Cirrhosis (of the liver are degenerative processes,)

Cirrhosis of the liver are degenerative processes, characterized by regeneration of parenchyma and proliferation of stroma, which leads to restructuring of the organ (Fissinger, Munn, Resle, de Jong, Askanazi). Infectious-toxic influences that cause cirrhosis also have a more widespread effect, primarily on the reticulo-endothelium; consequently, some forms of cirrhosis, in which this effect is particularly pronounced, belong to the group of hepatolienal diseases (see). All attempts to prove the primary role of one or another toxic factor in the etiology of cirrhosis have so far been unsuccessful. Particularly many controversies have arisen around the concept of the significant role of alcohol in the etiology of cirrhosis, which was previously recognized by authors (hence the name for Laennec's cirrhosis - 'alcoholic' cirrhosis). However, this opinion is not universal and is disputed by a number of statistical data (lack of parallelism between alcohol consumption and the frequency of cirrhosis, low percentage of cirrhosis cases among alcoholics, etc.). Experimentally, the cirrhotigenic properties of the most diverse substances damaging liver tissue have been tested. Upon administration of many of them (phosphorus, CCl₄, chloroform, ether, tetrachloroethane, etc.), it was possible to achieve death of liver parenchyma and rather pronounced development of connective tissue, however, these experiments do not have particular significance for clarifying the etiology of cirrhosis in humans. Of greater interest are experiments with the production of cirrhosis after administration of fatty acids, feeding with cholesterol, and the action of infectious agents (tubercle bacilli, Bact. coli). However, even these experiments have not solved the etiological problem of cirrhosis, all the more so because their results are very varied. Attention has also been drawn to the frequent presence in the spleen in cirrhosis, especially of the Banti type, of so-called siderofibrous nodules of Gandy-Gamna, which according to some contain mycelium of a fungus (see Hepatolienal diseases). Hence arose the hypothesis that cirrhosis (especially certain forms) develop on the basis of a fungal infection. However, since the presence of fungi in siderofibrous nodules is currently rejected, the hypothesis of a fungal infection in the etiology of cirrhosis is abandoned. In recent years, a number of authors have emphasized the importance of copper salts in the etiology of cirrhosis. This view arose from the comparison of the high frequency of cirrhosis in Switzerland and the use there of irrigation of vineyards with solutions of copper salts (Askanazi). It was also found that cirrhotic livers contain particularly high amounts of copper, and some (Mallory, Askanazi, Adrianov) managed to produce cirrhotic changes in the liver in rabbits and rats by feeding with copper salts. According to American data, this results in changes similar to hemochromatosis. However, these data were not subsequently confirmed (Oshima and Siebert, Flynn and Glahn, Paulson, Lubarsch, etc.). Increased copper content in the liver in cirrhosis was also found by other authors, but at the same time the same was found in cirrhosis of completely definite etiology, undoubtedly not associated with intoxication by copper salts (e.g., in cholangitic cirrhosis). Therefore, at present, the tendency is to conclude that copper, entering with food, is only retained in the liver in large quantities in cirrhosis and does not have significant importance in the development of cirrhosis. B. Relationship between liver cirrhosis and other diseases. Gallstones (of various types, predominantly pigment-limestone) are apparently encountered particularly frequently in cirrhosis, however, their significance in the pathogenesis of cirrhosis (except cholangitic) is unclear. Chronic cholecystitis is also common; in the gallbladder bile in cirrhosis, enterococcus, coli bacillus, and streptococcus are often found (according to some data in 80% of cases). As not infrequent findings in cirrhosis, the following are also noted: cirrhosis of the pancreas, sometimes leading to symptoms of diabetes, calcareous infarcts of the kidneys, fibrosis of the testicles, tuberculous peritonitis (in 4-5% of cases), vulgar chronic peritonitis. There are also indications of a higher frequency (up to 30%) of endocarditis in cirrhosis, which may speak in favor of an infectious origin of cirrhosis. Sometimes cirrhosis is accompanied by symptoms of hemorrhagic diathesis, which some explain by changes in blood due to liver insufficiency, others by damage to capillaries. The connection between cirrhosis and the development of liver cancer has been emphasized since ancient times (see Liver, pathological anatomy), which apparently depends on the sharply expressed phenomena of regeneration of liver tissue in cirrhosis. Areas of regenerated tissue often have the appearance of tumor nodules (adenomas), however, according to recent reports, cancer on the basis of cirrhosis develops only in isolated cases. Large figures are given only by reports from Japan and the Dutch East Indies, which is probably connected with the high frequency of zooparasitic cirrhosis in these countries. Some also point to a higher frequency of cancers of other organs (especially the stomach and intestines) in liver cirrhosis, however, more precise statistical data (Resle) refute this opinion. C. Distribution of cirrhosis. Liver cirrhosis in all countries is found in autopsy material on average in 1-3% of cases; lower figures are given by reports from the USSR (for Moscow 0.3%), Sweden, Estonia, Poland, Yugoslavia. Particularly high figures are given for Switzerland; from non-European countries - for Japan and the East Indies (zooparasitic cirrhoses). Men get sick much more often than women (ratio 2-3.5:1). The largest number of cases occurs in the age group 40-65 years.

N. Anichkov. The clinical picture of cirrhosis of the Laënnec type consists of gastrointestinal disorders and abdominal enlargement. The abdomen enlarges first due to meteorism, but mainly due to the accumulation of free fluid in the abdominal cavity. Even before the development of ascites, various signs of portal hypertension appear in the form of characteristic changes in diuresis, as well as the formation of collateral vessels, some in the esophagus, stomach, and intestines (which leads to rupture and bleeding from the digestive tract in the form of bloody vomiting or bloody stools), others on the skin of the abdomen in the form of a network of dilated veins, especially around the navel (the so-called caput medusae). On palpation, the liver is either not detected at all or its hard, rough edge is palpated in the depth of the subcostal region. The spleen is enlarged and densified. There is no jaundice. The temperature should not be elevated, at least in uncomplicated cases. As characteristic changes in the blood, leukopenia was indicated. - Cirrhosis of the Hanot type cannot be characterized as clearly as atrophic cirrhosis of Laënnec. Under the banner of the 'Hanot syndrome', various hepatic, as well as hepatosplenic diseases, were later described. But if we speak of the disease described by Hanot himself, it presents in the following form. Its etiology should be associated with various general infectious processes (among which the role of typhoid fever was emphasized); a specific causative agent was also considered. Unlike Laënnec's cirrhosis, a familial, congenital predisposition to Hanot's disease was noted (cases of two children in one family being affected, cases of the disease recurring in the family, etc.). The tendency of the disease to affect young age was also emphasized (unlike Laënnec's cirrhosis, which usually occurs in elderly individuals). Pathogenetically, the basis of Hanot's cirrhosis should be an inflammatory process in the bile ducts, especially in their smallest canals emerging from the liver lobules. The damage to intrahepatic bile ducts should explain the development of the main symptom of this disease-jaundice. On the basis of chronic cholangitis and pericholangitis, as well as bile stasis, proliferation of connective tissue occurs. Since the small bile canals, around which fibrosis occurs, are at some distance from the portal capillaries (between them lie the beams of liver cells), it was understandable that the fibrous tissue does not significantly disrupt the blood flow through the liver, and therefore ascites usually does not occur. The clinical picture of Hanot's disease, according to descriptions, is indeed sharply different from that in Laënnec's cirrhosis. The most prominent symptom is jaundice, although fluctuating in intensity, but sufficiently pronounced, accompanied by the usual phenomena characteristic of prolonged jaundice, such as itching and tendency to general bleeding. However, according to Hanot, the stool in this form of C. is not only not discolored, but is often even saturated with pigments (polycholia). The spleen is markedly enlarged; there are no signs of portal hypertension, including ascites and collaterals. The temperature is elevated, fever periodically intensifies, giving waves up to 38-39°. A high leukocytosis (up to 15-20 thousand) is determined. In this type of cirrhosis, enlargement of the axillary and inguinal lymph glands was also noted. If the disease affects people during the period of growth, various trophic disorders arise, including, for example, thickening of the terminal phalanges of the fingers (drumsticks). Hanot's disease is characterized by a course in attacks. As the doctrine of C. p. developed, other types of cirrhosis emerged that did not fit into the framework outlined by Laënnec and Hanot. Thus, the so-called simple hypertrophic cirrhosis (Hanot-Gilbert) was first distinguished. Judging by the descriptions, in this C. the liver is markedly enlarged, while in its other signs this form closely resembles the Laënnec type (tendency to form ascites and collaterals, gastrointestinal bleeding). The same factors that cause Laënnec's cirrhosis cause this type; histologically, annular proliferation of connective tissue is noted, and moreover, relatively young, without wrinkling; liver cells, according to original descriptions, are increased in volume and number. Then a special biliary C. with early and extremely large enlargement of the spleen [hypersplenomegalic biliary cirrhosis of Gilbert and Lereboullet] was distinguished. The description of this type of C. led to the theory of the splenic origin of certain forms of C. p., all the more so that by this time Banti had emerged with the characterization of his disease. Then the need arose to speak of simple biliary C. p., meaning by this C. with jaundice due to bile stasis in the liver with prolonged closure of the large bile ducts by a stone or tumor. Although this form of C. differs from 'Hanot's disease' in some symptoms apparently sharply enough (acholic stool in contrast to the pleiochromic in Hanot's disease, as well as sometimes the absence of splenomegaly), the presence of other symptoms common to both C.s, such as smooth large liver, jaundice, fever, and leukocytosis, led to confusion of these forms. It is not surprising that gradually physicians formed an extremely contradictory idea of cirrhosis of Hanot itself: sometimes this type includes the so-called simple hypertrophic C., as we saw, a type related to Laënnec's type, Banti's disease, and even 'biliary' cirrhosis on the basis of obstruction of the bile duct by a stone. Later, other forms of C. were described: 'fatty cirrhosis,' 'malignant hypertrophic cirrhosis,' etc. All this greatly confused the classification of cirrhoses. The division of C. into numerous types, independent in etiology, patho-anatomical picture, and symptomatology, ended, as was to be expected, with a reaction of the opposite kind. From different sides, objections were raised that the division of cirrhoses is based mainly on the morphological features of cases and was sometimes created simply by a combination of external anat.-clin. features without taking into account the development of the disease. Especially German authors began more and more often to speak of C. p. as a disease unified in its essence, without dividing it according to the established scheme, although this disease can be caused by various causes, can have this or that variants of course, this or that anat. and clin. features, etc. In this respect, a major role was played by the fact that with a more careful study of the course of Laënnec's disease, it was possible to notice the so-called preascitic stage, during which the liver is by no means atrophied, but significantly enlarged. Comparing the 'hypertrophic stage of atrophic cirrhosis' with the aforementioned variety of the so-called 'simple hypertrophic cirrhosis,' it was easy to make the first breach in the nosological isolation of individual types of cirrhosis: the 'simple hypertrophic cirrhosis' turned into the early 'hypertrophic stage' of Laënnec's cirrhosis, losing its significance as a separate disease form. On the other hand, the importance of cirrhosis of Hanot in the proper sense (i.e., not 'syndrome,' but 'Hanot's disease') turned out to have greatly decreased after it was necessary to exclude from this group diseases that had been included there only by formal similarity, but in fact represent completely different processes that affect the liver only secondarily, such as Banti's disease, cirrhosis on the basis of bile stasis in mechanical jaundice, etc. It was even suggested that Hanot's disease does not represent a primary hepatic disease, and under its banner perhaps severe cases of hemolytic jaundice complicated by inflammation of the bile ducts were described; attention was drawn to the fact that some features of Hanot's disease (familial nature, tendency to affect young age, and especially pleiochromia of stool) repeat the typical signs of icterus haemolyticus. The inadequacy of the old division of C. from a clinical point of view follows especially from the indisputable fact that in most cases of C. p. we are dealing with such a combination of data in which some of these data correspond to the picture of C. of one type, and others to the picture of C. of another type; in other words, the overwhelming frequency of the so-called mixed forms was established (80% of cases according to Eppinger). As examples of 'mixed' forms of C. may be mentioned cases of C. of alcoholic etiology, however giving jaundice relatively early, or cases of cirrhosis with a small liver and ascites and at the same time with jaundice, or cases where the clinical picture corresponded to the Hanot syndrome, while the anatomical one showed annular C., as well as cases where the clinical picture approached the Laënnec syndrome (cirrhosis with ascites), while the connective tissue was found to have developed inside the lobules.

Furthermore, very instructive are cases of cirrhosis in which, during the course of the disease, the clinical picture undergoes significant changes, as if cirrhosis of one type transitions into cirrhosis of another type (for example, cases in which the liver is initially sharply and uniformly enlarged, then jaundice develops, and later the liver begins to decrease in size and ascites develops); in such cases, adherents to the concept of the distinctness of individual forms of cirrhosis would be forced to sequentially change their diagnoses: first to recognize 'simple hypertrophic cirrhosis', then 'hypertrophic biliary cirrhosis of Hanot', and finally cirrhosis of Laennec. From the pathoanatomical point of view, the old classification of cirrhosis also encounters considerable difficulties. Thus, according to the data of Sternberg and others, it is difficult to speak in many cases of an annular or insular arrangement of connective tissue, since connective tissue proliferates both between and within lobules simultaneously, and unevenly. Indeed, in 'typical' cases the pattern is characteristic, but such cases are in the minority. Furthermore, one of the seemingly simple methods for evaluating the type of cirrhosis—according to the size of the liver—has proven unreliable. When speaking of hypertrophic cirrhosis and atrophic cirrhosis, it remains unclear whether this refers only to the size of the liver or whether it is meant to characterize the size of its tissues, in particular its parenchyma. But since connective tissue is always increased in any cirrhosis, it is obvious that the question of whether the liver is atrophied or hypertrophied can only concern the volume of its parenchyma. And it turns out that this question cannot be resolved based on the size of the liver alone; for example, the liver may be of normal size, but it must be designated as atrophic, because after subtracting the increased connective tissue, the mass of the parenchyma is found to be diminished. Even in the case where the liver exceeds normal size in its dimensions, it often cannot be called hypertrophic, but rather it would be more correct to call it atrophic if the increase is due to fibrous tissue and the actual liver tissue is diminished. Only in very few cases can we speak of a truly hypertrophied liver, i.e., an increase in the organ not only due to fibrous tissue but also to hyperplastic liver tissue. As for the attempt to use another morphological feature for the differentiation of cirrhosis—the character of the liver surface (List and others)—it is even less successful, since a smooth liver very often becomes granular in the later stages of the disease. From the pathogenetic point of view, the old classification of cirrhosis has also proven controversial. Thus, in cirrhosis corresponding anatomically to the type of Hanot, it was often not possible to detect the required cholangitis as per the scheme, and Eppinger even expressed the conviction that this type of cirrhosis is an example of liver parenchyma damage; it should be noted, however, that another great expert in liver pathology, Rössle, recently proposed to consider the so-called insular cirrhosis as a result of primary disease of the mesenchymal tissue of the liver. As for atrophic cirrhosis, the view appearing in the classical scheme of it as a result of interstitial inflammation of the liver was at one time criticized by Kretz; this pathologist showed that cirrhosis with an annular pattern of connective tissue is a product of primary degeneration of liver cells, that it is not fibrosis that leads to cell atrophy, but, on the contrary, cell death leads to cirrhosis. In addition, there is also a tendency to consider atrophic cirrhosis as a result of arteriolosclerotic changes in the liver vessels (Lepehne). All the above gives an idea of the tangle of contradictions in which the problem of cirrhosis in its old form is entangled. Modern state of the question. Many of the difficulties and contradictions set forth above should disappear if under the name cirrhosis we understand not a special disease, but only the final stage of certain liver diseases. For the physician, it is of course much more important to concentrate attention on these primary pathological processes rather than on the static picture of those consequences to which they ultimately lead. That is why clinical practice is beginning to move away from the diagnosis of cirrhosis and is putting the diagnosis of hepatitis in the forefront, understanding by this term various forms of infectious and toxic liver lesions of both inflammatory and degenerative nature (in the latter case, instead of the word 'hepatitis', some use the word 'hepatosis'). From this point of view, cirrhosis is only the outcome of hepatitis—in the case that hepatitis leads to significant proliferation of connective tissue in the liver. But not only hepatitis or hepatosis can lead to cirrhosis. It can be caused by prolonged stagnation of bile or blood in the liver. Thus, cirrhosis can naturally be subdivided into the following four types according to their causes of development: 1) Cirrhosis as a result of primary dystrophic changes in the liver (outcome of chronic hepatosis or epithelial hepatitis); 2) Cirrhosis as a result of primary inflammatory changes in the mesenchymal tissue of the liver (outcome of interstitial, mesenchymal hepatitis); 3) Cirrhosis as a result of prolonged bile stagnation (it is here that the old term 'biliary cirrhosis' can be used); 4) Cirrhosis as a result of prolonged cardiac congestion ('cardiac cirrhosis'). I. Cirrhosis on the basis of epithelial hepatitis or hepatosis. The etiology of this form of cirrhosis includes various toxic effects on the liver. Among them, alcohol stands first. Among patients with cirrhosis, persons who abused alcoholic beverages are encountered extremely frequently. Thus, out of 135 cases collected by Naunyn, constant consumption of alcohol occurred in 83 cases, 18 of whom could be called drunkards. Price and Simmonds note alcoholism in 60% of cases of cirrhosis. According to the data of Myasnikov, this percentage is significantly lower (30). At one time, disputing the role of alcohol in the development of cirrhosis, reference was made to the fact that not all alcoholics develop cirrhosis. But, if we take cases of such an obviously alcoholic disease as delirium tremens, it also affects only a small part of drunkards. The connection between alcoholism and cirrhosis is shown by the following statistical data. Cirrhosis undoubtedly occurs more frequently among those professional groups of the population whose representatives easily become victims of alcoholism. Thus, Dickinson among sellers of wine shops found cirrhosis in 22 out of 149 people, i.e., in 15%. Between mortality from alcoholism and mortality from cirrhosis, a certain parallelism can be noted: thus, during the 5 years from 1871 to 1875 in England, per million inhabitants, there were 72 cases of death from cirrhosis and 37 from alcoholism per year; during the 5 years from 1901 to 1905, per million there were 121 cases of death from cirrhosis and 78 from alcoholism. It is true that suggestions have been made that it is not alcohol itself that acts on the liver, but abnormal products of fermentation and putrefaction formed in the intestine during its alcoholic catarrh (d'Amato and others). Others claimed that the properties of a liver poison are possessed not by alcohol itself, but by various impurities introduced with wine (extracts, aldehydes, copper salts, etc.). After a series of unsuccessful attempts, it has recently been possible to reproduce cirrhosis experimentally by prolonged administration of alcohol (Saltykov, Strauss and Bloque, Moon and others), although morphologically not entirely identical with human cirrhosis, which is natural and should not serve as a reason to diminish these data. The experiments of Bergmann and Eibott with the injection of bilirubin into the blood of humans showed that after taking a large dose of alcoholic beverages, the injected bilirubin is not excreted by the liver for much longer than before the consumption of alcohol. This means that alcohol has a toxic effect on the liver epithelium, temporarily paralyzing its function. Consequently, it is alcohol itself that is the culprit of cirrhosis, and its impurities, as well as products of intestinal putrefaction or fermentation, can only be assigned the role of additional factors. In second place among the etiological sources of this group of cirrhoses is syphilitic intoxication. The matter here concerns some poisonous products that are formed in late or congenital syphilis and that cause various dystrophic changes in some internal organs. Third place in the etiology of this kind of cirrhosis is occupied by those infectious-toxic factors that cause acute hepatitis. Acute hepatitis can pass into chronic and end in cirrhosis. Eppinger was one of the first to point out the connection of 'catarrhal jaundice' with cirrhosis. In some cases, this transition occurs quickly within a few months; these are the cases that are sometimes designated as 'subacute atrophy of the liver'. Such an outcome is especially frequent in malignant hepatitis, called 'yellow atrophy'. In other cases, acute hepatitis gives rise to a slow, at first even hidden, suffering of the liver, which only after several years takes on the features of cirrhosis. Among the rarer causes of cirrhosis of this group are tuberculous intoxication, the 'tuberculous fatty cirrhosis' of Hutinel and Sabourin, which is the culmination of toxic-tuberculous 'fatty hepatitis'.

In this case, it is not so much about infection of the liver with Koch's bacilli, but about the action of endotoxins diffusely damaging the parenchyma, as has been proven in the experiments of Courcoux and Ribadeau-Dumas, as well as A. M. Levin. It should be mentioned as causes of Cirrhosis of this group malarial intoxication, hemolytic poisons, professional harmful substances such as lead, benzene, copper, arsenic. Finally, various harmful products entering the liver from the gastro-intestinal tract in chronic dysfunction of this tract or improper one-sided nutrition are also of importance. The pathogenesis of this form of Cirrhosis should be conceived as follows: the breakdown of liver cells causes a reaction from the neighboring mesenchymal elements of the organ, as a result of which new connective tissue begins to form. Some authors believe that this irritation of the mesenchymal tissue of the liver is created not by products of breakdown of liver epithelium, but arises in parallel - under the influence of the main etiological factor. A bright proof of the secondary nature of the mesenchymal-fibrous reaction in Cirrhosis of this type is provided by the results of experiment. Particularly interesting are the experiments of Jaffe. The author introduced chloroform and other liver poisons to rabbits in different dosages and studied the liver at different stages of its damage. In experiments where the poison was introduced in large amounts, extensive necrosis of liver epithelium developed, while from the side of the stroma only a weak reaction was noted; in experiments where the poison was introduced in smaller dosages and gradually, the damage to the epithelium seemed less severe, but the changes in the interstitial tissue became more significant; finally in experiments with prolonged introduction of small doses of the same poison, it was possible to obtain a picture in which the proliferation of connective tissue came to the forefront, while in the liver cells the microscope noted almost no pathological features. Obviously, different tempo and degree of damage to liver parenchyma create different outcomes: in some cases - rapid death of cells before connective tissue has time to proliferate, in others - slow atrophy of cells leading gradually to massive formation of connective tissue. There is no doubt that in hepatitis the etiological factor acts not only on the liver, but on the whole organism, on its other organs or tissues, but it is still difficult to decide which of the extrahepatic changes in Cirrhosis really develop parallel to liver changes, and which are secondary, in connection with those disorders which the liver process brings into the organism. Thus, such a characteristic symptom of Cirrhosis as enlargement of the spleen can be explained in two ways: both as a consequence of liver disease (e.g., stagnation, secondary reaction) and as a manifestation of a general systemic process affecting the liver and spleen simultaneously. In recent times, it has been increasingly asserted that in Cirrhosis the pancreas is also affected in parallel with the liver, as well as the bone marrow in the form of hyperplasia of the latter. The boundaries of liver Cirrhosis thus expand and Cirrhosis begins to acquire the significance of a general disease of the organism, with only more intense damage to certain organs, especially the liver. Pathological anatomy. Cirrhosis on the basis of epithelial hepatitis gives different pictures depending on the stage of the disease and its etiology. In the earlier period of cirrhosis the liver is enlarged in volume, and its surface is more or less smooth. In the late stages the liver turns out to be sharply diminished, and its surface acquires either a fine- or coarse-grained appearance. The density of the liver is comparatively not so great in the stage of its hypertrophy and is extremely sharply expressed in its atrophy. All these external transformations of the liver are connected with the state of the proliferated connective tissue in it. In those cases where connective tissue for a long time does not give wrinkling (elephantiasis type, according to Resle), the liver remains large and smooth; conversely, where connective tissue comparatively early begins to wrinkle, the liver becomes granular and diminishes in volume. It is not yet clear what the difference in the fate of connective tissue depends on. In the histological picture the distinguishing feature of Cirrhosis of this type is the presence of damage to liver epithelial cells. True, alongside cases in which liver epithelial cells are strongly changed (various degrees and forms of degeneration/multiple necroses), there are also those in which these changes seem insignificant. The slower the hepatitis develops and the more benign it is, the less damaged the remaining cells turn out to be in the stage of Cirrhosis (a different question is how many of them remain). The more acute and malignant the hepatitis, the greater the chances of finding in Cirrhosis more active morphological signs of cell damage. Along with dystrophic changes in the liver in Cirrhosis, regeneration from the side of the epithelium can always be established, often concentrated in certain areas; thus small or large nodules of newly formed cells are formed, distorting the structure of the organ. From the side of the mesenchymal tissue of the liver, what first strikes the eye is the sharp development of fibrous fibers - in some cases mainly around the lobules, in others - inside them, in thirds - along the course of both portal and liver veins (so-called bi-venous type); in fourth type cases (most often) - without a definite system or in a mixed manner. In the connective tissue septa a small small-cell infiltration is also noticeable. It is extremely important to emphasize that connective tissue usually proliferates precisely in those places of the lobules where liver cells turn out to be damaged. If cells degenerate and necrotize along the periphery of the lobules, then connective tissue is increased precisely between the lobules, creating the so-called annular type of Cirrhosis; if cells degenerate and necrotize in the center of the lobules, then connective tissue proliferates in the lobules themselves, creating the so-called insular type of Cirrhosis. These facts once again emphasize the secondary nature of fibrosis. As an intermediate link between cell damage and the development of fibrosis can serve the changes from the side of Kupffer cells and the so-called reticular fibers, this finest mesenchymal scaffold of the liver. Namely, in the fresher forms of Cirrhosis it is possible to observe, again especially in the neighborhood of dying epithelium, from the side of Kupffer cells hyperplasia and hypertrophy, and sometimes also enhanced erythrophagocytosis, while the reticular fibers swell and break down. Such a reaction of reticulo-endothelial elements of the liver obviously represents the starting point for the development of fibrous elements (since the possibility of transformation of Kupffer cells into fibroblasts follows from the data of Moiseev and others). In the late stages Kupffer cells are already diminished. As for extrahepatic changes, from them first of all one must stop at the vascular collaterals forming as a result of difficulty in outflow of portal blood through the shrunken liver. The main of them are: 1) connections between the portal vein and the superior vena cava: a) through the veins of the stomach, veins of the esophagus, v. intercostalis-v. azygos; b) along the superficial path through the abdominal wall - through v. paraumbilicalis-v. xiphoidea-v. mammaria interna; c) along the deep path through the abdominal wall - through v. paraumbilicalis-v. epigastrica sup. prof. sin.-v. mammaria interna. 2) Connection between the portal vein and the inferior vena cava: a) superficial path through the abdominal wall along v. paraumbilicalis-v. epigastrica inf. tegument.-v. femoralis; b) deep path along the umbilical system - vein of Burov-v. epig. inf. prof.; c) through the upper and lower hemorrhoidal veins-v. pudenda inf.-v. hypogastrica; d) through the left coronary vein of the stomach - lower diaphragmatic veins; e) through the veins of some other organs (capsule of the kidneys, colon, bladder, diaphragm). The indicated anastomoses expand, the walls of the veins become thicker, especially abundant are varicose nodes in the esophagus and rectum. In the spleen the changes come down to hyperplasia of reticulo-endothelial elements, hemosiderosis, sclerosis of the pulp, overflow of blood into the sinuses and hematomas. Peri-hepatitis and peri-splenitis are rarely expressed (in cases of prolonged or complicated peritonitis). Angiocholecystitis belongs only to the number of complications. Changes in the pancreas consist in fatty degeneration, necroses, hemorrhages; part of them are caused by stagnation. In the ascitic period stagnation is noticeable also in the kidneys and other organs. The clinical picture of Cirrhosis of this group is colored by the symptoms of the original process, the outcome of which is Cirrhosis. The complaints of patients at the beginning are different. In some they relate more to digestive disorders (poor appetite, belching, nausea, constipation, diarrhea, bloating, pains from the stomach and intestines, etc.). In others Cirrhosis begins with jaundice, weakness, itching, pressure in the hypochondria, bleeding, etc. The most important objective symptom of the disease in the earlier period are the morphological and functional changes of the liver itself. The organ is first enlarged, uniform; sensitivity is usually small and independent pains from the liver are comparatively rare.

As a rule, there is jaundice, which in some cases can be obvious and intense, while in others it is weak and hidden (in which case it only gives subictericity of the sclera and a dusky complexion of the skin or can be detected by examining bilirubin in the blood). This jaundice is caused by damage to the liver parenchyma and is accompanied by other functional disorders from the liver, among which high urobilinuria should be placed in the first place, which in this type of Cirrhosis is usually sharply expressed. Bile acids are retained in the body. The amount of amino acids in the blood and urine is slightly increased. Tests with a galactose load and other types of sugar are often positive. In severe cases, acetone bodies and lactic acid accumulate in the blood, and cholesterol also falls. Almost a constant symptom of the disease is splenomegaly. The spleen in Cirrhosis can increase very early, but in many cases it is still possible to trace that it begins to be palpable later than the liver (for example, in cases where cirrhosis develops from the 'fatty liver' of alcoholics or when it is the outcome of chronic hepatitis that developed after acute). It is undoubtedly that the spleen enlarges long before the appearance of ascites, therefore its increase cannot be explained only by stagnation. It is explained by irritation of its reticulo-endothelial elements, coinciding with a similar condition of the hepatic department of the reticulo-endothelium and constituting part of the general reaction of the reticulo-endothelial system in Cirrhosis (for this type of Cirrhosis, this reaction compared with the underlying parenchymal liver damage is apparently secondary). An echo of this reaction is the often observed in the early period of Cirrhosis monocytosis. In other respects, the blood picture is characterized by a tendency to leukopenia, lymphocytosis and anemia. Anemia is obviously caused by a decrease in erythropoiesis, since the number of reticulocytes is reduced, but in some cases blood breakdown is also intensified (pleochromatic stool). In the late stage of Cirrhosis, the liver becomes dense and rough to the touch or ceases to be palpable, hiding due to ascites; the spleen as well. The symptoms of portal hypertension, so characteristic of the type of Cirrhosis described by Laennec (see above), come to the fore. Its picture consists of a violation of diuresis, the development of collaterals and ascites. The afternoon rise in diuresis shifts to the night hours ('opsiuria'). Later, diuresis becomes uneven during the day ('anuria') or its physiological fluctuations are smoothed out ('isuria'). Finally, it decreases.-Collaterals can be detected upon examination in the area of the navel: they represent thick tortuous venous trunks surrounding the navel and going mainly upward; generally wide, bluing through the skin veins of the abdominal wall are striking. Upon examination of the esophagus and rectum, varicose nodes can also be found.-Ascites develops after a more or less prolonged period of the disease; ascitic fluid accumulates most often gradually, but sometimes surprisingly rapidly (e.g., after an intercurrent infection or strong abuse of alcohol) (description of ascitic fluid, the shape of the abdomen in ascites and methods of its determination - see Ascites). The amount of ascitic fluid can be enormous - up to 15 liters. With the development of ascites, some cardiovascular disorders appear (the mass of circulating blood decreases, venous pressure in the general circle decreases, blood filling of the heart decreases, systolic volume decreases, arterial pressure decreases, shortness of breath appears, and in the severe period - cyanosis and edema). The ascitic fluid compresses the inferior vena cava, which also leads to the formation of edema on the lower extremities.-One of the characteristic symptoms of Cirrhosis in the severe stage are bleeding. They are caused mainly by trauma to varicose veins in the area of collaterals. Such are hemorrhoidal bleedings, which can begin very early in Cirrhosis. Such are gastric bleedings, which sometimes simulate an ulcer. Bleeding can cause significant anemia. Bleeding can also occur from the upper and middle parts of the intestines, from the bladder, kidneys, etc. In addition to the mechanical factor in the pathogenesis of bleeding in cirrhotics, a hemorrhagic diathesis (disorder of blood clotting due to damage to the liver parenchyma) also plays a role.-The digestive tract suffers in cirrhosis both independently and due to impaired bile secretion and stagnation (disorders with stool, subacidic catarrh of the stomach, meteorism, steatorrhea, decrease in enzymes of the pancreas, etc.). The general condition is significantly disturbed, since in the end all the vital functions of the body suffer. Upon examination of cirrhotics in the later period, the contrast between the large abdomen and the emaciated face and hands is striking. The nose becomes pointed, the cheekbones protrude, the cheeks sink in and are covered with dilated venous networks, the skin is dry, hard, the muscles are atrophied. Work capacity sharply decreases. Weakness of mental perception, vision and hearing, apathy, bad mood, irritability, insomnia, headaches appear. The temperature is subfebrile, normal, or subnormal. The course of this type of Cirrhosis can be characterized by the following variants. In some cases, hepatitis and cirrhosis during life do not give any sign of themselves, proceeding asymptomatically and being accidentally discovered upon autopsy. These hidden forms demonstrate how long liver disease can be compensated, even if it has already caused extensive scarring. In other cases, the disease in a typical form lasts for many years, patients continue their activities, jaundice or ascites appear and then disappear. Acute forms of cirrhosis have already been discussed. Depending on the severity of individual symptoms in the clinical picture of the disease, one can speak of the jaundice and ascitic variants of cirrhosis. Different etiological forms are more likely to give one or another variant. Thus, alcoholic Cirrhosis proceeds very slowly, accompanied by a slow rate of degeneration, but on the other hand by strong regenerative phenomena from the parenchyma, an enormous accumulation of connective tissue in the liver, which later strongly shrinks; it is clear that jaundice and other functional disorders should recede to the background in this case, while ascites, the development of collaterals, etc. come to the fore. On the contrary, some other Cirrhoses (e.g., syphilitoxic) proceed with more significant changes from the liver parenchyma, and in such cases the patient may die from the phenomena of jaundice and hepatic insufficiency before ascites develops.-Death in Cirrhosis occurs: a) from hepatic coma; b) from progressive decline of strength (cachexia is contributed to by diarrhea, disorders of absorption of food substances, depletion of the body of proteins due to their loss with ascitic fluid, anemia, violation of intermediate metabolism, stagnation in organs, etc.); c) from heart weakness in ascites; d) from acute causes (profuse bleeding, shock after draining ascites, etc.) and especially e) from the addition of some infection (angina, pneumonia, sepsis, severe colitis, erysipelas).-From complications in Cirrhosis, in addition to the tendency to acute infections, which take a bad course, the frequency of peritonitis should also be noted. Chronic peritonitis occurs in about one tenth of all cases of Cirrhosis; most often it is of tuberculous character. Tuberculosis generally easily flourishes in Cirrhosis in other organs as well. II. Cirrhosis on the basis of mesenchymal, interstitial hepatitis. This type of Cirrhosis represents the completion of primary inflammatory changes in the interstitial tissue of the liver. In this case, it is a matter of damage to the liver, although not exclusively, by the microbes themselves. Among the etiological sources of this type of Cirrhosis, syphilis (pale spirochetes), tubercle bacilli, malarial plasmodia, brucellosis, as well as microbes entering the interstitial tissue of the liver from the bile ducts during their inflammation, are of particular importance. In the liver, specific and non-specific productive-infiltrative processes play out, which are usually described as gummatous hepatitis, tuberculous hepatitis, malarial hepatitis, periangiocholitis, etc. Following these processes, in more persistent and severe cases, there is an increase in connective tissue. It should be said that some authors do not agree to consider Cirrhosis the extensive fibrous changes left behind by these inflammatory processes. They refer to such changes as 'secondary' and contrast them with 'primary' or 'true' cirrhosis.-It should be emphasized that the anatomical picture of Cirrhosis of this group often bears a strong imprint of the basic pathological conditions. For example, in Cirrhosis on the basis of syphilitic (interstitial) hepatitis, elements specific to this form (miliary or solitary gummas, characteristic changes in vessels, etc.) may be present in the liver. In Cirrhosis on the basis of tuberculous hepatitis, typical tubercles, etc., may be found. For Cirrhosis on the basis of malaria, changes in Kupffer's cells, as well as the deposition of pigments - hemosiderin and melanin - will be typical. A feature of Cirrhosis on the basis of angiocholitis will naturally be severe changes in the bile ducts and around them. In brucellosis Cirrhosis, special granulomas are described.

From this, one cannot yet draw the conclusion that all these hepatitis cases with fibrosis are fundamentally different from cirrhosis. If we consider the nature of connective tissue proliferation, we find that in this group as well, the same variants of its development occur as in 'true' C. Thus, in malarial C., there is an interlobular, annular type of fibrosis with granular shrinkage of the liver (Kelsch, Kiener), just as in some forms of tubercular hepatitis. Indeed, in other forms, for example, in gummatous hepatitis, the fibrous tissue is distributed quite unevenly, forming coarse scars and giving the liver a highly deformed appearance (hepar lobatum). What morphologically distinguishes this type of C. from C. in cases of epithelial liver damage is, first, the tendency to produce limited focal changes, second, the presence in many cases of perihepatitis, and third, the absence of any clear signs of damage to the liver parenchyma (except for individual areas). In the clinical picture of these forms of C., on the one hand, there are many distinctive features related to the etiological nature of individual cases, and on the other hand, there are common features that allow differentiation of these forms of C. from C. in cases of epithelial liver damage. As for the features related to etiology, examples can be cited in the form of gummatous hepatitis. The syndrome of this hepatitis is quite distinctive (nodular liver, severe pain, fever, often positive Wassermann reaction, other syphilitic changes, etc.). Tubercular hepatitis rarely comes to the physician's attention, and the merit of F. O. Gausmann is that he emphasized the importance of this form. Enlargement of the liver in the presence of tuberculosis is of course not yet C. p., but cases have been observed of hardening of the liver, enlargement of the spleen, and ascites in tuberculosis with nodules in the liver and proliferation of connective tissue on autopsy, and in these cases, tubercular changes in other organs receded into the background. The existence of malarial C. was at one time questioned; everyone knows how quickly the liver of malaria patients, which had previously seemed cirrhotically dense, can shrink under the influence of quinine, but it is still incorrect to deny the existence of malarial C. In C. on the basis of peri cholangitis, a feature of the clinical picture is abundant inflammatory admixtures in the portion of bile obtained by duodenal probing, as well as other symptoms of cholangioitis (temperature, pain, leukocytosis, etc.). For the diagnosis of brucellosis C., the history, specific Wright and Burne tests, muscle and joint pains, etc., are of great importance. As for the common features of this group of C., which allow to a certain extent to contrast them with C. in cases of epithelial liver damage, they are briefly as follows: 1) absence of functional disorders from the liver; 2) usually also absence of jaundice, unless there are mechanical causes for it (e.g., pressure of a large gumma on the common bile duct); 3) presence of significant painful phenomena from the liver—independent, severe, and persistent pains and tenderness on palpation (depending on the so characteristic perihepatitis of these forms); 4) often uneven enlargement of the liver, palpation of nodularities and indentations, enlargement of one lobe, etc.; 5) fairly often elevated temperature and leukocytosis. The course is significantly more favorable, because the main process can stop or pass (under the influence, for example, of specific treatment) at a stage when the fibrous tissue in the liver has not yet proliferated strongly. Special mention must be made of those forms of C. that are caused by primary damage to the reticuloendothelium of the liver. Formally, these conditions can also be classified as a group of mesenchymal hepatitis, but unlike the usual infectious granulomas in syphilis, tuberculosis, etc., they have the character of diffuse irritation or damage to the liver endothelium, i.e., intraliver, mainly portal capillaries. This capillitis as a partial moment also appears in infectious granulomas, but sometimes it occurs as an independent process. Such forms of C., due to primary changes in the liver reticuloendothelium, to an even greater extent than others, must be accompanied by extensive changes in other parts of this apparatus. It is possible that some unclear cases of hepatosplenic diseases belong precisely to this group. In particular, C. in blood diseases—polycythemia, hemolytic jaundice—are described. Cirrhotic changes in the liver are known in splenomegalies of the Banti type. It can be assumed that the basis of these C. lies in the effect on the liver of products of abnormal blood breakdown. Thus, Eller was able to observe changes in the mesenchyme of the liver when introducing foreign red blood cells. But it has not yet been clarified what these products primarily affect: the epithelium or the endothelium of the liver? In this sense, the experiments of Gye and Pardy are very important, who introduced colloidal silicon into the vein of laboratory animals and obtained a sharp increase in the number and size of Kupffer cells, which then transformed into fibrous elements. These experiments show that toxic products that primarily affect the liver endothelium and thereby cause the development of connective tissue can indeed exist. A clinical example of this possibility is the so-called pigmentary C., or hemochromatosis (see). In this disease, due to disturbance of iron metabolism and the effect of colloidal iron particles on the liver endothelium (as well as other organs, such as the spleen and pancreas), capillitis (Resle) occurs with subsequent fibrosis. It is possible that this is also the nature of some other C., for example, malarial one. It is still necessary to mention the new mechanism that has recently been proposed by Resle and Eppinger to explain certain forms of cirrhosis. The question is about the so-called serous inflammation of the liver, i.e., a peculiar lesion of the organ's capillaries, in which their walls become permeable to plasma; plasma proteins exude into the surrounding tissue, displacing the parenchyma; subsequently, collagen fibers form in this mass. III. Cirrhosis on the basis of bile stasis. This type of C. occurs in various mechanical jaundices, if they persist for a long time. Such is, for example, calculous C. in gallstone disease. In some patients, a few weeks of complete obstruction of the ducts are sufficient for the initial signs of C. to develop, while in others, even obstruction lasting many months may not lead to C. The reason for the development of connective tissue in this case is the death of liver cells under the influence of prolonged bile stasis, as well as the accompanying infection (peri cholangitis). Connective tissue proliferates according to a mixed type, mainly inside the lobules and around the bile ducts. The liver is initially enlarged and smooth; over time, it becomes smaller and acquires a slightly granular appearance. In the clinical picture, the symptoms of gallstone disease predominate; to them are added physical changes from the liver, and in severe forms and stages, some functional hepatic disorders, including hemorrhagic diathesis. Occasionally, slight ascites develops, and the spleen begins to be palpable. Other causes of this cirrhosis are cancer of the bile ducts, chronic pancreatitis, etc. IV. Cirrhosis on the basis of cardiac stasis. The changes in the liver in cardiac stasis consist of engorgement of the central veins and capillaries with blood and secondary degeneration and atrophy of liver cells (from pressure and from disturbance of nutrition)—the so-called nutmeg liver and cyanotic atrophy. Does connective tissue proliferation also occur in the stasis liver as a result of these changes? Gerlach, in his review in the Henke-Lubarsch handbook, rejects cardiac C., citing the experiments of Permantier and others. However, significant proliferation of connective tissue in the atrophied stasis liver is described by Rindfleisch, Ziegler, and many others. As shown by the research of Herxheimer, first there is thickening and proliferation of reticular fibers in the lobules, later this tissue turns into fibrous tissue, which can shrink; the liver takes on a granular appearance, and on cross-section begins to crunch. In the clinical picture of cardiac C., in addition to jaundice and urobilinuria (which are characteristic of the stasis liver even before cirrhosis), sometimes symptoms of portal hypertension and especially ascites, disproportionate to other cardiac-stasis symptoms, attract attention. Treatment. Since C. p. is already an irreversible condition, treatment cannot claim significant success. Its task is to stop or reduce the underlying process that created the C. Specific therapeutic methods should always be tried. These include iodine, mercury, bismuth in syphilis (salvarsan is contraindicated), quinine and plasmoquine in malaria. Specific treatment helps very little in C., even in the initial stages, if it develops on the basis of liver parenchymal damage. On the contrary, in interstitial hepatitis, even when it has reached cirrhotic changes, specific remedies can give success, although of course incomplete.

It is only necessary to carry out treatment cautiously, avoiding harmful effects on liver cells (control - functional tests) and too rapid resolution of inflammatory foci, because in such cases sometimes a stimulus is created for too rapid scarring, and the condition only worsens. Specific measures should include treatment with vaccines in brucellosis, perhaps sometimes tuberculin, as well as systematic fight against infection of the bile ducts, giardiasis, etc. Among non-specific therapeutic measures, diet is of primary importance. Food in C. should be composed so as not to burden the stomach, intestines, and liver. It is advisable to eat more often but in small amounts, with the calculation that a sufficient amount of easily digestible nutrients is introduced. Dishes that irritate the digestive tract should be eliminated. In this, one cannot fail to take into account the individual characteristics of patients and their appetite. In parenchymal forms of C., the diet should be composed with special care, and animal proteins should be excluded, while fats should be reduced with only emulsified, easily absorbable ones retained. In such cases, a milk-vegetable diet is usually prescribed, but with such a selection that there is as little coarse fiber as possible. Unfortunately, milk is sometimes poorly tolerated due to diarrhea. A sufficient amount of vitamins must be ensured. Injections of glucose (100-200 cm³ of a 10-20% solution), systematically repeated in the form of monthly courses, can only help in cases of liver epithelial damage that have not progressed far, and can also moderate the manifestations of liver functional insufficiency, including the tendency to hemorrhagic diathesis. It is appropriate to use this method also in addition to a course of specific therapy in syphilitic C.-Administration of alkaline and alkaline earth mineral waters, as well as sulfate and salt solutions (MgSO₄, Na₂SO₄, Na₂CO₃, etc.) acts well on the stomach and intestines, regulating their function and reducing the catarrhal condition. At the same time, these solutions, upon absorption, also enter the liver and produce some positive effect (since their therapeutic effect was empirically noted by old doctors). Partially they improve bile secretion, reducing the catarrh of the bile ducts. As for special cholagogues, their effect is doubtful. Prescription of urotropine, salol, etc. is usually made in the hope of their bactericidal properties, but in hepatitis they are unlikely to bring much benefit. More valuable are mercury preparations, at least calomel, on the advice of Zakharin, are also used with some success in 'biliary' cirrhoses. The fight for diuresis is one of the most important tasks in the therapy of C. Among diuretics, mercury preparations, especially soluble ones like novazur, ciarsal, salyrgan, which are not deposited in tissue, act best; after each injection, for example, an ampule of novazur, diuresis shows a sharp increase. It is useful to also add the prescription of ammonium chloride or Liq. Kali acetici (10%, several spoonfuls a day). Calcium chloride in large doses (up to 15-20 g a day) undoubtedly also belongs to the means of fighting ascites. On the contrary, diuretics from the group diuretin-theocin give little effect, as do adonis, scilla, etc.-The release of ascites is performed when it interferes with breathing, creates swelling of the legs, when the abdominal walls are sharply tense. It is better to release it a little earlier than too late, because in the first case the fluid accumulates more slowly. As a result of the puncture, patients get immediate relief. In most cases, the fluid accumulates again and the puncture has to be repeated. Each time, hundreds of grams of protein are removed from the body, because a new transudate soon accumulates in place of the released one. It is easy to understand how these 'bloodlettings' must exhaust the patients, although it must be admitted that in isolated cases after repeated evacuation, ascites may stop accumulating for a long time. Apparently in such cases collateral circulation is established. Surgical methods have also been proposed for the treatment of ascites. Their principle is quite logical: to create artificial connections between the systems of the portal and inferior vena cava in addition to those that the body itself forms. Such is Talma's omentopexy, the method of Kalb, Mayo, Bogoraz, Krestovsky, etc. The result so far is not very encouraging due to the serious condition of the patients, poor survival of their tissue, etc. It is also necessary to prescribe general strengthening treatment, cardiac agents, remedies for pain, etc., required by the symptoms of the disease. Cirrhotics are mostly disabled, and the question is only how to use their remaining capacity for work. They tolerate mental work much better than physical work. Sending to a resort in cirrhosis should be done in the earlier stages of its development. Prevention of C. coincides with that of hepatitis and consists in eliminating their causes (wholesome nutrition, overcoming alcoholism, fighting syphilis and malaria and their timely treatment, treatment of diseases of the stomach, intestines and bile ducts, rational therapy of acute jaundices and proper regime after them, improvement of working conditions in industries associated with the use of lead, copper, etc.).