The Role of Nitric Oxide in Chronic Liver Disease: A Review

Nitric oxide (NO) is a crucial regulator of hepatic and systemic vascular tone. Abnormal distribution of NO in various anatomical locations is a pathogenetic characteristic of portal hypertension. Under normal portal pressure conditions, liver sinusoidal endothelial cells produce NO, which promotes both vasodilation and hepatic stellate cell relaxation. In portal hypertension, endothelial dysfunction, imbalance of asymmetric dimethylarginine levels, and production of superoxide result in impaired intrahepatic NO availability, leading to activation and contraction of hepatic stellate cells and worsening portal hypertension. Excess extrahepatic NO levels in the splanchnic vasculature result in systemic vasodilation, hyperdynamic circulation, and collateral vascular formation, worsening portal pressure. Abnormal clearance and production of NO can lead to extrahepatic complications, including hepatorenal syndrome and hepatopulmonary syndrome. Therapies including statins, phosphodiesterase-5 inhibitors, and midodrine have been developed to restore NO homeostasis but have achieved only partial success in modulating NO production, bioavailability, and distribution. The aim of this review is to update the understanding of the mechanisms and effects of NO dysregulation in cirrhosis as they relate to current and future therapeutic options.