Non-selective betablockers (NSBBs) represent the cornerstone of pharmacological treatment of portal hypertension.
Grand RoundsBeta adrenergic blockade and decompensated cirrhosis
Section snippets
Clinical scenario 1
A 42-year-old male patient with cirrhosis due to hereditary hemochromatosis with large esophageal varices at endoscopy has been treated with propranolol 120 mg/d for primary prophylaxis of variceal bleeding for 4 years. The patient is undergoing regular phlebotomies to maintain serum ferritin levels of 50–100 μg/L. He presents at the outpatient clinic and reports dizziness and reduced exercise capacity together with weight gain. Edema and new-onset ascites were noted at clinical examination. The
Pathophysiology (Fig. 1)
Both increased intrahepatic vascular (sinusoidal) resistance and increased portal blood flow contribute to the elevated portal pressure in patients with cirrhosis. Clinically significant portal hypertension (CSPH) is defined by a hepatic venous pressure gradient (HVPG) of ⩾10 mmHg. In these patients, porto-systemic collaterals (e.g., esophageal varices) and ascites may develop. Due to progressive splanchnic and peripheral vasodilation, portal hypertension ultimately leads to a hyperdynamic
Diagnostic and prognostic biomarkers
Currently, invasive measurement of HVPG is the only accurate method for diagnosis of portal hypertension [15]. Clinical signs that indicate CSPH are the presence of collaterals on imaging, varices in upper GI endoscopy, or ascites [16]. However, some patients might have CSPH without varices or ascites. Biomarkers such as liver stiffness [17] and spleen stiffness [18] measured by elastography, spleen diameter [19], [20], von-Willebrand factor [21], or simply the platelet count be can used as
Current management with supporting evidence
Endoscopic band ligation is a safe and effective strategy for primary prophylaxis of variceal bleeding in case of intolerance to NSBBs.
Non-selective β-blockers (NSBBs) have been shown to effectively reduce the risk of variceal bleeding [43], [44], [45] and rebleeding [46], [47] due to a reduction of portal pressure. Thus, Baveno VI [16] and AASLD [48] guidelines recommend NSBBs for primary prophylaxis and for secondary prophylaxis (in combination with EBL) of variceal bleeding in patients with
Are NSBBs effective and safe in cirrhotic patients with ascites?
There is no prospective study that assessed the efficacy and safety of NSBBs to prevent variceal bleeding or rebleeding specifically in patients with cirrhosis and ascites. As mentioned previously, most studies on primary and secondary prophylaxis excluded patients with refractory ascites and renal failure. Even if a small number of patients with ascites were included, this does not necessarily imply that NSBBs are as effective and safe in patients with cirrhosis and ascites. We would like to
Therapy beyond guidelines
Based on the currently available data, an individualized NSBB regimen tailored to the specific pathophysiological stage of cirrhosis is likely to be the best strategy to optimize patient management at this point [66]. Treatment recommendations are summarized in Table 2.
Primary prophylaxis: Several studies have demonstrated the superiority of carvedilol over propranolol in reducing portal pressure [63], [67], [68]. However, it is important to point out that carvedilol is also associated with a
Financial support
No financial support was received in relation to this manuscript.
Conflict of interest
T.R. received payments for lectures from Roche, MSD, Boehringer-Ingelheim, and Gore. T.R. received travel support from Gilead, MSD, and Roche. M.M. received honoraria for consulting from Janssen, payments for lectures from Bristol-Myers Squibb, Janssen, Gore, and Roche, as well as travel support from AbbVie, Gilead, MSD, and Roche.
Authors’ contributions
Literature search (T.R., M.M.), concept of the article (T.R., M.M.), extraction of data (T.R., M.M.), drafting of the manuscript (T.R., M.M.), revision for important intellectual content (T.R., M.M.).
References (75)
Pathophysiology of portal hypertension
Clin Liver Dis
(2014)- et al.
A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis
Gastroenterology
(2004) - et al.
Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis
Hepatology
(2003) - et al.
Betablockers induce cardiac chronotropic incompetence
J Hepatol
(2012) - et al.
Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study
J Hepatol
(2011) - et al.
Hepatorenal syndrome: Current concepts related to diagnosis and management
Ann Hepatol
(2016) - et al.
Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension
J Hepatol
(2015) - et al.
Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis
Gastroenterology
(2012) - et al.
Detection of early portal hypertension with routine data and liver stiffness in patients with asymptomatic liver disease: a prospective study
J Hepatol
(2014) - et al.
Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding
Gastroenterology
(2009)
Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis
J Hepatol
Clinical significance of worsening portal hypertension during long-term medical treatment in patients with cirrhosis who had been classified as early good-responders on haemodynamic criteria
J Hepatol
A randomized, controlled trial of medical therapy vs. endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis
Gastroenterology
Keep the sick from harm in spontaneous bacterial peritonitis: Dose of beta blockers matters
J Hepatol
Beta blockers in cirrhosis: The window re-opens
J Hepatol
Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites
J Hepatol
Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites
Gastroenterology
Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure
J Hepatol
Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis
J Hepatol
Hemodynamic events in a prospective randomized trial of propranolol vs. placebo in the prevention of a first variceal hemorrhage
Gastroenterology
The Beneficial Effect of Beta-Blockers in Patients With Cirrhosis, Portal Hypertension and Ascites
Am J Med Sci
Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis
J Hepatol
The anti-inflammatory role of propranolol in cirrhosis: preventing the inflammatory exhaustion?
J Hepatol
When should the beta-blocker window in cirrhosis close?
Gastroenterology
Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis
Hepatology
Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites
Gastroenterology
Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis
World J Gastroenterol
Development of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with portal hypertension
Hepatology
Nonselective beta-blockers in cirrhotic patients with no or small varices: A meta-analysis
World J Gastroenterol
Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis
N Engl J Med
Prevention of progression from small to large varices: are we there yet? An updated meta-analysis
Gut
Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis
Liver Int
The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease
Gut
Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis
Gastroenterology
Measurement of portal pressure and its role in the management of chronic liver disease
Semin Liver Dis
Noninvasive screening for liver fibrosis and portal hypertension by transient elastography–a large single center experience
Wien Klin Wochenschr
Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: The “Anticipate” study
Hepatology
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