Abstract at EASL 2013

Résumé accepté

Two abstracts will be presented at meeting of the European Association for the Study of the Liver.

The 48^th Annual Meeting European Association for the Study of the Liveris held April 24^th-28^th, in Amsterdam, The Netherlands.

Two posters will presented during "Cirrhosis and its complications: Pathophysiology" session on April 26^th.

Related Publications

Attenuation of oxidative stress protects the brain in rats with “acute-on-chronic” liver failure.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Background: Acute-on-chronic liver failure (ACLF) is defined as an acute decompensation of chronic liver disease. Brain edema is frequently observed in hepatic encephalopathy associated with both acute and chronic liver disease. While in acute liver failure, toxic levels of ammonia induce cerebral oxidative stress and brain edema, in chronic liver disease, systemic (not central) oxidative stress and hyperammonemia synergistically cause brain edema. This study investigated the role of both systemic and central oxidative stress and ammonia in relation to brain edema in a rat model of ACLF. Methods: ACLF was induced in male Sprague-Dawley rats by portacaval shunt (PCA), followed 4 weeks later by hepatic artery ligation (HAL). Acute liver failure (ALF) induced by concomitant PCA and HAL, PCA (4 weeks) and SHAM-operated rats were used as controls. ACLF rats were divided into 2 groups that were sacrificed at: 1) coma stage of hepatic encephalopathy (defined as loss of corneal reflex) (ACLF-C) and 2) in parallel with ALF-induced coma (ACLF-P) rats. Brain edema (specific gravimetric technique), ammonia levels (commercial kit) and oxidative stress markers (plasmatic and cerebral reactive oxygen species, fluorescence spectroscopy) were evaluated along with hepatic function (routine biochemistry, haematoxylin-phloxine-saffron histopathology). Results: Coma was delayed by 8h in ACLF compared to ALF rats (p< 0.01). Liver biochemistry markers did not differ between ACLF-C, ACLF-P and ALF rats; liver histopathology showed mild necrosis in ACLF-P, moderate in ALF and severe in ACLF-C. Brain water content was significantly attenuated in both ACLF-C and ACLF-P vs. ALF rats (p< 0.01). Arterial ammonia concentration followed a similar pattern: they were attenuated in ACLF-C: 0.35±0.07 mM and ACLF-P: 0.49±0.14 mM vs. ALF: 1.34±0.09 mM (p< 0.001), but remained high compared to SHAM: 0.06±0.01 mM (p< 0.001). Systemic oxidative stress was present in both ACLF and ALF rats, while cerebral oxidative stress was present only in ALF rats. Conclusion: Brain edema, ammonia levels and oxidative stress are reduced in ACLF rats compared to ALF rats. These findings suggest that during chronic liver failure, compensatory mechanisms that prevent the apparition of brain edema and attenuate oxidative stress during an acute deterioration are developed.

Systemic oxidative stress induction aggravates hepatic encephalopathy in hyperammonemic portacaval-shunted rats.

Cristina R. Bosoi, Mélanie Tremblay, Christopher F. Rose.

Background: Liver failure/disease leads to hyperammonemia, a central component in the pathogenesis of hepatic encephalopathy. There is increasing evidence that oxidative stress exacerbates the neuropsychological effects of hyperammonemia in patients with liver disease, possibly by inducing brain edema. The latter represents a common entity in cirrhotic patients with hepatic encephalopathy. Since rats following 4-week portacaval anastomosis (PCA) become hyperammonemic but do not develop oxidative stress or brain edema, we aimed to investigate the impact of oxidative stress on the development of brain edema in this rat model. Methods: Oxidative stress was induced following glutathione (GSH) depletion by diethyl maleate (DEM). PCA and SHAM-operated rats received DEM (1 mg/kg/day intraperitoneally) for 10 days starting at day 18 after surgery. Rats were sacrificed at day 28 and oxidative stress markers, such as glutathione (GSH), malon-dialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) were assessed in arterial plasma and brain (frontal cortex) tissue. Plasma ammonia and liver function markers (AST, ALT, bilirubin) were also evaluated. Brain water content was measured using a specific gravimetric technique. Results: DEM induced a significant decrease in plasmatic GSH, which lead to an increase in arterial MDA (2.5 fold) and HNE (1.4 fold) levels in PCA rats compared to non-treated PCA rats. An increase in brain water content was observed in DEM-treated PCA rats vs non-treated PCA rats (PCA+DEM: 78.45 ± 0.13% vs PCA: 77.38 ± 0.11%, p< 0.001). In the brain, oxidative stress markers measured in the frontal cortex did not differ between the two groups. DEM treatment did not affect the degree of hyperammonemia or lead to an alteration in liver function in comparison to non-treated PCA rats. Conclusions: DEM induced systemic, not central, oxidative stress in PCA rats. This, imposed on hyperammonemia, resulted in an increase in brain water content. Since oxidative stress and brain edema were not detected in non-treated hyperammonemic PCA rats, together our findings suggest that a synergistic effect between hyperammonemia and systemic oxidative stress is implicated in the pathogenesis of brain edema in hepatic encephalopathy.