Pharmacologic treatment of portal hypertension.

Variceal formation and rupture are dreaded complications of chronic liver disease and portal hypertension. The pharmacologic treatment of portal hypertension should be able to stop as well as to prevent variceal hemorrhage. There are two principal types of vasoactive drugs in the treatment of portal hypertension: vasoconstrictors and vasodilators. Vasoconstrictors reduce the splanchnic blood flow, thereby decreasing the portal blood flow and portal pressure. Vasodilators act by different mechanisms, including by relaxation of myofibroblasts in the fibrous septa and presinusoidal areas of the liver and by direct vasodilation of the collateral circulation. In addition, paradoxically, they could decrease portal flow and pressure by inducing a baroreflex-mediated mesenteric arterial vasoconstriction. A miscellaneous group of drugs is also available. These drugs reduce the blood flow and pressure in the gastroesophageal variceal system by mechanisms other than vasoconstriction or vasodilation. The success of these pharmacologic agents is limited once the varices have ruptured. The use of beta-blockers in the prophylaxis of the first variceal bleeding has been proven of benefit in this respect. Future research should be aimed at elucidating the role that humoral and endothelial factors play in development of the hyperdynamic circulatory state that characterizes patients with portal hypertension. Once these etiologic factors have been identified and new knowledge is acquired about their role in the complications of chronic liver disease, the challenge will rest on developing novel pharmacologic therapies specifically targeting these factors.     

Pathogenesis of Portal Hypertension: Extrahepatic Mechanisms

Chronic liver diseases, including hepatic cirrhosis, chronic hepatitis, alcoholic liver disease, and hepatocellular carcinoma, are one of the commonest causes of death and liver transplantation in adults worldwide. They are accompanied by profound disturbances that are not limited to the intrahepatic circulation, but involve also the splanchnic and systemic vascular beds. These hemodynamic disturbances are responsible for the development of portal hypertension, the most frequent and severe of cirrhosis. This syndrome is characterized by a pathological increase of blood pressure in the portal vein and concomitant increases in splanchnic blood flow and portosystemic collateral vessel formation. Increased blood flow in splanchnic organs draining into the portal vein augments in turn the portal venous inflow. Such increased portal venous inflow perpetuates and exacerbates portal pressure elevation and determines the formation of ascites during chronic liver disease. In addition, portosystemic collateral vessels include the gastroesophageal varices, which are particularly prone to rupture causing massive gastroesophageal bleeding. Collateral vessels are also responsible for other major consequences of chronic liver disease, including portosystemic encephalopathy and sepsis. Extrahepatic mechanisms are clearly of major importance for disease progression and aggravation of the portal hypertensive syndrome. Accordingly, most of the therapies currently used in portal hypertension do not act inside the liver but they actually target the increased splanchnic blood flow. This paper reviews the consequences of the splanchnic circulatory abnormalities in portal hypertension and the complex signals capable of increasing vasodilatation, hyporesponsiveness to vasoconstrictors and angiogenesis in the splanchnic vascular bed and the portosystemic collateral circulation in this pathological setting.     

Update on the management of gastrointestinal varices

Cirrhosis of liver is a major problem in the western world. Portal hypertension is a complication of cirrhosis and can lead to a myriad of pathology of which include the development of porto-systemic collaterals. Gastrointestinal varices are dilated submucosal veins, which often develop at sites near the formation of gastroesophageal collateral circulation. The incidence of varices is on the rise due to alcohol and obesity. The most significant complication of portal hypertension is life-threatening bleeding from gastrointestinal varices, which is associated with substantial morbidity and mortality. In addition, this can cause a significant burden on the health care facility. Gastrointestinal varices can happen in esophagus, stomach or ectopic varices. There has been considerable progress made in the understanding of the natural history, pathophysiology and etiology of portal hypertension. Despite the development of endoscopic and medical treatments, early mortality due to variceal bleeding remains high due to significant illness of the patient. Recurrent variceal bleed is common and in some cases, there is refractory variceal bleed. This article aims to provide a comprehensive review of the management of gastrointestinal varices with an emphasis on endoscopic interventions, strategies to handle refractory variceal bleed and newer endoscopic treatment modalities. Early treatment and improved endoscopic techniques can help in improving morbidity and mortality.     

Development of Gastroesophageal Varices and Risk of Variceal Bleeding in Patients With Cirrhosis

Abstract: We studied the relationships between portal pressure measured using the portal venous pressure gradient, the development of gastroesophageal varices, and the risk of variceal bleeding in 56 patients with cirrhosis. Portal pressure was higher in patients with varices than in those without (P>0.01), and 11 mmHg was the lowest portal pressure measured in the patients with varices. The size of the varices was not associated with the portal pressure. There was no difference in the value of portal pressure measurements for the patients with variceal bleeding and those without and there was no linear-relationship between the degree of portal hypertension and the rate of variceal bleeding. 12 mmHg was the lowest portal pressure measured in the patients with variceal bleeding. The size of the varices was related to the rate of variceal bleeding (P>0.05). We conclude that (a) a portal pressure of 11 mmHg is necessary for the formation of varices, (b) 12 mmHg of portal pressure is necessary for variceal bleeding to occur but the degree of portal hypertension has no predictive value for the risk of variceal bleeding, and (c) the size of the varices does not depend on the degree of portal hypertension but is associated with the risk of variceal bleeding.     

Clinical pharmacology of portal hypertension

Portal hypertension is an increase in pressure in the portal vein and its tributaries. It is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. Although this gradient defines portal hypertension, a gradient of 10 mm Hg or greater defines clinically significant portal hypertension, because this pressure gradient predicts the development of varices, decompensation of cirrhosis, and hepatocellular carcinoma. The most direct consequence of portal hypertension is the development of gastroesophageal varices that may rupture and lead to the development of variceal hemorrhage. This article reviews the pathophysiologic bases of the different pharmacologic treatments for portal hypertension in patients with cirrhosis and places them in the context of the natural history of varices and variceal hemorrhage.     

Assessment of portal hypertension in humans

Patients suspected of having portal hypertension (either by clinical history, physical examination, or previous diagnosis) should undergo ultrasonography and upper gastrointestinal endoscopy. Ultrasonography, preferably using the duplex technique, can disclose the patency of the portal venous system, the presence of signs of portal hypertension (splenomegaly, portocollateral vessels, repermeabilization of the umbilical vein, and so forth) and provide additional information about liver, biliary, or pancreatic diseases that may be the cause of portal hypertension. Endoscopy can assess the presence and size of gastroesophageal varices, the appearance of the variceal wall, and the presence and severity of portal hypertensive gastropathy. Patients showing a patent portal vein should have hepatic vein catheterization to evaluate the presence of presinusoidal, sinusoidal, or postsinusoidal portal hypertension. Patients in whom presinusoidal portal hypertension is suspected (those having esophageal varices with an HVPG below 10 mm Hg) should have liver biopsy and percutaneous transhepatic measurement of portal pressure. In sinusoidal portal hypertension, the results of endoscopy and HVPG measurement are decisive for the therapeutic management of the patients. The authors' results indicate that, before starting prophylactic therapy with beta-blockers, all patients should undergo at least an hepatic vein catheterization to assess HVPG; it would be preferable to have a variceal pressure measurement also. These measurements must be repeated 3 to 4 weeks after the final dose of therapy has been reached to assess the risk of variceal bleeding or rebleeding.     

Varizenblutung

Esophageal variceal bleeding remains the most feared complication of portal hypertension and is associated with a significant mortality; thus, endoscopic screening of these patients is recommended. To date, neither medical nor interventional therapy can prevent the development of varices. However, the risk of variceal bleeding can be reduced using nonselective beta-blockers. Endoscopic prophylaxis is only recommended for patients with large varices that do not tolerate sufficient beta-blocker therapy. Endoscopic variceal ligation in combination with antibiotic prophylaxis as well as vasoactive agents, such as terlipressin, are the treatment of choice in acute variceal hemorrhage. If these measures fail to stop variceal bleeding, alternatives that include local compression of varices using special self-expanding stents or by reducing portal venous pressure with transjugular portosystemic shunts should be evaluated. Secondary prophylaxis consists of endoscopic variceal ligation and medical reduction of portal venous pressure.     

Treatment of portal hypertension

Portal hypertension is the main complication of cirrhosis and is defined as an hepatic venous pressure gradient (HVPG) of more than 5 mmHg. Clinically significant portal hypertension is defined as HVPG of 10 mmHg or more. Development of gastroesophageal varices and variceal hemorrhage are the most direct consequence of portal hypertension. Over the last decades significant advancements in the field have led to standard treatment options. These clinical recommendations have evolved mostly as a result of randomized controlled trials and consensus conferences among experts where existing evidence has been reviewed and future goals for research and practice guidelines have been proposed. Management of varices/variceal hemorrhage is based on the clinical stage of portal hypertension. No specific treatment has shown to prevent the formation of varices. Prevention of first variceal hemorrhage depends on the size/characteristics of varices. In patients with small varices and high risk of bleeding, non-selective β-blockers are recommended, while patients with medium/large varices can be treated with either β-blockers or esophageal band ligation. Standard of care for acute variceal hemorrhage consists of vasoactive drugs, endoscopic band ligation and antibiotics prophylaxis. Transjugular intrahepatic portosystemic shunt (TIPS) is reserved for those who fail standard of care or for patients who are likely to fail ("early TIPS"). Prevention of recurrent variceal hemorrhage consists of the combination of β-blockers and endoscopic band ligation.     

Gastric Varices: Profile, Classification, and Management

Development of gastric varices is an important manifestation of portal hypertension. In segmental portal hypertension, gastric varices originate from short gastric and gastroepiploic veins. In generalized portal hypertension, intrinsic veins at cardia participate in the formation of gastric varices. Endoscopy and/or splenoportovenography and a high index of suspicion are required for the diagnosis of gastric varices. The incidence of gastric varices in patients with portal hypertension has been variably reported (2-70%), probably due to difficulties in diagnosis. In a small proportion of patients with gastric varices, chronic portal-systemic encephalopathy or significant variceal bleeding develops. Gastric varices can be classified, depending on their anatomical location, into gastroesophageal varices (a continuation of esophageal varices) or "isolated" gastric varices (fundal or ectopic varices). This distinction is necessary for management. Whereas surgery is recommended for bleeding fundal varices, in acute bleeding from gastroesophageal varices, sclerotherapy could be attempted successfully. In more than a quarter of patients, gastric varices disappear after obliteration of esophageal varices. Prophylactic sclerotherapy of gastric varices is not recommended.     

内镜下预防食管胃静脉曲张再出血对门静脉系统血流动力学影响的研究

目的评价内镜下预防食管胃静脉曲张患者再出血（二级预防）对门静脉系统血流动力学的影响,以指导临床治疗方案的确定。方法运用超声检查对有出血史的食管胃静脉曲张患者的门静脉系统压力和血流压力包括血管内径、横截面积和平均血流速度进行评价,在二级预防静脉曲张根除后,再次用超声检查评价门静脉系统血流动力学。结果 42例患者在二级预防治疗后1-27个月的随访时间内,达到静脉曲张完全根除,治疗前后超声检查对门静脉系统血流动力学的评估显示,肝动脉内径和肝动脉横截面积显著增宽,其他评估指标治疗前后差异均无统计学意义。结论二级预防治疗静脉曲张再出血,可能使门脉压力有所升高,这需要更大的样本量和长期的跟踪随访来进一步证实。     

What's new in portal hypertension?

Portal hypertension is defined as increased pressure in the portal venous system. The most common cause of portal hypertension is cirrhosis. In this setting, there is an increase in intrahepatic resistance leading to an increase in portal pressure. By increasing portal blood flow, splanchnic vasodilation further aggravates portal hypertension. New pathogenic pathways are being established which might result in new therapeutic strategies. The presence of varices at endoscopy and/or other abdominal portosystemic collaterals confirms the diagnosis of portal hypertension. The role of non‐invasive and imaging tests in the diagnosis and prognosis of portal hypertension has been clarified. Non‐selective beta‐blockers decrease both the risk of variceal haemorrhage and hepatic decompensation. Terlipressin, somatostatin or octreotide, in combination with early endoscopic therapy, are recommended for the treatment of acute variceal haemorrhage. Early Transjugular intrahepatic portosystemic shunt (TIPS) is effective as salvage therapy in acute variceal bleeding in selected patients and prevents rebleeding more effectively than endoscopic and medical therapy resulting in an increased survival.     

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.     

Utility of endoscopic ultrasound in patients with portal hypertension

Endoscopic ultrasound(EUS) has revolutionized the diagnostic and therapeutic approach to patients with gastrointestinal disorders. Its application in patients with liver disease and portal hypertension is increasing. Patients with chronic liver disease are at risk for development of portal hypertension sequale such as ascites, spontaneous bacterial peritonitis and gastroesophageal varices. Bleeding esophageal and gastric varices are among the most common causes of mortality in patients with cirrhosis. Thus, early detection and treatment improve the outcome in this population. EUS can improve the detection and diagnosis of gastroesophageal varices and collateral veins and can provide endoscopic therapy of gastroesophageal varices such as EUS-guided sclerotherapy of esophageal collateral vessels and EUS-guided cynoacrylate(Glue) injection of gastric varices. EUS can also provide knowledge on the efficacy of pharmacotherapy of portal hypertension. Furthermore, EUS can provide assessment and prediction of variceal recurrence after endoscopic therapy and assessment of portal hemodynamics such as E-Flow and Doppler study of the azygous and portal veins. Moreover, EUS-guided fine needle aspiration may provide cytologic diagnosis of focal hepatic tumors andanalysis of free abdominal fluid.Using specialized EUSguided needle biopsy,a sample of liver tissue can be obtained to diagnose and evaluate for chronic liver disease.EUS-guided fine needle injection can be used to study portal vein pressure and hemodynamics,and potentially could be used to assist in exact measurement of portal vein pressure and placement of intrahepatic portosystemic shunt.     

Primary prophylaxis of variceal bleeding in cirrhosis

Variceal bleeding is the result of portal hypertension, which is a major complication of liver cirrhosis and carries a high mortality rate. Because of the mortality associated with variceal bleeding, strategies for prevention of the first bleed is important. Risk stratification is important in determining those at risk of bleeding from varices and current data suggest that patients with large varices with red signs, severe underlying liver disease and those who have a hepatic venous pressure gradient of greater than 12 mmHg are at high risk of bleeding. Surveillance for varices in patients with cirrhosis is therefore important. The current review evaluates the role of various treatments in the primary prophylaxis of variceal bleeding. The current first choice treatment is non-selective beta-blockers; which is cheap, easy to administer, and reduces the risk of first variceal haemorrhage significantly. Combination of beta-blockers and nitrates looks promising but needs further evaluation. Endoscopic variceal band ligation compares favourably with non-selective beta-blockers in preventing the first bleeding episode in cirrhotic patients and may be an alternative for patients who cannot tolerate, or have contraindications to beta-blockers. The role of monitoring the hepatic venous pressure gradient in those being treated with pharmacological agents, the role of newer drugs such as non-selective beta-blockers with intrinsic alpha-adrenergic activity and angiotensin receptor blockers require further evaluation.     

卡维地洛对肝硬化门静脉高压食管胃静脉曲张出血的防治作用研究进展

门静脉高压是食管胃静脉曲张出血的主要原因,有效降低门静脉压力梯度是预防食管胃静脉曲张出血的关键。卡维地洛是一类具有潜在的非心脏选择性的β受体和α受体阻滞剂,可通过降低门静脉压力进而减少食管胃静脉曲张的出血风险。本文就卡维地洛相比于传统的β受体阻滞剂如普萘洛尔或奈比洛尔、内镜下套扎、β受体阻滞剂联合硝酸酯类等治疗方案对食管胃静脉曲张出血的防治作用和不良反应进行分析,以期更好的指导临床治疗。     

Variceal hemorrhage

Opinion statement Reducing morbidity and mortality from esophageal varices remains a challenge for physicians managing patients with chronic liver disease. For patients who have never bled from varices, prophylactic therapy with nonselective beta-blockers reduces the risk of initial variceal bleeding and bleeding-related death. Thus, patients with newly diagnosed cirrhosis should be considered for endoscopic variceal screening. All patients with Child’s class B and C cirrhosis should be offered endoscopic screening, whereas those with Child’s class A with evidence of portal hypertension (eg, platelet count less than 140,000 per milliliter, portal vein diameter larger than 13 mm, evidence of splenic varices on ultrasound) should be screened. The principal risk factors for variceal bleeding are variceal size, the presence of color changes on the variceal wall (indicative of decreased wall thickness), and degree of liver dysfunction. Patients with moderate or large sized varices and those with varices exhibiting color changes (eg, red wale marks, cherry red spots) should be treated with beta-blockers. Individuals without varices and those with small varices should undergo repeat endoscopy at approximately 2-year intervals. Patients unwilling or unable to take beta-blockers do not need to be screened. For patients with acute variceal bleeding, the combination of pharmacologic therapy plus endoscopic therapy is superior to either therapy alone. Octreotide is the drug most often used as initial therapy in the United States. Terlipressin is the preferred agent; however, it is not available in the United States. Endoscopy is performed as early as possible, and endoscopic injection sclerotherapy or endoscopic variceal band ligation is employed if variceal bleeding is confirmed or suspected. Endoscopic therapy should be repeated until the varices are obliterated completely. The addition of beta-blockers to endoscopic sclerotherapy or ligation may decrease the rate of rebleeding compared with receiving endoscopic treatment alone. Patients with bleeding refractory to combined medical plus endoscopic therapy should be considered for transjugular intrahepatic portosystemic shunts or shunt surgery.     

Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis

Portal hypertension is a clinical syndrome which leads to several clinical complications,such as the formation and rupture of esophageal and/or gastric varices,ascites,hepatic encephalopathy and hepato-renal syndrome.In cirrhosis,the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow.However,also an increase in splanchnic blood flow worsens and maintains portal hypertension.The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow.Several vasoactive systems/substances,such as nitric oxide,cyclooxygenase-derivatives,carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation.Moreover,an impaired reactivity to vasoconstrictor systems,such as the sympathetic nervous system,vasopressin,angiotensinⅡand endothelin-1,plays a role in this process.The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels,but also through the generation of new vessels.Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome,a syndrome which occurs in pa-tients with portal hypertension and is characterized by increased cardiac output and heart rate,and decreased systemic vascular resistance with low arterial blood pressure.Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.     

The effects of ethanol administration on portal pressure and gastroesophageal collateral blood flow in patients with alcoholic cirrhosis

The pathogenesis of variceal hemorrhage is not well understood. Portal pressure and gastroesophageal collateral (azygous) blood flow are similar in patients with cirrhosis with or without a history of variceal bleeding. However, acute increases in these parameters in individual patients might predispose them to variceal rupture. Fifteen patients with alcoholic cirrhosis and portal hypertension were evaluated to test the hypothesis that ethanol intake acutely increases portal pressure or gastroesophageal blood flow and is a possible risk factor in variceal hemorrhage. A 10% solution of ethanol in 5% dextrose in water was infused intravenously at a rate sufficient to raise the blood-alcohol level to 100 mg/dl over 30 min. Eight patients received ethanol 5% dextrose in water; seven patients received a placebo (5% dextrose in water alone). Ethanol did not produce a significant change in wedged hepatic-vein pressure, free hepatic-vein pressure, azygous blood flow, mean arterial pressure or heart rate compared with the effects of 5% dextrose in water alone. Acute administration of ethanol does not increase portal pressure or gastroesophageal blood flow. It is unlikely that acute ethanol ingestion is a risk factor for variceal hemorrhage.     

Preventing the development of varices in cirrhosis

Gastroesophageal varices are a direct consequence of portal hypertension. Nonselective beta-adrenergic blockers decrease portal pressure and are effective in preventing variceal hemorrhage. However, a large multicenter placebo-controlled trial demonstrates that nonselective beta-adrenergic blockers are not effective in preventing the development of varices and are associated with a significant rate of adverse events. This therapy is, therefore, not recommended in compensated cirrhotic patients without varices at large. In this very compensated group of patients with cirrhosis (stage 1, ie, without varices and without ascites or encephalopathy) the predictive value (both for the development of varices and for the development of clinical decompensation) of a baseline hepatic venous pressure gradient greater than 10 mm Hg is confirmed, supporting this threshold level as one that defines a clinically significant portal hypertension. Importantly, reductions in hepatic venous pressure gradient >10% are associated with a significant reduction in the development of varices, a therapeutic goal that could be achieved through the use of beta-blockers or other drugs being developed for the treatment of portal hypertension.     

A commonsense approach to esophageal varices

Variceal hemorrhage is one of the most serious complications of portal hypertension and cirrhosis and is associated with a mortality of at least 20% at 6 weeks, despite improvements in therapy over the last decade. Variceal hemorrhage predisposes cirrhotic patients to worsening hepatic decompensation, infection, or renal insufficiency, which contribute to mortality. Providing primary prophylaxis against first variceal hemorrhage, general management of an acute bleeding episode, and treatment after variceal hemorrhage--mainly prevention of rebleeding--are equally important components of care for the cirrhotic patient who has gastroesophageal varices. This article describes a practical approach to the management of cirrhotic patients who have gastroesophageal varices.