The window hypothesis: haemodynamic and non-haemodynamic effects of β-blockers improve survival of patients with cirrhosis during a window in the disease: Figure 1

Abstract

Cirrhosis is one of the most frequent and severe chronic diseases worldwide. In the initial stages it has few or no symptoms, but advanced stages of cirrhosis are characterised by reduced liver function, complications due to portal hypertension and neuroendocrine abnormalities with increased activity of the sympathetic nervous system (SNS) and renin-aldosterone axis. The prognosis is severe, with an increasing frequency of complications including variceal bleeding, ascites and spontaneous infections with subsequent development of hepatic encephalopathy and hepatorenal syndrome. More than one-third of patients diagnosed with cirrhosis develop oesophageal varices within 3 years after the diagnosis is made. Varices develop and later bleed when the portal pressure is increased and the hepatic vein pressure gradient (HVPG) is more than 10–12 mm Hg. Life-threatening spontaneous bacterial infections are another common complication of advanced cirrhosis. The infections are mainly triggered by gut bacterial translocation, which is the migration of microorganisms from the intestinal lumen to the mesenteric lymph nodes or other extraintestinal sites.1 Small intestinal bacterial overgrowth of Gram-negative rods, structural and functional alterations of the intestinal mucosa and deficiencies in defence mechanisms contribute to bacterial translocation.2 Increased serum levels of lipopolysaccharide binding protein and circulating bacterial DNA are markers of bacterial translocation and both predict a poor outcome in cirrhosis and ascites.3 4 Selective gut decontamination prevents spontaneous bacterial infections and improves survival in advanced cirrhosis.5 Non-selective β-blockers (BB) are the only drugs shown to improve survival in patients with cirrhosis and medium to large oesophageal varices.6 BB inhibit the binding of catecholamines (norepinephrine and epinephrine) to the β1 and β2 adrenoreceptors. β1 blockade reduces the cardiac output and β2 blockade leads to splanchnic …