Portal hypertension gastropathy

　　First, etiology

　　1. Mucosal circulation disorder:Normal gastric mucosa can concentrate HCl a million times, maintaining a high concentration gradient between the gastric lumen and the gastric wall. The gastric mucosa relies on abundant blood flow to clear HCl entering the gastric wall. After the increase in portal pressure, there is a change in hemodynamics, submucosal blood vessel dilation, arteriovenous shunting, varicose veins, venous congestion, increased submucosal blood flow, and a reduction in mucosal blood supply, causing ischemia and hypoxia.

　　2. Liver Function Status:18.6% of patients with normal or slightly impaired liver function develop acute gastric mucosal lesions and bleeding, and 55.5% of patients with severe liver dysfunction do so.

　　3. Bile Reflux:During portal hypertension, gastrointestinal congestion and high gastrinemia inhibit the regulation of the pyloric sphincter and Oddi sphincter by cholecystokinin and secretin, causing relaxation, and bile and duodenal contents reflux into the stomach, causing bile reflux gastritis.

　　4. Endotoxemia:Patients with portal hypertension often have sepsis, which is more common in patients with liver dysfunction, such as 66% to 100% with sepsis in acute liver failure; the incidence rate of encephalopathy is about 93%; and the incidence rate of gastrointestinal bleeding is 53.8%.

　　5. Infection:There is hepatitis B virus in the gastric mucosal epithelial cells, which forms antigen-antibody complexes and deposits in the microvascular endothelial cells, causing an inflammatory reaction and destroying the gastric mucosal barrier.

　　6. Stress reaction:Severe patients, including severe liver patients, often have stress reactions, causing a reduction in gastric mucosal blood flow, ischemia and hypoxia, and a series of secondary pathophysiological changes.

　　Second, pathogenesis

　　1. Mucosal circulation disorder:Normal gastric mucosa can concentrate HCl a million times, maintaining a high concentration gradient between the gastric lumen and the gastric wall. The gastric mucosa relies on abundant blood flow to clear HCl entering the gastric wall. After the increase in portal pressure, there is a change in hemodynamics, submucosal blood vessel dilation, arteriovenous shunting, varicose veins, venous congestion, increased submucosal blood flow, and a reduction in mucosal blood supply, causing ischemia and hypoxia. Experimental studies by Womack et al. and Nishiwaki's study on patients with liver cirrhosis and controls have confirmed this change. Ischemia and hypoxia of the gastric mucosa increase permeability, causing edema and bleeding; increased reverse diffusion of HCl increases the pH value of the gastric wall; the reduction in the mucosal generation and secretion of mucus decreases the barrier function of the mucosa, which can be depleted and lose its barrier function during ischemia; mucosal ischemia causes metabolic disorders, reduced oxidative phosphorylation, energy deficiency, and at the same time, vitamin deficiency, decreased albumin, decreased mucosal resistance, reduced mucosal epithelial cell proliferation, and increased destruction, which cannot maintain its integrity.

　　Recently, some scholars have noticed that the incidence of portal hypertension-related gastric mucosal lesions increases after esophageal varices are treated with sclerotherapy. This may be due to increased esophageal variceal resistance after sclerotherapy, which changes hemodynamics, causing further expansion of submucosal blood vessels, increased blood flow, and further reduction in mucosal blood flow.

　　2. Liver Function Status:18.6% of patients with normal liver function or mild liver damage develop acute gastric mucosal lesions and bleeding, while the rate reaches 55.5% in patients with severe liver dysfunction. Sato reported on 24 cases of liver cirrhosis, with similar results. When liver function is impaired, metabolic capacity decreases, such as the reduction in the inactivation of histamine in the liver, resulting in an increase in histamine content in portal and peripheral blood, which promotes gastric acid secretion. Pepsin acts under acidic conditions, and when ischemia and acid are present, it can enhance the autodigestion of the mucosa, damage the mucosa, and lead to ulcer formation. The plasma gastrin concentration in patients with liver cirrhosis is higher than that in the control group; the basal concentration of plasma gastric inhibitory peptide is slightly lower than that in the control group, but it is significantly higher than that in the control group after eating. Orcoff et al. found in experimental liver cirrhosis animals that the intestines secrete a gastrointestinal phase hormone that promotes gastric acid secretion. The incidence rate of gastric ulcers in patients with portal hypertension is high, mainly related to hypergastrinemia. The remnants of gastrin with physiological activity (G4, G5) are cleared by the liver, and the clearance is reduced during liver cirrhosis. At the same time, somatostatin and glucagon lose their negative regulatory effect on gastrin, and they can also slow down the movement of the stomach, extending the emptying time, aggravating mucosal damage. Moreover, somatostatin reduces visceral blood flow, and glucagon increases local metabolism and oxygen consumption, further reducing the defensive capacity of the gastric mucosa.

　　3. Bile Reflux:During portal hypertension, gastrointestinal congestion and hypergastrinemia inhibit the regulation of cholecystokinin and secretin on the pyloric sphincter and Oddi sphincter, causing them to relax, and bile and duodenal contents reflux into the stomach, leading to bile reflux gastritis. Huang Ziping found 13 cases in 57 cases of portal hypertension, and Chen Shengjian et al. found 8% of 138 cases of bile reflux gastritis caused by liver disease. The duodenal contents contain bile salts, hemolytic lecithin, and pancreatic enzymes, which damage the gastric mucosa when refluxed into the stomach, change the characteristics of the mucus layer, cause the disintegration of epithelial cells, and increase H+ reverse diffusion. Taurine bile acid can inhibit the activity of Na, K-ATPase, hinder cellular metabolism, and can completely inhibit the activity of Na, K-ATPase at a concentration of 8mmol. Gastric acid also aids in the absorption of bile salts, accelerates mucosal damage, and even cell collapse.

　　4. Endotoxemia:Patients with portal hypertension often have concurrent endotoxemia, which is more common in patients with decompensated liver function, such as in acute liver failure, where 66% to 100% have concurrent endotoxemia; the incidence rate of hepatic encephalopathy is about 93%; and the incidence rate of gastrointestinal bleeding is 53.8%. Conversely, in patients with endotoxemia, about 48.5% have concurrent gastrointestinal bleeding, and it can be as high as 77.8%. In 7 cases of cirrhosis with gastric mucosal lesions reported by Clemente, 6 cases were positive in the LALT examination. In fact, endotoxins can interfere with each cell, provoke cellular reactions, cause cellular metabolism disorders, and even destruction; besides the direct pathogenic effect, during endotoxemia, many soluble regulatory substances are produced in the body, playing an important role. For example, endotoxins can activate the complement system, and after C3 and C5 are enzymatically cleaved, C3a and C5a can increase capillary permeability and smooth muscle contraction; endotoxins also promote the metabolism of arachidonic acid, and the metabolites include thromboxane A2 with strong vasoconstrictive effects, which all have important pathogenic effects.

　　5. Infection:The onset of gastritis and ulcers is related to Helicobacter pylori infection, Morris and Nieholson gave the normal gastric mucosal and fasting gastric content pH

　　Most patients with liver cirrhosis in China are secondary to hepatitis B. Kirk once pointed out that the occurrence of acute gastric mucosal ulcer seems to be related to HBsAg positivity. Peng Xiaojun confirmed that there is hepatitis B virus in the gastric mucosal epithelial cells, which forms antigen-antibody complexes and deposits in the microvascular endothelial cells, causing inflammatory reactions and destroying the gastric mucosal barrier.

　　6. Stress reaction:Severe patients, including severe liver patients, often have stress reactions, causing a decrease in gastrointestinal mucosal blood flow, ischemia and hypoxia, and a series of secondary pathophysiological changes, leading to the destruction of mucosal integrity and causing acute gastrointestinal mucosal lesions. The rapid deterioration of pre-existing peptic ulcers. The incidence of acute gastrointestinal mucosal lesions during portal hypertension due to liver cirrhosis is high, and stress reactions play a certain pathogenic role.

　　In summary, the pathogenesis of portal hypertension-induced gastrointestinal mucosal lesions is complex, but it is mainly due to hemodynamic changes, reduced mucosal blood flow, increased destruction of mucosal epithelial cells, decreased repair ability, barrier function damage, and susceptibility to various pathogenic factors.

　　Enlarged spleen, hypersplenism, vomiting blood or black stools, ascites or non-specific systemic symptoms (such as fatigue, drowsiness, anorexia). Once the varices of the esophagus and gastric fundus rupture, acute massive hemorrhage occurs immediately, vomiting bright red blood. Due to liver dysfunction causing coagulation dysfunction, and due to hypersplenism causing thrombocytopenia, bleeding is not easy to stop. Due to severe hemorrhage causing severe hypoxia of liver tissue, it is easy to lead to hepatic coma. There may also be other signs of chronic liver disease such as spider angiomas, palmar erythema, gynecomastia, testicular atrophy, etc. The main clinical manifestations of severe PHG are upper gastrointestinal bleeding. Most are small amounts of vomiting blood and black stools, which may be accompanied by anemia. A few cases may experience massive upper gastrointestinal bleeding, leading to hemorrhagic shock, and may trigger complications such as hepatic encephalopathy, infection, and hepatorenal syndrome.

　　Most PHG cases are mild, with no specific clinical symptoms, often discovered during gastroscopy. Over time, mild PHG can progress to severe PHG. The main clinical manifestations of severe PHG are upper gastrointestinal bleeding, mostly in the form of small amounts of vomiting blood, black stools, which may be accompanied by anemia. A few cases may experience massive upper gastrointestinal bleeding, leading to hemorrhagic shock, and may trigger complications such as hepatic encephalopathy, infection, and hepatorenal syndrome. The recurrence rate of bleeding after bleeding is very high.

　　Avoid overexertion, which can lead to insufficient blood supply to the gastrointestinal tract, disorder of gastric mucosal secretion, and can also lead to various gastric diseases. Abstain from irregular diet. Uneven diet can lead to an empty stomach during hunger, which is an adverse stimulus to the gastric wall from gastric acid and pepsin secreted by the gastric mucosa. Overeating can also cause excessive expansion of the gastric wall, and food can stay in the stomach for too long, which will cause great harm to the stomach.

　　Liver cirrhosis patients often have varying degrees of anemia, mostly normocytic or microcytic anemia, occasionally macrocytic anemia. In the late stage, there may be erythropoiesis inhibition. When splenomegaly occurs, the total blood cell count decreases, and it also promotes bleeding. The prothrombin time and coagulation time are prolonged, especially明显 when obstructive jaundice occurs. Therefore, some patients can correct it with vitamin K. In acute hemorrhage, white blood cell count increases, and returns to normal after hemostasis. When bleeding is obvious and extensive, DIC should be noted. If the platelet count decreases or decreases progressively, fibrinogen 600mg/L, 3P test positive, and the euglobulin lysis time is shortened, the diagnosis can be established. If the prothrombin time is prolonged, the euglobulin lysis time is significantly shortened, and the platelet count is normal, the 3P test is negative, it is primary fibrinolysis. After bleeding, the blood ammonia level may increase, water and electrolyte imbalance, and renal function impairment may occur.

　　During the decompensated stage of liver cirrhosis, cholesterol esters are lower than normal, albumin decreases, globulin increases, and the albumin/globulin ratio is inverted. Transaminases slightly increase. In some cases of post-hepatitis cirrhosis, hepatitis B or hepatitis C viral serological markers can be detected. In patients with sepsis, the limulus test is positive.

　　1. Endoscopic examination

　　Endoscopy mainly manifests as erythema of the mucosa, with the mucosa showing white and yellowish fine reticular structures, which separate the red or pale red edematous mucosa into snake skin-like patterns, known as the snake skin sign (snakesign) or mosaic sign (mosaicsign), which is a characteristic manifestation of the disease. Severe cases may show scattered cherry red spots and punctate hemorrhages. Endoscopic grading is currently not unified. McCormack et al. divided the endoscopic manifestations of PHG into mild and severe types, with mild type characterized by slight mucosal erythema, striated erythema, snake skin sign or mosaic sign, and severe type characterized by scattered cherry red spots or disseminated hemorrhagic lesions. Tanoue et al. divided the endoscopic manifestations into 3 grades: Grade I, slight erythema, mosaic sign; Grade II, severe congestion; Grade III, on the basis of Grade II, accompanied by punctate hemorrhage. This grading method divides the mild type in McCormack's classification into two grades, as the boundaries between grades are clear and easy to remember. Literature reports that endoscopic PHG accounts for more than half of liver cirrhosis, mostly mild, and mosaic sign is the most common.

　　2. Endoscopic ultrasound

　　Diffuse thickening of the gastric wall, with obvious small vein dilatation as a characteristic.

　　3. Histological characteristics

　　Submucosal vein dilatation, with or without mild inflammatory cell infiltration, is a characteristic manifestation. Other manifestations include submucosal small arteriovenous wall thickening, veno-arterialization, the cross-sectional area of mucosal capillaries is larger than normal, poor development of gastric mucosal capillaries, scattered exposed in the gastric cavity, without epithelial tissue covering the surface, gastric mucosal small arteries become straight, the helical degree is reduced, and small vessel injection studies have found that submucosal arteriovenous shunts are widely open. Electron microscopy shows significant expansion of capillaries, enlargement of endothelial small holes, loose connection between vascular endothelium and basement membrane, the appearance of gaps, discontinuous vascular basement membrane, the distance between the basal membrane of capillaries and the basal membrane of epithelial cells becomes wider, epithelial cells swell and change, red blood cells extrude from the damaged epithelium and appear between the epithelial spaces. Because the biopsy material taken by endoscopy is small and superficial, only 50% of the biopsy specimens show capillary dilatation in pathology.

　　Dietary therapy for portal hypertension of the gastric disease: light, not greasy, not spicy. Pay attention to anti-inflammatory for foods like white rice porridge, oatmeal porridge, white noodles, etc. Avoid eating spicy and irritating foods.

　　1. Treatment

　　1. Drug therapy

　　(1) Propranolol (Inderal): Propranolol can reduce portal vein blood flow and portal vein pressure by constricting splanchnic small arteries, achieving the effects of controlling bleeding, improving endoscopic gastric mucosal lesions, and preventing recurrence. Animal experiments have found that propranolol can alleviate the gastric mucosal damage caused by alcohol under portal hypertension. Studies on rats with portal hypertension and patients with liver cirrhosis and portal hypertension have shown that propranolol acts by reducing portal vein pressure and gastric mucosal blood flow. Double-blind controlled trials have confirmed that propranolol is the only drug currently used to prevent recurrence of PHG. Some patients may have a poor or no response to propranolol. The recommended initial dose of propranolol in foreign literature is 10-20mg, 2-3 times a day, and the dose is gradually increased to 80-160mg/day, which is generally higher in foreign countries. The appropriate dose for Chinese people needs to be explored, and individualization should be achieved, with a reduction of heart rate by 25% after medication as a general guideline. For patients with PHG treated with propranolol for a long time, if the drug is discontinued, it often leads to recurrence of bleeding, which should be paid attention to.

　　(2) Vasopressin: The posterior pituitary hormone improves portal vein hemodynamics, controlling bleeding. However, these drugs reduce gastric mucosal blood perfusion, decrease hemoglobin concentration and oxygen saturation, leading to ischemia and hypoxia of the gastric mucosa. Therefore, for PHG bleeding, it is generally believed that small-dose continuous intravenous infusion is appropriate. In recent years, the vasopressin derivative terlipressin (triglycine lysine vasopressin) has been synthesized, which has a significant effect on reducing splanchnic blood flow and lowering portal vein pressure, with few side effects. Although it significantly reduces gastric mucosal blood flow, the decrease in oxygen saturation is slight.

　　(3) Somatostatin: Somatostatin (Stanozolol) and its analog octreotide (Octreotide) reduce the wedge pressure of hepatic vein and the blood flow of gastric mucosa, which can be used for the treatment of PHG bleeding. The mechanism of action of somatostatin and octreotide is mainly indirect. They act by antagonizing glucagon and other vasodilatory substances, improving the hyperdynamic circulation state during portal hypertension of liver cirrhosis.

　　2. Interventional Treatment

　　(1) Transjugular intrahepatic portosystemic shunt (TIPS): It is a radiological interventional method for treating portal hypertension, suitable for esophageal variceal bleeding and refractory ascites that cannot be controlled by drugs and gastroscopy. Due to the fact that TIPPS surgery can both reduce portal vein pressure for a long time and has a smaller impact on the patient's body, compared with traditional portosystemic shunt surgery, TIPS surgery has wider indications and is suitable for Child C patients. In recent years, more and more reports on the use of TIPS to treat PHG have been published, but the incidence of postoperative hepatic encephalopathy is high. For patients with poor drug efficacy and recurrent bleeding, TIPS can be chosen.

　　(2) Transcatheter arterial embolization of splenic artery (TSAE): Splenic artery embolization can reduce the blood flow of splenic vein, improve the hemodynamics of portal vein, reduce the hemoglobin content of gastric mucosa, slightly increase the oxygen saturation, and significantly improve PHG, which can be used for hemostasis and prophylactic treatment of PHG bleeding, especially suitable for PHG patients with macrocytic splenomegaly and splenic dysfunction.

　　3. Surgical Treatment

　　For the gastric mucosal bleeding caused by PHG, simple lesion suture, gastric resection, vagotomy with pyloroplasty, and other methods cannot achieve the purpose of hemostasis. The shunt operation can worsen PHG and should be listed as contraindication. Portosystemic shunt surgery can effectively reduce portal vein pressure and has definite efficacy for upper gastrointestinal bleeding caused by PHG. For patients with ineffective drug treatment, surgical treatment can be considered. Endoscopic follow-up after portosystemic shunt surgery shows that the gastric mucosa of most patients returns to normal morphology. Portosystemic shunt treatment for PHG is safe and effective, can stop bleeding quickly and lastingly, and the main complications of surgery are hepatic encephalopathy.

　　II. Prognosis

　　Whether there is rebleeding after PHG treatment and the decompensation of liver cirrhosis are related, so the key to prognosis lies in whether the primary disease can be improved or eliminated.