Abstract accepted at EASL2009

Accepted abstract

Abstract was accepted to a liver disease meeting European Association for the Study of the Liver (EASL).

Abstract Synergistic effect of systemic oxidative stress and hyperammonemia are associated with brain edema in rats with chronic liver failure was accepted by European Association for the Study of the Liver (EASL).

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Related Publication

Dose dependent effects of AST-120 (spherical carbon adsorbent) on arterial ammonia, brain edema, and systemic inflammatory marker (TNF-a) in bile duct ligated rats.

Cristina R. Bosoi, Christian Parent-Robitaille, Mélanie Tremblay, Christopher F. Rose.

Background: Ammonia is central in the pathogenesis of hepatic encephalopathy (HE) and clinical sequelae are exacerbated by systemic inflammation. Sequestration of ammonia in the gut represents a primary treatment target for HE. AST-120 (spherical carbon adsorbent), an oral adsorbent of engineered activated carbon microspheres with surface areas exceeding 1600m2/g works as a sink for neuro- and hepato–toxins present in the gut. In this study, we evaluated the capacity of AST-120 to lower arterial ammonia, brain edema and systemic inflammatory markers in cirrhotic rats. Methods: Cirrhosis was induced in rats by bile duct ligation (BDL). BDL and SHAM-operated rats received AST-120 dispersed in methylcellulose by gavage at a dose of 0.1, 1 or 4g/kg/day for 6 weeks. Ammonia and the pro-inflammatory cytokine TNF-α were measured in arterial plasma using a commercially available kit and ELISA technique respectively. Brain water content was measured in the frontal cortex, cerebellum and brain stem using the specific gravimetric technique. Results: Arterial ammonia increased in non-treated BDL vs SHAM-operated controls (166.9±21.1uM vs 70.5±14.4uM, p<0.01). All doses of AST-120 decreased ammonia in BDL to similar levels found in respective SHAM-operated controls; 0.1g/kg/day (117.2±12.6uM vs 100.4±7.3uM, p>0.05); 1g/kg/day (78.9±22.3uM vs 78.1±8.9uM, p>0.05) and 4g/kg/day (48.8±19.6uM vs 49.9±14.7uM, p>0.05). Ammonia levels significantly correlated with doses of AST-120 (r=-0.66, p<0.0001). Brain water content increased in frontal cortex, cerebellum and brain stem in BDL vs SHAM-operated and was normalized in all AST-120 treatment groups compared to respective controls. Circulating levels of TNF-α were significantly increased in BDL vs SHAM-operated rats (p<0.05). AST-120 treatment did not attenuate TNF-α levels compared to respective SHAM-operated controls. Conclusion: AST-120 treatment dose-dependently decreased arterial ammonia levels, which resulted in normalization of multi-foci brain edema. This response was not correlated with differences in levels of circulating TNF-α. AST-120 treatment is a safe, non-antibiotic alternative demonstrating a significant ammonia-lowering effects, as well as a protective effect on the development of brain edema in rats with chronic liver disease. AST-120 represents a useful tool to elucidate further the relationship between circulating ammonia and gut-derived or systemic inflammatory components of liver disease.