Latent or sub-clinical hepatic encephalopathy is a recognized complication of cirrhosis and is thought to represent one end of the spectrum of neuropsychiatric impairment, which occurrs as a result of portal-systemic shunting. We studied the psychometric, analyzed electroencephalography (EEG), and venous blood ammonia responses to an oral glutamine challenge in 17 patients with cirrhosis and in 4 normal controls. The cirrhotics were attending for liver transplant assessment and had no clinical evidence of hepatic encephalopathy. The oral glutamine challenge was repeated following liver transplantation. Five of sixteen patients (31%) showed impaired performance on at least one of the baseline psychometric tests. There was a correlation between fasting venous ammonia and choice reaction time (r = .7, P < .01). Following glutamine challenge there was a significant increase in blood ammonia from a mean fasting value ranging between 58 micromol/L to 120 micromol/L (P < .01), between significant prolongation of reaction times of 387 ms to 428 ms (P < .01), and an increase in mean EEG amplitude between 68.5 microV to 78.6 microV (P < .001). Four normal controls who were challenged with glutamine and 6 cirrhotic patients who were challenged with water showed no change in any of these parameters. Following orthotopic liver transplantation (OLT) the eight patients studied had normal baseline psychomotor performance with significant improvements in digit symbol, digit span, information processing, number connection tests (P < .05), and reaction time (P < .005). Posttransplantation, there were no significant changes in blood ammonia, analyzed EEG, or choice reaction time in response to oral glutamine challenge (six patients). We conclude that short lived changes in blood ammonia (in cirrhotics) can cause significant impairment of sensitive tests of brain function and that psychometric performance is improved following OLT.