Alimentary Pharmacology & Therapeutics | 2021
Editorial: Beta blockers and cirrhosis—more than just portal hypertension?
Abstract
The global burden of chronic liver disease (CLD) is still substantial and shows a rising trend, mostly due to the metabolic syndrome and ongoing alcohol misuse. As a result, mortality has increased in recent years.1 Efforts to improve survival concentrate on treating the cause of CLD. The Nobel laureates Alter, Houghton and Ricethe in 2020 were accredited for their discovery of HCV; equally impressive has been the speed and determination to find its cure and thus improve survival. Furthermore, counteracting mechanisms in decompensated liver disease such as systemic inflammation, oxidative stress and circulatory dysfunction improve survival rates. For instance, the use of antibiotics and, more recently, albumin have impacted outcome in decompensated cirrhosis.2 Hypercoagulability and liver sinusoidal endothelial stress provide additional scientific basis that link circulatory dysfunction to mortality in liver cirrhosis. Finally, the onset of portal hypertension is the main driving force that precedes the deterioration of liver disease. Complications such as ascites, variceal bleeding or hepatic encephalopathy mark the transition from compensated to decompensated cirrhosis and decrease median survival dramatically.3 Since propranolol has been proposed for portal hypertension exactly 40 years ago, nonselective beta blockers (NSBBs) have not left the scene. Splanchnic vasoconstriction, and reduction of heart rate and cardiac output are achieved through β-adrenergic blockade, which leads to reduction in portal venous inflow. Several clinical trials have demonstrated the efficacy of NSBBs in preventing variceal (re)-bleeding and decompensation.4 There has been some controversy on survival with NSBBs especially when refractory ascites is present. However, most studies and meta-analyses have not found solid arguments to withhold NSBBs from these patients.5 Carvedilol is a NSBB that has additional intrinsic anti-α1-adrenergic effects causing intrahepatic vasodilation, which further decreases portal pressure. Comparison to variceal ligation showed increased reduction in bleeding with carvedilol which supports its use first-line for primary prophylaxis.6 Survival benefit of carvedilol can be gathered from three trials involving less than 200 patients. These trials have not shown survival benefit, but had few events and short follow up to draw firm conclusions.7 The debate is ongoing whether primary prophylaxis with carvedilol improves survival by preventing mortality from variceal bleeding or that other mechanisms could be in play.8 MacDowell et al recently reported on the follow up of the cohort consisting of 152 patients who received carvedilol as primary prophylaxis compared to endoscopic band ligation with follow up to 20 years.9 Even although the study has its limitations due to the retrospective design, it demonstrated improved survival but, more important, that this benefit cannot be fully explained by merely reducing liver-related mortality. It is tempting to speculate what additional effects of carvedilol may be responsible. For instance, carvedilol has a metabolic profile that causes less insulin resistance or dyslipidemia.10 NSBBs have also been proposed in the treatment of different cancer types, especially breast cancer, and demonstrated to have a pronounced inhibitory effect on liver cancer cells.11 We should perhaps expand our view on NSBBs in light of survival benefit not only in terms of prevention from bleeding and decompensation but also beyond the liver.