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

Zwingmann, Claudia; Chatauret, Nicolas; Rose, Christopher F.; Leibfritz, Dieter; Butterworth, Roger F.

doi:10.1016/j.brainres.2003.11.048

Cited by 53 publications

(25 citation statements)

References 35 publications

(58 reference statements)

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“…Similar results have been observed following ammonia-infusion in portacaval shunted rats pre-treated with MSO (Master et al, 1999 andWillard-Mack et al, 1996). However, following ammonia-lowering treatments, which are beneficial in attenuating brain edema and the onset of coma in animal models of ALF, a decrease in high cerebral glutamine levels was not observed Zwingmann et al, 2004). These studies suggest that in the setting of ALF, brain glutamine levels do not correlate with astrocyte swelling and brain edema.…”

Section: Glutamine/glutamatesupporting

confidence: 79%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed. HighlightsBrain edema is a common feature in ALF and CLD. HE is inconsistently associated with the presence of brain edema. Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

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Section: Glutamine/glutamatesupporting

confidence: 79%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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“…This suggests glutamine accumulation is not an important pathogenetic factor in the development of brain edema in HE. Interestingly, this observation has also been described in animal models of acute liver failure, in which high cerebral glutamine levels persisted following ammonia-lowering treatments and resolution of ICP, brain edema and HE [19] and [24]. Moreover, 4-week hyperammonemic portacaval-shunted rats, with an increase in brain glutamine, do not develop brain edema [18].…”

Section: Discussionmentioning

confidence: 56%

Increased brain lactate is central to the development of brain edema in rats with chronic liver disease

Bosoi

Zwingmann

Marin

et al. 2014

Journal of Hepatology

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The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis.Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor).Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine.Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE.Canadian Institutes of Health Research. CB:Fonds de recherche du Québec – Sant

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“…Mild cooling may result in a reduction of the delivery of ammonia to the brain (Inamasu and Ichikizaki 2002;Polderman 2004;Vaquero and Blei 2005;. In patients with severe hyperammonaemia due to hepatic encephalopathy without elevations of intracranial pressure (ICP), mild hypothermia appeared to reduce the risks of developing elevated ICP (BelangerQuintana et al 2003;Jalan et al 2004;Zwingmann et al 2004).…”

Section: Hypothermiamentioning

confidence: 99%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

191

152

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SummaryThe urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1 H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

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

Cited by 53 publications

References 35 publications

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Increased brain lactate is central to the development of brain edema in rats with chronic liver disease

Neurological implications of urea cycle disorders

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