Introduction Induction of hyperammonaemia from glutaminase action in the small intestine1 or systemic catabolism of oral amino acids2 3 is well recognised but, although suggested in 1959 by Walser and Bodenlos,4 ureolysis resulting in hyperammonaemia has not been demonstrated from urea delivered to the colon. Hepatic encephalopathy (HE) is now thought to be caused by cerebral oedema.
Aim We hypothesised that if hyperammonia is a key factor in hepatic encephalopathy, induced hyperammonaemia from oral amino acid or urea challenge would lead to transient changes in brain water distribution and metabolite concentration.
Method Amino acid (mixture of equal parts of glycine, serine and threonine) or urea challenges were undertaken in 18 patients with stable cirrhosis 5 of whom gave a history of hepatic encephalopathy. Sequentail blood ammonia concentration was determined with the ammonia checker and brain water and metabolites with magnetic resonance diffusion tensor imaging and spectroscopy.
Results Oral urea and amino acids (delivered to the colon by coating) resulted in peak increments in blood ammonia of 146±SD 164 and 55±51 μmol/l while for uncoated amino acids the mean increment was 58 (±41) μmol/l. The latter was accompanied by a significant increase in ADC of 9% (p=0.004). Increased ADC was significantly correlated with blood ammonia (r=0.58, p=0.04). The change in ammonia levels also correlated with the increase in glutamine levels (r=0.78, p=0.002). Myo-inositol concentration decreased significantly by 0.7 (±0.7) mMol/l between scans and this correlated with the mean difference in ADC (r=0.59, p<0.04).
Conclusion These results show that hyperammonia can be derived from nitrogenous substrates in the colon and can directly drive changes in brain water distribution as a mechanism for cerebral oedema development. Since cerebral astrocytes contain glutamine synthetase, our MRS data suggests intracerebral formation of glutamine from ammonia. Developments in therapy for hepatic encephalopathy need to focus on amelioration of colonic ammonia formation.
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