ornithine-phenylacetate and Brain-Edema

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.

Topics: Albumins; Ammonia; Anti-Bacterial Agents; Bile Acids and Salts; Brain; Brain Edema; Cognitive Dysfunction; Dipeptides; Energy Metabolism; Gastrointestinal Agents; Hepatic Encephalopathy; Humans; Lactulose; Liver Cirrhosis; Ornithine; Portasystemic Shunt, Surgical; Prognosis; Psychometrics; Severity of Illness Index; Synaptic Transmission

In liver failure, inflammation synergistically exacerbates the deleterious cerebral effects of ammonia. The aims were to test whether treatment with the ammonia-lowering agent ornithine phenylacetate (OP) and/or anti-TNF-α (infliximab) prevent the deleterious brain consequences of lipopolysaccharide (LPS) in cirrhotic rats.. Rats 4 weeks following bile duct-ligation (BDL), sham-operation (sham) and/or 7 days hyperammonemic feed (HD), were randomized to receive LPS (1 mg/kg) or saline, and treatment with either 3 days intraperitoneal injections of OP (0.6 g/kg) and/or infliximab, 10 mg/kg. Animals were sacrificed at coma stages or at 3 h.. In sham rats, both HD and LPS increased brain water, with an increase in ammonia in the former and brain cytokines in the latter but with no effect on consciousness. BDL + HD rats caused significantly higher plasma ammonia, TNF-α and IL-6 levels compared to sham. LPS significantly worsened coma stage, increased brain water and plasma and brain TNF-α. OP significantly delayed LPS-induced progression to coma stages (P < 0.009), reduced arterial ammonia and brain water (P < 0.001 and P < 0.01 respectively), which was associated with a significant reduction in cytokines. Infliximab significantly reduced plasma and brain cytokines, but not brain water. OP + infliximab attenuated increase in brain water and delayed occurrence of coma, which was not different to OP alone. In BDL rats, OP reduced the expression of brain iNOS and NFκB.. Reduction in ammonia with OP in cirrhotic rats prevents LPS-induced brain edema and delays coma, suggesting that ammonia may prime the brain to the deleterious effect of LPS, possibly through effects on iNOS and NFκB related mechanisms.

Topics: Animals; Antibodies, Monoclonal; Bile Ducts; Blotting, Western; Body Water; Brain; Brain Edema; Cytokines; Hyperammonemia; Infliximab; Injections, Intraperitoneal; Interleukin-6; Ligation; Lipopolysaccharides; Liver Cirrhosis; Ornithine; Rats; Tumor Necrosis Factor-alpha