ornithine-phenylacetate and Hypertension--Portal

Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin).. Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation).. This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.

Topics: Amino Acids, Aromatic; Amino Acids, Branched-Chain; Ammonia; Dipeptides; Fecal Microbiota Transplantation; Frailty; Gastrointestinal Agents; Gastrointestinal Microbiome; Glycerol; Hepatic Encephalopathy; Humans; Hypertension, Portal; Lactulose; Liver Cirrhosis; Ornithine; Phenylbutyrates; Polyethylene Glycols; Probiotics; Rifaximin; Trace Elements; Zinc

Hepatic stellate cells (HSCs) are vital to hepatocellular function and the liver response to injury. They share a phenotypic homology with astrocytes that are central in the pathogenesis of hepatic encephalopathy, a condition in which hyperammonemia plays a pathogenic role. This study tested the hypothesis that ammonia modulates human HSC activation in vitro and in vivo, and evaluated whether ammonia lowering, by using l-ornithine phenylacetate (OP), modifies HSC activation in vivo and reduces portal pressure in a bile duct ligation (BDL) model.. Primary human HSCs were isolated and cultured. Proliferation (BrdU), metabolic activity (MTS), morphology (transmission electron, light and immunofluorescence microscopy), HSC activation markers, ability to contract, changes in oxidative status (ROS) and endoplasmic reticulum (ER) were evaluated to identify effects of ammonia challenge (50 μM, 100 μM, 300 μM) over 24-72 h. Changes in plasma ammonia levels, markers of HSC activation, portal pressure and hepatic eNOS activity were quantified in hyperammonemic BDL animals, and after OP treatment.. Pathophysiological ammonia concentrations caused significant and reversible changes in cell proliferation, metabolic activity and activation markers of hHSC in vitro. Ammonia also induced significant alterations in cellular morphology, characterised by cytoplasmic vacuolisation, ER enlargement, ROS production, hHSC contraction and changes in pro-inflammatory gene expression together with HSC-related activation markers such as α-SMA, myosin IIa, IIb, and PDGF-Rβ. Treatment with OP significantly reduced plasma ammonia (BDL 199.1 μmol/L±43.65 vs. BDL+OP 149.27 μmol/L±51.1, p<0.05) and portal pressure (BDL 14±0.6 vs. BDL+OP 11±0.3 mmHg, p<0.01), which was associated with increased eNOS activity and abrogation of HSC activation markers.. The results show for the first time that ammonia produces deleterious morphological and functional effects on HSCs in vitro. Targeting ammonia with the ammonia lowering drug OP reduces portal pressure and deactivates hHSC in vivo, highlighting the opportunity for evaluating ammonia lowering as a potential therapy in cirrhotic patients with portal hypertension.

Topics: Ammonia; Animals; Cell Proliferation; Cells, Cultured; Endoplasmic Reticulum; Hepatic Stellate Cells; Humans; Hypertension, Portal; Male; Ornithine; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species