Shawcross, D.L.; (2007) Ammonia, infection and inflammation in hepatic encephalopathy. Doctoral thesis , University of London.

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Abstract

For over a century, we have known that ammonia is important in the pathogenesis of hepatic encephalopathy. Studies in patients with acute liver failure have shown rapid progression to severe encephalopathy in those patients with evidence of a systemic inflammatory response, suggesting a possible link between inflammation and encephalopathy. In view of the growing evidence to support the role of inflammation in increasing the susceptibility of the brain to the effects of hyperammonemia in liver disease, 3 hypotheses were explored: 1: Inflammation and infection are important in hepatic encephalopathy. 2: Inflammation and infection act synergistically with ammonia. 3: Ammonia makes the immune system more susceptible to infection. In the first of 2 clinical studies, inflammation was shown to be an important determinant of the presence and severity of minimal hepatic encephalopathy. In a second study, significant deterioration of neuropsychological test scores in patients with cirrhosis following induced hyperammonemia during the inflammatory state, but not after its resolution, suggested that inflammation may be important in modulating the cerebral effect of ammonia in liver disease, supporting the first hypothesis. Ammonia and inflammation were shown to be synergistic in the bile duct ligated rat which showed increased brain water and astrocyte swelling exacerbated by endotoxin and accompanied by a rise in nitric oxide and brain nitrotyrosine, but not in plasma ammonia, suggesting nitric oxide may play an important synergistic role in the pathogenesis of hepatic encephalopathy. Ammonia was shown to impair neutrophil function by reducing phagocytosis, inducing spontaneous respiratory burst and cell swelling. The p38"MAPK pathway was shown to be important and a p38"MAPK agonist prevented neutrophils from swelling in the presence of ammonia and improved phagocytosis. While cultures of muscle cells were a potentially interesting direction to take to investigate the effect of inflammation on the muscle uptake of ammonia, unfortunately the resulting data demonstrated a low glutamine synthetase activity. In conclusion, these studies illustrate the important factors that modulate the manifestation of symptoms of hepatic encephalopathy in cirrhosis, the most important of which is the synergistic role of inflammation and ammonia. Furthermore, the ammonia-induced impairment of neutrophil function may, in part, account for the increased susceptibility to infection found in patients with cirrhosis.

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