Changes in brain metabolism during hyperammonemia and acute liver failure: Results of a comparative1H-NMR spectroscopy and biochemical investigation

Bosman, D. K.; Deutz, Nicolaas E. P.; Graaf, Albert A. de; Hulst, Rene W. N. Vd; Eijk, Hans M.H. van; Bovée, W.M.M.J.; Maas, Marjolein; Jörning, G.G.A.; Chamuleau, R. A. F. M.

doi:10.1002/hep.1840120215

Cited by 106 publications

(77 citation statements)

References 51 publications

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“…Normal rats show an EEG left index of -0.60 and rats in coma -0.80-0.90. These logarithmic values are comparable with the linear values of 5-10 for normal rats and 15-25 for rats in coma, published by our group previously (17). During the development of hepatic encephalopatby MDF decreases from 16 to 18 Hz to 11-13 Hz (own observations).…”

Section: Methodssupporting

confidence: 90%

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

Vogels¹,

Steynen²,

Maas³

et al. 1997

Journal of Hepatology

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The effects of ammonia and portal-systemic shunting on brain metabolims, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy Vogels, B.A.P.M.; van Steynen, B.; Maas, M.A.W.; Jorning, G.G.A.; Chamuleau, R.A.F.M. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Background/Aims: The pathogenetic factors contributing to encephalopathy in portacaval shunted rats with hyperammonaemia were studied. Methods: Hyperammonaemia was induced by ammonium-acetate infusions in portacaval shunted rats (2.8 mmol-kg bw-'*h-l; AI-portacaval shunted rats) and in sham-portacaval shunted rats (6.5 mmol-kg bw-l-h-'; AI-NORM rats). Severity of encephalopathy was quantified by clinical grading and EEG spectral analysis. Changes in brain metabolites were assessed by amino acid analysis of brain cortex homogenates, whereas changes in amino acids with neurotransmitter activity were assessed in cerebrospinal fluid; brain water content was measured by subtracting dry from wet brain weights and intracranial pressure was measured by a pressure transducer connected to a cisterna magna cannula. Results:Although similar increased blood and brain ammonia concentrations were obtained in both experimental groups, only AI-portacaval shunted rats developed encephalopathy, associated with a significant increase in intracranial pressure. HEPATIC encephalopathy (HE) is generally regarded to be a reversible neuropsychiatric syndrome in patients with liver failure. It is often associated with portal-systemic shunting of blood, which may occur spontaneously or be surgically induced. Although the pathogenesis of HE is probably multi- Conclusions: These results indicate that hyperammonaemia alone does not induce encephalopathy, whereas portal-systemic shunting adds an essential contribution to the pathogenesis of encephalopathy. It is hypothesised that the larger increase in brain glutamine in AI-portacaval shunted rats than in AI-NORM rats is responsible for increased brain concentrations of aromatic amino acids, for cell swelling and for extracellular release of glutamate and aspartate. This might promote encephalopathy. If cell swelling is not restricted, intracranial hypertension will develop

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Section: Methodssupporting

confidence: 90%

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

Vogels¹,

Steynen²,

Maas³

et al. 1997

Journal of Hepatology

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“…20,21 Ammonia is detoxified in brain mainly by glutamine synthetase, an astrocytic enzyme. Increased brain glutamine has been demonstrated by in vivo 1 H NMR spectroscopy in animal models 22,23 and in patients with ALF. 24,25 Results of the present study show that brain glutamine concentrations as well as its biosynthesis from glucose either via entry of pyruvate into the TCA cycle through PDH, or via PC, an astrocytic enzyme, are not further increased at coma (vs. precoma) stages of encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study

2003

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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. (HEPATOLOGY 2003;37:420-428.) H epatic encephalopathy and brain edema are serious central nervous system complications of acute liver failure (ALF), which are accompanied by significant alterations of brain metabolites. For example, biochemical studies in brain tissue from animals with ALF resulting from hepatectomy, 1 hepatic devascularization, 2-4 or toxic liver injury 5 as well as autopsied brain tissue from patients with ALF 6 reveal significant increases in concentrations of glutamine and a concomitant reduction of glutamate. Several of these studies also show that brain lactate concentrations are elevated as a function of the deterioration of central nervous system function in ALF, a finding that has been attributed to decreased pyruvate oxidation because of ammonia exposure. 7 Although these biochemical studies provide important hints on metabolic derangements in ALF, they do not permit the elucidation of rates of synthesis/degradation of these metabolites, nor do they provide information on the cellular localization of the altered metabolism. The use of nuclear magnetic resonance (NMR) spectroscopy and stable isotope precursors provides an effective approach to the study of metabolic turnover in the brain. In particular, ...

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“…In addition, ammonia-induced taurine release is not necessarily related to a cell volume regulatory response [33] and [34]. It remains to be determined whether previously reported taurine release into the extracellular space [4] or changes in cerebrospinal fluid (CSF) taurine concentrations [31] are implicated in the pathogenesis of encephalopathy or brain edema in ALF.…”

Section: Discussionmentioning

confidence: 99%

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia

et al. 2004

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Zwingmann, C. et al., 2004. Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia. Brain Research, 999(1), ABSTRACTThe principal cause of mortality in patients with acute liver failure (ALF) is brain herniation resulting from intracranial hypertension caused by a progressive increase of brain water. In the present study, ex vivo highresolution 1 H-NMR spectroscopy was used to investigate the effects of ALF, with or without superimposed hypothermia, on brain organic osmolyte concentrations in relation to the severity of encephalopathy and brain edema in rats with ALF due to hepatic devascularization. In normothermic ALF rats, glutamine concentrations in frontal cortex increased more than fourfold at precoma stages, i.e. prior to the onset of severe encephalopathy, but showed no further increase at coma stages. In parallel with glutamine accumulation, the brain organic osmolytes myo-inositol and taurine were significantly decreased in frontal cortex to 63% and 67% of control values, respectively, at precoma stages (p<0.01), and to 58% and 67%, respectively, at coma stages of encephalopathy (p<0.01). Hypothermia, which prevented brain edema and encephalopathy in ALF rats, significantly attenuated the depletion of myo-inositol and taurine. Brain glutamine concentrations, on the other hand, did not respond to hypothermia. These findings demonstrate that experimental ALF results in selective changes in brain organic osmolytes as a function of the degree of encephalopathy which are associated with brain edema, and provides a further rationale for the continued use of hypothermia in the management of this condition.

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Changes in brain metabolism during hyperammonemia and acute liver failure: Results of a comparative1H-NMR spectroscopy and biochemical investigation

Cited by 106 publications

References 51 publications

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia

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