Low myo-inositol and high glutamine levels in the brain are associated with neuropsychological deterioration following induced hyperammonemia

Background: The neuropsychological effect of hyperammonemia is variable. This study tests the hypothesis that the effect of ammonia on the neuropsychological function in patients with cirrhosis is determined by the ability of the brain to ‘buffer’ ammonia-induced increase in glutamine within the astrocyte by losing osmolytes like myo-inositol (mI) and not by the magnitude of the ‘induced hyperammonemia’. Methods: Fourteen cirrhotic patients with no evidence of overt HE were given a 75 gram amino acid (aa) solution mimicking the hemoglobin molecule to induce hyperammonemia. Measurement of a battery of neuropsychological function tests including immediate memory, ammonia, aa and short-echo time proton magnetic resonance spectroscopy were performed prior to and 4 hours after administration of the aa solution. Results: Eight patients showed deterioration in the Immediate Memory Test at 4 hours. Demographic factors, severity of liver disease, change in plasma ammonia and aa profiles following the aa solution were similar in those that showed a deterioration compared with those who did not. In the patients who showed deterioration in the memory test, the mI/creatine ratio was significantly lower at baseline than those that did not deteriorate. In contrast, the Glx/creatine ratio was significantly greater in the patients that deteriorated. Conclusions: The observation that the deterioration in the memory test was greater in those with lower mI/creatine ratio supports the hypothesis that the neuropsychological effects of induced hyperammonemia is determined by the capacity of the brain to handle the ammonia-induced increase in glutamine. INTRODUCTION Ammonia has consistently been shown to be important in the pathogenesis of Hepatic Encephalopathy (HE). (7; 26) Current hypotheses support the ammonia-glutaminebrain swelling hypothesis of neuropsychological dysfunction in cirrhosis. Astrocytes are the site of ammonia detoxification in the brain and eliminate ammonia by the synthesis of glutamine through amidation of glutamate. Accordingly, accumulation of glutamine in astrocytes induced by hyperammonemia produces osmotic stress and astrocyte swelling. (18) In patients with HE, the observation that myoinositol (mI; a sugar involved in the synthesis of phosphoinositides) is reduced with increasing concentrations of glutamine suggests that mI may be an important osmotic regulator within the astrocyte. (13; 22; 34) Recent studies in patients with cirrhosis (11) have shown that the metabolic disturbances are associated with an increase in brain water, the severity of which correlates with worsening of the neuropsychological state. In keeping with these observations, we have recently demonstrated that oral administration of a solution mimicking the amino acid (aa) composition of the hemoglobin molecule led to a significant alteration in neuropsychological function, an increase in brain glutamine/glutamate signal (Glx) and a reduction in mI. The increase in Glx was associated with a reduction in magnetization transfer ratio (suggesting an increase in brain water) supporting the ammonia-glutamine-brain swelling hypothesis of HE. (2) However, the correlation between the aa-induced increase in ammonia concentration was not directly related to the change in neuropsychological function suggesting that the neuropsychological effects of hyperammonemia may be determined, not by the degree of hyperammonemia, but by the ability of astrocytes to maintain the osmotic equilibrium by using mI as a compensatory mechanism for the ammonia-induced increase in glutamine. According to this hypothesis a low mI level prior to administration of the aa solution would increase the susceptibility of the brain to the effects of induced hyperammonemia. Therefore, the aims of this study were to evaluate the neuropsychological changes following induction of hyperammonemia and correlate these changes with the brain mI and Glx measured with proton magnetic resonance spectroscopy (1H-MRS).