Ornithine Phenylacetate: A Novel Strategy for the Treatment of Hepatic Encephalopathy

Over the past 100 years a central role of ammonia in the pathogenesis of hepatic encephalopathy (HE) has been hypothesized. Treatment of hyperammonemia and HE are unmet clinical needs. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. Ammonia-mediated mechanisms include changes in neurotransmitter synthesis and release, neuronal oxidative stress, impaired mitochondrial function, and osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine. Systemic hyperammonemia has been largely found in patients with HE with underlying cirrhosis and acute liver failure (ALF). The mechanism by which OP directly reduces ammonia levels in cirrhosis is by increasing muscle glutamine synthesis activity, subsequently trapping and increasing ammonia excretion as phenylacetylglutamine, with the concomitant normalization of gut glutaminase activity. The reduction of ammonia (by OP) leads to a reduction in intracranial hypertension in models of ALF and is associated with an improvement in inflammation and nitric oxide availability in the context of cirrhosis. Studies to date have indicated that it is safe and patient studies in minimal HE and overt HE are underway to establish OP as a treatment for this major complication of liver disease.