Metabolic Brain Disease

, Volume 28, Issue 2, pp 201–207

Pathogenesis of hepatic encephalopathy: lessons from nitrogen challenges in man

Original Paper

DOI: 10.1007/s11011-012-9362-2

Cite this article as:
Mardini, H. & Record, C. Metab Brain Dis (2013) 28: 201. doi:10.1007/s11011-012-9362-2


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.


AmmoniaAmino acidsHepatic encephalopathy

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Institute of Cellular Medicine, The Medical SchoolNewcastle UniversityNewcastle u TyneUK
  2. 2.Royal Victoria InfirmaryNewcastle u TyneUK