Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?
Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of β-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient.
Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. Electronic address: maja.thiele@rsyd.dk.
Maja
M
Thiele
Reiner
R
Wiest
Lise Lotte
LL
Gluud
Agustín
A
Albillos
Aleksander
A
Krag
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control*; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000517:prevention & control
D000319:Adrenergic beta-Antagonists
BT; HCC; HCV; HVPG; LPS; NSBB; PAMP; TIPS; TLR4; Toll Like Receptor 4; VEGF; bacterial translocation; beta-adrenoceptors; hepatic venous pressure gradient; hepatitis C virus; hepatocellular carcinoma; lipopolysaccharide; non-selective beta-blockers; pathogen-associated molecular pattern; transjugular intrahepatic portosystemic shunt; vascular endothelial growth factor; β-AR