Hepatic tissue endothelin-1 levels in chronic liver disease correlate with disease severity and ascites.

Objectives: Plasma endothelin-1 (ET-1) levels are increased in patients with cirrhosis and ET-1 production is increased in the liver itself during experimental injury. These data suggest a possible role for this vasoactive peptide in intrahepatic microcirculatory changes that contribute to the pathogenesis of portal hypertension in cirrhosis. Therefore the aims of this study were to determine whether ET-1 levels were abnormal in the livers of patients with cirrhosis and to investigate possible clinical correlates of altered hepatic ET-1 in cirrhosis.

Methods: Liver specimens were obtained from explants at the time of liver transplantation in 62 cirrhotic patients; 49 without pretransplantation transjugular intrahepatic portosystemic shunt (TIPS) and 13 with pretransplantation TIPS. The presence of ascites was evaluated by physical examination and ultrasonography. Control specimens consisted of livers with normal morphology obtained from patients who died from nonliver-related causes. Hepatic ET-1 was measured by enzyme immunoassay.

Results: Hepatic ET-1 levels in cirrhotics without (0.17 pg/mg liver tissue) or with TIPS (0.12 pg/mg) were higher than in control patients [0.04 pg/mg (p = 0.02 for ET-1 levels in cirrhotics with or without TIPS vs. control)]. In cirrhotics without ascites who had not had TIPS, ET-1 levels (0.07 pg/mg [0.04-1.00]) were similar to those of the controls. In contrast, ET-1 content was increased in cirrhotics with small (0.11 pg/mg; p = 0.0002) and moderate-to-large (0.69 pg/mg; p = 0.0002) amounts of ascites compared to patients without ascites. There was a modest correlation between ET-1 levels and Child-Pugh score (correlation coefficient 0.32; p = 0.03) and ET-1 levels were significantly higher in patients with Child-Pugh score of 13 or greater (0.88 pg/mg; p = 0.02) than in those with Child-Pugh score of 12 or less (0.16 pg/mg).

Conclusions: Hepatic tissue ET-1 levels are increased in the liver of patients with cirrhosis. This increase appears to be proportional to the severity of both liver disease and ascites. These data raise a possible role for ET-1 in modulation of intrahepatic resistance in cirrhotic portal hypertension.