Acute liver failure (ALF) results in alterations of energy metabolites and of
glucose-derived
amino acid neurotransmitters in brain. However, the dynamics of changes in
glucose metabolism remain unclear. The present study was undertaken using (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of
glucose into
amino acids and
lactate via cell-specific pathways in relation to the severity of
encephalopathy and
brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of
encephalopathy were accompanied by significant 2- to 4.5-fold (P <.001) increases of total brain
glutamine and
lactate concentrations. More severe (
coma) stages of
encephalopathy and
brain edema led to a further significant increase in brain
lactate but no such increase in
glutamine. Furthermore, (13)C isotopomer analysis showed a selective increase of de novo synthesis of
lactate from [1-(13)C]
glucose resulting in 2.5-fold increased fractional (13)C enrichments in
lactate at
coma stages. [2-(13)C]
glutamine, synthesized through the astrocytic
enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at
coma stages of
encephalopathy. (13)C-label incorporation into [4-(13)C]
glutamate, synthesized mainly through neuronal
pyruvate dehydrogenase, was selectively reduced at
coma stages, whereas brain
GABA synthesis was unchanged at all time points. In conclusion, increased brain
lactate synthesis and impaired
glucose oxidative pathways rather than intracellular
glutamine accumulation are the major cause of
brain edema in ALF. Future NMR spectroscopic studies using stable
isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans.