Portocaval anastomosis (PCA) in the rat leads, within 4 weeks, to severe liver
atrophy, sustained
hyperammonemia, and increased brain
ammonia. Because brain is not equipped with an effective
urea cycle, removal of
ammonia involves
glutamine synthesis and PCA results in significantly increased brain
glutamine.
Glutamine synthetase activities, however, are decreased by 15% in cerebral cortex and are unchanged in brainstem of shunted rats. Administration of
ammonium acetate to rats following PCA results in severe
encephalopathy (loss of righting reflex and, ultimately,
coma).
Glutamine concentrations in brainstem of
comatose rats are increased a further two-fold, whereas those of cerebral cortex are unchanged. Consequently,
ammonia levels in cerebral cortex reach disproportionately high levels (of the order of 5 mM). These findings suggest a limitation in the capacity of cerebral cortex to remove additional blood-borne
ammonia by
glutamine formation following PCA. Such mechanisms may explain the
hypersensitivity of rats with PCA and of patients with portal-systemic shunting to small increases of blood
ammonia. Disproportionately high levels of brain
ammonia in certain regions, such as cerebral cortex, may then result in alterations of inhibitory neurotransmission and, ultimately, loss of cellular (astrocytic) integrity.