Relationship between Tetrahydrobiopterin and Portal Hypertension in Patients with Chronic Liver Disease

Tetrahydrobiopterin (BH4) is an essential cofactor in NO synthesis by endothelial nitric oxide synthase (eNOS) enzymes. It has been previously suggested that reduced intrahepatic BH4 results in a decrease in intrahepatic NO and contributes to increased hepatic vascular resistance and portal pressure in animal models of cirrhosis. The main aim of the present study was to evaluate the relationship between BH4 and portal hypertension (PHT). One hundred ninety-three consecutive patients with chronic liver disease were included in the study. Liver biopsy, measurement of BH4 and hepatic venous pressure gradient (HVPG) were performed. Hepatic fibrosis was classified using the Laennec fibrosis scoring system. BH4 levels were determined in homogenized liver tissues of patients using a high performance liquid chromatography (HPLC) system. Statistical analysis was performed to evaluate the relationship between BH4 and HVPG, grade of hepatic fibrosis, clinical stage of cirrhosis, Child-Pugh class. A positive relationship between HVPG and hepatic fibrosis grade, clinical stage of cirrhosis and Child-Pugh class was observed. However, the BH4 level showed no significant correlation with HVPG or clinical features of cirrhosis. BH4 concentration in liver tissue has little relation to the severity of portal hypertension in patients with chronic liver disease. Graphical Abstract Keywords: Hypertension, Portal; Nitric Oxide; Liver Cirrhosis INTRODUCTION Portal hypertension (PHT) is a common clinical consequence of chronic liver disease that is characterized by a pathological increase in portal venous pressure and is associated with significant morbidity and mortality (1-3). Portal pressure can be increased by a rise in portal blood flow, an increase in vascular resistance, or both. In cases of cirrhosis, increased intrahepatic resistance to portal blood flow is the primary factor leading to PHT. Although this increase is largely attributable to the structural changes of the liver architecture caused by the cirrhotic process, there is also a dynamic and reversible component that represents up to 30%-40% of the total increased intrahepatic vascular resistance in cirrhosis (4). Various vasoactive substances contribute to the development of PHT. Among these, nitric oxide (NO) is one of the important mediators that paradoxically regulates the intrahepatic and splanchnic/systemic circulation (5-7). Splanchnic overproduction and intrahepatic deficit of endothelial NO contributes to the hyperdynamic circulation. Impairment of the endothelium-dependent response to vasodilatation, a condition that has been called "endothelial dysfunction", is considered one of the mechanisms that leads to the increased vascular tone of cirrhotic liver (8). Indeed, endothelial dysfunction has been attributed to reduced NO bioavailability and to increased vasoconstrictor cyclooxygenase-1 derived prostanoids (9, 10). Tetrahydrobiopterin (BH4) is an essential cofactor for the adequate generation of NO by nitric oxide synthase enzymes (11-13). If adequate quantities of BH4 are not present, NOS uncoupling will occur and the production of NO is decreased. Previous studies have shown that there is a deficiency of BH4 in cirrhotic livers, secondary to a reduction in the expression and activity of the rate-limiting enzyme in BH4 synthesis, guanosine triphosphate-cyclohydrolase I (GTPCH), which is associated with decreased NOS activity and NO availability (14). In a study of carbon tetrachloride (CCl4)-induced cirrhosis in rats, the exogenous administration of BH4 for 3 days increased liver NOS activity and cyclic guanosine monophosphate (cGMP) levels and significantly reduced portal pressure (15). However, clinical studies of BH4 have not been conducted. The present study evaluated the relationship between BH4 and PHT, the histological grades of hepatic fibrosis using the Laennec scoring system, the clinical stage of cirrhosis and the grade of varices. In addition, we investigated the relationship between PHT and clinical outcomes.