Hepatic encephalopathy hyperammonemia

Ferenci P, Pappas SC, Munson PJ, Jones AE Changes in glutamate receptors on synaptic membranes associated with hepatic encephalopathy or hyperammonemia in the rabbit. Hepatology 1984 4 25-29. 

Carbonic anhydrase inhibitor-induced alkalinization of the urine decreases urinary excretion of NH4+ (by converting it to rapidly reabsorbed NH3) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis. 

Valproate-induced hyperammonemic encephalopathy has been reviewed (1177). Proton magnetic resonance spectroscopy was performed in a patient with valproate-induced hyperammonemic encephalopathy there was a significant fall in the choline and myoinositol resonances and an increase in glutamine in the hyperintense basal ganglia lesions (1178). A similar pattern has been observed in other hyperammonemic encephalopathies, such as hepatic encephalopathy. In another study in seven patients with valproate-related hyperammonemia serum or cerebrospinal fluid glutamine concentrations were initially raised in most patients, sometimes in the absence of hyperammonemia (1179). 

Rao K. V. and Norenberg M. D. (2001). Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis. 16 67-78. 

Because the CNS is sensitive to ammonia, its metabolism in the brain and the neurotoxicity associated with hyperammonia and hepatic encephalopathy (the proximate source of damage in the latter is also ammonia) is reviewed here. Hepatic encephalopathy (HE) or congenital and acquired hyperammonemia result in excessive ammonia accumulation within the CNS. The condition is due... 

Hyperammonemias are caused by inborn errors of ureagenesis and organic acidemias, liver immaturity (transient hyperammonemia of the newborn), and liver failure (hepatic encephalopathy). Neonatal hyperammonemias are characterized by vomiting, lethargy, lack of appetite, seizures, and coma. The underlying defects can be identified by appropriate laboratory measurements (e.g., assessment of metabolic acidosis if present and characterization of organic acids, urea cycle intermediates, and glycine). 

Als-Nielsen, B., L.L. Gluud, and C. Gluud, 2004. Non-absorbable disaccharides for hepatic encephalopathy Systematic review of randomised trials. Bmj, 328(7447) p. 1046 Azzopardi, J., et al.2002. Lack of evidence of cerebral oedema in adults treated for diabetic ketoacidosis with fluids of different tonicity. Diabetes Res CUn Pract, 57(2) pp. 87-92 Bachmann, C., 2002. Mechanisms of hyperammonemia. CUn Chem Lab Med, 40(7) pp. 653-662 Bhowmick, S.K., Levens, K.L. andRettig, K.R. 2005. Hyperosmolar hyperglycemic crisis An acute life-threatening event in children and adolescents with type 2 diabetes mellitus. Endocr Pract, 11(1) pp. 23-29... 

Verkhratsky A, Kirchhoff F. NMDA receptors in gUa. The Neuroscientist, 13(1), 2S-37, 2007 Vogels BA, Maas MA, Daalhuisen J, Quack G, Chamuleau RA. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology, 25, 820-827, 1997 Weber EL Jr, Veach GL. The importance of the small intestine in gut ammonium production in the fasting dog. Gastroenterology, 77, 235-240, 1979... 

As hyperammonemia is considered to be the main cause of hepatic encephalopathy, specific therapy for HE is aimed at the reduction of anunonia production and resorption. Protein restriction has been recommended for a long time to reduce ammonia production. But patients with cirrhosis are hypercatabolic. They may require up to 1.5 g/kg protein per day. Therefore protein restriction has been limited to patients with severe hepatic encephalopathy, and a reduction to less than 1 g protein per kg body weight has been discouraged in the past. A recent clinical study even showed no benefits of protein restriction (Cordoba et al., 2004). 30 cirrhotics who were admitted to the hospital with hepatic encephalopathy were randomized to a low-protein diet or normal protein diet. After two weeks of treatment, the groups did not significantly differ with regard to the course of hepatic encephalopathy. 

Transient rises of transaminase levels have been observed, without evidence of liver toxicity. Hyperammonemia with encephalopathy has been observed with therapeutic levels and in overdose, and without other evidence of hepatic dysfunction. 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

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