Cirrhosis is a common chronic liver disease that can be caused by one or more causes of liver damage, with progressive, diffuse, fibrous lesions in the liver. These three changes are repeatedly intertwined, resulting in the gradual alteration of liver lobular structures and blood circulation pathways, causing liver deformation and stiffening, leading to cirrhosis. In the early stage of the disease, there are no obvious symptoms, but in the later stage, a series of different degrees of portal hypertension and liver dysfunction occur until death from complications such as upper gastrointestinal bleeding and hepatic encephalopathy.
There are many causes of cirrhosis, and the main causes vary from region to region. In Europe and America, alcoholic cirrhosis is the main cause, while in China, hepatitis cirrhosis is common (slow hepatitis B), followed by schistosomiasis liver fibrosis, and alcoholic cirrhosis is increasing year by year. Studies have confirmed that 2 causes acting on the liver successively or simultaneously are more likely to produce cirrhosis. For example, schistosomiasis or long-term heavy drinkers combined with viral hepatitis B, etc.
(A) Hepatitis cirrhosis
It refers to the development of viral hepatitis to the late stage of cirrhosis. It is known that there are hepatitis A, B, C, D, E and other types of hepatitis viruses. Recent studies have concluded that hepatitis A and E without chronicity do not form cirrhosis except in acute severe cases. Hepatitis B and C tend to become chronic, i.e., chronic active hepatitis and cirrhosis.
In 1974, Shikatu reported that HBsAg (hepatitis B surface antigen) could be revealed by immunofluorescence method. Under the microscope, the cell pulp containing HBsAg appears as hairy glass, and the hepatocyte pulp containing HBsAg can be stained with lichen red (Orecein) stain to a bright orange color. After years of preservation of cirrhotic specimens, this method can also reveal HBsAg-containing hepatocytes, making a reliable basis for cirrhosis caused by hepatitis B virus. Hepatitis B patients 10% to 20% have a chronic course with long-term HBsAg positivity and intermittent or persistent abnormal liver function. The continuous replication of hepatitis B virus in the liver can cause lymphocytes to infiltrate in the liver, releasing a large number of cytokines and inflammatory mediators, causing degeneration and necrosis of hepatocytes while removing the virus. 68% of hepatitis C has a chronic course, and 30% of chronic hepatitis C develops into cirrhosis. Hepatitis D can co-infect with or overlap with hepatitis B. It can slow down the replication of the hepatitis B virus, but often exacerbates the activity of the lesion and accelerates the onset of cirrhosis.
In the acute severe form of viral hepatitis, large necrotic fusion of hepatocytes extends from the lobular center to the confluent area, causing collapse of the reticular scaffold, close together, and formation of fibrous septa. It also produces bridging from the center of the lobules to the confluent area, and forms large nodular cirrhosis. In chronic active hepatitis cirrhosis, there is significant inflammation and fibrosis in the confluent area, forming wide irregular “active” fibrous septa that extend intra- and interlobularly, causing the adjacent lobules to be separated and destroyed by fibrous septa. At this point, although the liver structure is modified, it is not yet cirrhosis, but the fibrotic stage. When the inflammation extends from the edges of the lobules to the center, causing punctate necrosis and mononuclear cell infiltration, the fibrous septa continue to expand to the center and divide the lobules. At the end of the disease, the inflammation and hepatocyte necrosis can disappear completely, but there are only a majority of nodules of different sizes in the fibrous septum, and the nodules are multi-lobular, forming large nodular cirrhosis. If the hepatitis lesions are milder and the disease progresses more slowly, small nodular cirrhosis, mixed cirrhosis or regenerative nodular inconspicuous cirrhosis (incomplete segregative cirrhosis) can also be formed.
The progression from viral hepatitis to cirrhosis has been shown to be independent of the amount of antigen infected. Rather, there is a significant relationship with viral virulence and the immune status of the body. Genetic factors are associated with a tendency to chronicity, and there seems to be a relationship with the lack of human leukocyte antigens HL-A1 and HL-A8, but further studies are pending.
(ii) Alcoholic cirrhosis
Alcoholic cirrhosis has a high incidence in Western countries and is caused by alcoholism. In recent years, the consumption of alcohol in China has increased, and the incidence of fatty liver and alcoholic cirrhosis has also increased. According to statistics, the occurrence of cirrhosis is directly proportional to the amount and duration of alcohol consumption. Drinking 80g of alcohol per day can cause an increase in serum glutathione aminotransferase, and fatty liver or alcoholic hepatitis can occur in most people who continue to drink a lot of alcohol for several weeks to months. If a person continues to drink a lot of alcohol for more than 15 years, 75% of them can develop cirrhosis.
After alcohol enters hepatocytes, it is transformed into acetaldehyde by the action of ethanol dehydrogenase and microsomal ethanol oxidase, and then acetaldehyde is transformed into acetic acid, which causes excessive transformation of coenzyme I (NAD) into reduced coenzyme I (NADH), thus reducing NAD and increasing NADH, and the ratio of the two decreases. In addition, the excess of NADH in the liver promotes the synthesis of fatty acids, which strengthens the power of fatty acid formation from body fat and causes excessive triacylglycerol in the liver, exceeding the processing capacity of the liver, and fatty liver occurs. Long-term heavy alcohol consumption can cause further degeneration, necrosis and secondary inflammation of hepatocytes, and alcoholic hepatitis can occur on the basis of fatty liver, which can be seen microscopically as widespread degeneration of hepatocytes and the infiltration of polymorphonuclear leukocytes and mononuclear cells in the confluent area and the proliferation of bile ducts and fibrous tissue, finally forming small The final result is the formation of small nodular cirrhosis. The central veins of the lobules of alcoholic cirrhosis can undergo acute sclerotic hyaline necrosis causing fibrosis and lumen occlusion, exacerbating portal hypertension. The fibrosis in the central part of the lobe may extend to the peripheral parts, and may also form a “bridge” with the confluent area.
(C) Parasitic cirrhosis
If schistosomes or liver flukes reside in the portal system, the eggs are deposited in the liver with the portal blood flow, causing embolism of small branches of the portal vein. The eggs are larger than the diameter of the portal vein input branch of the liver lobules, so the embolism causes inflammation, granuloma and fibrous tissue proliferation in the confluence area, which enlarges the confluence area, destroys the border plate of the liver lobules and involves the hepatocytes at the edge of the lobules. The regenerative nodules of hepatocytes are not obvious, which may be related to the blockage of small branches of portal vein by the eggs of the worms and insufficient nutrition of hepatocytes. Significant esophageal varices and splenomegaly were evident due to portal vein obstruction and portal hypertension. Adult worms cause a cellular immune response and secretion of toxins, which are responsible for the formation of intrahepatic granulomas. The eggs cause a humoral immune response, producing antigen-antibody complexes, which may be responsible for inflammation and fibrosis in and around the portal branches of the liver. Parasitic cirrhosis is morphologically a regenerative nodular non-significant cirrhosis.
(iv) Toxic cirrhosis
Damage to the liver by chemical substances can be divided into two categories: one is direct toxicity to the liver, such as carbon tetrachloride, methotrexate, etc.; the other is indirect toxicity to the liver. Such toxicity is independent of the amount of the drug, and causes an allergic reaction first to patients with specific qualities, and then causes liver damage. A few patients can cause cirrhosis, such as isonicotinyl, iproniazid (iproniazid), halothane. The lesions are similar to post-hepatitis cirrhosis. Carbon tetrachloride is a direct toxicant to the liver, and the damage to the liver is proportional to the size of the dose, causing diffuse fatty infiltration of the liver and necrosis in the center of the lobules. The continued damage to the liver is attenuated by the destruction of microstructures within the hepatocytes and reduced metabolism of carbon tetrachloride by drug-metabolizing enzymes. After recovery, the patient’s liver function mostly returns to normal. Large nodular cirrhosis only occasionally occurs with repeated or prolonged exposure to carbon tetrachloride. Repeated administration of carbon tetrachloride to rats in animal studies allows for drug accumulation that can cause cirrhosis. Methotrexate, an anti-folate drug, is commonly used clinically to treat leukemia, lymphoma, psoriasis (psoriasis), etc., and has been reported to cause small nodular cirrhosis.
(E) Biliary cirrhosis
The cause and pathogenesis of primary biliary cirrhosis are unclear and may be related to autoimmunity. Secondary biliary cirrhosis is caused by various causes of bile duct obstruction, including stones, tumors, benign strictures and various causes of external pressure and congenital and acquired bile duct occlusion. It is mostly caused by benign diseases. This is because malignant tumors tend to die before the patient develops cirrhosis.
Complete bile duct obstruction from all causes has a course of 3 to 12 months before cirrhosis can develop. The incidence is about 10% or less of such patients.
In the early stages of bile duct obstruction, the bile becomes dark in color, but can soon turn white. Due to bile stasis and bile duct dilatation, the pressure in the bile duct increases, which inhibits bile secretion, and the bile can change from green to white, forming the so-called “white bile”. Microscopically, it can be seen that the small bile ducts in the confluence area are highly dilated, or even the bile ducts are ruptured, and the bile overflow causes necrosis and inflammation in the confluence area and the peripheral area of the liver lobules. This is a characteristic manifestation of mechanical bile duct obstruction. As the lesion continues to progress, the necrosis and inflammation in the peripheral area cause the fibrous tissue in the confluence area to proliferate and extend to the interlobular area to form fibrous compartments. The fibrous septa in each confluent area are interconnected, dividing the lobules and presenting incompletely segregated cirrhosis. It is different from post-hepatitis cirrhosis and alcoholic cirrhosis in which the fibrous septum from the center to the confluent area is different. However, if the lesion continues to develop, the fibrous septa and hepatocyte regeneration nodules from the confluent area to the central area of the lobules may appear in the advanced stage and lose their characteristic manifestations, so that they are not easily distinguished from other cirrhosis in terms of pathology and clinical manifestations. Portal hypertension and ascites may also be present.
The principle of bile duct obstruction forming cirrhosis may be due to compression of intrahepatic vessels by enlarged bile ducts and extravasation of bile, and ischemic necrosis of hepatocytes. Fibrous tissue extends towards the bile ducts to surround the lobules and spreads among the hepatocytes, eventually forming cirrhosis. Incomplete bile duct obstruction rarely progresses to biliary cirrhosis.
Bile duct infection is not known to be required for the development of cirrhosis. It has been reported that complete bile duct obstruction without infection is more common to develop into biliary cirrhosis.
(vi) Circulatory disorders (stasis) cirrhosis
Also known as cardiogenic cirrhosis and stasis cirrhosis. Budd-chiari syndrome is due to chronic obstruction of the hepatic veins causing long-term hepatic stasis, which also occurs in the exact same way as cardiogenic cirrhosis.
In cardiac insufficiency, blood perfusion in the liver decreases due to a decrease in the volume of blood pulsed by the heart, and the oxygen content of blood is higher at the margins of the hepatic lobules and progressively decreases as it flows to the center of the lobules. Cardiac insufficiency is accompanied by increased central venous pressure, dilatation of the central vein and its surrounding hepatic sinusoids, stasis, compression of hepatocytes, degeneration, atrophy, and even hemorrhagic necrosis. Both hypoxia and necrosis can stimulate collagen proliferation and fibrosis, and even sclerosing fibrosis of the central vein, which gradually expands from the center to the periphery, and the fibrin of adjacent lobules are linked to each other, i.e., the center-to-center fibrous compartment. The confluent area, on the other hand, is relatively less invaded. This is characteristic of circulatory disorder cirrhosis. In the later stages, as portal fibrosis continues to progress, the liver parenchyma continues to regenerate after necrosis and the bile ducts regenerate then finally lose their stasis cirrhosis characteristics. This type of cirrhosis shows small nodular or incompletely segregated cirrhosis in the pathological pattern.
(VII) Malnutrition cirrhosis
It has long been believed that malnutrition can cause cirrhosis. However, there has been a lack of direct evidence. Animal studies have shown that a diet lacking in protein, choline and vitamins can cause changes in cirrhosis, but the lesions are reversible and lack the secondary vascular changes often seen in cirrhotic patients. Some authors have observed patients with malnutrition and found that their liver damage was fatty liver and did not develop cirrhosis. Only children occasionally have diffuse fibrous hyperplasia in the liver, resembling cirrhosis, and when given a protein-rich diet, the lesions can be reversed and the liver returns to normal, with only mild fibrous hyperplasia in some cases. Therefore, it is not certain whether malnutrition can directly cause cirrhosis. Most people believe that nutritional disorders reduce the resistance of the liver to other pathogenic factors, such as chronic atopic or non-atopic enteritis, which causes digestion, absorption and malnutrition, and the toxins produced by pathogens in the intestine enter the liver through the portal vein, and the liver is unable to remove them, leading to hepatocyte degeneration and necrosis and cirrhosis. Therefore, malnutrition is considered to be an indirect cause of cirrhosis. Another example is cirrhosis caused after small intestine bypass surgery, which is thought to be caused by malnutrition, lack of basic amino acids or vitamin E, imbalance of sugars and proteins in the diet and absorption of large amounts of toxic peptides from food as well as stone bile acids that are toxic to the liver.
(viii) Cryptogenic cirrhosis
Some patients with cirrhosis have an unknown cause, which may be related to a fatty liver, or a congenital deficiency of some enzyme system in the liver.
(ix) Metabolic cirrhosis
Due to genetic defects, certain substances are metabolized and deposited in the liver, causing degeneration and necrosis of hepatocytes and proliferation of connective tissue, thus developing into cirrhosis. For example, copper is deposited in the liver in hepatomegaly and iron is deposited in the liver in hemochromatosis.
(X) Autoimmune cirrhosis
It is mainly caused by autoimmune liver disease, the pathogenesis of which is not fully understood, and is currently believed to be closely related to genetic factors. Due to the defective immune regulatory function of the patient, the body reacts to its own hepatocyte antigens, which is manifested by cell-mediated cytotoxic effects and immune reactions arising from the combination of hepatocyte surface-specific antigens and autoantibodies, and the latter is predominant (primary biliary cirrhosis is also autoimmune cirrhosis).
(XI) Congenital syphilitic cirrhosis
The liver is involved in 80% of patients with congenital syphilis, probably because the syphilis spirochetes pass through the placenta, enter the umbilical vein and finally reach the liver and cause liver damage. Although this disease is uncommon, it should be taken seriously because of its high mortality rate.