Nuclear magnetic resonance studies of energy metabolism and glutamine shunt in hepatic encephalopathy and hyperammonemia

Hepatic encephalopathy (HE) in both acute and chronic liver failure is more likely a reversible functional disease rather than an irreversible pathological lesion of brain cells. Metabolic alterations underlie many of the mechanisms leading to HE. This paper summarizes in vivo and ex vivo H-1-, C-13-, and N-15-nuclear magnetic resonance (NMR) spectroscopy data on patients and experimental models of HE. In vivo NMR spectroscopy provides a unique opportunity to study metabolic changes noninvasively in the brain in vivo, and to quantify various metabolites in localized brain areas, and ex vivo NMR permits the high-resolution measurement of metabolites and the identification of different metabolic pathways. In vivo and ex vivo H-1-NMR investigations consistently reveal severalfold increases in brain glutamine and concomitant decreases in myo-inositol, an important osmolyte in astrocytes. An osmotic disturbance in these cells has long been suggested to be responsible for astrocyte swelling and brain edema. However, ex vivo C-13-NMR studies have challenged the convention that glutamine accumulation is the major cause of brain edema in acute HE. They rather indicate a limited anaplerotic flux and capacity of astrocytes to detoxify ammonia by glutamine synthesis and emphasize distortions of energy and neurotransmitter metabolism. However, recent N-15-NMR investigations have demonstrated that glutamine fluxes between neurons and astrocytes are affected by ammonia. Further NMR studies may provide novel insights into the relationship between brain edema and/or astrocyte pathology and changes in inter- and intracellular glutamine homeostasis, which may secondarily alter brain energy metabolism. (c) 2007 Wiley-Liss, Inc.