Pathogenesis and morphogenesis

The mechanisms determining the development of chronic hepatitis and cirrhosis, and their further progression, are not yet clear.
Many researchers have attributed the disease progression with the continuing action of the basic primary hepatotropic factor. In this connection first of all discussed long-term preservation (persistence) of the virus in the body (with E. M. Tareev, 1958, 1966, E. N. Ter-Grigorova, 1963; Stokes and others, 1954). The assumption is based on the observations of the occurrence of epidemic of hepatitis when the infection from patients with chronic hepatitis and liver cirrhosis (E. G. Peschanenko, 1956; Creutzfeld and others, 1962) and positive results, indirect virologic studies (see section "Etiology"). Such arguments convince us that the number of patients with chronic hepatitis and liver cirrhosis are carriers of the virus epidemic of hepatitis. But this circumstance determines the progression of chronic hepatitis is not clear. In particular, it is bad consistent with what the majority of carriers of the virus is unable to detect liver disease (Maskau, Whitengam, 1968).
In the progression of chronic liver diseases play an important role of endogenous pathological mechanisms capable of autonomously, without continuing or re-intervention etiological factor, to ensure the progression of the disease. Among them the leading place many researchers (Maskau and others, 1956, 1965, 1968; Popper, 1965; H. I. Burstein, 1968) assign immunological disorders, resulting from the interaction of its own antigens with foreign antigens and antibodies.
Evidence immunopathological nature of active chronic hepatitis find in hypergammaglobulinemia, in particular in the increase of immunoglobulins, in the presence of lymphoid aggregates and plasma cells in the liver, in the frequent combination with other syndromes, autoimmune nature of which is proved; in the emergence of a number of patients cells of systemic lupus erythematosus (LE)cells, in a positive therapeutic effects from the immunosuppressive drugs, particularly of azathioprine (imuranom), which do not have direct anti-inflammatory action.
The main evidence is the presence of serum antibodies. Antibodies against liver in the serum of patients with chronic hepatitis and liver cirrhosis. encountered by many researchers (C. O. Sarkisyan, 1963; Popper, Schaffner, 1965; A. M. Nogales, 1969; A. M. Yartseva, 1967, 1969; H. I. Burstein, 1968). Considerable interest is designed Mackau with employees in 1965 serological reaction, showing fluorescence with antigen cytoplasm of smooth muscles (SMA). This reaction is very specific for chronic active hepatitis. She turned positive in 81 % of cases of so-called lupoid hepatitis, in 48% of cases other chronic active hepatitis, and was negative in other diseases of the liver, in patients with systemic lupus erythematosus and healthy people. Serum containing SMA, also reacts with the cytoplasm of cells of kidney glomeruli, most of the cells of the spleen and lymph nodes. This fact is an additional argument in favor of the autoimmune nature of chronic active hepatitis. The fact that serum containing SMA, weakly reacting with renal cell indicates that the antigen responsible for the products of the SMA, is not the liver. According to Maskau, Whittengham (1968), that is the spleen.
X. M. Veksler and A. F. of Bluger (1967, 1970), A. M. Yartseva (1969), Popper (1966) through intradermal tests liver extract and reactions of blasttransformation proved the value in maintaining the activity of chronic hepatitis so-called delayed type of Allergy that is associated with the formation of lymphocytes, bearing fixed antibodies.
There is a parallelism between the indices of immune reactions and activity of the pathological process in the liver (A. M. Noveller and G. M. Smolyakova, 1968; H. I. Burstein, 1968; A. M. Yartseva, 1969; Goldstein, 1967).
All these facts conclusively indicate a pronounced role of immunological disorders in the progression of chronic hepatitis.
The authors of this concept Mackau and Whittengham (1968) believe that chronic active hepatitis in most cases arises as a consequence of the epidemic of hepatitis or liver damage other agents) of individuals with genetically caused by abnormalities of immune tolerance and a tendency to perverse reaction to the release of the various components of liver cells that are found in many autoimmune serological reactions. Autoimmune reaction, once established, tend to continue, because the immune cells continue to be stimulated by antigen released from the liver cells, originally damaged immune agent, and further already suffering due to the autoimmune reaction.
Immune process causing damage to the liver tissue, is still poorly studied. It is possible that plasma cells in the liver or spleen can produce antibodies that directly affect hepatic cell. Hepatocellular injury can be made lymphoid cells that can specifically react with liver antigens or to engage in damaging contact with liver cells through specific autoantibodies (Schaffner, etc., 1963; A. F. of Bluger, X. M. Veksler, 1968).
How lymphoid cells acquire the ability to answer the autoantigens, which normally would have to initiate tolerance? Theory Burnet (1964) on the selection of clones suggests that this ability is acquired somatic mutation lymphoid cells, leading to population "samoopredelenie Smoking clones lymph cells, genetically predisposed to the production of specific antibodies (Mackau, Burnet, 1963; Klemm, 1968).
It is possible that the hepatocytes are suffering because of attacks on them specific and active immune cells, as when rejection gomotransplantatov. Steiner, Paronnetto, Popper (1965) believe that non-specific for liver complexes antigen - antibody can be detected in hepatocytes and thereby define the future of their defeat. This opinion is based on the experiment, during which managed to reproduce cirrhosis of the liver through the introduction of complex antigen - antibody in the portal circulation and in the biliary system, as well as after the introduction of alien protein pre-sensitised animals.
3. A. Bondar with employees (1969) showed that autoimmune mechanisms occupy a significant place in the development of hypersplenism in patients with chronic liver disease.
There are many reasons for primary biliary cirrhosis be regarded as an autoimmune suffering liver, in which the primary target-tissue is epithelium cholangio. On the role of immunological disorders in the Genesis of the disease indicate the accumulation of V-Th of immunoglobulins in the cells surrounding the bile canals, increase of deposits of immunoglobulins in the serum of patients (Sherlock, 1968; A. M. Yartseva, 1970); the appearance in the serum of patients circulating antibodies against the bile duct epithelium, antinuclear and antimitochondrial autoantibodies (Paronnetto, Schaffner, Popper, 1961). The latter is highly specific for this disease. Popper and others (1966) found them in 30 out of 31 cases of primary biliary cirrhosis, but does not revealed none of the 30 patients suffering from secondary biliary cirrhosis.
Liver damage is supported and changes in the internal environment of the organism (a shift in the protein spectrum of blood, violations of the acid-base equilibrium and elektrolitnogo balance, the increase of a number of hormones and enzymes, accumulation of vasoactive substances, and so on). One of the most significant pathogenetic factors of progression. chronic hepatitis and liver cirrhosis is hypoxia liver tissue associated with the restructuring of the blood flow in the liver, and reduced pulmonary aeration and a violation of the activity of oxidation-reduction enzymes liver cells (Hoenig, 1960; A. G. Fischer, 1961; A. F. of Bluger, 1964; P. X. Abdullayev, 1968).
Many researchers (Loiselle, 1960; M. P. Sinelnikova and O. I. Kartashova, 1966; B. B. Zolotarevsky, 1968) is shown that in patients with chronic hepatitis and liver cirrhosis in hepatocytes located in the state of necrobiosis, decreases the activity of oxidation-reduction enzymes, mitochondria lose adenosintriphosphate of connection, also increases the activity of hydrolytic enzymes released from lysosomes and destroying the cytoplasm of a cell.
In addition, the level of oxidative processes and reduced due to reduced oxygen saturation in arterial blood in patients with chronic hepatitis and liver cirrhosis (VP Bezugly, 1968; B. A. Pilipenko, 1967).

To a significant restriction in blood supply to the liver parenchyma, resulting in a restructuring of the hepatic circulation, closely connected with the morphogenesis of liver cirrhosis.
Focuses on three main morphogenetic the development of cirrhosis of the liver, leading to the formation of the main morphological variants. Morphogenetic differences between various types of cirrhosis relief only in the initial stage of the disease. Starting from the stage of Mature cirrhosis in all cases joins a single pathological mechanism - circulatory disorders of the liver parenchyma, resulting in the signs, initially distinguished cirrhosis different morphogenesis, shaded (Popper, Schaffner, 1957).
Essential as a "trigger mechanism" in the morphogenesis of cirrhosis belongs massive or submissives necrosis parenchyma. In place Poggibonsi liver cells reticulosis skeleton liver subsided (collaborate). The result is a limited scar. This scar as such is not yet an cirrhosis, but in spasams plot stroma vessels portal tract closer to Central Vienna. The conditions under which the blood from the hepatic artery and portal vein can be transported in Central Vienna, bypassing sinusoid lying next intact areas of the liver. In addition, vessels in collaborando plot bent, change their clearance and thereby restrict blood flow to the neighboring areas. As a result of impaired blood supply to an adjacent liver parenchyma, and it may be subject ischemic necrosis. Furthermore, hypoxia causes collagenase reticulin fibers framework of connective tissue and fibrosis. Necrosis of liver cells causing regeneration of the liver parenchyma. Products of disintegration of liver cells called in circumference necrosis inflammation that leads to the development of fibrosis.
To the development of the portal (septal) cirrhosis leads to sequential progression of chronic hepatitis. For the latter characterized by the penetration of periportal infiltrates into the segments, however, are isolated and are necrobiotic changes for individual hepatocytes (the so-called piece-sea-necrosis by Popper and others, 1960), but at the place infiltrates are formed connective tissue septum. Septa may arise in lobular parenchyma, resulting spadenia fatty cysts, due to the emergence of connective tissue membranes in cracks caused by uneven stretching areas parenchyma. Education connective tissue beyond the scope of fibrosis of the time when using connective tissue walls connects the Central area slices with portal tracts and fragmented hepatic lobule. This created "pseudodevice", which together with proliferating liver cells in the centers of periportal necrosis become a source of regeneration of liver cells.
The development of biliary cirrhosis is characterized productive inflammation with the growth of fibrous connective tissue around the bile ducts (perepolnyali). From the moment developing tubular trabeculae will connect the portal tracts with Central area cloves, dissecting the latest on false cloves, disease deserves the name of cirrhosis.
Thus, any type of morphogenesis cirrhosis leads to the violation of lobular architectonics of the liver, and further progression is determined by the processes common to all cirrhosis: a nodular regeneration and reconstruction of the vascular bed of the liver.
Regeneration of liver cells stimulated humoral factors resulting from necrosis of the liver parenchyma. Initial substrate for nodular regeneration are surviving with necrosis of the liver cells and fragments of hepatic lobules.
Sites regenerativa liver tissue are newly formed reticular stroma, capillaries and, apparently, the newly formed portal tract. The regeneration process may stop, then nodules become Mature. In other cases, the restructuring of the vascular bed of the liver leads to insufficient blood supply of the Central areas of knots, resulting in a new cycle of necrosis of liver cells with secondary collapse. The remaining cells give rise new knots, and so on, So explains the observed continuous cycle of education knots, typical for progressive liver cirrhosis.
The restructuring of the vascular bed in cirrhotically altered liver is determined by two main mechanisms: by pressing of branching veins knots regenerativa hepatic parenchyma and education or, more precisely, an increase of anastomosis between the portal vein and hepatic artery, and the hepatic vein.
Regeneration sites squeeze their surrounding tissue, causing losing reticular stroma with flowing in her veins. Mostly crushed hepatic vein that leads to disturbance of blood outflow and increase of portal pressure. Along with this formed anastomosis - shunts between the portal vein and hepatic vein, the portal vein and hepatic artery first described Kretz (1894).
The increased production of proteins and fibers leads to the deposition of these substances in the spaces of the thesis, formed the basement membrane, i.e. is "capillarization" sinusoidal. The exchange between the liver cells and blood riverbed is broken.
In cirrhotic liver intensive anastomoses blood from the portal vein is forwarded directly to the system of the hepatic veins, bypassing sine waves and, consequently, bypassing the liver parenchyma. This significantly affects the blood supply to the last. In addition, the direct transfer of portal blood into the General blood flow in portorecanati shunts and through extra-hepatic venous collaterals may explain the decline of the liver in the absence of visible damage of hepatocytes, which allows Popper and Schaffner (1961) to distinguish between liver and Mechanochemistry failure.
They argue that described circulatory disorders parenchyma are responsible for hypoxic Central necrosis, occur in the regeneration sites. Such necrosis with secondary collapse may cause further progression of cirrhosis, even in cases where the primary etiologic factor has ceased to act. Thus, the development of vascular anastomoses, leads to irreversible stage of cirrhosis.
The progression of the cirrhotic process occurs by type a kind of chain reaction: necrosis - regeneration - reconstruction of the vascular bed - ischemia parenchyma - necrosis.