The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

Background/Aims: The pathogenetic factors contributing to encephalopathy in portacaval shunted rats with hyperammonaemia were studied. Methods: Hyperammonaemia was induced by ammonium-acetate infusions in portacaval shunted rats (2.8 mmol . kg bw(-1). h(-1); AI-portacaval shunted rats) and in sham-portacaval shunted rats (6.5 mmol . kg bw(-1). h(-1); AI-NORM rats). Severity of encephalopathy was quantified by clinical grading and EEG spectral analysis. Changes in brain metabolites were assessed by amino acid analysis of brain cortex homogenates, whereas changes in amino acids with neurotransmitter activity were assessed in cerebrospinal fluid; brain water content was measured by subtracting dry from wet brain weights and intracranial pressure was measured by a pressure transducer connected to a cisterna magna cannula. Results: Although similar increased blood and brain ammonia concentrations were obtained in both experimental groups, only AI-portacaval shunted rats developed encephalopathy, associated with a significant increase in intracranial pressure. Other significant differences were: higher concentrations of brain glutamine and aromatic amino acids, higher concentrations of cerebrospinal fluid glutamine, aromatic amino acids, glutamate and aspartate in AI-portacaval shunted rats than in AI-NORM rats. Conclusions: These results indicate that hyperammonaemia alone does not induce encephalopathy, whereas portal-systemic shunting adds an essential contribution to the pathogenesis of encephalopathy. It is hypothesised that the larger increase in brain glutamine in AI-portacaval shunted rats than in AI-NORM rats is responsible for increased brain concentrations of aromatic amino acids, for cell swelling and for extracellular release of glutamate and aspartate. This might promote encephalopathy. If cell swelling is not restricted, intracranial hypertension will develop.