Esophageal and gastric fundus varices and bleeding

　　1. Etiology

　　Esophageal and gastric fundus varices are the main clinical manifestations of portal hypertension. Portal hypertension is mainly caused by liver cirrhosis and is one of the main pathophysiological changes of liver cirrhosis. The direct consequence of portal hypertension is the establishment and opening of collateral circulation between the portal vein and the systemic circulation. The most clinically significant in the portal-systemic collateral circulation is the esophageal and gastric fundus varices. Due to the fact that the varicose veins in this area are easily affected by the increase in portal vein pressure; the negative pressure of the thoracic cavity causes an increase in venous return blood flow; the reflux of acidic substances in the stomach erodes the esophageal mucosa; and injuries caused by rough or hard food or alcohol consumption, etc., varices are prone to rupture and bleeding, and become the most common complication and cause of death in patients with liver cirrhosis and portal hypertension. In addition to varices, the other two major causes of upper gastrointestinal bleeding in liver cirrhosis patients are peptic ulcers and acute gastric mucosal lesions, which are also related to the increase in portal vein pressure to some extent. Studies have shown that bleeding rarely occurs when the portal vein pressure is below 2.65 kPa (27 cmH2O) or the hepatic venous pressure gradient is less than 1.6 kPa (16 cmH2O). Therefore, the main purpose of treating portal hypertension is to reduce portal pressure to control and prevent the first and recurrent bleeding in patients with esophageal and gastric fundus varices.

　　2. Pathogenesis

　　After the portal vein pressure increases, many collateral circulation is formed, especially at the lower esophagus and stomach base, but it can also occur at other parts of the stomach and intestines. The pressure in the varicose veins is directly affected by the portal vein pressure. When the portal vein pressure suddenly increases, the varicose veins can rupture, which is why they often rupture and bleed after exertion or vomiting. The continuous increase in portal vein pressure leads to an increase in pressure within the varicose veins, thinning of the vessel wall, an increase in vessel radius, and becomes the basic condition for rupture. It is generally believed that varicose veins with a portal vein pressure gradient (portal pressure minus inferior vena cava pressure) below 11 to 12 mmHg (1.466 to 1.6 kPa) will not rupture and bleed. The tissue support around the varicose veins is of great importance. Once the varicose veins reach a certain degree, if there is strong tissue support around them, they are not likely to rupture. However, the mucosal surface of the supporting tissue can be damaged due to local factors such as inflammation and erosion, which weakens the tissue support and makes it easier to rupture.

　　The tension of varicose vein walls is regulated by the interaction of various factors, which can be expressed by the following formula according to Laplace's law:

　　The tension of the varix wall = (P1 - P2) × r / w

　　In this formula, P1 is the pressure inside the varix, P2 is the pressure in the esophageal cavity, r is the radius of the varix, and w is the thickness of the varix wall. It can be seen that large varices and increased pressure inside the varices promote the increase in tension of the varix wall. According to the degree of varix.

　　If the varices reach the Ⅳ° degree, the wall is thin, and cherry red spots can be seen under endoscopy. Even if the pressure inside the varices is not very high, the risk of bleeding is still great. If the tissue support is not strong or the esophageal cavity is under negative pressure during inspiration, the risk of bleeding will be further increased. Therefore, when the tension of the varices reaches a highly dangerous level, any factor that increases portal pressure, or any defect in the surrounding supporting tissue, will promote the rupture of varices. In fact, these changes have a certain development process and are related to the course of the disease. About 1/4 of the cases will have hematemesis and/or black stools within 3 to 4 years after the diagnosis of liver cirrhosis.

　　Portal hypertension caused by non-cirrhotic intrahepatic diseases and extrahepatic factors can also lead to esophageal varices and rupture bleeding. The more obvious the esophageal varices, the greater the risk of bleeding, and the higher the recurrence rate.

　　Recently, histological studies have found that in the specimens of esophageal varices, there are many expanded channels under the epithelium. Under the electron microscope, these channels are bounded by atypical endothelial cells and are positive for factor VIII-related antigen staining. Moreover, these channels are consistent with the cherry red spots seen during endoscopic examination. It is believed that these channels are of great significance in the rupture and bleeding of varices.

　　Gastric varices are generally large and deep in location, and there are fewer cases of rupture and bleeding. However, once they rupture and bleed, the amount of blood loss can be very large.

　　Gingival, subcutaneous, and mucosal bleeding in liver cirrhosis patients is a common symptom. If there is significant gastrointestinal bleeding (vomiting blood and black stools), the main source of bleeding is the rupture of varices and portal hypertension-related gastric disease. The varices are mainly esophageal varices, but can also occur in other parts of the stomach or any part of the intestines. Large and rapid blood loss can cause immediate hemodynamic changes, rapid decrease in blood volume, reduced return blood volume, decreased cardiac output, decreased blood pressure, decreased pulse compression, increased heart rate, insufficient perfusion of organs and tissues throughout the body, oxygen deficiency, leading to functional and morphological damage, making the condition more complex.

　　Large blood loss reduces cerebral blood flow, causing the patient to become restless, indifferent, or unconscious. When cerebral blood flow decreases to 50%, these phenomena become very obvious, and hepatic encephalopathy may also occur.

　　Patients with portal hypertension often have three clinical manifestations:

　　1. Manifestations of the primary disease:90% of portal hypertension is caused by liver cirrhosis, and liver cirrhosis patients often have fatigue, weakness, decreased appetite, weight loss, and 10% to 20% of patients have diarrhea. The skin may appear dark and even black or with mild jaundice, subcutaneous or mucosal hemorrhagic spots, spider veins, palmar erythema, splenomegaly, and endocrine disorders, such as low libido, irregular menstruation (amenorrhea or excessive menstruation), and breast development in males.

　　2. Manifestations of portal hypertension:There are ascites and edema, varices on the abdominal wall and hemorrhoidal veins, and splenomegaly.

　　3. Bleeding and its secondary effects:Gingival, subcutaneous, and mucosal bleeding in patients with liver cirrhosis are common symptoms.

　　If there is significant gastrointestinal bleeding (vomiting blood and black stools), the main source of bleeding is the rupture of varices and portal hypertension-related gastric disease. The varices are mainly esophageal and gastric fundus varices, but they can also occur in other parts of the stomach or any part of the intestines. Large and rapid blood loss can cause immediate hemodynamic changes, rapid reduction in blood volume, reduced return blood volume, decreased cardiac output, decreased blood pressure, reduced pulse compression, increased heart rate, insufficient perfusion of organs and tissues in the body, hypoxia, leading to functional and morphological damage. The condition becomes more complex. After bleeding, through the body's regulatory function, sympathetic nervous system excitation occurs first, causing vasoconstriction of the capacitance vessels, and the blood circulation does not immediately undergo significant hemodynamic changes. If bleeding continues, vasoconstriction of the resistance vessels occurs, and peripheral skin temperature decreases, but the sympathetic nervous system excitation has an insignificant vasoconstrictive effect on the vascular system of the viscera (heart, brain, etc.), which allows a larger amount of circulating blood volume to be supplied to vital organs. When this compensatory effect cannot make the vascular bed adapt to the reduction in blood volume, the ventricular filling pressure decreases, the cardiac output decreases, the central venous pressure decreases, the heart rate accelerates, and the blood perfusion of organs and tissues is insufficient, followed by metabolic disorders, accumulation of acidic metabolic products, resistance vessels cannot maintain their high tension, and they no longer respond to adrenergic stimulation, causing increased capillary permeability, fluid leakage, and further hemodynamic changes, leading to severe tissue damage. Therefore, there may be arrhythmia, heart failure, and further deterioration of liver function, even jaundice, increased edema and ascites, and hepatorenal syndrome. The patient may be restless, indifferent, or unconscious, which may be caused by a decrease in cerebral blood flow due to a large amount of blood loss. When cerebral blood flow decreases to 50%, these phenomena become very obvious, and encephalopathy may also occur later.

　　In patients with bleeding, the wrinkles on the palm become pale when the fist is stretched after clenching, indicating a 50% loss of blood volume. If the patient experiences shock while lying flat, the blood volume loss is about 50%; if shock occurs only when standing, the blood loss is about 20% to 30%. If the patient's head is raised 75°, and the blood pressure drops by 20 to 30 mmHg after 3 minutes, or if the blood pressure and heart rate when the patient is lying flat are checked and compared with the results when standing, a decrease of 10 mmHg in blood pressure and an increase of 20 beats/min in heart rate are observed in the standing position, then the blood loss exceeds 1000ml. Therefore, the approximate blood loss can be estimated based on clinical symptoms.

　　After a large amount of bleeding, the spider nevus and liver palm can temporarily disappear, and the spleen can also shrink. After blood volume is replenished and the circulatory function is restored, they can recover.

　　It is crucial to actively and effectively treat liver disease, prevent the portal hypertension caused by liver cirrhosis, and the varices and bleeding in the esophagus and fundus of the stomach.

　　2. Treat gastric mucosal erosion, inflammation, or ulcers, and prevent the occurrence of esophageal-gastric fundus varices.

　　3. Abstain from alcohol consumption, reasonable nutrition, and pay attention to avoid using drugs that damage the stomach. For patients who have been diagnosed, appropriate reduction in labor intensity should be made to prevent the occurrence of complications, maintain health, and prolong life.

　　Patients often have varying degrees of anemia, but most are mild anemia. White blood cell count is reduced, and patients with hypersplenism have a decrease in all blood cells, but an increase in reticulocytes and an active bone marrow. Patients often have abnormal liver function, decreased serum albumin, increased serum globulin, and often appear albumin/globulin inversion, mild elevation of transaminases, prolonged prothrombin time. After a large hemorrhage, white blood cell count temporarily increases and returns to the original level after bleeding stops. It takes 6 to 24 hours (even 72 hours) for blood to be diluted, and hemoglobin, red blood cells, and hematocrit begin to decrease. Blood urea nitrogen increases and blood ammonia increases, making it easy to induce coma after bleeding.

　　1. Fiberoptic gastroscopy examination

　　It is the simplest and most effective examination method. Although examination after bleeding cessation is safe, it cannot see the active bleeding focus; however, when examined during bleeding, the blood often covers the focus, making it difficult to see clearly. Classen et al. summarized research data from the United States, United Kingdom, Germany, Switzerland, and Australia, and believed that early gastroscopy can make a definite diagnosis in 85% to 97% of cases. Chinese scholars' accumulated experience suggests that, except for patients with shock, severe cardiovascular and pulmonary diseases, and extremely exhausted patients, most patients can safely undergo gastroscopy. Currently, it is recommended to perform gastroscopy within 48 hours of bleeding to determine the location and nature of the bleeding focus.

　　Under normal circumstances, the esophagus inferior end observed by gastroscopy shows submucosal blood vessels centered at the cardia with a diameter less than 0.1cm, distributed in a radial pattern, uniform and orderly. During portal hypertension, the submucosal blood vessels become thickened, presenting as bead-like or earthworm-like prominences. The varicose veins near the esophagus inferior end and the cardia are in a ring-like prominence. If a blood blister-like prominence of about 0.2cm in size is seen at the center of the prominence, it indicates an impending hemorrhage. In addition, the varicose veins have reached the middle segment of the esophagus, with more than 2 varicose veins. The prominent varicose veins protrude into the esophageal lumen and cannot be flattened after inflation. The mucosa on the surface of the varicose veins is congested, with cherry red spots, all indicating an impending hemorrhage. When observing the gastric fundus veins, the head can be elevated by 15° to 20°, and a flushing tube can be inserted through the biopsy hole to flush clean, making it easier to observe. Although the degree of varicose veins in the stomach is more severe than that in the esophagus, the location is deeper, and the changes in the covering mucosa are not obvious, making gastroscopy easy to miss. Sometimes, large varicose veins can be misdiagnosed as tumors, and smaller ones are not easy to distinguish from mucosal folds. Therefore, for the diagnosis of gastric varices, gastroscopy is not as good as X-ray; for the examination of esophageal varices, gastroscopy is superior to X-ray. Okuda et al. compared the examination effects of gastroscopy and X-ray on gastric varices, and found that only 80% of the 46 cases of gastric varices found by X-ray could be correctly diagnosed by gastroscopy. We found that some patients with normal esophageal X-ray examination had esophageal varices detected by gastroscopy.

　　After the portal vein pressure increases, many collateral circulations are formed, and varices often occur in the esophagus and fundus of the stomach, and may also occur in other locations, or occur alone in other locations, such as the corpus, antrum, pylorus, and intestines. In a few cases, they can also occur in locations outside the digestive tract, such as the peritoneum, gallbladder, common bile duct, vagina, and bladder, and are called ectopic varices. Lebrec et al. believe that about 1% to 3% of patients with liver cirrhosis develop ectopic varices, and the incidence in patients with extraportal hypertension is much higher, reaching 20% to 30%, especially in those who have undergone abdominal or pelvic surgery, the incidence rate is significantly increased. Once these ectopic varices rupture and bleed, it is often difficult to determine the source of bleeding and the nature of the lesion, but they are equally life-threatening. When intestinal varices occur in the colon, they are most common below the hepatic flexure of the colon, and colonoscopy can determine the lesion and whether there is bleeding. Intestinal varices occurring in the small intestine are rare, and sometimes it is necessary to use small intestinal endoscopy or other methods during surgery to detect them.

　　Two, Vascular Angiography and Selective Vascular Angiography

　　If endoscopic examination fails, or if it is not possible to perform endoscopic examination due to the condition, vascular angiography should be considered. This method has almost completely replaced spleno-portal angiography and can detect the minimum bleeding rate of 0.5ml/min. If the bleeding rate exceeds this, contrast agent extravasation from the blood vessels can be seen on a series of X-ray films, and the bleeding location can be determined accordingly. Abnormal tortuosity of the hepatic artery can also be seen, and basic information about the portal vein, superior mesenteric vein, and splenic vein patency can be obtained. For patients with esophageal and gastric variceal bleeding, although the contrast agent has been diluted when it reaches the venous system, the phenomenon of contrast agent extravasating from varices can still be seen, especially suitable for small intestinal bleeding, with better results than other methods. If bleeding is too much and too fast, even with blood transfusion, it is difficult to maintain the stability of the circulatory state, and it is not possible to perform angiography. In addition, the contrast agent is hypertonic, which can cause hypertonic diuresis, and caution should be exercised for patients with renal insufficiency.

　　Three, Portal Vein Angiography

　　Currently, there are various methods of portal vein angiography, which can all show the condition of the portal vein system and its branches. Early liver cirrhosis may not show any abnormalities. As the condition progresses, portal vein dilatation, elongation, tortuosity, and a large number of collateral blood vessels filling, tortuosity, some resembling trees in the wind, when the portal vein or its branches outside the liver are blocked, narrowing or interruption at the blockage site can be seen, collateral blood vessels lead to the diaphragm, chest wall, or abdominal wall, and the area near the blockage gradually shows spongy changes due to collateral circulation, and the branches inside the liver are not clear.

　　A safe and reliable method is umbilical-portal vein angiography, through the umbilical vein catheter to the left branch of the portal vein, the range of portal vein imaging depends on the position of the catheter tip and the pressure of the contrast agent injection. During portal hypertension, increased pressure injection can cause retrograde blood flow of the portal vein blood, thus obtaining the image of the portal venous system and confirming the condition of collateral circulation.

　　Hepatic vein angiography and retrograde portal vein angiography, through the femoral or median cubital vein, the catheter is inserted into the inferior vena cava to reach the hepatic vein, the contrast agent is injected to observe the situation of the hepatic vein and its branches, and then the catheter is advanced to the embedded position, the contrast agent is injected to image the portal vein branches, hence the name 'embedded hepatic vein angiography' or 'retrograde portal vein angiography'. It is very valuable for the diagnosis of liver cirrhosis, which can understand the abnormalities of the portal venous system.

　　Percutaneous transhepatic portal vein angiography, which displays the portal vein, splenic vein, and portal-systemic collateral circulation well, but the operation technique is more complex and the safety is lower than other methods. Percutaneous puncture angiography to the omental vein during open surgery or laparoscopy may have good effects, but the patient may not be able to tolerate it.

　　Digital subtraction portal vein angiography via the arterial route, with the catheter placed in the splenic artery or superior mesenteric artery, the contrast agent is injected after which the portal venous system is imaged. The main observation includes the morphology of the portal vein and its branches, whether there is obstruction, the formation of collateral circulation, and the blood flow direction, which is very important for the staging of the disease, the selection of treatment plans, and the judgment of prognosis.

　　Four, X-ray examination of the chest

　　The abdominal X-ray film only shows the outline size of the liver and spleen, with increased left paravertebral shadow, which may be caused by the outward rotation between the aorta and the spine due to the expansion of the hemiazygos vein and the pleural reflection. When the collateral circulation adjacent to the esophagus is significantly expanded, similar shadow of mediastinal mass can appear on the chest film. If mediastinal X-ray tomography is performed, it can reveal the expansion of the azygos vein. During the barium meal examination of the esophagus and stomach, both dilute and concentrated barium should be prepared. Under fluoroscopy, the patient should swallow the barium while observing the esophageal movement and filling. The patient should change positions to observe the mucosal morphology from different angles. Then, a film of the esophagus should be taken at the end of inspiration. The normal esophageal mucosal image is arranged in a fine, elongated line pattern. Varicose veins are manifested as filling defects, most commonly seen in the lower third of the esophagus, which can also extend to the entire esophagus. It is often accompanied by varices of the gastric fundus, resembling a worm crossing the gastroesophageal junction to the gastric base. Some patients are only affected by the esophagus and not the stomach, while it is rare to have isolated gastric varices without esophageal varices. Generally, esophageal varices can be easily detected by X-ray barium meal examination. When varices are not obvious, an endoscopy is required to detect them. X-ray examination is superior to endoscopy for detecting gastric varices, especially with air-barium double contrast, which can reach a detection rate of over 80% for varices. The filling defects shown by varicose veins should be distinguished from mucosal folds. The anteroposterior film after air-barium double contrast is particularly clear. The varices of the gastric fundus sometimes appear lobulated, resembling a tumor. Portography can effectively differentiate them. Samuel once summarized the X-ray signs of gastric varices into 4 points:

　　1. Thick and tortuous folds like polyps, located on the large curvature and extending to the cardia.

　　2. Appearance of vesicular round areas in mucosal morphology.

　　3. Concurrent esophageal varices.

　　4. Enlarged spleen.

　　The collateral circulation of the stomach and esophagus is also affected by the increased portal pressure, and the esophagus is more affected by the negative pressure in the thoracic cavity, which may be the reason why esophageal varices are more common than gastric varices. Of course, even if varices are found by X-ray barium meal, it does not necessarily mean that there is bleeding.

　　X-ray double contrast barium study of the small intestine plays an important role in the diagnosis of small intestinal diseases. For cases of small intestinal varices and bleeding, it can be initially inserted into the small intestine using the Miller-Abbott tube, and the intestinal fluid is aspirated at regular intervals. Local barium enema can be performed at the site where blood-containing intestinal fluid is aspirated, which is helpful for diagnosis. However, it is not suitable for patients with acute massive bleeding to undergo small intestinal contrast, and selective arteriography should be preferred.

　　X-ray barium enema examination is of great value in the diagnosis of colonic lesions and bleeding, especially low-pressure barium enema, which can clearly show the fine changes of colonic mucosa.

　　Fifth, radioactive nuclide scanning:For those with slight bleeding, when the bleeding rate is 0.1ml/min, it is suitable for radionuclide scanning. Use 99mTc-labeled patient's red blood cells for intravenous injection. The half-life of 99mTc in blood is about 3 minutes, and most of it is rapidly cleared by the reticuloendothelial system. The labeled red blood cells overflow at the bleeding site, forming a hyperchromic area, from which the bleeding site can be judged. This method has a long monitoring time, but it can appear false positives and mislocation, and it is necessary to combine with other examinations for comprehensive analysis to determine the diagnosis.

　　It is required to have food with sufficient calories, high in protein, sugar, and rich in vitamins. Generally, the total calorie intake for an adult is about 35-40kCal per kilogram of body weight per day, and the protein requirement is slightly higher than that of the general population, at 1.5-2g/kg body weight per day. The supply should be adjusted according to the patient's tolerance. Patients with precursors of hepatic encephalopathy should limit protein intake, and the intake can gradually increase as the condition improves. If the daily protein intake is less than 30g, it can hinder the regeneration of liver cells, so protein intake should be reduced or suspended.

　　Maintaining the content of glycogen in liver cells is beneficial to protecting the liver's detoxification function, so liver cirrhosis patients need an adequate amount of carbohydrates, but not too much to avoid fat accumulation, which may even lead to fatty liver. The amount of fat in the diet is generally maintained at 30-50g/d. Liver cirrhosis patients are prone to deficiencies in vitamins A, B1, B2, C, and E, and should be supplemented.

　　In addition, zinc, manganese, selenium, and other elements should be appropriately supplied in the diet of liver cirrhosis patients. Foods should be chosen that are low in roughage, soft, and easy to digest, and alcohol should be avoided.

　　First, treatment

　　1. Basic treatment:Esophageal varices at the fundus of the stomach itself indicates the presence of portal hypertension, and 90% of portal hypertension is caused by liver cirrhosis, so the focus of treatment should be on the liver disease.

　　(1) Rest: There should be enough time for bed rest to reduce physical exertion in patients, improve liver circulation, and promote liver tissue regeneration. Work and life should be arranged according to the severity of the disease. Patients with mild disease can engage in general work, avoiding heavy physical or mental labor, while those with severe disease must remain in bed.

　　(2) Diet: requires a diet that is sufficient in calories, high in protein, high in sugar, low in fat, and rich in vitamins. The total daily calorie intake for an average adult is generally 35-40kCal per kilogram of body weight. The protein requirement is slightly higher than that of the general population, with a daily supply of 1.5-2g/kg body weight. However, it should be adjusted according to the patient's tolerance. Patients with preclinical signs of hepatic encephalopathy should limit their protein intake, which can be gradually increased as the condition improves. If the daily protein intake is less than 30g, it can hinder the regeneration of liver cells. Therefore, during the period of reducing or suspending protein intake, intravenous infusion of human serum albumin (albumin), plasma, or fresh whole blood should be administered. Liver disease patients have different tolerance levels to proteins in various foods, with better tolerance to milk and casein than to meat proteins, producing less ammonia after eating. Plant proteins contain less methionine, aromatic amino acids, and thiols, which can change the intestinal flora, reducing ammonia production. Carbohydrates are the most important source of energy in the body's metabolic process and are also important components for the synthesis of glycoproteins, antibodies, enzymes, and cell structure. Maintaining the content of glycogen in liver cells is beneficial to protecting the liver's detoxification function, so liver cirrhosis patients need an adequate amount of carbohydrates, but not too much to avoid fat accumulation, which may even lead to fatty liver. The amount of fat in the diet is generally maintained at 30-50g/d. Liver cirrhosis patients are prone to deficiencies in vitamins A, B1, B2, C, and E, and should be supplemented. In addition, zinc, manganese, selenium, and other elements should be supplied appropriately. The diet of liver cirrhosis patients should be low in roughage, soft, and easy to digest, avoiding rough and hard foods, and alcohol should be avoided.

　　(3) Enhancing immunity: Human blood gamma globulin, transfer factor, immunoribonucleic acid, thymosin (thymic peptide), poria polysaccharide, or香菇多糖 can be selected.

　　(4) Protecting the liver: There are many types of liver-protecting drugs available, but their efficacy is not确切. Usually, vitamin B complex, C, E, and folic acid, as well as inosine, glucuronic acid (glutathione), coenzyme A, and ubiquinone (coenzyme Q10) are used. To alleviate liver fibrosis, colchicine 1mg/d can be used for 5 days a week, for 5 to 10 years, which can improve symptoms without significant adverse reactions. There are also cases where malotilate has been used to improve the condition. Traditional Chinese medicine such as Astragalus, Angelica sinensis, Bupleurum chinense, Salvia miltiorrhiza, Radix paeoniae rubra, and Cordyceps sinensis have certain effects. However, it is necessary to pay attention to the adverse drug reactions in long-term treatment and avoid all factors that may damage the liver.

　　2. Treatment of the etiology:For patients with portal hypertension, if caused by extrinsic factors, as long as the primary disease is not fatal, such as tumor compression or tumor thrombus blocking the portal vein or hepatic vein, it is expected that through the active collaboration of surgeons and internists, a cure can be achieved or the mortality rate can be reduced to the lowest. If caused by intrinsic factors, a few patients can eliminate the cause, such as schistosomiasis can be treated with praziquantel, nithiocyanamine, and other drugs; alcohol-induced cases should abstain from alcohol; while the majority of portal hypertension is caused by liver cirrhosis related to hepatitis virus, which is difficult to eliminate clinically. Generally, α-interferon, arabinoside, monophosphoryl arabinoside, acyclovir (acyclovir), polyinosinic-polycytidylic acid, and ribavirin (virazole) can be used, and they can be used in combination with immunomodulatory drugs.

　　3. Reducing portal pressure:The occurrence of portal hypertension is mainly determined by portal blood flow and vascular resistance, both of which are influenced by many factors. For example, sympathetic nervous system activation and catecholamines can cause vasoconstriction of small arteries; VIP, glucagon (pancreatic glucagon), and gastrin can dilate visceral vessels; acidic metabolites can relax the pre-sinusoidal vascular sphincter, reducing resistance; an increase in blood glucose can directly reduce the resistance of visceral vessels. The liver itself also has an autonomous regulatory mechanism; when the blood flow of the hepatic artery increases, the portal resistance increases while the blood flow decreases; when the portal blood flow increases, the blood flow of the hepatic artery decreases. Therefore, the portal system has a great adaptive capacity.

　　The treatment of portal hypertension with medication is to adjust the constriction and dilation of blood vessels by the drug's action, or to cause the lower esophageal sphincter to contract, in order to change blood flow and vascular resistance, achieving the goal of reducing portal pressure. Bosch once proposed that the ideal drug for the treatment of portal hypertension should be effective for each patient, without contraindications and adverse reactions, not requiring complex equipment or special medical supervision, well-absorbed orally, can be used for a long time, not metabolized by the liver, and not excreted through the bile duct. Unfortunately, such a drug is still difficult to obtain at present.

　　(1) Vasopressin (vasopressin): It has been used clinically for over 30 years. It mainly causes vasoconstriction of the mesenteric artery and other visceral vessels, reducing the blood flow entering the portal vein, thereby lowering portal pressure. During bleeding from variceal rupture, intravenous infusion is often used, with an initial dose of generally 0.2 U/min and a maintenance dose of 0.1 U/min. The effects of intravenous or arterial administration are similar, with a hemostatic effect of about 44%-71%. Comparative studies have shown that 3 of 29 patients required surgery within 24 hours after drug administration, while 10 of the 31 patients treated with placebo needed surgical treatment. The adverse reactions of vasopressin are mainly strong constriction of the systemic circulation, which can raise blood pressure and even cause intracranial hemorrhage; due to coronary artery constriction, the posterior load on the heart increases, leading to myocardial ischemia, which can cause arrhythmias and even myocardial infarction. Vasopressin can activate the fibrinolysis system, hinder hemostasis, and have antidiuretic effects. It cannot be taken orally, but intraperitoneal injection has a hemostatic rate of 91.3%.

　　Triglycyl-lysine vasopressin is artificially synthesized, which is slowly released into lysine vasopressin after enzymatic cleavage in the body. It has a longer biological half-life, less systemic effect, no serious adverse reactions to the heart, does not activate the fibrinolysis system, can be infused in large quantities, and has a good hemostatic effect. Generally, it is administered intravenously at 2 mg every 4-6 hours. Or start with 2 mg, followed by 1 mg, every 4 hours, with a total dose of 10 mg within 32 hours, which can reduce portal pressure.

　　Octapeptide vasopressin and glucose vasopressin are also derivatives of vasopressin and can be selected for use.

　　(2) Somatostatin and its analogs: Somatostatin can inhibit the secretion of growth hormone and most gastrointestinal hormones, reducing visceral blood flow. It is metabolized by the liver and other organs, with a plasma half-life of 2-4 minutes. In patients with liver cirrhosis, intravenous infusion of 2.5-7.5 mg/min can progressively reduce the blood flow of the hepatic artery, but increasing the dose does not increase this effect. After intravenous injection of 0.5-1 mg/kg, due to the constriction of the mesenteric artery, the portal pressure is significantly reduced. The effect of somatostatin on reducing the blood flow of the azygos vein is stronger than that of vasopressin, and this effect is more persistent than the effect of reducing portal pressure. Studies by Kravetz et al. and Zhang Darong et al. show that in terms of controlling esophageal variceal bleeding, somatostatin and its analogs are similar to vasopressin, but they have much fewer adverse reactions than vasopressin.

　　Recent research shows that octreotide (Octreotide) or octreotide (Sandostatin) can cause visceral vasoconstriction, reduce portal trunk blood flow by 25% to 35%, and decrease portal pressure by 12.5% to 16.7%. The dosage is: initially with 100μg, followed by 25μg/h intravenous infusion for 24 to 48 hours, and the dose can be appropriately increased if necessary. The hemostasis rate for esophageal variceal bleeding is 70% to 87%, and the hemostasis rate for peptic ulcer and erosive gastritis is 87% to 100%. In a few cases, gastrointestinal reactions such as nausea, abdominal pain, and increased frequency of bowel movements may occur after taking the medication.

　　(3) Beta-blockers: After oral administration of propranolol (Propranolol), cardiac output can decrease, visceral blood vessels can constrict, portal blood flow can decrease, and portal pressure can decrease. Studies have shown that when the dose of propranolol reduces heart rate and cardiac output by 25%, portal blood flow can decrease by 34%, portal pressure can decrease by 25% to 35%, and the blood flow in the azygos vein can decrease by 32%. Although portal blood flow decreases and pressure decreases, the blood flow into the liver remains relatively constant due to the relative increase in hepatic arterial blood flow. Garcia-Tsao et al. and Groszmann's research on patients with portal hypertension due to alcoholic cirrhosis suggests that even with increased doses of propranolol, 20% of patients do not see a decrease in portal pressure, which may be related to increased portal resistance. Ferrari et al. believe that if patients can tolerate propranolol, it can prevent the first variceal bleeding in patients with compensated cirrhosis. Lebrec et al.'s research indicates that at a dose that reduces heart rate by 25%, propranolol can prevent the recurrence of esophageal variceal bleeding in Child-Pugh A patients. Prospective randomized controlled studies by Grace et al. and Pagliaro et al. have all shown that beta-blockers can effectively reduce portal pressure and variceal pressure, and reduce the blood flow in varices. When the hepatic venous pressure gradient is below 12mmHg, varices do not bleed, thereby reducing fatal bleeding and mortality. Long-term use of beta-blockers does not increase the mortality rate of liver failure, and the preventive effect on bleeding in patients with a high risk of esophageal variceal bleeding is significant. For patients with moderate or severe varices or with red signs, beta-blockers are indicated, but they should not be used in patients with advanced liver cirrhosis or heart rate less than 60 times/min. It must also be noted that the medication should not be discontinued abruptly to avoid a rebound in portal pressure.

　　The dose of propranolol is 20-30mg, taken 2-3 times a day, and the dose can be increased to 80-100mg, 2-3 times a day thereafter. This medication is well absorbed orally and can be taken for a long period, with the treatment duration lasting from 0.5 to 2 years. The drug is metabolized by the liver, and liver and kidney function should be monitored. It is contraindicated in patients with heart failure, bronchial asthma, and unstable diabetes.

　　Oxhydroxymetazoline is a non-selective beta-blocker, with effects similar to those of propranolol. It is not metabolized in the body and is excreted unchanged by the kidneys. The initial dose is 40 to 80mg/day, and the maintenance dose is 80 to 240mg/day. Atenolol (amylxin) and metoprolol (metoprolol) are both well absorbed orally, are not metabolized by the liver, and do not cause beta2 receptor blockade, thus they can be used as alternatives.

　　(4) Nitroglycerin: It has an inhibitory effect on myofibroblasts around the fibrous septa and sinusoids in the hardened liver, reducing the intraportal resistance of liver blood flow. It is usually taken sublingually at a dose of 0.4mg, as its half-life is short, it needs to be taken every 15 to 30 minutes to maintain its effect. A 2% nitroglycerin patch can be absorbed continuously through the skin, extending the duration of action. Isosorbide dinitrate (disodium isosorbide dinitrate) is a long-acting vasodilator. Mills et al. advocate its combined use with prazosin (alpha-receptor antagonist), with a reduction of 17% in portal pressure gradient after oral administration for 3 weeks and 8 weeks, while there was no significant decrease in cardiac output, but orthostatic hypotension may occur. It has been used to add 1ml (10mg) of 1% nitroglycerin to 400ml of normal saline and slowly infused intravenously at a rate of 15 to 20 drops/minute, which can reduce the portal vein pressure in liver cirrhosis by 24.7%, and reduce the extraportal portal hypertension by 27.3%.

　　(5) Calcium channel blockers: These drugs can relax myofibroblasts, reduce portal blood flow resistance within the liver, lower portal vein pressure, and improve the ability of albumin to diffuse into the vascular interstitial space, thus enhancing the liver microcirculation. Verapamil, nifedipine (nifedipine), diltiazem (thiazide), cilostazol (cerebral ginseng), and hamamelisine (stephania tetrandra) belong to this class of drugs, among which hamamelisine also has the effect of inhibiting liver fibrosis.

　　(6) Serotonin receptor antagonists: In liver cirrhosis, the systemic circulation is sensitive to serotonin, which can increase portal vein vascular resistance. Ketanserin can dilate the portal vein bed and reduce portal vein pressure. In clinical studies, Hadongue et al. administered 10mg ketanserin intravenously to 11 patients with liver cirrhosis and measured systemic and visceral hemodynamics before and after injection. It was found that the mean arterial pressure decreased by 11.9%, with the maximum effect at 5 minutes after administration, which was related to the severity of liver cirrhosis. The cardiac index and systemic vascular resistance did not change, the wedge pressure in the hepatic vein decreased by an average of 13.7%, the hepatic venous pressure gradient decreased by an average of 22.5%, and the blood flow in the azygos vein decreased by an average of 26.7%. These phenomena were not related to the decrease in arterial pressure, and the liver blood flow remained unchanged.

　　（7）Angiotensin-converting enzyme inhibitors (ACEI): Captopril (captopril) is an example. It can inhibit the conversion of angiotensin to its active form, causing the vascular resistance to decrease and the portal pressure to drop. The usual dose is 25mg, three times a day, taken orally. Although captopril can lower blood pressure, it is rarely seen to cause a continuous decrease in blood pressure in people with normal blood pressure. Currently, the second and third generations of ACEI are already being used in clinical practice.

　　（8）Combination therapy: Due to the adverse effects of vasopressin, it can be combined with vasodilator drugs to dilate the portal vein and sinusoids, thereby reducing the resistance within the liver. Nitroglycerin is a powerful venous dilator and also slightly dilates arteries, reversing the adverse effects caused by vasopressin and reducing the increased portal resistance caused by vasopressin, thereby enhancing its effect in reducing portal pressure. When combined with vasopressin, the dosage of nitroglycerin should be maintained to keep systolic pressure above 90mmHg. Therefore, the combination of vasopressin and nitroglycerin is the first-line therapy for the treatment of acute variceal hemorrhage. Other vasodilator drugs can also be combined with vasoconstrictor drugs.

　　Recently, Li Junqian and others reported that by inserting three catheters into the bilateral femoral arteries, the tips of the catheters were inserted into the proper hepatic artery, superior mesenteric artery, and inferior mesenteric artery respectively, and phenylephrine, nitroglycerin, and posterior pituitary extract were administered. As a result, in 32 cases of variceal hemorrhage, 22 cases achieved hemostasis within 8 hours, 9 cases within 24 hours, and 1 case was ineffective. The effect was significantly better than that of 31 cases treated with posterior pituitary extract via the superior mesenteric artery and 24 cases treated with phenylephrine and posterior pituitary extract via intravenous infusion. The satisfactory results were achieved through the 3-tube interventional therapy using dilating and constricting vascular drugs, but it requires special equipment conditions and catheterization techniques, making it difficult to popularize.

　　（9）Medications that increase the pressure of the lower esophageal sphincter: The hemostatic effect of vasopressin on variceal hemorrhage may be partly related to the contraction of the esophageal smooth muscle, which compresses the varices. Lunderquist et al. demonstrated by angiography that some drugs can selectively increase the pressure of the lower esophageal sphincter, causing esophageal muscle contraction, and reducing the blood flow into the varices. Mastai et al. studied 33 cases of portal hypertension in liver cirrhosis and found that metoclopramide (Antivert) and domperidone (Motilium) reduced the blood flow in the azygos vein by 11.5% and 15.6% respectively, while the control group with placebo showed no change. It is believed that the two drugs reduce the blood flow in the azygos vein due to their selective action on the lower esophageal sphincter.

　　4. Hemostatic agents:Common hemostatic agents include vitamin K, carbacrol (Anloc blood), 6-aminohexanoic acid, aminomethylbenzoic acid (hemostatic acid), thrombin, Yunnan Baiyao, and raw rhubarb powder, etc. To correct coagulation mechanism disorders, dried thrombin complex 200 to 400U can be used for intravenous drip, 1 to 2 times a day, and the dose should be reduced after hemostasis for 2 to 3 days. Alternatively, batroxobin (Reptilase) can be used, which is a coagulation enzyme extracted from the venom of the Brazilian rattlesnake and has the effects of thrombokinase and thrombin. It only acts locally at the site of vascular damage and does not cause intravascular coagulation. For bleeding patients, 1ku can be injected intravenously and intramuscularly, and for severe cases, 1ku can be injected intramuscularly 6 hours later, and then 1ku should be injected intramuscularly every day for 2 to 3 days, with a hemostasis rate of over 80%.

　　5. Blood transfusion:For patients with large blood loss, it is urgent to supplement the blood volume. It is best to transfuse whole blood, and the amount and speed of blood transfusion depend on the amount and speed of blood loss. A simple estimation method is the tilt test. If the heart rate increases by 30 beats/min after tilting (elevating the upper body) for 3 minutes, about 500ml of blood needs to be transfused; if shock occurs when sitting up, 1000ml of blood needs to be transfused; if shock occurs when lying flat, about 2000ml of blood needs to be transfused. The speed of blood transfusion can be indicated by systolic blood pressure. When the systolic blood pressure is 90mmHg, 500ml of blood should be transfused within 1 hour; when the blood pressure drops to 80mmHg, 1000ml of blood should be transfused within 1 hour; if the systolic blood pressure drops to 60mmHg, 1500ml of blood should be transfused within 1 hour. Of course, this estimation method is not accurate, and it also depends on whether the patient's circulatory state becomes stable after blood transfusion. If the systolic blood pressure rises, the pulse pressure reaches 30mmHg, the pulse rate slows down and becomes strong, thirst is relieved, and irritability is no longer present, the limbs become warm, and urine output increases, indicating that the blood volume has been restored. The shock index (pulse rate/systolic blood pressure) reflects the loss and recovery of blood volume. A shock index of 1 indicates a blood volume loss of 20% to 30%, and greater than 1 indicates a blood volume loss of 30% to 50%; if the index drops to 0.5 after blood transfusion, it indicates that the blood volume has been restored.

　　For the rescue of patients with severe bleeding, a high-position great saphenous vein incision should be used, and a larger catheter should be inserted into the inferior vena cava to ensure the input required, and the central venous pressure should be monitored at all times. If the central venous pressure returns to normal after blood transfusion while the blood pressure does not rise, attention should be paid to correct myocardial dysfunction and acidosis.

　　Due to the poor hemostatic ability of blood stored for a long time in the blood bank, the content of blood ammonia is also high. When a large amount of blood is transfused, at least half should be fresh blood (within 3 days of storage in the blood bank), and calcium should be supplemented appropriately.

　　If the circulatory state cannot be stabilized even with large and rapid blood transfusion, then arterial pressurized transfusion should be used.

　　When varicose vein bleeding occurs, part of the blood flows downward to the intestines, of which 75% of the water can be absorbed. The blood becomes diluted and the hematocrit decreases 6 to 24 hours after bleeding, at this time red blood cells should be transfused, and the blood volume should not be excessively supplemented, because for every 100ml of blood volume increase, the portal pressure can rise by 1.4±0.7cmH2O, and at the same time, it will increase the cardiac workload.

　　6, Balloon Compression for Hemostasis:For patients who continue to bleed after active treatment, to gain time for surgical preparation, balloon compression for hemostasis can be used, commonly using Sangstaken-Blakemore tube (SBT) or the modified type with 4 tubes; if it is confirmed to be gastroesophageal varices, it is better to use the Linton-Nachlas tube with a larger stomach balloon capacity. If the patient refuses surgery or cannot tolerate surgery, balloon compression should not be used because this method can only stop bleeding temporarily, with an overall hemostasis rate of about 40% to 60%, a recurrence rate of 6% to 60%, and an overall mortality rate of 74% to 90%, which cannot improve the prognosis and can cause many serious complications, even death (2% to 22%).

　　7, Sclerotherapy:For patients with variceal bleeding, sclerotherapy is one of the commonly used therapies, especially for esophageal variceal bleeding, with a success rate of controlling bleeding over 80%, while it cannot be used for gastroesophageal varices. Since sclerotherapy does not directly affect the blood perfusion of the entire liver or liver function, its indications are relatively broad. Over the years, many clinical experiences have been gained, but complications and recurrence rates are still issues that should be paid attention to. Conn and others believe through comparative studies that sclerotherapy cannot improve survival rates and is only a temporary hemostatic measure, and portal hypertension-related gastric disease may actually increase after sclerotherapy. There is also controversy about using sclerotherapy as a preventive measure for bleeding. Yu Zhonglin and others recently reported a method of combining endoscopic sclerotherapy and ligation therapy to treat 12 patients with esophageal varices, with sclerotherapy followed by ligation, where the red sign was significantly reduced after one treatment, the varices became thinner and flatter after two treatments, 83.3% of the varices disappeared, and it is considered a safe therapy. Wu Yunlin and others reported that octreotide (octreotide) can reduce the pressure of esophageal varices and reduce bleeding from the injection site of the sclerosing agent. Wen Liming and others used endoscopic ligation of esophageal varices, with 55 patients having a total of 193 varices, except for 8 varices with a diameter

　　8, Interventional Radiological Treatment

　　(1) Percutaneous transhepatic portal vein embolization (PTO): Percutaneous puncture of the liver to the intrahepatic portal vein branches, and then selectively inserting a catheter into the胃冠状静脉 or 胃短静脉, using embolic materials to occlude the vessels to achieve the purpose of stopping variceal bleeding. The embolic material depends on the size of the vessel, with a diameter

　　(2) Percutaneous transcatheter splenic artery embolization: Indicated for cases of liver cirrhosis with portal hypertension and splenic hyperactivity, without surgical conditions, or for those who cannot control variceal bleeding with other treatments, or for patients with refractory ascites. Goldman treated 12 patients with upper gastrointestinal bleeding due to portal hypertension with conventional treatment being ineffective, and switched to splenic artery embolization, where all bleeding stopped and the short-term effects were good. Zhu Juren and others treated 5 cases of esophageal variceal bleeding with splenic artery embolization, with one case experiencing rebleeding after 1 year and the rest without recurrence. Postoperative abdominal pain and pulmonary complications may occur, but there have been no reported deaths. Splenic artery embolization therapy is contraindicated for patients with severe jaundice, peritonitis, and obvious bleeding tendency.

　　(3) Transjugular Intrahepatic Portosystemic Shunt (TIPS): This is a new technology developed in recent years, mainly used for the treatment of variceal bleeding due to portal hypertension, and can also treat refractory ascites and portal hypertension caused by various reasons. The clinical application effect is significant, receiving wide attention, and the number of foreign users is increasing. Sanyal reported that in 29 cases of acute esophageal-gastric fundus variceal rupture bleeding, all patients' bleeding was controlled after TIPS treatment. Hauenstein treated 262 patients with portal hypertension due to liver cirrhosis, more than 70% were Child B and C class, with a success rate of 98%, the portal pressure decreased by an average of 50%; follow-up (16±6) months, the recurrence rate was 10%. Crecelius et al. reviewed relevant literature data, among 652 cases of TIPS treatment, the success rate was 92% to 100%, the hemostasis rate of acute bleeding was 85.7% to 96.6%, the recurrence rate was 5.5% to 15.1%, and the 30-day mortality rate was 3.6% to 19.6%. Zhang Jinshan reported that in 16 cases treated with TIPS, the portal pressure decreased from (3.98±0.24) kPa [(29.5±2) mmHg] to (2.4±0.16) kPa [(18±1.2) mmHg], the disappearance rate of varices was 93%, and 4 cases with ascites disappeared after surgery. Wang Maoqiang et al. treated 102 cases with TIPS, the results were: a success rate of 92.2%, the portal pressure decreased from (3.97±0.44) kPa to (2.3±0.34) kPa [(17±3.8) mmHg], the main portal blood flow velocity increased from (14±4.5) cm/s to (46.5±14.5) cm/s; 81 cases were followed up for 3 to 18 months (average 8.5 months), 6 cases had stenosis of the shunt, 3 cases were blocked, 5 cases recanalized successfully; the incidence rate of complications was 0.5% to 3%, severe complications included portal and hepatic artery injury, hepatic capsule rupture leading to massive intra-abdominal hemorrhage, and injury to larger bile ducts and gallbladder. Once identified, they should be repaired in a timely manner. Wu Xingjiang et al. used self-made stent for TIPS treatment in 60 cases, with a success rate of 94.5%, disappearance of coronary vein and esophageal varices after surgery, increased portal blood flow, but 18.2% had complications, 1 case of rebleeding, 1 case of liver function failure, and a mortality rate of 5.5%.

　　The clinical application of TIPS is still in the development stage. With the improvement of instruments and the mastery of technical operations, complications will gradually decrease. How to prevent channel stenosis and occlusion, and reduce the incidence of encephalopathy, remains to be further studied.

　　9. Surgical Treatment:Patients with portal hypertension variceal bleeding who have been treated actively for more than 24 hours and still have a large amount of bleeding, with clear consciousness, no jaundice or only mild jaundice, bilirubin

　　Each type of surgery has its advantages and disadvantages. Recently, some people have combined the use of shunt and ligation surgery to achieve satisfactory results. The effect of shunt surgery depends on the size of the anastomosis. A larger anastomosis results in a larger shunt volume, significant reduction in portal vein pressure, good immediate hemostasis, but often leads to liver failure; a smaller anastomosis can maintain a part of the portal vein blood flow to the liver, which is beneficial to maintain liver cell function, reduce blood ammonia, but has a poor effect on reducing portal vein pressure. Liu Chuanshou et al. believe that the optimal anastomosis size is 0.8 to 0.9 cm. Splenorenal shunt can improve hypersplenism, but the shunt volume is small, the effect of reducing portal vein pressure is poor, and the anastomosis is prone to thrombosis. Distal splenorenal shunt can ensure portal vein blood flow to the liver, with a low incidence of postoperative encephalopathy and rebleeding rate, but cannot reduce the sinusoidal pressure. For patients whose splenic vein is not suitable for anastomosis, portal vein occlusion, or patients who have had their spleen removed, enteral or coronary venous shunt can be performed. Over the years, although surgical methods have been improved, the effect of shunt surgery is not very ideal. To avoid encephalopathy after shunt surgery, for critically ill patients or those not suitable for shunt surgery, various ligation, transection, or transection of blood vessels are used to achieve good immediate hemostasis, rarely resulting in encephalopathy, which is beneficial to maintain or restore liver function. Recently, the combined use of shunt and ligation surgery has achieved good results. For patients with portal hypertension syndrome who have bled or have bleeding signs, shunt surgery combined with ligation surgery should be used first.

　　10. Liver Transplantation:For patients with advanced liver cirrhosis and portal hypertension syndrome for whom other treatments are ineffective, the only way to save life is liver transplantation. The transplantation technology has gradually matured, and the 1-year survival rate can reach 44% to 60%, even higher, and the 3-year survival rate can reach over 40%. Therefore, patients with advanced liver cirrhosis who have no hope of treatment should make the decision to undergo liver transplantation treatment.

　　II. Prognosis

　　Patients with esophageal varices and bleeding due to liver cirrhosis have poor prognosis. The mortality rate for the first bleeding is 40% to 84%, and the 5-year survival rate of survivors is very low, so it is worth paying attention to.