Morphological features of three models of portal-systemic encephalopathy in the rat were studied and compared with plasma ammonia levels and clinical observations. Carbon tetrachloride-induced cirrhosis with terminal coma produced a wide variety of structural changes in the brain whose severity was related to plasma ammonia levels at the time of death. These changes included diffuse gliosis, Alzheimer cells and focal neuronal necrosis but did not include spongiform changes in cerebral or cerebellar cortex. Porta-caval anastomosis (PCA) did not appear to produce any significant neurological symptoms. Rats with PCA of durations 1-30 weeks were studied and over this time the structural changes included astrocytic nuclear swelling, swelling of perivascular astrocytic foot-processes and spongiform change in the molecular layer of the cerebellum. No evidence of Alzheimer cells or gliosis was seen and plasma ammonia levels at no stage exceed twice the normal levels. Porta-caval anastomosis followed by gavage feeding with ammoniated cationic exchange resin produced severe neurological symptoms and marked hyperammonaemia. In these animals not only astrocytes but oligodendrocytes and neurons showed nuclear and cytoplasmic swelling and numerous Alzheimer type II cells were seen, together with a diffuse gliosis, but no evidence of spongiform change in the cerebral or cerebellar cortex was seen. It is concluded that ammonium ions are important in the genesis of morphological changes in the brain in rat models of portal-systemic encephalopathy, but the relevance of these changes to neurological dysfunction is uncertain.

The water content and amounts of sodium, potassium and chloride were measured in the brains of normal rats, rats with PCA, normal rats fed ammoniated cationic exchange resin, and rats with PCA fed the resin. Plasma electrolytes and ammonia levels were also measured, and sodium and chloride spaces were calculated. Rats with PCA showed increased water content, sodium space and chloride space in the brainstem compared to controls. Rats with PCA fed ammoniated resin showed increased chloride content and Na+:K+ ratio in the brainstem, and an increased chloride space in the brainstem. In these rats the chloride spaces in the cerebrum and cerebellum exceeded the sodium spaces. It is concluded that high circulating ammonia levels can in vivo produce ionic shifts which may interfere with nervous function. It is also concluded that increased cytoplasmic osmolarity produced by ammonium ion-induced stimulation of (Na+ + Ka+) ATPase may result in the appearance of swollen astrocytes in conventional electron micrographs.