Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension

Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5 mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.     

Albumin administration in patients with cirrhosis: Current role and novel perspectives

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.     

Pharmacological therapy of portal hypertension--focused on Korean data]

Portal hypertension as a consequence of liver cirrhosis is responsible for serious complications such as variceal bleeding, ascites and hepatic encephalopathy. Successful pharmacological treatment of portal hypertension can prevent the risk of the variceal bleeding, and contribute to reduce the morbidity and mortality in patients with liver cirrhosis. To identify the effect of drugs on portal hypertension, portal pressure was evaluated accurately before and after the drug administration. The hepatic venous pressure gradient has been accepted as the gold-standard method for assessing the severity of portal hypertension and the response to drug treatment. The mean hepatic venous pressure gradient was 15.1+/-5.4 mmHg in Korean cirrhotic patients who had experienced variceal bleeding. Non-selective beta blockers are the treatment of choice for primary and secondary prevention of variceal bleeding. The dose of propranolol should be subsequently adjusted until the resting heart rate had been reduced by 25% or less than 55 beats per minute. It has been reported that the optimal dose of propranolol is variable due to racial differences in cardiovascular receptor sensitivity. In Korean patients with portal hypertension and liver cirrhosis, the mean required dose of propranolol to reach target heart rate was 165 mg (range; 80-280 mg). This review covers mainly the results of the pharmacological therapy of portal hypertension in Korean cirrhotic patients.     

The transjugular intrahepatic portosystemic shunt in the treatment of portal hypertension

The transjugular intrahepatic portosystemic shunt (TIPS) represents a major advance in the treatment of complications of portal hypertension. It is most commonly used in the management of refractory variceal bleeding, where it can be life-saving. Two other indications have been studied in randomized controlled trials: prevention of variceal rebleeding and refractory cirrhotic ascites. These trials have demonstrated that TIPS is superior to standard therapy but is associated with a higher rate of hepatic encephalopathy and with no improvement in survival. Consequently, TIPS is considered a second-line therapy in these situations. TIPS has also been used successfully in the treatment of hepatic hydrothorax, hepatorenal syndrome, severe portal hypertensive gastropathy, Budd-Chiari syndrome and veno-occlusive disease. Its use in these indications has only been reported in small uncontrolled series. TIPS usefulness is limited by two major problems: shunt dysfunction and hepatic encephalopathy. Shunt dysfunction is frequently responsible for the recurrence of complications of portal hypertension, and requires a surveillance program to monitor shunt patency. The use of polytetrafluoroethylene-covered stents may help prevent this complication.     

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.     

Pharmacologic therapy of portal hypertension

Portal hypertension is a progressively debilitating complication of cirrhosis and a principal cause of mortality in patients who have hepatic decompensation. During the last few decades, significant clinical advances in the prevention of initial variceal hemorrhage, the management of acute variceal hemorrhage, and the prevention of recurrent variceal hemorrhage have reduced the morbidity and mortality of this lethal complication of cirrhosis. This article discusses the pharmacologic treatment of portal hypertension, including preprimary prophylaxis, prevention of a first variceal hemorrhage, treatment of acute variceal hemorrhage, and secondary prophylaxis of a variceal hemorrhage.     

Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis

In cirrhotic patients under pharmacologic treatment for portal hypertension, a reduction in hepatic venous pressure gradient (HVPG) of >or=20% of baseline or to or=20% of baseline or to or=20% or to 相似文献   

Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis

OBJECTIVES: A reduction in hepatic venous pressure gradient (HVPG) of > or =20% of baseline or to < or =12 mmHg (responders) is associated with a reduced risk of first variceal bleeding. The aim of this study was to evaluate whether this protective effect is maintained in the long term and if it extends to other portal hypertension complications. METHODS: Seventy-one cirrhotic patients with esophageal varices and without previous variceal bleeding who entered into a program of prophylactic pharmacological therapy and were followed for up to 8 yr were evaluated. All had two separate HVPG measurements, at baseline and after pharmacological therapy with propranolol +/- isosorbide mononitrate. RESULTS: Forty-six patients were nonresponders and 25 were responders. Eight-year cumulative probability of being free of first variceal bleeding was higher in responders than in nonresponders (90% vs 45%, p= 0.026). The lack of hemodynamic response and low platelet count were the only independent predictors of first variceal bleeding. Additionally, reduction of HVPG was independently associated with a decreased risk of spontaneous bacterial peritonitis (SBP) or bacteremia. No significant differences in the development of ascites, hepatic encephalopathy, or survival were observed. CONCLUSIONS: The hemodynamic response in cirrhotic patients is associated with a sustained reduction in the risk of first variceal bleeding over a long-term follow-up. Reduction of HVPG also correlate with a reduced risk of SBP or bacteremia.     

Complications of liver cirrhosis

The occurrence of complications increases the mortality in patients with cirrhosis of the liver. Therefore, early detection and treatment of complications of cirrhosis is of major importance. Following diagnosis of cirrhosis, a screening gastroscopy detects esophageal varices. Primary prevention of variceal bleeding can be initiated with β-receptor antagonists or variceal band ligation. With the first episode of ascites or the manifestation of other complications of cirrhosis such as hepatic encephalopathy and hepatorenal syndrome, a paracentesis excludes spontaneous bacterial peritonitis. Hepatorenal syndrome can be treated with a combination of vasopressors and albumine. Furthermore, occurrence of complications in patients with cirrhosis of the liver should prompt the evaluation of an indication for liver transplantation.     

Komplikationen der Leberzirrhose

The occurrence of complications increases the mortality in patients with cirrhosis of the liver. Therefore, early detection and treatment of complications of cirrhosis is of major importance. Following diagnosis of cirrhosis, a screening gastroscopy detects esophageal varices. Primary prevention of variceal bleeding can be initiated with ??-receptor antagonists or variceal band ligation. With the first episode of ascites or the manifestation of other complications of cirrhosis such as hepatic encephalopathy and hepatorenal syndrome, a paracentesis excludes spontaneous bacterial peritonitis. Hepatorenal syndrome can be treated with a combination of vasopressors and albumine. Furthermore, occurrence of complications in patients with cirrhosis of the liver should prompt the evaluation of an indication for liver transplantation.     

Management of ascites

The evaluation of ascites includes a directed history, focused physical examination, and diagnostic paracentesis with ascitic fluid analysis. Dietary sodium restriction and oral diuretics are the mainstay of therapy for the majority of patients with cirrhotic ascites. Transjugular intrahepatic portocaval shunt has emerged as the treatment of choice for selected patients with refractory ascites, although serial large-volume paracenteses should be attempted first. Early diagnosis, broad-spectrum antibiotics, and albumin infusion contribute to the successful management of spontaneous bacterial peritonitis (SBP). Referral for liver transplant evaluation should be considered at the first sign of decompensation and should not be delayed until development of ominous clinical features, such as refractory ascites and SBP.     

Treatment for cirrhotic ascites

Common complications of decompensated liver cirrhosis are esophageal varices, hepatic encephalopathy and ascites. After the onset of complications, the prognosis worsens. In patients with ascites, the 5‐year mortality rate is 44%. Furthermore, hyponatremia, spontaneous bacterial translocation and hepatorenal syndrome also greatly worsen the prognosis. Effective treatment of cirrhotic ascites improves the quality of life and survival rate. Recently, the newly produced diuretic, tolvaptan (vasopressin V2 receptor antagonist), was reported to be effective in the treatment of refractory ascites in liver cirrhosis; however, there has not been an associated positive effect on the prognosis. There are various types of treatment for ascites, such as large‐volume paracenteses, a cell‐free and concentrated ascites reinfusion therapy, a transjugular intrahepatic portosystemic shunt, and a peritoneo‐venous shunt. Although they improve the prognosis, liver transplantation remains the ultimate form of treatment. The present article discusses the therapeutic management of cirrhotic ascites.     

Transjugular intrahepatic portosystemic shunt--role in treating intractable variceal bleeding, ascites, and hepatic hydrothorax

Transjugular intrahepatic portosystemic shunt (TIPS) patency can be improved by the use of covered stents. Although this technical advance may lower the costs associated with TIPS, the overall role of TIPS in the management of portal hypertension may not change. Currently, bare metal TIPS is indicated in the treatment of acute refractory variceal hemorrhage, in the secondary prevention of variceal hemorrhage, for the management of ascites refractory to both medical management and large-volume paracentesis, and in the control of hepatic hydrothorax refractory to medical management.     

The critically ill liver patient: the variceal bleeder

Esophageal varices develop in patients with cirrhosis once portal pressure, measured by hepatic venous pressure gradient, and exceeds 10 mm Hg. At a portal pressure of 12 mm Hg, variceal bleeding may develop that is associated with a mortality of 30% to 50% per episode. In addition to an elevated portal pressure, other risk factors for the development of variceal hemorrhage include: variceal size, endoscopic features on the variceal wall (i.e., red wales), and Child-Pugh class. In patients with suspected variceal hemorrhage, the treatment of the acute episode includes intravascular volume expansion, hemostasis through the use of pharmacological agents and endoscopy, and the prevention and treatment of potential complications associated with variceal hemorrhage such as aspiration pneumonia, spontaneous bacterial peritonitis and hepatic encephalopathy. Given a high rate of rebleeding, long-term prevention through secondary prophylaxis should be instituted in all patients who have survived an episode of variceal bleeding. Current prophylactic options include: non-selective beta-blockers alone (first line) or in combination with long-acting nitrates (isosorbide mononitrate) and/or endoscopic variceal obliteration achieved through sclerotherapy or preferably, band ligation.     

Editorial: Beta-blockers and the prevention of decompensation in cirrhosis: worth the trouble

Non-selective beta-blockers have been a cornerstone of therapy for prevention of esophageal variceal bleeding in cirrhosis patients for more than two decades. When lowering the hepatic vein portal pressure gradient (HVPG) below 12?mm?Hg or decreasing the pressure by 20% from baseline, these drugs are of proven benefit in reducing variceal bleeding and improving survival in this patient population. The recent work by Hendández-Gea et al., suggests that initiation of the beta-blocker nadolol in cirrhosis patients with high-risk varices can delay or prevent the first occurrence of clinically evident ascites. This finding comes with some caveats, however. The beneficial effect was only seen in patients who had an improvement by 10% or more from baseline HVPG pressure (only 51% of the treated patients in this study). This class of medications has some risk and tolerance issues, and many patients do not respond, even when the heart rate is optimally decreased. Despite this, the use of beta-blockers may be beneficial in the primary prevention of the formation of ascites and further decompensation of cirrhosis.     

Management of acute variceal bleeding

Portal hypertension as a consequence of liver cirrhosis is responsible for its most common complications: ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy and the most important one--variceal hemorrhage. Variceal bleeding results in considerable morbidity and mortality. This review covers all areas of importance in the therapy of acute variceal hemorrhage--endoscopic and pharmacological treatment, transjugular intrahepatic portosystemic shunt, surgery and balloon tamponade. Indications and limitations of these therapeutic modalities are widely discussed.     

Gut microflora in the pathogenesis of the complications of cirrhosis

The gut flora plays an important role in the pathogenesis of the complications of cirrhosis. Cirrhotic patients are prone to develop bacterial infections, mainly the 'spontaneous' infection of ascites or spontaneous bacterial peritonitis. Other complications of cirrhosis, such as variceal haemorrhage and ascites, occur mostly or solely as a consequence of portal hypertension. Portal pressure increases initially as a consequence of an increased intrahepatic resistance but, once collaterals have formed, high portal pressure is maintained by an increased splanchnic blood inflow secondary to vasodilatation. Splanchnic vasodilatation is the initiating event in the hyperdynamic circulatory state that aggravates the complications of cirrhosis. The gut flora plays a role in both the development of infections and in the hyperdynamic circulatory state of cirrhosis and, although less prominently, it also plays a role in the pathogenesis of hepatic encephalopathy. This chapter presents evidence regarding gut flora and its modification in the pathogenesis and management of these complications of cirrhosis.     

The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension

Transjugular intrahepatic portosystemic shunt (TIPS) is an interventional radiology technique that has shown a 90% success rate to decompress the portal circulation. As a non-surgical intervention, without requirement for anesthesia and very low procedure-related mortality, TIPS is applicable to severe cirrhotic patients, who are otherwise untreatable, for example, nonsurgical candidates. TIPS constitutes the most frequently employed tool to achieve portosystemic shunting. TIPS acts by lowering portal pressure, which is the main underlying pathophysiologic determinant of the major complications of cirrhosis. Regarding esophagogastric variceal bleeding, TIPS has excellent hemostatic effect (95%) with low rebleeding rate (<20%). TIPS is an accepted rescue therapy for first line treatment failures in 2 settings (1) acute variceal bleeding and (2) secondary prophylaxis. In addition, TIPS offers 70% to 90% hemostasis to patients presenting with recurrent active variceal bleeding. TIPS is more effective than standard therapy for patients with hepatic venous pressure gradient >20mm Hg. TIPS is particularly useful to treat bleeding from varices inaccessible to endoscopy. TIPS should not be applied for primary prophylaxis of variceal bleeding. Portosystemic encephalopathy and stent dysfunction are TIPS major drawbacks. The weakness of the TIPS procedure is the frequent need for endovascular reintervention to ensure stent patency. The circulatory effects of TIPS are an attractive approach for the treatment of refractory ascites and hepatorenal syndrome, yet TIPS is not considered first line therapy for refractory ascites owing to unacceptable incidence of portosystemic encephalopathy. Pre-TIPS evaluation taking into account predictors of outcome is mandatory. The improved results achieved with covered-stents might expand the currently accepted recommendations for TIPS use.     

Issues of malnutrition and bone disease in patients with cirrhosis

Malnutrition is a frequent complication of cirrhosis, and many studies have demonstrated the adverse influence of malnutrition on clinical outcomes in patients with cirrhosis. The coexisting complications of fluid overload and ascites may mask the severity of malnutrition, particularly in the early stages of its development. During periods of decompensation, protein and energy requirements are higher, and many patients have inadequate nutritional intake at these times. Further, protein supplementation should not be restricted ad hoc in cirrhotic patients, as for the vast majority of patients dietary protein does not precipitate hepatic encephalopathy. The impairment of hepatic glycogen storage in cirrhotic patients effects a state of accelerated starvation with catabolism of fat and protein to provide substrates for gluconeogenesis. Recent studies have demonstrated the efficacy of nocturnal nutritional supplements in improving nitrogen balance. Resistance to the actions of the anabolic growth factors insulin and growth hormone (GH) is common in cirrhosis, and recent studies have shown that GH resistance, in particular, may be overcome with exogenous GH therapy. Hypermetabolism may be observed in up to one-third of cirrhotic patients. The recent exciting observation that beta-blocker therapy can decrease energy expenditure and catecholamine levels in these patients indicates the need for further intervention studies of beta-blockers as metabolic therapy in cirrhosis.     

Transjugular intrahepatic portosystemic shunt: current status

The transjugular intrahepatic portosystemic shunt (TIPS) was developed in the 1980s for treatment of complications of portal hypertension. Once it was shown that the shunt could be placed with relative ease, TIPS was rapidly applied to the treatment of many of the complications of portal hypertension. These complications include actively bleeding gastroesophageal varices, prevention of rebleeding from varices, control of refractory cirrhotic ascites and hepatic hydrothorax, and treatment of hepatorenal failure and hepatopulmonary syndrome. TIPS has also been used as therapy for Budd-Chiari syndrome and veno-occlusive disease. Despite these broad applications, TIPS has been compared with other forms of therapy in only 2 situations: prevention of rebleeding from varices and control of refractory cirrhotic ascites. In the trials, TIPS was shown to provide better control of these 2 complications of portal hypertension than standard forms of therapy. However, there was no improvement in survival and the incidence of encephalopathy was greater for patients receiving a TIPS. Thus, the use of TIPS for the control of ascites and prevention of rebleeding from varices should be limited to a select group of patients. There have been no controlled trials for the other indications listed. Despite the apparent efficacy of TIPS in many of these situations, its use should be limited to salvage therapy pending the publication of controlled trials showing it is a better treatment than other forms of therapy.