirrhosis is caused by alcohol, it is important to stop drinking alcohol.
   • If cirrhosis is caused by viral hepatitis (hepatitis B or C), treatment should be aimed at suppressing the virus with antiviral drugs.
   • Other causes of cirrhosis, such as fatty liver disease or autoimmune diseases, should also be treated with appropriate methods.

2. Proper nutrition:

   • Patients with cirrhosis are advised to follow a diet that eases the burden on the liver. This includes reducing the intake of salt, fat, and sugar.
   • Some patients may require special diets, such as high-protein diets, to meet their nutritional needs.

3. Inspection and monitoring:

   • Regular check-ups with a physician, gastroenterologist or hepatologist are necessary to monitor the condition of the liver and the effectiveness of treatment.
   • Performing liver function tests, including blood tests and liver enzyme levels.

4. Prevention of complications:

   • Liver cirrhosis can cause various complications, such as intra-abdominal bleeding, ascites (fluid accumulation in the abdominal cavity), vascular plexus in the liver, and others. Treatment and prevention of these complications may require drug therapy or procedures.

5. Avoiding medications and substances harmful to the liver:

   • Patients with cirrhosis should avoid medications and substances that can damage the liver.
   • Uncontrolled use of drugs, alcohol, nicotine and other harmful substances can worsen liver condition.

6. Liver transplantation:

   • In cases of severe cirrhosis that does not respond to conservative treatment, liver transplantation may be required. Patients should be evaluated and prepared for transplantation.

7. Prevention of infections:

   • Patients with cirrhosis may be advised to receive hepatitis A and B vaccinations to prevent further liver damage.

It is important to emphasize that the management of liver cirrhosis requires an individual approach and should be carried out under the supervision of a doctor. Patients with liver cirrhosis should follow all recommendations and regularly consult with a medical specialist to effectively manage their condition.

Forecast

Liver cirrhosis often has an unpredictable prognosis. It depends on a number of factors, such as etiology, severity of damage, presence of complications, concomitant diseases, body condition and effectiveness of treatment.

Patients who continue to drink alcohol, even in small quantities, have a very poor prognosis. The Child-Turcotte-Pugh classification is used to assess the severity of the disease, surgical risk, and overall prognosis based on clinical and laboratory data.

It is generally believed that liver cirrhosis is irreversible, but observations in patients with hemochromatosis and Wilson's disease show that fibrosis can be reversed with treatment, so the concept of irreversibility of liver cirrhosis has not been proven.

Liver cirrhosis does not always progress; treatment can stop its further development.

The development of liver transplantation methods has increased the demands on predicting the course of cirrhosis: in order to refer a patient for surgery in a timely manner, it is necessary to know the most accurate prognosis possible.

The Child prognostic criteria system (groups A, B and C) takes into account the presence of jaundice, ascites, encephalopathy, serum albumin level and nutrition quality. It allows for a fairly accurate short-term prognosis. In the modified Child-Pugh prognostic system, instead of nutrition quality, the prothrombin level and the severity of the listed signs in points are taken into account. Based on the total number of points, patients are assigned to one of the groups: A, B or C, however, the literature data is ambiguous, since the assessment of signs in points is arbitrary.

The prognostic index is calculated based on the Cox proportional hazard regression model. An unfavorable prognosis is indicated by an increase in prothrombin time, significant ascites, gastrointestinal bleeding, older age, daily high alcohol intake, high bilirubin and high alkaline phosphatase activity, low albumin, and poor nutrition.

In a large study conducted in southern Italy, the incidence of decompensation in patients with liver cirrhosis was 10% per year. The first manifestation of decompensation was usually ascites. In decompensated cirrhosis, the 6-year survival rate was 21%. Significant signs of increased risk of death were older age, male gender, encephalopathy, bleeding, esophageal varices, increased prothrombin time, HBsAg carriage and, of course, hepatocellular carcinoma.

After the first episode of spontaneous bacterial peritonitis, the 1-year survival rate of patients with liver cirrhosis is 30-45%. Liver function tests usually do not provide additional prognostic information compared with the Child criteria system, although the aminopyrine breath test has been shown to be useful for patients with alcoholic liver cirrhosis belonging to Child prognostic groups A and B.

Prognostic value of individual factors:

1. Etiology of cirrhosis. In alcoholic cirrhosis, complete abstinence from alcohol provides a better prognosis than in cryptogenic cirrhosis.
2. If the cause of decompensation is bleeding, infection, or alcohol consumption, the prognosis is better than with spontaneous decompensation because the action of the provoking factor can be eliminated.
3. Treatment effectiveness. If there is no improvement within 1 month of inpatient treatment, the prognosis is unfavorable.
4. Jaundice, especially persistent, is an unfavorable prognostic sign.
5. Neurological complications. The significance of these complications depends on the nature of their occurrence. Thus, neurological disorders that develop against the background of progressive hepatocellular insufficiency indicate a poor prognosis, while disorders that develop slowly and are associated with portosystemic shunting are easily corrected by limiting protein in the diet.
6. Ascites worsens the prognosis, especially if its treatment requires high doses of diuretics.
7. Liver size: The larger the liver, the better the prognosis, as more functioning cells are retained.
8. Bleeding from esophageal varices. Along with assessing hepatocyte function, it is necessary to determine the severity of portal hypertension. If hepatocyte function is preserved, the patient will be able to tolerate bleeding satisfactorily; if the function is impaired, hepatic coma with a fatal outcome may develop.
9. Biochemical parameters. If the serum albumin level is below 2.5 g%, the prognosis is unfavorable. Hyponatremia below 120 mmol/l, if not associated with diuretic administration, also indicates a poor prognosis. Transaminase activity and serum globulin levels have no prognostic value.
10. Persistent hypoprothrombinemia, accompanied by spontaneous formation of hematomas and bruises, is a poor prognostic sign.
11. Persistent arterial hypotension (systolic blood pressure below 100 mmHg) is a poor prognostic sign.
12. Histological changes in the liver. Biopsy allows assessing the severity of necrosis and inflammatory infiltration. In case of fatty liver infiltration, treatment is usually effective.

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