What Are the Different Types of Portal Hypertension Treatment?

According to the analysis of 3,500 cases of the National General Surgery Conference in 1982, intrahepatic portal hypertension accounted for 97.81%, while extrahepatic accounted for only 2.19%. In 1998, Huang Yiting and other groups collected data on 9,980 cases of portal hypertension performed in 24 hospitals in 13 provinces and cities across the country. The epidemiological data are: 71.86% of hepatitis B surface antigens are positive, and 28.14% are negative. Intrahepatic type accounted for 97.06% of which necrotic accounted for 75.74%, schistosomiasis accounted for 15.38%, alcoholic accounted for 2.97%, bile accounted for 1.62%; extrahepatic accounted for 2.94%. It can be seen from the hepatitis B surface antigen and liver pathology that intrahepatic necrosis and schistosomiasis cirrhosis are still the main types of cirrhosis in China, and hepatitis B is still the main cause of cirrhosis in China. Portal hypertension with liver cancer has been valued. Of the 8,327 cases surveyed in this survey, 205 were liver cancer, accounting for 2.46%, which was significantly higher than the general population, indicating the close relationship between hepatitis B and liver cancer.

Portal hypertension

Portal hypertension, English name: portal hypertension, alias: portal hypertension; portal hypertension is too high; portal hypertension; PHT. Portal hypertension refers to a series of clinical manifestations caused by increased pressure in the portal vein system. It is a clinical condition and is a comprehensive clinical manifestation of portal vein blood circulation disorders caused by various causes. It is not a single disease. Portal hypertension and / or increased blood flow can cause portal hypertension. Therefore, patients with portal hypertension often show symptoms of portal hypertension and primary disease. figure 1

Epidemiology of portal hypertension

According to the analysis of 3,500 cases of the National General Surgery Conference in 1982, intrahepatic portal hypertension accounted for 97.81%, while the extrahepatic type accounted for only 2.19%. In 1998, Huang Yiting and other groups collected data on 9,980 cases of portal hypertension performed in 24 hospitals in 13 provinces and cities across the country. The epidemiological data are: 71.86% of hepatitis B surface antigens are positive, and 28.14% are negative. Intrahepatic type accounted for 97.06% of which necrotic accounted for 75.74%, schistosomiasis accounted for 15.38%, alcoholic accounted for 2.97%, bile accounted for 1.62%; extrahepatic accounted for 2.94%. It can be seen from the hepatitis B surface antigen and liver pathology that intrahepatic necrosis and schistosomiasis cirrhosis are still the main types of cirrhosis in China, and hepatitis B is still the main cause of cirrhosis in China. Portal hypertension with liver cancer has been valued. Of the 8,327 cases surveyed in this survey, 205 were liver cancer, accounting for 2.46%, which was significantly higher than the general population, indicating the close relationship between hepatitis B and liver cancer.

Causes of portal hypertension

Portal hypertension can be divided into pre-hepatic, intra-hepatic and post-hepatic types. Intra-hepatic type is the most common in China, accounting for more than 95%. In the intrahepatic type, pre-sinus obstruction, hepatic sinus and post-sinus obstruction can be divided into two types according to the pathological morphology. A common cause of presinus obstruction is schistosomiasis cirrhosis. Schistosoma matures and lays eggs in the portal vein system, forming worm egg emboli, which follow the portal blood flow to the small branches of the portal vein in the hepatic interlobular manifold area, causing the embolism of these small branches, endometritis and other The surrounding fibrosis caused the blood flow of the portal vein to be blocked and the pressure of the portal vein increased. The pre-sinus obstruction is advanced, which leads to secondary malnutrition of the liver cells and hepatic lobular atrophy. In the Yangtze River Basin, portal hypertension caused by schistosomiasis cirrhosis is more common.

Figure 2 Portal hypertension

The common cause of hepatic sinus and post-sinus obstruction is post-hepatic cirrhosis. The main lesions are fibrous tissue proliferation and hepatocyte regeneration in the hepatic lobules. Due to the squeezing of fibroblasts and regenerating hepatocyte nodules (false leaflets), hepatic lobules The internal hepatic sinus becomes narrow or occluded, so that portal vein blood does not easily flow into the central vein or sublobular vein of the hepatic lobules, blood flow is stagnated, and portal pressure increases. Due to the narrowing or occlusion of the hepatic sinus in many hepatic lobules, some high-pressure hepatic arterial blood flows through the arteriovenous communication branch of the hepatic interlobular manifold area, and the low-pressure portal vein branches are directly injected back into the portal vein pressure. Increased shape (Figure 1). In addition, in the sinus and posterior sinus obstruction, the intrahepatic lymphatic duct network is similarly compressed and distorted by proliferating fibrous cords and regenerating hepatocyte nodules, resulting in obstruction of intrahepatic lymphatic return and the pressure of the intrahepatic lymph duct network is significantly increased. Increased pulse pressure also has an effect.

The main cause of prehepatic type is thrombosis of the main portal vein (or the presence of splenic vein thrombosis at the same time). This pre-hepatic obstruction also obstructs the portal blood flow and increases portal pressure. Intraabdominal infections such as appendicitis, cholecystitis, etc., or trauma near the portal vein and splenic vein can cause thrombosis of the portal vein trunk. In children, the prehepatic type is mostly congenital malformations, such as atresia of the portal trunk or cavernous sinus-like lesions.

Pathogenesis of portal hypertension

Banti proposed in the clinical observation report of patients with splenomegaly and portal hypertension that increased splenic arterial blood flow is the main cause of splenomegaly and portal vein hemodynamic changes. However, with the progress of the pathological research on cirrhosis of the liver, the theory that increased portal venous system resistance is the main cause of portal hypertension has been dominated. This is the backward flow theory. According to this theory, due to hepatic fibrosis and the formation of pseudolobules, the intravenous hepatic veins and hepatic sinus are compressed, and portal vein reflux is blocked. Some authors believe that hepatic sinus compression and hepatic sinus capillary changes are the main causes of elevated portal vein pressure. the reason. Recently, it has been found that active substances such as norepinephrine, serotonin, and angiotensin in portal vein blood increase during liver cirrhosis, and they act on the small branch of the portal vein and the wall of the posterior lobular vein, causing it to contract continuously. Therefore, in the theory of backward blood flow theory, not only the mechanical obstruction caused by liver disease, but also the pathophysiological factors caused by vasoactive substances, the backward blood flow theory mainly reveals portal hypertension from the pathological changes of liver cirrhosis. Mechanism.

Figure 3 Portal hypertension

But backward blood flow theory does not fully explain the hemodynamic changes in portal hypertension. It is often challenged in animal experiments and clinical practices. For example, Vorobioff found in his experiments that the resistance of the portal vein system Animals with non-portal hypertension were comparable, but portal blood flow increased significantly in the experimental group. He believes that the high blood flow status of the portal vein system is the decisive factor for maintaining portal hypertension. Huang Cuiting et al. Found that portal vein pressure and spleen size had no significant correlation with the pathological degree of liver cirrhosis. Idiopathic portal hypertension has no cirrhosis, and schistosomiasis cirrhosis has no external hepatic portal vein or hepatic vein obstruction. This cannot be explained by the backward blood flow theory. Clinically, it is often seen in patients with liver cirrhosis that limbs are warm and heart rate increases. , Increased cardiac output, pulse flooding and other high dynamic phenomena. Ultrasound Doppler measurement of portal vein blood flow in patients with liver cirrhosis is significantly higher than the normal population, especially the significant increase in splenic artery blood flow in some patients has caused special clinical attention. Animal experiments found that visceral arterial resistance in cirrhotic animals decreased and blood flow increased. These all indicate the existence of systemic hyperdynamic circulation during cirrhosis and portal hypertension. It is believed that the root cause of this phenomenon is that patients with liver cirrhosis have reduced inactivation of vasoactive substances due to liver lesions and liver function decline, and the proportion of vasodilators in the blood has increased. The overall result shows decreased vascular resistance and tissue oxygen utilization. The rate decreases and cardiac output increases. This change is most pronounced in the abdominal circulation. This is the forward flow theory.

Clinical manifestations of portal hypertension

History of portal hypertension

Whether the patient has a history of hepatitis or contact with hepatitis patients, as well as a history of blood transfusions and a history of oral treatments such as tooth extraction can all indicate whether hepatic cirrhosis has occurred. Drinking history is an important basis for the diagnosis of alcoholic liver disease, but not all long-term drinkers develop alcoholic cirrhosis. It is generally believed that alcoholic liver cirrhosis is more likely to occur if men drink 160g a day and women 80g a day for more than 10 years. In addition, there is a history of schistosomiasis, heart disease, history of taking estrogen, non-steroidal drugs, malnutrition and family history of liver and gallbladder diseases, etc., which can indicate whether there is congenital or idiopathic portal hypertension.

Clinical manifestations of portal hypertension

Portal hypertension can cause three major clinical manifestations such as open collateral circulation, splenomegaly and hypersplenism, and ascites. Other symptoms include spider nevus, liver palms, and hypofunction. Most patients can make a diagnosis of portal hypertension based on clinical manifestations.

(1) Opening of the collateral circulation: The opening of the collateral circulation is a unique manifestation of portal hypertension and is an important basis for the diagnosis of portal hypertension. The main parts of the collateral circulation are: the adjoining cardia esophagus, which causes the esophagus and stomach Base varicose veins; Perirectal veins that cause hemorrhoidal varicose veins; Peri-umbilical or abdominal wall varicose veins appear in the veins around the hepatic sickle ligament; Retroperitoneal space veins. Varicose veins vary in meaning. For example, esophageal varices have a diagnostic value for portal hypertension, while abdominal varicose veins, hemorrhoidal varicose veins, and retroperitoneal varices, you need to pay attention to other factors. In 15% to 50% of patients, varicose veins in the lower end of the esophagus and the bottom of the stomach cause vomiting and blood in the stool. The amount of bleeding is often large, which can be accompanied by shock and life-threatening. Varicose hemorrhoids can occur in different degrees of blood in the stool. Varicose veins of the abdominal wall generally appear in the upper umbilicus, and then extend to the periphery of the umbilicus, below the umbilicus and lower chest. Physical examination revealed that the umbilical veins were significantly dilated, with the umbilical cord as the center to radiate the varicose veins above the umbilical veins in the direction of blood flow upward, and the direction of the blood flow below the umbilicus downward. In severe cases, a varicose vein appears around the umbilical cord, forming a "sea snake head". The vein "yingying" sound can be heard on auscultation, and it can be enhanced when the spleen is pressed. This sign has diagnostic significance for portal hypertension.

(2) Splenomegaly and hypersplenism: Splenomegaly is a necessary condition for portal hypertension. The liver of patients with portal cirrhosis becomes smaller as the liver becomes smaller. Splenomegaly may be accompanied by hypersplenism. Patients present with leukopenia, thrombocytopenia, and proliferative anemia, and about a quarter of patients with cirrhosis are accompanied by hypersplenism. The splenomegaly caused by cirrhosis is usually more pronounced and the texture is generally harder. The difference is that the splenomegaly caused by acute infection (typhoid, sepsis, etc.) is usually mild, soft and has a lymphosarcoma or chronic myelogenous leukemia. The swelling is mostly severe.

(3) Ascites and signs of liver disease: Ascites is one of the clinical manifestations of many diseases, but it is mainly caused by portal hypertension caused by various liver diseases (about 80%). The manifestations of primary disease and laboratory tests can often distinguish cirrhosis and ascites from other systemic diseases. Patients with advanced liver cirrhosis often have ascites and liver signs, liver palms, spider moles, jaundice and other signs. The liver can be palpable and nodules, and the advanced liver can be reduced. In general, ascites without cirrhosis often start slowly and respond well to treatment; portal hypertension (Budd-Chiari syndrome) caused by hepatic vein outflow tract obstruction often starts faster and often causes acute obstruction There is upper abdominal pain, liver enlargement, a large amount of ascites can appear quickly and it is refractory ascites. In addition to the general symptoms of fatigue, loss of appetite, bloating, and nausea in patients with decompensated liver function, jaundice, spider moles, palms of the liver, skin pigmentation, and coagulopathy and endocrine disorders may appear. Severe complications such as hepatic encephalopathy and hepatorenal syndrome may occur in the advanced stage.

Complications of portal hypertension

1. Gastric fundus, esophageal varices rupture and bleeding is the most common and most dangerous complication of portal hypertension.

2. Hepatic encephalopathy Patients with cirrhosis of the liver who suffer from upper gastrointestinal bleeding, whether it is varicose vein rupture or bleeding, or gastric mucosa or ulcer bleeding, are prone to occur and are the most serious complications.

Figure 4 Portal hypertension

3. Gastrointestinal bleeding This bleeding mainly comes from esophagus, gastric varicose veins, acute gastric mucosal erosions and duodenal or gastric ulcers, mainly caused by portal hypertension, belonging to portal gastric disease and portal bowel disease Category is the most common serious complication of chronic liver disease.

4. Hepatorenal syndrome Patients with portal cirrhosis who have upper gastrointestinal bleeding may cause liver function and systemic failure, which can easily cause hepatorenal syndrome.

Diagnosis of portal hypertension

The diagnosis of portal hypertension is generally not difficult, and there are many methods for diagnosis. In addition to clarifying the diagnosis of portal hypertension, the purpose of these tests is mainly to establish the etiology and type of portal hypertension and provide evidence for treatment. The clinical diagnosis of portal hypertension includes three aspects: inquiring about the relevant medical history in detail; accurately judging the significance of the relevant clinical manifestations; correctly analyzing the results of the auxiliary examination; thus achieving the existence of portal hypertension, The etiology of portal hypertension was also clarified.

There are many criteria for the classification of portal hypertension, which can help to choose the operation method and estimate the prognosis.

1.Child classification Surgical mortality of patients with portal hypertension is closely related to their liver function compensation status. Child categorizes liver function in patients with cirrhosis into 3 levels based on clinical and laboratory tests. Among them, the surgical mortality of grades A and B is significantly lower than that of grade C, and the treatment effect is better.

2. Chinese Portal Hypertension Hepatic Function Grading Standards According to the decision of the first portal hypertension symposium held in Wuhan in 1983, the liver function of patients with portal hypertension was divided into 3 levels.

Figure 5 Portal hypertension

3. Staging of contrast blood flow imaging Warren proposed the staging of portal hypertension based on the results of portal angiography in 1967. The catheter was inserted into the hepatic vein or splenic vein, and a contrast agent was injected to perform hepatic vein and splenic vein angiography, respectively, to observe the portal vein filling. In the early stage of portal hypertension, it can be seen that the portal vein is well filled and that all or most of the contrast medium flows into the liver, suggesting that the portal vein blood flow is toward the liver. With the worsening of the disease, the blood flow to the liver is blocked, the contrast agent stays in the portal vein system, and there is a clear intrahepatic portal vein branch. When the condition is severe, no contrast agent can be displayed in the portal vein, and blood flow to the liver is severely blocked, suggesting that the portal vein is separated from the liver.

Differential diagnosis:

1. Patients with vomiting as the main symptom First, bleeding from ulcers and gastric cancer must be excluded, and the possibility of biliary bleeding should be considered. Most patients with ulcer disease have a history of typical ulcers such as abdominal pain and acid reflux. Most of the blood that has been exacerbated before bleeding is arterial blood with red color and less blood clots. It is associated with esophageal or gastric vein rupture. The resulting dark purple blood clots are different. The liver and spleen should be free of swelling and ascites, and liver function tests should be normal. Patients with gastric cancer may also vomit a lot of blood. Advanced patients with extensive lymph node metastasis can also compress the spleen vein and cause splenomegaly or ascites due to peritoneal metastasis. However, patients with gastric cancer often have a long history of anorexia and are often accompanied by pyloric obstruction. There is a clear history of melena before major bleeding and a history of repeated vomiting of coffee-like food. The upper abdomen can be lumped, and ascites can sometimes find cancer cells. Gastroscopy X-ray examination can further confirm the diagnosis.

2. Secondary splenomegaly may also be accompanied by hypersplenism, sometimes difficult to distinguish from portal hypertension. Although most of these patients have a history of primary diseases that may cause splenomegaly, such as malaria, black fever, and schistosomiasis, most of the patients have no significant lesions in the liver except for the splenomegaly, normal liver function, and no other symptoms of cirrhosis such as esophageal varices or ascites. However, it is sometimes difficult to determine whether it is the early manifestation of liver cirrhosis and extrahepatic portal hypertension.

3. Diseases with ascites as the prominent symptoms require careful identification in addition to liver cirrhosis. Certain heart diseases such as mitral valve stenosis or constrictive pericarditis, which have already experienced heart failure, often have significant ascites production. And there may be abdominal varicose veins and liver enlargement, etc. Sometimes it may be misdiagnosed as cirrhosis and portal hypertension. However, if you ask the patient carefully, you often have a history of rheumatic fever, pericarditis, hypertension, or angina pectoris and long-term shortness of breath, and often have lower limb edema before the occurrence of ascites. Physical examination can often find that the heart and lungs are abnormal, and the liver is enlarged and Tenderness, and most of the spleen swelling is not obvious.

Portal hypertension treatment

Surgical treatment of portal hypertension is mainly for its complications, especially those with upper gastrointestinal bleeding from esophageal gastric varices should actively take surgical treatment. As for the performance of splenomegaly and hypersplenism and ascites, when strict When medical treatment is ineffective, it is necessary to consider surgical treatment.

Esophageal gastric varices bleeding

Varicose vein rupture and hemorrhage is the most serious and most difficult complication of portal hypertension. About 40% to 60% of patients with cirrhosis have esophageal and gastric fundus varicose veins, and only 50% to 60% of patients may have varicose vein rupture and bleeding. That is to say, about 30% of cirrhotic patients with no previous history of bleeding will have varicose vein rupture and bleeding in their lifetime. However, once the varicose veins rupture and bleed, the mortality rate is very high, reaching 30% to 50%. Obviously, the prediction of bleeding risk is important. Risk factors for bleeding include: Liver function: When liver function deteriorates in patients with liver cirrhosis and portal hypertension, the risk of bleeding will greatly increase. Child-Push classification is often used to evaluate liver function. The higher the score, the worse the liver function. Easy bleeding; Varicose vein size, color, and tension: Red and severe varicose veins under endoscope have a much greater risk of bleeding than white and mild bleeding. The tension of the varicose vein wall is related to the size and internal pressure of the varicose vein plexus It is also considered to be the key factor for venous rupture and bleeding; Hepatic hemodynamic factors: The hepatic hemodynamic status can reflect the pathophysiological changes of varicose vein rupture and bleeding. Hepatic venous pressure gradient (HVPG) It is an independent risk factor for varicose vein rupture and bleeding. If the HVPG is less than 12mmHg, there will be no bleeding.

Treatment of splenomegaly and hypersplenism

Almost all patients with portal hypertension have splenomegaly, and most have hypersplenism with varying degrees. Patients with obvious splenomegaly and significant hypersplenism should strive for splenectomy. Clinically, it has been proved that spleen artery ligation alone cannot completely correct the phenomenon of hypersplenism, and after splenectomy, not only can hypersplenism be corrected, but also indirect help for esophageal varices and ascites. Follow-up results showed that those who had not had a history of vomiting before the operation and did not bleed more after the operation seemed to have the effect of preventing bleeding or delaying the course of the disease. After splenectomy, in addition to the complications that may occur after major surgery, there are still some more special complications that need to be properly prevented and treated: intra-abdominal bleeding: intra-abdominal bleeding after resection of giant spleen is common and severe One of the complications can sometimes lead to death. The cause of bleeding is not necessarily due to poor management of the large blood vessels of the spleen pedicle, but more often due to adhesions between the spleen and the surrounding tissues such as the diaphragm. Such small bleeding may not be detected during surgery due to poor exposure, and due to emptiness of the spleen after surgery, the diaphragm muscle moves up and down, coupled with poor liver function, coagulation dysfunction, and coagulation difficulties, often can accumulate a large amount of bleeding, It even causes shock. Therefore, during splenectomy, small bleeding points around the spleen such as the diaphragm, pancreatic tail, and spleen pedicle should be particularly careful to stop bleeding. After the splenectomy, a rubber is often placed under the spleen or near the spleen. Drainage of the tube can be found immediately in case of bleeding; Thrombosis: Platelets often increase significantly after splenectomy, sometimes up to more than 1 million, and last for 2 to 3 weeks; In addition, the vein wall may be injured during surgery. Sometimes infection can occur in the posterior abdomen (there is more chance for pancreatic tail resection), and because the patient often stays in bed for a long time after surgery, it may cause thrombosis in the splenic vein, and even extend to the superior mesenteric vein and portal vein, causing ascites, Liver failure, etc .; therefore, patients with excessive platelet elevation after surgery should consider using heparin anticoagulants and give a large number of antibacterial drugs; long-term fever: high fever after splenectomy Non-returning (above 39 ° C for about 2 weeks) is quite common, and the literature reports about 10% or more; the reason for this persistent fever is the multiple infections of the above-mentioned submental hematomas and intravenous thrombosis. One of the reasons is that the pancreatic juice leaks out after the pancreatic tail is injured, and the nearby tissue is digested to generate heat absorption, which is also possible. In short, the fever after splenectomy is still an inflammatory manifestation, especially the secondary infection of sub-hemipal hematoma is the most common.

Treatment of ascites

The mechanism of the occurrence of ascites is more complicated. The reasons are multifaceted, so comprehensive treatment should generally be adopted. However, ascites due to cirrhosis itself rarely becomes an indication for surgery. It is mainly based on medical treatments, such as increasing nutrition, improving anemia, limiting salt intake, and using various diuretics [such as hydrochlorothiazide (dihydrogram urine plug), 3 times / d. , Each time 25 ~ 50mg] to increase the excretion of ascites, clinically have a certain effect. Surgical treatment methods include ascites internal jugular vein bypass, shunt, TIPS, liver transplantation and so on.

Prognosis and prevention of portal hypertension

Prognosis of portal hypertension

In the treatment of portal hypertension, the effect of liver transplantation is significant. This treatment method has greatly changed the outcome of such patients. In the 1980s, the 5-year survival chance of such patients was only 20%. Choosing a transplant has a 5-year chance of survival of 75% to 80%. So far, no other method can achieve this effect.

Portal hypertension prevention

1. Crowd prevention The population prevention of this disease is mainly implemented for schistosomiasis cirrhosis and post-hepatitis cirrhosis. The method is the same as that for schistosomiasis liver disease and cirrhosis.

2. Personal prevention

(1) Primary prevention:

Prevention and treatment of viral hepatitis.

Prevention and treatment of schistosomiasis liver disease.

Pay close attention to early treatment of liver cirrhosis.

(2) Secondary prevention: The disease can be asymptomatic in the early stage and once symptoms appear, it is often more dangerous. Therefore, it is necessary to follow up patients with post-hepatitis cirrhosis and schistosomiasis cirrhosis in combination with health checkups in order to detect early, Early treatment.

(3) Tertiary prevention: Tertiary prevention of portal hypertension is for esophageal varices bleeding, refractory ascites, and hepatic encephalopathy. Non-surgical and surgical treatments can be used for esophageal vein rupture and bleeding. Non-surgical treatments include triple-lumen tube balloon compression, endoscopic hemostasis, local perfusion of hemostatic drugs, intravenous infusion of posterior pituitary hormones, and so on. It has been reported that the use of somatostatin-octreotide (sandostatin) in the treatment of esophageal varicose vein rupture and bleeding has achieved significant results. The surgical treatment is the same as the above. The emergency treatment is appropriate to stop the flow. The most effective surgical measure for refractory ascites is abdominal venous Flow. Hepatic encephalopathy focuses on prevention, and its common causes include upper gastrointestinal bleeding, infection, application of strong diuretics, large amounts of ascites, hypokalemia, abuse of sedatives, uremia, etc. Avoiding the above inducements can reduce the incidence of hepatic encephalopathy. Incidence.

Portal hypertension shunt effect

About one-quarter of patients with liver cirrhosis are accompanied by hypersplenism (referred to as hypersplenism). Schistosomiasis and alcoholic cirrhosis have a higher incidence of hypersplenism, and the larger the spleen, the greater the possibility of hypersplenism. Symptoms of hypersplenism include splenomegaly, leukopenia, thrombocytopenia or hyperplasia, and anemia.

The mechanism of the occurrence of hypersplenism is unclear. In the past, some scholars believe that the cause of hypersplenism is mainly due to the formation of high pressure during liver cirrhosis, spleen congestion and enlargement, which causes blood to accumulate in the liver, which increases the mechanical damage to the blood. Patients undergoing portal shunts have a decreased portal vein pressure and often have a Swelling and hypersplenism were also relieved. However, studies have now found that a considerable part of patients (about 25%) have not been relieved from hypersplenism after shunting, and even some patients with liver cirrhosis have hypersplenism after shunting. The reason may be that the collateral circulation of the liver is open during portal hypertension, and some antigenic substances in the intestine do not pass through the liver, avoiding the monitoring and killing of Kupffer cells in the liver, but directly enter the systemic circulation to stimulate the spleen mononuclear macrophages. Cell proliferation, which destroys blood cells and forms hypersplenism. ^[1]