Metabolic Abnormalities and Grade of Encephalopathy in Acute Hepatic Failure

Abstract

Acute hepatic failure is associated with many biochemical abnormalities in plasma and brain . Changes that correlate well with the degree of behavioral impairment may be important factors in the development of encephalopathy . We measured the concentrations of intermediary metabolites, ammonia, and amino acids in brain and plasma and the rate of whole-brain glucose utilization in rats with an acutely devascularized liver . In all rats an estimate of the grade of encephalopathy (reflected by behavioral impairment) was made . Rats underwent portacaval shunting and hepatic artery ligation (or sham operation) and were kept normoglycemic and normothermic thereafter . We sampled blood and whole brain (by near-instantaneous freeze-blowing) 2, 4, or 6 h later. There were no alterations in levels of high-energy phosphate metabolites in the brain or in metabolites associated with the glycolytic pathway and Krebs cycle, except lactate and pyruvate . Brain glucose use was decreased similarly at all times after surgery. Levels of ammonia and many amino acids were increased in brain and plasma ; brain aspartate, glutamate, and arginine levels were decreased . The increases in content of plasma ammonia and brain glutamine, proline, alanine, and aromatic amino acids and the decreases in brain aspartate and glutamate were most strongly correlated with behavioral impairment .

1H NMR spectroscopy of rat brain in vivo at 14.1Tesla: Improvements in quantification of the neurochemical profile

“…The concentration of GABA measured at 14.1 T is similar to the concentration of 1.8 mmol/kg found in the whole rat brain and to the average value of 1.25 and 2.21 mmol/kg found in rat cortex and striatum, respectively, by enzymatic-fluorometric analysis of brain extracts [23]. The LCModel estimate at 14.1 T for the Gly concentration was in excellent agreement with the value of 1.0 mmol/kg determined by high performance liquid chromatography in brain extracts [24] and by in vivo spectroscopy of rat brain at a longer echo time [25].…”

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

“…These observations challenge the notion of glutamine as the major determinant of brain edema in ALF. Glutamine, however, is not the only organic osmolyte or solute altered in ALF; increases of glucose, alanine and lactate and decreases of glutamate, aspartate, myo-inositol and taurine have also been noted [90], [91], [92] and [93]. Increases of brain lactate and alanine correlate better than glutamine with the grade of encephalopathy and brain edema in hepatic devascularized rats [91] and [92].…”

“…Since the brain cannot synthesize urea, detoxification of ammonia relies almost entirely on glutamine synthetase localized in astrocytes [88]. An increase of brain glutamine is a major feature in hyperammonemia or ALF [87], [89], [90], [91], [92], [93] and [94], and inhibition of glutamine synthesis attenuates ammonia-induced brain edema [87] and [89]. The osmotic effects of glutamine may partly explain the selective astrocytic swelling in ALF.…”

“…Increased brain lactate is common in animal models [77], [93], [94] and [121], and peaks of lactate in brain microdialysate preceding surges of ICP have been described in patients with ALF [98]. Increased brain lactate correlated with worsening encephalopathy and intracranial hypertension in experimental models [92] and [121], and it was due to increased de novo synthesis from circulating glucose.…”

Hypothermia in Acute Liver Failure

“…Clinically, extracellular brain lactate concentrations were found to increase in association with increased ICP in patients with ALF (Tofteng et al, 2002). It has also been demonstrated that alanine is elevated in the hyperammonemic brain (Hilgier et al, 1999;Mans et al, 1994;Swain et al, 1992) and more recently in rats with ALF using nuclear magnetic resonance (NMR) spectroscopy (Chatauret et al, 2003). Increased lactate and alanine production indirectly suggest that anaerobic pathways (increased glycolytic activity) may be stimulated to compensate for a decreased pyruvate oxidation (due to ammonia inhibition on the enzyme alpha-ketoglutarate dehydrogenase in the tricarboxylic acid cycle (Lai and Cooper, 1986)) and maintain ATP production.…”