Beta-adrenergic blockade in cirrhosis – harmful or helpful?

ABSTRACT

Introduction

Portal hypertension exacerbates the disease course of cirrhosis and is responsible for major complications, including bleeding from esophageal varices, ascites, and encephalopathy. More than 40 years ago, Lebrec and colleagues introduced beta-blockers to prevent esophageal bleeding. However, evidence now suggests that beta-blockers may cause adverse reactions in patients with advanced cirrhosis.

Areas covered

This review addresses current evidence for the pathophysiology of portal hypertension, focusing on the pharmacological effects of treatment with beta-blockers, indications for preventing variceal bleeding, their effects on decompensated cirrhosis, and the risk of treating patients suffering from decompensated ascites and renal dysfunction with beta-blockers.

Expert opinion

The diagnosis of portal hypertension should be based on direct measurements of portal pressure. Carvedilol or nonselective beta-blockers are the first-line treatment for patients with medium-to-large varices as primary or secondary prophylaxis, in Child C patients with small varices, and sometimes for patients with clinically significant portal hypertension (HVPG ≥ 10 mm Hg, irrespective of the presence of varices) to prevent decompensation. Caution should be used when treating decompensated patients who are suspected of imminent cardiac and renal dysfunction. Future strategies for managing patients with portal hypertension should aim for more personalized treatment that takes into account the disease stage.

KEYWORDS:

• Portal hypertension
• cardiovascular dysfunction
• hyperdynamic circulation
• esophageal varices
• bleeding
• renal failure
• propranolol
• carvedilol

Article highlights

• Portal hypertension develops in cirrhosis as a consequence of increased intrahepatic resistance and arterial vasodilatation. The primary mechanism for it is increased portal venous inflow.

• The most severe complications of portal hypertension are bleeding from esophageal varices, ascites, and encephalopathy.

• Use of nonselective beta-blockers (NSBB) is now routine in the treatment of patients at risk of variceal bleeding, as they significantly reduce the risk of bleeding, further decompensation, and mortality.

• NSBB, including carvedilol, can exert harmful effects in patients with advanced disease, including refractory ascites and cardiac and renal impairment.

• Carvedilol is the most powerful NSBB for reducing portal pressure and has more potent arterial hypotensive effects because of its alpha-adrenergic activity.

• Patients with decompensated cirrhosis and treated with NSBB should be placed under close surveillance for their cardiocirculatory and renal function.

• Refractory ascites, spontaneous bacterial peritonitis, and acute kidney injury are not incompatible with NSBB, but the dose should be carefully adjusted to avoid severe hypotension.

• A personalized and dynamic strategy should be adopted for patients being treated with NSBB, including frequent and temporary dose adjustments.

Abbreviations

ACLF	=	Acute-on-chronic liver failure
AKI	=	Acute kidney injury
DAMPs	=	Damage-associated molecular patterns
eNOS	=	Endothelial nitric oxide synthase
ET	=	Endothelin
HVPG	=	Hepatic venous pressure gradient
HRS	=	Hepatorenal syndrome
HSC	=	Hepatic stellate cells
IHRV	=	Intrahepatic vascular resistance
LPS	=	Lipopolysaccharides
NSBB	=	Non-selective beta-blocker
PAMP	=	Pathogen-associated molecular patterns
SBP	=	Spontaneous bacterial peritonitis
SEC	=	Sinusoidal endothelial cell
SVR	=	Systemic vascular resistance
TIMP	=	Tissue inhibitor of metalloproteinase 1
VEGF	=	Vascular endothelial growth factor

Declaration of interest

This work was supported by grants from Ferring Pharmaceuticals and the Hvidovre Hospital Research Foundation. SM and FB participated in research studies financed by Boehringer Ingelheim and Astra. The authors have no other conflicts of interest to declare.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.