title: Pathogenesis of hepatic encephalopathy: lessons from nitrogen challenges in man.
abstract: Induction of hyperammonaemia with nitrogen challenge in man can be used to study the pathogenesis and treatment of hepatic encephalopathy complicating cirrhosis. Initially 20 g of glutamine was given orally as a flavored solution which resulted in doubling of blood ammonia concentration and this was associated with a deterioration in performance of the choice reaction time. The effect could have been due to a direct effect of glutamine rather than the ammonia generated so in subsequent experiments a glutamine free mixture of amino acids resembling the composition of haemoglobin was used (gastrointestinal bleeding is a known precipitant of hepatic encephalopathy). In Child grade B and C patients, 2-3 h after 54 g, slowing of the EEG was observed. The cerebral effects of induced hyperammonaemia were studied with diffusion weighted imaging and MR spectroscopy after giving 54 g of a mixture of threonine, serine and glycine when apparent diffusion coefficient increased. Also the change in ammonia levels correlated with the change in cerebral glutamine levels (r = 0.78, p = 0.002) suggesting intra cerebral formation of glutamine from ammonia and this may have accounted for the fall in cerebral myoinositol concentrations observed. Finally a colonic source for ammonia was confirmed by administering urea using colon coated capsules when ammonia concentrations slowly increased from 5 h after administration and rapidly after 10 h. In two patients the hyperammonaemia was ameliorated by pre treatment with Rifaximin 1200 mg per day for 1 week. Nitrogen challenge studies are thus a valuable model for studying new treatments for hepatic encephalopathy without the need to simultaneously treat precipitating factors.
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, NE2 4HH Newcastle u Tyne, UK.
authors.forename: Hanan
authors.initials: H
authors.lastname: Mardini
authors.forename: Christopher
authors.initials: C
authors.lastname: Record
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000097:blood / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000378:metabolism; D005973:Glutamine; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000473:pathology*; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D005973:Glutamine; D000641:Ammonia; D009584:Nitrogen