Portal hypertension and its complications (variceal bleeding, encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome) are the main cause of death and liver transplantation in patients with cirrhosis. Diminishing portal hypertension by drugs (beta-blockers) is associated with a protection in the development of complications from portal hypertension. For this reason it is important to investigate and develop drugs that can reduce the portal pressure in liver cirrhosis. Tetrahydrobiopterin has been shown to decrease portal pressure in animal models of cirrhosis by improving intrahepatic resistance and by increasing nitric oxide bioavailability (eNOS co-factor). These effects were not associated to deleterious effects on systemic hemodynamics.~This study aims to test if sapropterin (an oral analogue of tetrahydrobiopterin) can play a role in the management of portal hypertension. For this, patients with liver cirrhosis and clinically significant portal hypertension will be randomized to receive sapropterin or placebo for two weeks. Patients will undergo an hepatic vein catheterization to asses the hepatic venous pressure gradient (HVPG), and those having and HVPG of 10 mmHg or higher will be randomized to receive sapropterin or placebo. Swan-Ganz catheterization, systemic measurements, and hepatic blood flow by indocyanine green method will also be performed. Patients will receive sapropterin or placebo for two weeks at a dosage of 5 mg/kg/d in the first week, increasing to 10 mg/kg/d in the second week if there are no adverse events or intolerance. A second systemic and hepatic hemodynamic study will be performed after 2 weeks of treatment to assess changes.~Changes in laboratory tests, liver function (Child-Pugh and MELD scores), endothelial dysfunction and oxidative stress markers (Von Willebrand Factor, Malondialdehyde) will be monitored during the study. As sapropterin has been never evaluated in cirrhotic patients, tolerance and adverse effects related to the medication will be registered.~The study will be stratified according to previous beta-blocker therapy (receiving or not receiving beta-blockers).
The purpose of this study is to determine whether sapropterin (an oral analogue of tetrahydrobiopterin) could have a role in the treatment of portal hypertension secondary to liver cirrhosis. Sapropterin or placebo will be given for two weeks in patients with liver cirrhosis and clinically significant portal hypertension. Systemic and hepatic hemodynamics studies will be performed at baseline and after the intervention to assess the effect of sapropterin.