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Pathogenesis of hepatic encephalopathy: lessons from nitrogen challenges in man

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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.

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Authors and Affiliations

  1. Institute of Cellular Medicine, The Medical School, Newcastle University, NE2 4HH, Newcastle u Tyne, UK

    Hanan Mardini & Christopher Record

  2. Royal Victoria Infirmary, Ward 48 Office, Newcastle u Tyne, NE1 4LP, UK

    Christopher Record

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  1. Hanan Mardini
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  2. Christopher Record
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Correspondence to Christopher Record.

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Mardini, H., Record, C. Pathogenesis of hepatic encephalopathy: lessons from nitrogen challenges in man. Metab Brain Dis 28, 201–207 (2013). https://doi.org/10.1007/s11011-012-9362-2

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  • DOI: https://doi.org/10.1007/s11011-012-9362-2

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