Javier Vaquero

Mechanisms of brain edema in acute liver failure and impact of novel therapeutic interventions

Abstract Continued elucidation of the mechanisms of brain edema in acute liver failure (ALF) has established ammonia and the astrocyte as major players in its pathogenesis. The metabolism of ammonia to glutamine appears to be a requisite, and is followed by an osmotic disturbance in the brain, mitochondrial dysfunction with oxidative/nitrosative stress, and alterations of brain glucose metabolism. Cerebral blood flow (CBF) is also altered in ALF and strongly influence the development of brain edema and intracranial hypertension. Additional factors such as systemic inflammation, alterations of the brain extracellular concentration of amino acids and neurotransmitters, and others have been identified and may contribute to the cerebral alterations of ALF. Such pathophysiologic insights are reflected in the various clinical trials of novel therapeutic interventions using ammonia-lowering agents, N-acetylcysteine, hypertonic saline, indomethacin, high-volume plasmapheresis, bio-artificial liver assist devices, albumin dialysis and mild hypothermia.

N-Acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms

N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100xa0µg/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2xa0g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.

The brain glutamate system in liver failure

Liver failure results in significant alterations of the brain glutamate system. Ammonia and the astrocyte play major roles in such alterations, which affect several components of the brain glutamate system, namely its synthesis, intercellular transport (uptake and release), and function. In addition to the neurological symptoms of hepatic encephalopathy, modified glutamatergic regulation may contribute to other cerebral complications of liver failure, such as brain edema, intracranial hypertension and changes in cerebral blood flow. A better understanding of the cause and precise nature of the alterations of the brain glutamate system in liver failure could lead to new therapeutic avenues for the cerebral complications of liver disease.

Lack of assessment of body temperature in mice with acetaminophen toxicity

1. Cammà C, Bruno S, Di Marco V, Di Bona D, Rumi M, Vinci M, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. HEPATOLOGY 2006;43:64-71. 2. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;126:586-597. 3. Lonardo A, Carani C, Carulli N, Loria P. Endocrine NAFLD. A hormonocentric perspective of Non-Alcoholic Fatty Liver Disease pathogenesis. J Hepatol 2006;44:1196-1207. 4. Carulli L, Lombardini S, Lonardo A, Leonardi F, Bertolotti M, Ricchi M, et al. Non-alcoholic fatty liver (NAFLD). Is female sex safer? [Abstract]. J Hepatol 2004;40(Suppl):168A. 5. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. HEPATOLOGY 2003;37:917-923. 6. Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005;330:932-937. 7. Johnson CL, Rifkind BM, Sempos CT, Carroll MD, Bachorik PS, Briefel RR, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993;269:3002-3008. 8. McKenzie J, Jaap AJ, Gallacher S, Kelly A, Crawford L, Greer IA, et al. Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk? Clin Endocrinol (Oxf) 2003;59:682-689. 9. Marchesini G, Avagnina S, Barantani EG, Ciccarone AM, Corica F, Dall’Aglio E, et al. Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome. J Endocrinol Invest 2005;28;333-339. 10. Lonardo A, Lombardini S, Scaglioni F, Carulli L, Ricchi M, Ganazzi D, et al. Hepatic steatosis and insulin resistance: Does etiology make a difference? J Hepatol 2006;44:190-196.