Shawcross, D.L.; Davies, N.A.; Deutz, N.E.P.; Williams, R.; Jalan, R.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA104
Academic Journal
Background: The neuropsychological effects of hyperammonaemia in cirrhosis are well described. However, the amount of ammonia (NH[sub 3]) generated bears little relation to the manifest symptoms. It is probable that other factors in addition to hyperammonemia are required to cause the observed mental deterioration. We hypothesise that inflammatory mediators, such as nitric oxide (NO) and proinflammatory cytokines, exacerbate the response to NH[sub 3]. To test this, we compared patients with cirrhosis during and after recovery from infection. Methods: 10 patients with cirrhosis of varying aetiology (6 male, mean age 52 (43-61)) were studied within 24 hours of admission for infection, and post-antibiotic therapy, mean 9 (7-12) days, afterwards. Hyperammonaemia was induced via a simulated upper gastrointestinal bleed by the administration of a haemoglobin mimic, amino acid solution. Blood sampling and a battery of neuropsychological tests were undertaken. Results: The NH[sub 3] generated in response to the simulated bleed did not differ on admission and following antibiotic therapy (p = 0.6). No differences were found in indices of liver function. Inflammatory markers were reduced with resolution of the infection (White cell count (WCC) p < 0.001, C reactive protein (CRP) p < 0.001), as were measured inflammatory mediators (NO[sub x] p < 0.001, Interleukin 6 (IL 6) p < 0.001). The deterioration in neuropsychological function brought about by induced hyperammonemia and assessed by digital symbol substitution test, randt memory and choice reaction time were significantly greater when the patients showed evidence of on going inflammation. Conclusion: Our results support a critical role for NH[sub 3] in the pathogenesis of hepatic encephalopathy. We show for the first time that the neuropsychological effects of hyperammonemia in cirrhosis may be modulated by the inflammatory state of the patient.


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