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TRANSLATIONAL PHYSIOLOGY

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

¹Liver Failure Group, Institute of Hepatology, University College London, London, WC1E 6HX United Kingdom; ²The Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW; ³Department of Surgery, Academic Hospital, Maastricht University, 6229 HX Maastricht, The Netherlands; ⁴Division of Clinical Sciences, Western General Hospital, Edinburgh EH4 2XU; and ⁵Department of Medical Physics, University of Edinburgh, Edinburgh EH3 9YW, Scotland

Submitted 9 March 2004 ; accepted in final form 5 May 2004

ABSTRACT

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. Fourteen cirrhotic patients with no evidence of overt hepatic encephalopathy were given a 75-g 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 before and 4 h after administration of the aa solution. Eight patients showed deterioration in the Immediate Memory Test at 4 h. Demographic factors, severity of liver disease, change in plasma ammonia, and aa profiles after the aa solution were similar in those that showed a deterioration compared with those who did not. In patients who showed deterioration in the memory test, the mI-to-creatine ratio (mI/Cr) was significantly lower at baseline than those that did not deteriorate. In contrast, the glutamate/glutamine-to-Cr ratio was significantly greater in the patients that deteriorated. The observation that deterioration in the memory test scores was greater in those with lower mI/Cr supports the hypothesis that the neuropsychological effects of induced hyperammonemia is determined by the capacity of the brain to handle ammonia-induced increase in glutamine.

neuropsychological function; amino acid solution; magnetic resonance spectroscopy; hepatic encephalopathy