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 development of subsequent hepatic insufficiency and portal hypertension.

[1], [2], [3], [4], [5], [6]

Epidemiology

Mortality from cirrhosis is in different countries from 14 to 30 cases per 100 000 population.

In connection with the irreversibility of cirrhosis in assessing its prevalence among the population, the main criterion is not so much morbidity indicators, as mortality. In the countries of Western Europe and the USA, the frequency according to autopsies ranges from 3-9%.

[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]

Causes of the liver cirrhosis

Cirrhosis of the liver is a progressive fibrosis, leading to diffuse disorganization of the normal structure of the liver, characterized by the formation of regenerative nodes surrounded by dense fibrous tissue. Symptoms often do not appear for many years and are often non-specific (loss of appetite, up to anorexia, fatigue, and loss of body weight). Symptoms in the terminal stage include portal hypertension, ascites, and liver failure. Diagnosis often requires a 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 with fibrosis. In developed countries, the majority of 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 unknown etiology is becoming less and less frequent, as many causes of its development have been discovered (for example, chronic hepatitis C, steatohepatitis).

Fibrosis is not synonymous with cirrhosis. For example, congenital liver fibrosis is not accompanied by the development of cirrhosis; the latter also does not occur in zone 3 fibrosis in heart failure, in zone 1 fibrosis characteristic of biliary tract obstruction, as well as in interlobular fibrosis observed in granulomatous lesions of the liver.

The formation of nodes without fibrosis, which is observed during partial nodal transformation of the liver, is also not cirrhosis.

According to autopsy criteria, liver cirrhosis is an irreversible diffuse process characterized by a pronounced fibrosis reaction, restructuring of the normal architectonics of the liver, nodal transformation and intrahepatic vascular anastomoses.

Viral hepatitis

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

The end result in cirrhosis of the liver can end , chronic hepatitis B, chronic hepatitis C, chronic hepatitis D, and probably chronic hepatitis G. In 30% of cases (and according to some - 50% ) chronic active viral hepatitis evolves into cirrhosis. Among chronic carriers of HBsAg liver cirrhosis is formed in 10% of cases, and according to morphological studies of biopsy specimens, in 20-60% of cases. Chronic hepatitis B is transformed into cirrhosis in 2.3% of cases.

Liver cirrhosis develops in 20–25% of patients with chronic hepatitis C, and in histological control of biopsy specimens in 50%.

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

The main feature of chronic hepatitis D is its high cirrhosis. Liver cirrhosis develops in 13–14% of patients with chronic hepatitis D, moreover, at an earlier date than with other viral hepatitis, sometimes for only a few months.

There is a point of view that cirrhosis of the viral etiology is characterized by faster rates progressed and, consequently, a shorter lifespan. In viral cirrhosis, as early as 5 years after diagnosis, mortality is 70%, and in case of alcoholic cirrhosis (subject to the complete cessation of alcohol intake), 30%.

Autoimmune Hepatitis

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

[18], [19], [20], [21], [22], [23], [24]

Chronic Alcohol Abuse

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

[25], [26], [27], [28], [29]

Genetically caused metabolic disorders

[30], [31], [32], [33], [34], [35]

Deficiency of α1-antitrypsin

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

[36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47]

Galactose-1-phosphate uridyltransferase deficiency

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

[48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58]

Diseases of glycogen accumulation

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

[59], [60], [61], [62], [63]

Hemochromatosis and hepatocerebral dystrophy (Wilson-Konovalov disease)

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

[64]

Chemical toxic substances and drugs

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

• industrial poisons (carbon tetrachloride, dimethylnitrosamine, chloroform, benzene, nitro and amino compounds, etc.);
• salts of heavy metals (chronic mercury intoxication, etc.);
• fungal poisons (phalloidin, phalloin, beta-amanitin) cause massive liver necrosis, followed by the formation of cirrhosis;
• aflatoxins (found in overwintered grains, maize, rice).

In addition, some medicinal substances with their prolonged use can cause the development of cirrhosis of the liver:

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

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

[65], [66], [67], [68], [69], [70]

Obstruction of the extrahepatic and intrahepatic biliary tract

Intrahepatic biliary obstruction of autoimmune genesis leads to the development of primary biliary cirrhosis. Secondary biliary cirrhosis develops as a result of long-term disruption of bile outflow at the level of large intrahepatic and extrahepatic bile ducts (cholelithiasis, inflammatory and scar diseases of the digestive system, narrowing of the biliary tract; tumors of the hepato-pancreatoduodenal zone, congenital extrahepatic biliary ducts, cystic extension s intrahepatic bile codes - Caroli disease ). The most favorable background for the development of cirrhosis is incomplete obstruction of the bile duct. Cirrhosis develops in 3-18 months. After violation of patency.

[71], [72], [73], [74], [75], [76], [77], [78], [79], [80]

Prolonged venous stasis in the liver

Prolonged venous congestion in the liver contributes to the development of cirrhosis of the liver. Venous congestion is most often caused by heart failure (especially in tricuspid insufficiency), less commonly by constrictive pericarditis and hepatic vein endoflebitis (Budd-Chiari disease).

[81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92]

The combined effect of etiological factors

About 50% of all cirrhosis of the liver develops under the influence of several etiological factors. Active viral hepatitis B and alcohol abuse, congestive heart failure and chronic alcoholism are most often combined. Other combinations of etiological factors are possible.

Randyu-Osler disease

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

[93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106]

Cryptogenic cirrhosis

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

The cause of cirrhosis can be other factors:

• Malnutrition.
• Infections. Malaria plasmodia does not cause cirrhosis. Cirrhosis in malaria appears to be due to malnutrition or viral hepatitis.
• Syphilis can cause cirrhosis only in newborns.
• In schistosomiasis, parasite eggs cause the growth of fibrous tissue in the portal areas. In some countries, the true cause of cirrhosis when combined with schistosomiasis may be another disease, such as viral hepatitis C.
• Granulomatosis Focal granulomas, such as brucellosis, tuberculosis and sarcoidosis, are resolved with the development of fibrosis, but there are no regeneration nodes.
• Cryptogenic cirrhosis is a collective concept and refers to cirrhosis of unclear etiology. Its frequency varies from country to country; in the UK, cryptogenic cirrhosis makes up 5-10% of all cirrhosis of the liver - and in countries with a higher prevalence of alcoholism, for example in France or in industrial areas of the United States, its frequency is even lower. A diagnosis of cryptogenic cirrhosis will be made less frequently as specific diagnostic tests grow. Development of methods detect HBsAg and antibodies to hepatitis C virus allowed to establish that many cases of cirrhosis, previously considered cryptogenic, are due to viral hepatitis. Detection of antibodies to mitochondria and to smooth muscles, as well as a more thorough analysis of histological changes in the liver, make it possible to attribute part of cryptogenic cirrhosis to autoimmune chronic hepatitis and PBC. In some patients, cryptogenic cirrhosis of the liver may be due to alcoholism, which they deny or which they have forgotten over the years. However, in some patients, cirrhosis has to be recognized as cryptogenic.

[107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118]

Pathogenesis

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

In response to damage, growth regulators induce hepatocellular hyperplasia (development of regenerative nodes) and arterial growth (angiogenesis). Cytokines and hepatic growth factors (for example, epithelial growth factor, hepatocyte growth factor, transforming growth factor alpha, tumor necrosis factor) are distinguished from growth regulators. Insulin, glucagon and intrahepatic blood flow are also crucial in the formation of nodes.

Angiogenesis leads to the formation of new vessels within the fibrous tissue surrounding the nodes; These intervascular "bridges" connect the vessels of the hepatic artery and portal vein with the hepatic venules, restoring intrahepatic blood flow. These vascular connections provide venous outflow of a relatively low volume with elevated pressure, which is not able to receive such a large volume of blood, thereby increasing the pressure in the portal vein. Such changes in the blood flow in the nodes along with compression of the hepatic venules and regenerative nodes contribute to the development of portal hypertension.

Liver cirrhosis can cause right-to-left intrapulmonary shunting and impaired ventilation / perfusion and, accordingly, hypoxia. Progressive loss of liver function leads to liver failure and ascites. Hepatocellular carcinoma often complicates the course of cirrhosis, especially cirrhosis, which is a consequence of chronic viral hepatitis B and C, hemochromatosis, alcoholic liver disease, a1-antitrypsin deficiency and glycogenosis.

[119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133]

Gistopathology

In this disease, the regeneration of nodes and fibrosis occur simultaneously. Completely unformed liver nodes, nodes without fibrosis (nodular regenerative hyperplasia) and congenital fibrosis (i.e. Widespread fibrosis without regenerative nodes) are not true cirrhosis. The disease may be micronodular or macronodular. The micronodular version is characterized by uniformly small nodes (<3 mm in diameter) and thick regular shaped tufts of connective tissue. As a rule, there is no lobular structure in the nodes; terminal (central) hepatic venules and portal triads are disorganized. Over time, the macronodular variant often develops, in which the nodes have a different size (from 3 mm to 5 cm in diameter) and contain some fairly normal lobular structure of portal triads and central venules. Wide fibrous bunches of various thickness surround large nodes. The destruction of the normal architectonics of the liver implies a concentration of portal triads within the fibrous cords. Mixed version (incomplete intermediate cirrhosis of the liver) combines elements of micronodular and macronodular variants.

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

Viral cirrhosis develops due to the persistence of a viral infection and the resulting immuno-inflammatory process, the cytopathic (hepatotoxic) effect of the hepatitis D virus and the hepatitis C virus, the development of autoimmune reactions.

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

In the pathogenesis of alcoholic cirrhosis, hepatocyte damage by alcohol and the product of its metabolism by acetaldehyde, the development of an autoimmune inflammatory process (in response to the deposition of alcoholic hyaline in the liver), and the stimulation of fibrosis in the liver under the influence of alcohol are of key importance.

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

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

The mechanism of self-progression of liver cirrhosis is as follows. The starting factor in cirrhosis morphogenesis is the death of the hepatic parenchyma. In postnecrotic liver cirrhosis, massive or submassive necrosis of the parenchyma occurs. On the place of the lost hepatocytes, the reticulin core subsides, an organic scar is formed. Vessels of the portal tract approaching the central vein. Conditions are created for the passage of blood from the hepatic artery and the portal vein into the central vein, bypassing sinusoids located near intact areas of the liver. Under normal conditions, the portal vein and hepatic artery through the terminal plate donate their blood to the sinusoids located between the beams of the hepatocytes in the lobule, and then the blood flows from the sinusoids to the central (hepatic) vein.

The blood flow, bypassing sinusoids in the intact areas of the liver, leads to their ischemization and then necrosis. With necrosis, substances that stimulate liver regeneration are secreted, regeneration nodes develop, which squeeze blood vessels and contribute to a further disruption of blood flow in the liver.

The decomposition products of hepatocytes stimulate the inflammatory response, inflammatory infiltrates are formed, which spread from the portal fields to the central parts of the lobules and contribute to the development of the postsynusoidal 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 pseudo-segments. The relationship between the portal vessels and the central vein is changed in the pseudo-segments, the central vein is not found in the center of the pseudo-segment, and there are no portal triads around the periphery. Pseudo-segments are surrounded by connective tissue septa containing vessels that connect the central veins with the branches of the hepatic vein (intrahepatic porto-caval shunts). The blood enters immediately into the system of the hepatic vein, bypassing the parenchyma parenchyma, causing ischemia and necrosis. This is also facilitated by mechanical compression of the venous vessels of the liver by connective tissue.

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

In the pathogenesis of all types of cirrhosis of the liver, 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 keshons in the pathogenesis of liver cirrhosis. Keylons are tissue-specific, but non-specific mitotic inhibitors that control tissue growth by suppressing cell division. They are found in the cells of all tissues. Keylons are peptides or glycopeptide, their action is carried out according to the principle of negative feedback. There are two types of chalons:

• the first type of chalones prevent the transition of cells preparing for division from the G phase of the cell cycle to the S phase;
• second type chalones block the transition of cells from the G2 phase to mitosis.

Scientific research has established that an extract of the liver of patients with active cirrhosis of the liver 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 the Keilons contribute to the development of regeneration nodes in cirrhosis of the liver.

[134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144]

Development of liver cirrhosis

Necrosis causes certain changes in the liver; the most important of them are the collapse of hepatic lobules, diffuse formation of fibrous septa and the appearance of regeneration nodes. Regardless of the etiology of necrosis, the histological picture in the study of the liver is always the same. Necrosis itself at autopsy can no longer be detected.

After necrosis of hepatocytes fibrosis develops. So, after portal hepatitis in port 1 appear portoportal fibrous septa. Drain necrosis in zone 3 leads to the development of port-central fibrosis. Following focal necrosis, focal (focal) fibrosis develops. In the areas of cell death, regeneration nodes are formed, which disrupt the normal architectonics of the liver and lead to the development of cirrhosis.

On the periphery of the regeneration nodes in the region of the central-septic septa, sinusoids are preserved. The blood supply from the portal vein of the functioning liver tissue, in particular the central part of the nodes (zone 3), is disrupted, which may contribute to the progression of cirrhosis even after the cause is eliminated. A pathological collagen matrix is formed in the Disse space, preventing the normal metabolism between the blood of sinusoids and hepatocytes.

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

Normally, the connective tissue matrix of the liver contains type IV collagen, laminin, heparan sulfate, proteoglycan and fibronectin. They are all located in the basement membrane. Damage to the liver entails an increase in the extracellular matrix, which contains collagen types I and III, forming 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 the processes of formation of the extracellular matrix over its destruction. These are complex and multicomponent processes.

Probably, in the future, a better understanding of them will make it possible to develop 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 a lipocyte, a fat-storage cell, an Ito cell, a pericyte) is a major participant in fibrogenesis. It is located in the Disse space between the endothelial cells and the surface of the hepatocytes facing the sinusoid. Similar perivascular cells are found in the kidneys and other tissues. At rest in the stellate cells of the liver are fat droplets containing vitamin A ; they contain the main reserves of the body's retinoids. Cells express desmin, a filament-forming protein found in muscle tissue.

Damage to the liver activates stellate cells. They proliferate and increase, fat drops containing retinoids disappear from them, the rough endoplasmic reticulum increases, a specific smooth muscle protein a-actin appears. The number of receptors to cytokines that stimulate proliferation and fibrogenesis increases. At present, the activation factors of stellate cells are poorly understood. Perhaps some importance is transforming growth factor-beta (TGF-beta), secreted by Kupffer's cells. In addition, the activation factors of stellate cells can also be secreted by hepatocytes, platelets and lymphocytes.

Cytokines that act on activated cells can cause proliferation (for example, platelet growth factor) and stimulate fibrogenesis (for example, 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 a (TNF-alpha). Some of them are secreted by Kupffer cells, as well as by stellate cells themselves, providing autocrine regulation. In addition, stellate cells are affected by acetaldehyde, which is formed during the metabolism of alcohol, and lipid peroxidation products, which are formed as a result of the damaging effect of alcohol or excess iron. Proliferation of stellate cells stimulates thrombin. Damage to the extracellular matrix by stellate cells contributes to their activation.

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

Another leading factor in the formation of fibrous tissue is the breakdown of matrix proteins. It is provided by a number of enzymes called metalloproteinases. There are 3 main groups of these enzymes: collagenase, gelatinase and stromelysins. Collagenases destroy interstitial collagen (types I, II and III), gelatinases - collagen of the basement membranes (type IV) and gelatin. Stromelysins can destroy many other proteins, including proteoglycans, laminin, gelatins and fibronectin. The synthesis of these enzymes occurs mainly in Kupffer cells and in activated stellate cells. The activity of metalloproteinases is suppressed by tissue inhibitors of metalloproteinases (TIMP). 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 cirrhotic and cirrhotic stages, the content of TIMP increases in the blood.

After liver damage, early changes in the matrix in the Disse space, the deposition of collagen types I, III and V, which make up the fibrils, and fibronectin, are of great importance. Sinusoids are transformed into capillaries (“capillary”), endothelium fenestra 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. The progression of fibrosis disrupts the architectonics of the liver and causes the development of cirrhosis and portal hypertension.

[145], [146], [147], [148], [149], [150], [151]

Cytokines and growth factors in the liver

In addition to participating 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 are involved in the regulation of the metabolism of amino acids, proteins, carbohydrates, lipids and minerals. They interact with such classic hormones as glucocorticoids. Since many cytokines, in addition to the specific pro-inflammatory effects, act like growth factors, attempts to separate cytokines and growth factors appear to be somewhat artificial.

Proinflammatory cytokines such as TNF-a, IL-1 and IL-6 are formed in the liver, mainly in Kupffer's cells. In addition, blood cytokines are inactivated in the liver, which weakens their systemic action. Perhaps a violation of this inactivation in cirrhosis is the cause of some of the observed immune disorders.

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

Cytokines cause some systemic manifestations of cirrhosis, such as fever and anorexia. TNF-a, IL-1 and interferon and enhance the synthesis of fatty acids, as a result of which develops fatty infiltration of the liver.

Cytokines inhibit liver regeneration. Under the influence of IL-6, IL-1 and TNF-α, the synthesis of proteins of the acute phase, including C-reactive protein, A-amyloid, haptoglobin, factor B complement and alpha1-antitrypsin, begins in the liver.

An unusually high ability of the liver to regenerate is known even after significant damage, for example, in viral hepatitis or as a result of its resection. Regeneration begins with the interaction of growth factors with specific cell membrane receptors.

Hepatocyte growth factor is the most powerful stimulator of DNA synthesis by mature hepatocytes, which initiates the regeneration of the liver after injury. However, it can be synthesized not only by the cells of the liver (including stellate cells), but also by the cells of other tissues, as well as tumor cells. Its synthesis is regulated by many factors, including IL-1a, IL-1beta, TGF-beta, 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. On the membrane of hepatocytes is a large number of EGF receptors; in addition, receptors are present in the hepatocyte nucleus. The most active EGF is absorbed in zone 1, where regeneration is particularly intense.

Transforming growth factor a. (TGF-alpha) has a chain portion that is 30-40% of the length of its molecule, which is homologous to EGF and can bind to EGF receptors, stimulating the reproduction of hepatocytes.

Transforming growth factor beta1 (TGF-beta1) is probably the main inhibitor of hepatocyte proliferation; during liver regeneration, it is released in large quantities by non-parenchymal cells. In the experiment on cell cultures, TGF-beta1 exerted both stimulating and inhibiting effects, which depended on the nature of the cells and the conditions of their cultivation.

The uptake of amino acids by the culture of hepatocytes under the influence of EGF is enhanced, and under the influence of TGF-beta decreases.

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

[152]

Fibrogenesis monitoring

The metabolism of connective tissue involves specific proteins and metabolic products, the content of which, when they enter the plasma, can be determined. Unfortunately, the data obtained here 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 liver fibrogenesis, in particular in patients with alcoholism. In chronic liver diseases, primary biliary cirrhosis (PBC) and hemochromatosis, an increased 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 insufficiency.

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

[153], [154], [155], [156], [157]

Pathogenesis of portal hypertension

Portal hypertension is the most important syndrome of cirrhosis of the liver 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 portal vein branches by nodes of regenerating hepatocytes or growths of fibrous tissue);
• perisinusoidal fibrosis;
• the presence of arteriovenous anastomoses in intralobular connective tissue septa (transmission of hepatic arterial pressure to the portal vein);
• portal infiltration and fibrosis;
• increased blood flow to the liver.

The first three of these factors lead to an increase in intra-sinusoidal pressure, 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 - porto-caval anastomoses, ascites, and splenomegaly develop.

A significant consequence of the development of porto-caval anastomoses and bypass surgery bypassing the liver parenchyma is its partial functional disabling. In turn, this contributes to the development of bacteremia (the result of the shutdown of the reticulohistiociary system of the liver, intestinal dysbiosis and impaired function), endotoxemia; insufficient inactivation of aldosterone, estrogen, histamine; decrease in hepatotropic substances entering the liver ( insulin, glucagon ) and impaired function of the hepatocytes.

The most serious and prognostically unfavorable consequence of porto-caval shunting is exogenous (porto-caval) coma.

[158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169]

Pathogenesis of hepatocellular failure

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

• the continued action of the primary pathogenic (etiological) factor and autoimmune processes;
• hemodynamic disorders in the liver (removal of blood from the liver through the porto-caval anastomoses, intrahepatic shunting of the blood and reduction of the blood supply to the liver parenchyma, impairment of intrageneral microcirculation).

Due to the action of the above factors, the mass of functioning hepatocytes decreases and their functional activity leads to the development of hepatocellular insufficiency, the most severe manifestation of which is hepatic coma.

[170], [171], [172], [173], [174], [175], [176], [177], [178], [179], [180], [181], [182]

Symptoms of the liver cirrhosis

Cirrhosis may be asymptomatic for many years. Often, the first symptoms of liver cirrhosis are uncharacteristic (general weakness, anorexia, malaise, and loss of body weight). The liver is usually palpable and compacted, with a blunt edge, but sometimes small and its palpation is difficult. Nodes are usually not palpated.

As a rule, malnutrition, along with anorexia and a depleted diet, insufficient secretion of bile cause malabsorption of fats and fat-soluble vitamins. Typically, in patients with cirrhosis due to alcoholic liver disease, enzymatic pancreatic insufficiency is observed, which contributes to malabsorption.

If cholestasis is present (for example, in case of primary biliary cirrhosis), jaundice, itchy skin, and xanthelasma may occur. Portal hypertension is complicated by gastrointestinal bleeding from varicose veins of the esophagus and stomach, gastropathy, or hemorrhoidal varicose veins; 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 symptoms may indicate chronic liver disease or chronic alcohol abuse, but they are not characteristic of cirrhosis of the liver: muscular hypotrophy, palmar erythema, parotid gland enlargement, white nails, Dupuytren contracture, spider veins (normally <10), gynecomastia, axillary hair loss, testicular atrophy and peripheral neuropathy.

[183]

Forms

The international classification of chronic diffuse liver diseases (World Association for the Study of diseases of the liver, Acapulco, 1974; WHO, 1978) distinguishes the following morphological forms of liver cirrhosis: micronodular, macronodular, mixed (macro-micronodular) and incomplete septal.

The main criterion for the separation of cirrhosis is the size of the nodules.

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

Liver with micronodular cirrhosis is not increased dramatically or has normal size. This form of cirrhosis is most characteristic of chronic alcoholism, bile duct obstruction, hemochromatosis, and prolonged venous stasis in the liver.

With macronodular cirrhosis, the liver is usually sharply deformed. Its surface is represented by irregularly located nodes of different size (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 pseudo-segments of various sizes; irregular network of connective tissue in the form of cords of various widths, often containing three or more closely spaced portal triads and central veins.

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

Usually, when mixed, the number of small and large nodes is almost the same.

Incomplete septal cirrhosis is characterized by the presence of connective tissue septa, dissecting the parenchyma and often ending blindly, without connecting the portal field with the central vein. There is a regeneration, but it becomes not nodular, but diffuse. Histologically, this is manifested in the form of double-row hepatic plates and pseudodulular proliferation of hepatocytes (“formation of rosettes”).

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

Typically, micronodular cirrhosis is monolobular (micronodular nodules consist of part of one lobule); macronodular multilobular (false lobules include the remains of many lobules); macromiconodular monomultilobular (the number of mono- and multilobular lobes is approximately the same).

[184], [185], [186], [187], [188]

Liver cirrhosis classification

Uniform classification of cirrhosis does not exist. Most experts consider it appropriate to classify cirrhosis depending on the etiology, morphological characteristics, stage of portal hypoxia and hepatocellular insufficiency, activity of the inflammatory process, course options.

[189], [190], [191]

Diagnostics of the liver cirrhosis

Liver cirrhosis is diagnosed when multiple sites are detected in it in combination with fibrosis. This can be done with direct imaging, such as laparotomy or laparoscopy. However, it is impractical to perform laparotomy specifically for the diagnosis of cirrhosis, because even with compensated liver function, it may be the cause of the development of liver failure.

With laparoscopy on the surface of the liver visible nodes that can be subjected to targeted biopsy.

When scintigraphy revealed a decrease in the absorption of radiopharmaceuticals, its uneven distribution and absorption by the spleen and bone marrow. Nodes are not rendered.

When ultrasound (ultrasound liver) symptoms of cirrhosis are uneven density and liver tissue areas of increased echogenicity. The tail portion is increased. However, before the appearance of ascites, ultrasound data do not allow for the diagnosis of cirrhosis. Regeneration sites may resemble areas of focal liver damage. To exclude their malignant nature, dynamic observation or determination of the level of and a-fetoprotein is necessary.

Diagnosis of cirrhosis and its complications using computed tomography (CT) is economically viable. CT scan of the abdominal cavity allows to estimate the size of the liver and to reveal the unevenness of its surface caused by the nodes. On computerized tomograms, it is impossible to distinguish the nodes of regeneration from the rest of the liver tissue. CT scan reveals fatty infiltration, an increase in the density of the liver tissue caused by iron deposition, and lesions. After intravenous administration of the contrast agent, the portal and hepatic veins, as well as collateral vessels and an enlarged spleen are visualized - reliable signs of portal hypertension. The identification 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. Detection of ascites is possible. In the presence of a gallbladder or in the common bile duct stones on computer tomograms, you can see their shadows. CT scan is an effective method for monitoring cirrhosis. Under CT control, you can perform targeted liver biopsy with minimal risk.

Diagnosing cirrhosis from a biopsy may be difficult. Coloring on reticulin and collagen allows revealing around the nodes the rim of fibrous tissue.

Lack of portal tracts, impaired vascular pattern, identification of branches of the hepatic artery not accompanied by branches of the portal vein, presence of nodes with fibrous septa, heterogeneity of sizes and appearance of hepatocytes in different areas, thickening of hepatic beams are of diagnostic importance.

[192]

Liver function evaluation

Liver failure manifested jaundice, ascites, encephalopathy, a low level of serum albumin, deficiency of prothrombin, which is not possible to fix the appointment deficiency vitamin k.

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

[193], [194], [195], [196], [197]

Examples of the formulation of the diagnosis of cirrhosis

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

1. Krupnouzlovoy progressive cirrhosis in the outcome of hepatitis B with hepatocellular insufficiency and portal hypertension.
2. Small-node regressing alcoholic cirrhosis with hepatocellular insufficiency and minimal signs of portal hypertension.
3. Mixed small and large node progressive cirrhosis due to stricture of the biliary tract with mild hepatocellular insufficiency and portal hypertension.

[198], [199], [200], [201], [202], [203]

Laboratory and instrumental data for liver cirrhosis 

1. Complete blood count : anemia (usually with decompensated liver cirrhosis), with the development of hypersplenism syndrome - pancytopenia; in the period of exacerbation of cirrhosis - leukocytosis (possible shift of the leukocyte formula to the left), an increase in the ESR.
2. General urinalysis: in the active phase of the disease, as well as in the development of the hepato-renal syndrome, proteinuria, cylindruria, microhematuria.
3. Biochemical analysis of blood: the changes are more pronounced in the active and decompensated phases of cirrhosis of the liver, as well as in the development of hepatocellular failure. Hyperbilirubinemia is noted with an increase in both conjugated and unconjugated fractions. bilirubin ; hypoalbuminemia, hyper alpha2 and y-globulinemia; high thymol and low sublimate samples; hypoprothrombinemia; decrease in the content of urea, cholesterol cholesterol ; high activity of alanine aminotransferase, y-glutamyltranspeptidase and organ-specific enzymes of the liver: fructose-1-phosphate-aldolase, arginase, ornitinase ornitinase, ornitinase, ornitinase, ornitinase, anthropogenic liver enzymes: fructose-1-phosphate-aldolase, arginase, ornitinase transfeptidase with active liver cirrhosis, biochemical manifestations of the inflammatory process are expressed - the content of haptoglobin, fibrin, sialic acids, seromucoid increases in the blood; the content of procollagen-III-peptide, a collagen precursor, is increased, which indicates the formation of connective tissue in the liver (normally, the content of the amino-terminal procollagen-III-peptide ranges from 5 to 12 ng / ml).
4. Immunological study of the blood: a decrease in the number and activity of T-lymphocyte suppressors, an increase in the level of immunoglobulins, the hypersensitivity of T-lymphocytes to a specific hepatic lipoprotein. These changes are more pronounced in the active phase of cirrhosis.
5. Ultrasound of the liver: in the early stages of cirrhosis, hepatomegaly is found, the liver parenchyma is homogeneous, sometimes hyperechogenic. As the disease progresses with micronodular cirrhosis of the liver, a homogeneous increase in the echogenicity of the parenchyma appears. In case of macronodular cirrhosis, the liver parenchyma is heterogeneous, regeneration nodes of increased density, usually less than 2 cm in diameter, are detected, and the liver contours may be abnormal due to regeneration nodes. A.I. Shatikhin and I.V. Makolkin (1983) suggest echo-switching up to 1 cm in diameter to be designated as small focal, and more than 1 cm - as large-focal acoustic inhomogeneity. At the same time, small-focal heterogeneity most often corresponds to micronodular cirrhosis of the liver, large-focal - to macronodular cirrhosis, and the presence of heterogeneity of both sizes - to the mixed macromicro-nodular liver cirrhosis. As the fibrosis progresses, the size of the right one decreases, and the left and caudate lobes of the liver increase. In end-stage cirrhosis liver can be significantly reduced in size. An enlarged spleen and manifestations of portal hypertension are also detected.
6. Laparoscopy. Macronodular cirrhosis has the following characteristic pattern - large (more than 3 mm in diameter) nodes of round or irregular shape are determined; deep cicatricial connective tissue grayish-white retraction between nodes; the newly formed nodes are bright red, and the previously formed knots are brownish in color. Micronodular cirrhosis is characterized by a slight deformation of the liver. The liver has a bright red or grayish-pink color, nodules are determined not more than 0.3 cm in diameter. In some cases, regeneration nodules are not visible, there is only a thickening of the liver capsule.
7. Needle biopsy of the liver. For micronodular cirrhosis, thin, equally wide connective tissue septa are common, dissecting the hepatic lobe into individual pseudo-segments, approximately equal in size. Pseudodolves 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 cirrhosis is characterized by pseudo-segments of various sizes, an irregular network of connective tissue in the form of cords of various widths, which often contain close portal triads and central veins. Mixed macromiconodular cirrhosis combines the features of micro- and macronodular cirrhosis.

For incomplete septal cirrhosis, the following manifestations are characteristic:

• connective tissue septa, dissecting the parenchyma (often ending blindly, without connecting the portal field with the central vein);
• regenerative nodules are not visible;
• regeneration acquires a diffuse character and manifests itself in the form of double-row hepatic plates and pseudodular proliferation of hepatocytes.

7. Radioisotope scanning reveals hepatomegaly, diffuse nature of changes in the liver, splenomegaly. When radioisotope hepatography revealed a decrease in the secretory-excretory function of the liver.
8. In viral cirrhosis in the serum markers of hepatitis B, C, D are detected.
9. Fegds and fluoroscopy of the esophagus and stomach reveal varicose veins of the esophagus and stomach, chronic gastritis, and in a number of patients - a stomach ulcer or 12 duodenal ulcer.

[204], [205], [206], [207], [208], [209], [210], [211], [212], [213]

Clinical and morphological relationships

1. The nature of power. With cirrhosis, fat reserves and muscle mass are often reduced, especially in people suffering from alcoholism and in patients belonging to Group C according to Child. Muscle atrophy is caused by a decrease in protein synthesis in the muscles associated with impaired protein metabolism in the body as a whole. As the disease progresses, the energy expenditure of the body in a state of rest increases. This pattern persists even after liver transplantation, if the patient is poorly nourished.

In patients with liver cirrhosis, taste and smell may be impaired. The lack of attention paid by patients (especially those suffering from alcoholism) to the state of the oral cavity and its hygiene leads to frequent damage to the teeth and periodontal, although in itself liver cirrhosis does not predispose to such diseases.

2. Eye symptoms. In patients with cirrhosis of the liver, compared with the population as a whole, retraction of the eyelids and lag of the upper eyelid from the eyeball are more common.

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

3. An increase in the parotid salivary glands and Dupuytren's contracture may also occur with alcoholic cirrhosis.
4. The symptom of "drumsticks" and hypertrophic osteoarthropathy can complicate cirrhosis, especially biliary. They can be caused by platelets that easily pass through pulmonary arteriovenous shunts into the peripheral bed and clog the capillaries, releasing platelet growth factor.
5. Muscle cramps in cirrhosis develop significantly more often 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 by the administration of quinine sulfate. Increases in effective circulating blood volume can be achieved by weekly transfusion of human albumin.
6. Steatorrhea is often found even in the absence of pancreatitis or alcoholism. Its cause may be a decrease in the secretion of bile acids by the liver.
7. Splenomegaly and dilatation of the venous collaterals on the anterior abdominal wall usually indicate the presence of portal hypertension.
8. Hernia of the abdominal wall with ascites develops frequently. They should not be radically treated if they are not life threatening or if ascites is not sufficiently compensated.
9. Gastrointestinal symptoms. Endoscopic examination reveals varicose veins. In a study conducted in 324 patients with liver cirrhosis, 11% had peptic ulcers. HBsAg carriers develop ulcers more often. 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 not suffering from cirrhosis.

Dysbacteriosis of the small intestine with alcoholic cirrhosis develops in 30% of cases, more often if present than in the absence of ascites (37% vs. 5%).

10. Primary liver cancer is a common complication of all forms of cirrhosis, with the exception of biliary and cardiogenic. It is believed that metastasis of tumors to the liver is rarely observed, since in cirrhosis, extrahepatic localization tumors rarely develop. However, when comparing the frequency of metastatic liver tumors in patients with and without cirrhosis of the liver, it turned out that the presence of cirrhosis does not affect it.
11. Gallstones. With ultrasound performed in patients with chronic liver diseases, gallstones (usually pigmented) were found in 18.59% of men and 31.2% of women, which is 4-5 times more often than in the population. The presence of stones does not affect survival. A low ratio of bile acids and unconjugated bilirubin and a very high level of mono-conjugated bilirubin in bile predispose to the development of pigment stones. In case of uncomplicated gallstone disease, one should refrain from surgical treatment, since the risk of surgery is very high.
12. Chronic recurrent pancreatitis and calcification of the pancreas are often found in alcoholic liver disease.
13. The defeat of the cardiovascular system. In patients with cirrhosis of the liver, atherosclerosis of the coronary arteries and aorta develops less frequently than in the general population. At autopsy of patients with cirrhosis, myocardial infarction occurs almost 4 times less frequently than in individuals without cirrhosis. With cirrhosis of the liver, cardiac output, heart rate, and total peripheral vascular resistance and blood pressure are increased. When testing with exercise, the maximum values of heart rate and cardiac output do not reach the expected values, signs of autonomic nervous system dysfunction are noted. Due to the reduced vascular tone, the reaction of the circulatory system and kidneys to an increase in circulating blood volume is not sufficiently pronounced. This is partly due to a decrease in sensitivity to catecholamines and increased synthesis in the vascular wall of nitric oxide. In patients with cirrhosis of the liver, belonging to group C according to Child, 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, the blood circulation in the kidneys is impaired. In particular, the blood supply to the cortical layer is deteriorating, which contributes to the development of the hepatorenal syndrome. 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 walls of the capillaries (cirrhotic glomerulosclerosis}. In the mesangium, IgA deposition is often detected, especially during alcoholism. These changes usually occur latently, but sometimes can be accompanied by a proliferative response and clinical manifestations of glomerular insufficiency. Against chronic hepatitis With developing cryoglobulinemia and membranoproliferative glomerulonephritis.

15. Infectious complications. In liver cirrhosis, phagocytic activity of the cells of the reticuloendothelial system is reduced, 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 cirrhosis of the liver.

In the terminal stage of cirrhosis, septicemia is often observed; it should be excluded in all cases of fever and deterioration of the patients. Septicemia often fails to diagnose in a timely manner. We must not forget about the possibility of spontaneous bacterial peritonitis. The level of IL-6 in plasma (more than 200 pg / ml) can serve as a sensitive indicator of infection in the hospitalization of patients with decompensated cirrhosis.

The incidence of tuberculosis in patients with liver cirrhosis has decreased, but tuberculous peritonitis still occurs and often remains unrecognized. It was also noted that respiratory tract infections in patients with cirrhosis of the liver began to flow more easily.

16. Metabolism of drugs. A liver biopsy reveals a decrease in drug metabolism due to a decrease in the number of functioning hepatocytes. The metabolic activity of the remaining hepatocytes is not reduced.

[214], [215], [216], [217], [218], [219], [220], [221], [222], [223]

Histocompatibility antigens (HLA)

The HLA-B8 antigen is detected in 60% of patients with chronic hepatitis who do not have HBsAg. Usually these are women younger than 40 years old, in whom corticosteroid therapy allows to achieve remission. When serological research revealed nonspecific antibodies and high levels of y-globulins. In HBsAg-positive chronic hepatitis, the HLA-B8 antigen is detected with a frequency characteristic of the general population. More often in patients with HBsAg-negative chronic hepatitis, the DL3 II class antigen of the HLA system is found.

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

The connection of idiopathic hemochromatosis with antigens A3, B7 and B 14 of the HLA system has been established. The presence of a genetic connection with the antigens A and B HLA allows you to identify a high risk of disease in the brothers and sisters of the patient.

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

[224], [225], [226], [227], [228], [229], [230], [231], [232], [233], [234], [235], [236], [237]

Hyperglobulinemia

Chronic liver diseases are accompanied by an increase in serum levels of globulins, especially γ-globulins. Electrophoresis usually reveals the polyclonal nature of hyper-y-globulinemia, although in rare cases it can be monoclonal. The increase in the level of γ-globulins is partly due to the increase in the level of tissue autoantibodies, for example, to smooth muscles. The main reason is a violation of the purification of intestinal antigens affected by the liver. Serum cirrhosis increases the level of antibodies to antigens produced in the gastrointestinal tract, especially to Escherichia coli antigens. These antigens bypass the liver, passing through portosystemic anastomoses or through intrahepatic shunts that form around the nodes in the liver. Getting into the systemic circulation, they stimulate the production of antibodies, especially in the spleen. Similarly, systemic endotoxemia can develop. In addition, IgA and their complexes with the antigen can enter the 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.

[238], [239], [240], [241], [242], [243], [244], [245], [246], [247], [248], [249], [250]

Diagnostic value of puncture biopsy of the liver

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

In order to obtain sufficiently large liver tissue samples and to avoid damage to other organs (especially the gallbladder) in case of liver cirrhosis, a targeted biopsy with an acute needle is shown under visual control during an ultrasound or CT scan.

[251], [252], [253], [254], [255], [256], [257], [258], [259], [260]

Treatment of the liver cirrhosis

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

Patients with varicose veins of the esophagus and stomach need appropriate treatment to prevent bleeding. A positive result of treatment may subsequently slow down the development of liver fibrosis. Liver transplantation should be performed at the terminal stage of liver failure in the respective candidates.

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

Compensated liver cirrhosis requires dynamic monitoring for the timely detection of hepatocellular insufficiency. Treatment for liver cirrhosis is effective only if you maintain a balanced diet and abstain from alcohol.

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 need not be prescribed. The refusal of butter and other fats, eggs, coffee and chocolate has no therapeutic value.

With a stable course of cirrhosis, it is not necessary to recommend supplementation of branched-chain amino acids. In severe dystrophy, a regular diet is useful to supplement with frequent extraordinary intake of small portions of food. Full enteral nutrition for 3 weeks is accompanied by an increase in the level of albumin and an improvement in the prognostic index determined according to Child’s criteria system.

With the development of hepatocellular insufficiency, accompanied by edema and ascites, restriction of sodium intake with food and the appointment of diuretics is shown; When encephalopathy is attached, protein intake should be limited and lactulose or lactitol should be administered.

With portal hypertension, special therapy may be required.

Preparations for the prevention of liver fibrosis

One of the objectives of the treatment of cirrhosis is blocking the synthesis of collagen.

Procollagen secretion requires microtubule polymerization. Drugs that sever microtubule complexes, such as colchicine, can block this process. It has been shown that taking colchicine at a dose of 1 mg / day 5 days a week leads to an increase in survival. However, in this study, patients treated with colchicine initially had a higher serum albumin level than in the control group; besides, patients were not sufficiently committed to treatment, control over many of them was lost in the long-term. The study is not sufficiently conclusive to recommend long-term use of colchicine for cirrhosis. The drug, however, is relatively safe, its only side effect is diarrhea.

Corticosteroids, along with anti-inflammatory effects inhibit propyl hydroxylase. They inhibit the synthesis of collagen, 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 provide collagen decomposition is expected. In the future, it is possible that a new treatment of liver cirrhosis will be developed - gene therapy, which allows you to directly block the synthesis of connective tissue proteins.

[261], [262], [263], [264], [265]

Surgical treatment of liver cirrhosis

With liver cirrhosis, any surgery is accompanied by a high risk of complications and death. The operative mortality in case of cirrhosis, which is not accompanied by bleeding, is 30%, and in 30% of the surviving patients complications develop. In groups of patients A, B and C according to Child, the operational mortality is 10, 31 and 76%, respectively. Especially unfavorable prognosis after surgery on the biliary tract, for peptic ulcer and after resection of the colon. Adverse prognostic factors considered low levels of serum albumin, opportunistic infections and an increase in prothrombin time.

If a patient is scheduled for liver transplantation, he should not perform operations on the upper gastrointestinal tract, since after them the transplantation is more difficult to perform.

Successful segmental resections for small carcinomas that form in the liver during cirrhosis.

[266], [267], [268], [269], [270], [271], [272], [273], [274], [275], [276]

Forecast

Cirrhosis often has an unpredictable prognosis. It depends on a number of factors, such as etiology, severity of the lesion, the presence of complications, comorbidities, the condition of the body and the effectiveness of treatment.

Patients who continue to consume alcohol even in small quantities have a very unfavorable prognosis. To assess the severity of the disease, surgical risk and general prognosis based on clinical and laboratory data, Childe-Turkotta-Pugh classification is used.

It is generally believed that liver cirrhosis is irreversible, but, as observations of patients with hemochromatosis and disease, the treatment of fibrosis may be reversed, so the concept of irreversibility of liver cirrhosis is not proven.

Cirrhosis of the liver does not always progress; treatment can stop its further development.

The development of liver transplantation methods has increased the requirements for predicting the course of cirrhosis: in order to send a patient to an operation in time, it is necessary to know as far as possible the exact prognosis.

Child's predictive criteria system (groups A, B and C) takes into account the presence of jaundice, ascites, encephalopathy, serum albumin level and the quality of nutrition. It allows you to make a fairly accurate short-term forecast. In the modified Child-Pugh prognostic system, instead of the quality of nutrition, they take into account the level of prothrombin and the degree of manifestation of the listed signs in points. Based on the total number of points, patients are assigned to one of the groups: A, B or C, however, the literature data are ambiguous, since the evaluation of signs in points is arbitrary.

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

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

After the first episode of spontaneous bacterial peritonitis, the survival of patients with liver cirrhosis during the year is 30-45%. The study of liver function indicators usually does not provide additional prognostic information in comparison with the Child’s criteria system, although it has been shown that the breathing test with aminopyrin is important for patients with alcoholic cirrhosis of the liver belonging to Child A and B prognostic groups.

The predictive value of individual factors:

1. Etiology of cirrhosis. With alcoholic cirrhosis, complete abstinence from alcohol consumption provides a better prognosis than with cryptogenic cirrhosis.
2. If the cause of decompensation was bleeding, infection or alcohol use, the prognosis is better than with spontaneous decompensation, because the action of the provoking factor can be eliminated.
3. The effectiveness of treatment. If after 1 month from the start of treatment in a hospital, the improvement does not occur, the prognosis is poor.
4. Jaundice, especially persistent, is an unfavorable prognostic sign.
5. Neurological complications. The significance of these complications depends on the nature of their appearance. Thus, neurological disorders that have developed 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 restriction of proteins in food.
6. Ascites worsens the prognosis, especially if its treatment requires large doses of diuretics.
7. The size of the liver. The larger the size of the liver, the better the prognosis, since this preserves a greater number of functioning cells.
8. Bleeding from esophageal varicose veins. Along with the evaluation of the function of hepatocytes, it is necessary to determine the severity of portal hypertension. If the function of the hepatocytes is preserved, the patient will be able to tolerate satisfactory bleeding; if the function is impaired, the development of a fatal hepatic coma is possible.
9. Biochemical indicators. At albumin in serum is below 2.5 g%, the prognosis is poor. Hyponatremia below 120 mmol / l, if it is not associated with diuretic intake, 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 hypotension (systolic blood pressure below 100 mm Hg) is a poor prognostic sign.
12. Histological changes in the liver. Biopsy allows you to assess the severity of necrosis and inflammatory infiltration. In case of fatty infiltration of the liver, the treatment is usually effective.

[277], [278], [279], [280], [281]