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.
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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.
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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.
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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.
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.
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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.
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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.
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