Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure
2014; Elsevier BV; Volume: 5; Linguagem: Inglês
10.1016/j.jceh.2014.02.004
ISSN2213-3453
Autores Tópico(s)Alcoholism and Thiamine Deficiency
ResumoNeuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. Acute liver failure (ALF), also referred to as fulminant hepatic failure, invariably leads to central nervous system dysfunction that may include encephalopathy, seizures and brain edema, a major cause of intracranial hypertension and brain herniation, a leading cause of mortality in ALF. An increase in cerebral blood flow frequently accompanies the onset of brain edema.1Aggarwal S. Kramer D. Yonas H. et al.Cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study.Hepatology. 1994; 19: 80-87Crossref PubMed Scopus (128) Google Scholar Neuropathological assessments of the brain in both human and experimental ALF reveals significant changes to neuroglia in general and to astrocytes and microglia, in particular. Astrocytes in brain sections from patients who died in ALF are swollen2Kato M. Hughes R.D. Keays R.T. Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure.Hepatology. 1992; 15: 1060-1066Crossref PubMed Scopus (192) Google Scholar as are their mitochondria (Figure 1). Based upon these observations, it is generally assumed that the brain edema that accompanies ALF is primarily, if not exclusively, cytotoxic in nature. Studies in experimental animals with ALF due to toxic liver injury show a similar pattern of changes as well as alterations in expression of genes coding for key astrocytic proteins.3Thumburu K.K. Dhiman R.K. Vasishta R.K. et al.Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure.J Neurochem. 2014; 128: 617-627Crossref PubMed Scopus (24) Google Scholar Although gross alterations of the blood-brain barrier (BBB) are not generally a feature of ALF, alterations of cerebrovascular endothelial cell function have occasionally been described.2Kato M. Hughes R.D. Keays R.T. Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure.Hepatology. 1992; 15: 1060-1066Crossref PubMed Scopus (192) Google Scholar, 4Potvin M. Morrison H.F. Hinchey E.J. et al.Cerebral abnormalities in hepatectomised rats with acute hepatic coma.Lab Invest. 1984; 50: 560-564PubMed Google Scholar On the other hand, material from ALF animals in which edema and encephalopathy were precipitated by infection manifest clear alterations of both BBB function and of expression of BBB tight junction proteins.5Chastre A. Belanger M. Nguyen B.N. Butterworth R.F. Lipo-polysaccharide precipitates hepatic encephalopathy and increases blood-brain barrier permeability in mice with acute liver failure.Liver Int. 2014; 34: 353-361Crossref PubMed Scopus (46) Google Scholar These latter findings suggest that, in ALF accompanied by significant infection/inflammation, brain edema may comprise both cytotoxic and vasogenic components. ALF leads to severe compromise of cerebral metabolism and includes increases of cerebral blood flow, decreases of the cerebral metabolic rate for oxygen (CMRO2) and failure of cerebrovascular autoregulation.6Vaquero J. Chung C. Cahill M.E. Blei A.T. Pathogenesis of hepatic encephalopathy in acute liver failure.Semin Liver Dis. 2003; 23: 259-269Crossref PubMed Scopus (127) Google Scholar These changes have been attributed to a variety of factors including ammonia, glutamine, oxidative/nitrosative stress and pro-inflammatory factors. A significant positive correlation has been reported between arterial ammonia and the presence of brain herniation in patients with ALF7Clemmesen J.O. Larsen F.S. Kondrup J. et al.Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentrations.Hepatology. 1999; 29: 648-653Crossref PubMed Scopus (520) Google Scholar and arterial ammonia concentrations may be a useful independent predictor of this complication.8Bernal W. Hall C. Karvellas C.J. et al.Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure.Hepatology. 2007; 46: 1844-1852Crossref PubMed Scopus (305) Google Scholar Brain ammonia removal relies almost exclusively on the synthesis of glutamine, the brain lacking an effective urea cycle. Brain glutamine synthesis from ammonia is an astrocytic responsibility since the enzyme responsible, glutamine synthetase, has a uniquely astrocytic localization. Ammonia has multiple actions on CNS function that include direct effects of the ammonium ion (NH4+) on both excitatory and inhibitory neurotransmission,9Butterworth R.F. Pathophysiology of hepatic encephalopathy: a new look at ammonia.Metab Brain Dis. 2002; 17: 221-227Crossref PubMed Scopus (271) Google Scholar inhibition of glucose (pyruvate) oxidation10Lai J.C.K. Cooper A.J.L. Alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution and effects of inhibitors.J Neurochem. 1986; 47: 1376-1386Crossref PubMed Scopus (270) Google Scholar and stimulation of glycolysis, altered mitochondrial function11Bai G. Rama Rao K.V. Murthy C.R. et al.Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes.J Neurosci Res. 2001; 66: 981-991Crossref PubMed Scopus (144) Google Scholar and impairment of key cellular transport systems.9Butterworth R.F. Pathophysiology of hepatic encephalopathy: a new look at ammonia.Metab Brain Dis. 2002; 17: 221-227Crossref PubMed Scopus (271) Google Scholar, 12Knecht K. Michalak A. Rose C. Butterworth R.F. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure.Neurosci Lett. 1997; 229: 201-203Crossref PubMed Scopus (153) Google Scholar Brain glutamine concentrations are significantly increased in ALF whether assessed biochemically in autopsy material13Record C.O. Buxton B. Chase R.A. et al.Plasma and brain amino acids in fulminant hepatic failure and their relationship to hepatic encephalopathy.Eur J Clin Invest. 1976; 6: 387-394Crossref PubMed Scopus (241) Google Scholar or by 1H-magnetic resonance spectroscopy (MRS).14McConnell J.R. Antonson D.L. Ong C.S. et al.Proton spectroscopy of brain glutamine in acute liver failure.Hepatology. 1995; 22: 69-74Crossref PubMed Google Scholar It was suggested, based upon these findings that the accumulation of glutamine in the brain in ALF was causally related to the encephalopathy and brain edema. Subsequent studies using 1H/13C MRS in an animal model of ALF confirmed the increase in concentrations and in synthesis of glutamine in brain.15Zwingmann C. Chatauret N. Liebfritz D. Butterworth R.F. Selective increase in brain lactate synthesis in experimental acute liver failure: results of a 1H-13C NMR study.Hepatology. 2003; 37: 420-428Crossref PubMed Scopus (171) Google Scholar However, these increases were not significantly correlated with either the severity of encephalopathy or the presence of brain edema in these animals suggesting that increased brain glutamine synthesis per se is not a major cause of these neurologic disturbances as had previously been postulated. The subject of the role of glutamine in the pathogenesis of the CNS consequences of hyperammonemic disorders has been the subject of a recent review.16Butterworth R.F. Pathophysiology of brain dysfunction in hyperammonemic syndromes: the many faces of glutamine.Metab Genet Med. 2014; (in press)Google Scholar In contrast, it has been proposed that the signal that triggers the increase in cerebral blood flow in ALF occurs following the generation of glutamine in the astrocytes.6Vaquero J. Chung C. Cahill M.E. Blei A.T. Pathogenesis of hepatic encephalopathy in acute liver failure.Semin Liver Dis. 2003; 23: 259-269Crossref PubMed Scopus (127) Google Scholar Other mechanisms proposed to explain the role of glutamine in the pathogenesis of encephalopathy and brain edema in hyperammonemia include its transamination to alpha-ketoglutaramate, a neurotoxic metabolite17Cooper A.J.L. Gross M. The glutamate transaminase-w-amidase system in rat and human brain.J Neurochem. 1977; 28: 771-778Crossref PubMed Scopus (34) Google Scholar and the suggestion that glutamine, by transport into the astrocyte mitochondrion, acts as a shuttle for the production of ammonia that goes on to lead to mitochondrial energy failure, a hypothesis that has been termed "The Trojan Horse Hypothesis".18Albrecht J. Norenberg M.D. Glutamine: a Trojan horse in ammonia neurotoxicity.Hepatology. 2006; 44: 788-794Crossref PubMed Scopus (360) Google Scholar However direct evidence for a role for these hypotheses in the pathogenesis of the CNS consequences of ALF await further evaluation. Brain energy metabolism has been the subject of intensive investigation using a variety of technical approaches over the last several decades. It is clear that brain concentrations of high energy phosphates such as phosphocreatine and adenosine triphosphate (ATP) are not significantly altered in experimental ALF until the onset of profound coma and isoelectric EEG stages.19Mans A.M. DeJoseph M.R. Hawkins R.A. Metabolic abnormalities and grade of encephalopathy in acute liver failure.J Neurochem. 1994; 63: 1829-1838Crossref PubMed Scopus (101) Google Scholar Similar negative observations have been reported using in vivo brain microdialysis20Deutz N.E.P. DeGraaf A.A. De Haan J.G. et al.In vivo brain 1H-NMR spectroscopy (1H-MRS) during acute hepatic encephalopathy (HE).in: Soeters P.B. Advances in Ammonia Metabolism and Hepatic Encephalopathy. Excerpta Medica, Amsterdam1988: 439-446Google Scholar or 1H-MRS.21Chatauret N. Rose C. Therrien G. Butterworth R.F. Mild hypothermia prevents cerebral edema and CSF lactate accumulation in acute liver failure.Metab Brain Dis. 2001; 16: 95-102Crossref PubMed Scopus (59) Google Scholar Glucose is the principal energy source for adult mammalian brain and there is increasing evidence to support the notion that brain glucose metabolism is modified early in the progression of the CNS consequences of ALF. Such modifications are not sufficient to result in brain energy failure but have the potential to result in abnormal CNS metabolism and function. Brain lactate concentrations are increased in a wide range of experimental animal models of ALF resulting from ischemic19Mans A.M. DeJoseph M.R. Hawkins R.A. Metabolic abnormalities and grade of encephalopathy in acute liver failure.J Neurochem. 1994; 63: 1829-1838Crossref PubMed Scopus (101) Google Scholar, 22Peeling J. Shoemaker L. Gauthier T. et al.Cerebral metabolic and histological effects of thioacetamide-induced liver failure.Am J Phys. 1993; 265: G572-G578Google Scholar or toxic23Tofteng F. Jorgensen L. Hansen B.A. et al.Cerebral microdialysis in patients with fulminant hepatic failure.Hepatology. 2002; 36: 1333-1340Crossref PubMed Scopus (84) Google Scholar liver injury as well as in brain microdialysates from ALF patients where increased brain lactate content was found to precede surges in intracranial hypertension.24Nyberg S.L. Cerra F.B. Gruetter R. Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog.Liver Transpl Surg. 1998; 4: 158-165Crossref PubMed Scopus (39) Google Scholar Worsening of neurological status in animal models of ALF is significantly correlated with increases of brain lactate concentrations15Zwingmann C. Chatauret N. Liebfritz D. Butterworth R.F. Selective increase in brain lactate synthesis in experimental acute liver failure: results of a 1H-13C NMR study.Hepatology. 2003; 37: 420-428Crossref PubMed Scopus (171) Google Scholar, 19Mans A.M. DeJoseph M.R. Hawkins R.A. Metabolic abnormalities and grade of encephalopathy in acute liver failure.J Neurochem. 1994; 63: 1829-1838Crossref PubMed Scopus (101) Google Scholar and by increased de novo lactate synthesis15Zwingmann C. Chatauret N. Liebfritz D. Butterworth R.F. Selective increase in brain lactate synthesis in experimental acute liver failure: results of a 1H-13C NMR study.Hepatology. 2003; 37: 420-428Crossref PubMed Scopus (171) Google Scholar (Figure 2). Increases of brain lactate have been shown to be related to intracranial hypertension and a poor outcome in dogs with ALF25Staub F. Baethmann Peters J. et al.Effects of lactic acidosis on glial cell volume and viability.J Cereb Blood Flow Metab. 1990; 10: 866-876Crossref PubMed Scopus (134) Google Scholar suggesting a role for increased brain lactate in the pathogenesis of brain edema and, in support of such a notion, exposure of cultured astrocytes to lactate results in significant cell swelling.26Eng L.F. GhirnikarR S. Lee Y.L. Glial fibrillary acidic protein: GFAP-31 years (1969–2000).Neurochem Res. 2000; 25: 1439-1451Crossref PubMed Google Scholar Astrocytes play important roles in the maintenance of CNS function by virtue of their interactions with other neural cells (neurons, endothelial cells) and their ability to modulate both excitatory and inhibitory neurotransmission being active participants in the synthesis, transport and degradation of major neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA). New evidence continues to accumulate demonstrating that ALF results in alterations in expression of genes coding for key astrocytic proteins with important roles in CNS function. Three classes of astrocytic protein have so far been shown to be modified in ALF. These include structural proteins, amino acid neurotransmitter transporters and receptor proteins. Glial fibrillary acidic protein (GFAP) constitutes the major component of astrocytic intermediate filaments implicated in the control of cell motility and morphology by providing structural stability to astrocyte processes.26Eng L.F. GhirnikarR S. Lee Y.L. Glial fibrillary acidic protein: GFAP-31 years (1969–2000).Neurochem Res. 2000; 25: 1439-1451Crossref PubMed Google Scholar, 27Belanger M. Desjardins P. Chatauret N. Butterworth R.F. Loss of expression of glial fibrillary acidic protein in acute hyperammonemia.Neurochem Int. 2002; 41: 155-160Crossref PubMed Scopus (68) Google Scholar ALF resulting from ischemic liver failure leads to a loss of expression of the GFAP gene28Norenberg N.D. Neary J.T. Norenberg L.O. et al.Ammonia-induced decrease in glial fibrillary acidic protein in cultured astrocytes.J Neuropathol Exp Neurol. 1990; 49: 399-405Crossref PubMed Scopus (67) Google Scholar and the extent of the loss of expression is correlated with the extent of hyperammonemia and with brain edema ischemic animals. In support of a role for ammonia, exposure of primary cultures of rat astrocytes to ammonia resulted in significant cell swelling.28Norenberg N.D. Neary J.T. Norenberg L.O. et al.Ammonia-induced decrease in glial fibrillary acidic protein in cultured astrocytes.J Neuropathol Exp Neurol. 1990; 49: 399-405Crossref PubMed Scopus (67) Google Scholar Loss of GFAP expression in brain in ALF appears to be selective; expression of a second glial filamentous protein S100 beta is unaltered in the same animal model. It was proposed that the loss of GFAP in ALF has the potential to alter the visco-elastic properties of the astrocyte and consequently to facilitate cell swelling and the resulting cytotoxic brain edema.27Belanger M. Desjardins P. Chatauret N. Butterworth R.F. Loss of expression of glial fibrillary acidic protein in acute hyperammonemia.Neurochem Int. 2002; 41: 155-160Crossref PubMed Scopus (68) Google Scholar, 28Norenberg N.D. Neary J.T. Norenberg L.O. et al.Ammonia-induced decrease in glial fibrillary acidic protein in cultured astrocytes.J Neuropathol Exp Neurol. 1990; 49: 399-405Crossref PubMed Scopus (67) Google Scholar Loss of GFAP expression was recently described in autopsied brain tissue samples from patients who died as a result primarily of brain herniation due to ALF.3Thumburu K.K. Dhiman R.K. Vasishta R.K. et al.Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure.J Neurochem. 2014; 128: 617-627Crossref PubMed Scopus (24) Google Scholar The astrocyte membrane is home to a range of high affinity amino acid transporters that include transporters for glutamate (EAAT-2), glycine (GLYT-1) and glutamine (SNAT-3 and SNAT-5) Expression of genes coding for many of these proteins has been shown to be down-regulated in brain extracts from animals with ALF due to ischemic liver failure. EAAT-2 is a cloned and well characterized high affinity transporter for glutamate that is located on the astrocyte membrane primarily in forebrain of mammals. Knock-down of the EAAT-2 gene results in increased synaptic (extracellular) concentrations of glutamate and this is accompanied by brain edema and seizures, two important neurological features of ALF. Not surprisingly, experimental ALF due to liver ischemia results in a loss of expression of EAAT-2 (previously known as GLT-1) in brain12Knecht K. Michalak A. Rose C. Butterworth R.F. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure.Neurosci Lett. 1997; 229: 201-203Crossref PubMed Scopus (153) Google Scholar resulting in increased extracellular brain glutamate29Michalak A. Rose C. Butterworth J. Butterworth R.F. Neuroactive amino acids and glutamate(NMDA) receptors in frontal cortex of rats with experimental acute liver failure.Hepatology. 1996; 24: 908-913Crossref PubMed Google Scholar at coma/edema stages of encephalopathy suggestive of a role for this loss of transporter expression in the pathogenesis of these complications. Moreover, since the astrocytic pool of glutamate is the obligate substrate for glutamine synthetase, the enzyme responsible for removal of excess brain ammonia, decreased uptake of glutamate as a result of EAAT-2 down-regulation in ALF could seriously limit the capacity of brain to remove ammonia, providing one cogent explanation for observation of brain ammonia accumulation in ALF. Loss of EAAT-2 gene and protein expression was recently reported in autopsied brain tissue from patients with ALF resulting primarily from viral hepatitis.3Thumburu K.K. Dhiman R.K. Vasishta R.K. et al.Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure.J Neurochem. 2014; 128: 617-627Crossref PubMed Scopus (24) Google Scholar Expression of a second glutamate transporter EAAT-1 was unchanged in this material. Synaptic concentrations of the neuroactive amino acid glycine are regulated by high affinity transporters, one of which, GLYT-1 is expressed in astrocytes of the forebrain where glycine functions as agonist for a neuromodulatory site on a subclass of high affinity glutamate receptor known as the N-methyl-d-aspartate (NMDA) receptor. ALF resulting from liver ischemia leads to a loss of expression of GLYT-1 and a concomitant increase in synaptic concentrations of glycine30Zwingmann C. Desjardins P. Hazell A. Butterworth R.F. Reduced expression of astrocytic glycine transporter GLYT-1 in acute liver failure.Metab Brain Dis. 2002; 17: 263-273Crossref PubMed Scopus (24) Google Scholar favoring stimulation of NMDA receptor-mediated excitatory transmission, a phenomenon that could relate to the hyperexcitability and seizures encountered in ALF. Several neutral amino acid transport systems (SNATs) have been characterized and have been recently renamed including SNAT-3 (sodium-coupled neutral amino acid transporter-3, previously SN-1) that favors the release of GLN, rather than its uptake, from astrocytes.31Chaudhry F.A. Krisaj D. Larsson P. et al.Coupled and uncoupled proton movement by amino acid transport system N.EMBO J. 2001; 20: 7041-7051Crossref PubMed Scopus (95) Google Scholar SNAT-5 is also expressed in the brain and, like SNAT-3, shares the Na+/H− coupling mechanism. SNAT-5 is expressed exclusively by astrocyte cell bodies and their processes that surround glutamatergic, GABAergic and glycinergic nerve terminals.32Cubelos B. Gonzales-Gonzales I.M. Gimenez C. et al.Amino acid transporter SNAT-5 localises to glial cells in the rat brain.Glia. 2005; 49: 230-244Crossref PubMed Scopus (66) Google Scholar A recent study showed that ALF in the rat led to significant down-regulation of SNAT-5.33Desjardins P. Du T. Jiang W. et al.Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined.Neurochem Int. 2012; 60: 690-696Crossref PubMed Scopus (68) Google Scholar This finding led the authors to suggest that restricted transfer of glutamine from the astrocyte (rather than its increased synthesis as had been previously suggested) offers a plausible explanation for the occurrence of brain edema in ALF. Moreover, GLN trapping within the astrocyte has the potential (by restricting its flow to neighboring nerve terminals) to limit neuronal excitability and hence encephalopathy in ALF. GLUT-1 is a cloned and characterized glucose transporter that regulates glucose delivery to the cell and across the BBB since the transporter protein is localized on the membrane of astrocytes and cerebrovascular endothelial cells.34Fischbarq J. Kuang K.Y. Vera J.C. et al.Glucose transporters serve as water channels.Proc Natl Acad Sci USA. 1990; 87: 3244-3247Crossref PubMed Scopus (166) Google Scholar It has been proposed that GLUT-1 also plays a role in the movement of water into the cell. Interestingly, GLUT-1 expression is significantly increased in parallel with brain water accumulation in experimental ALF.35Belanger M. Desjardins P. 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Microglia constitute the resident macrophages of the brain with the ability to respond (become activated) to a wide range of homeostatic challenges including tissue damage, vascular disturbances as well as changes in pH and impending energy failure. Microglial activation was first reported by Jiang et al38Jiang W. Desjardins P. Butterworth R.F. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline.J Neurochem. 2009; 109: 485-493Crossref PubMed Scopus (105) Google Scholar in rats with ALF resulting from ischemic liver failure. Subsequent reports from several groups went on to describe similar activation of microglia in a mouse model of ALF resulting from the toxic effects of azoxymethane at various time during the progression of liver failure.39McMillin M. Galindo C. Frampton G.A. et al.Increased neuronal chemokine (CCL2/MCP1) expression is associated with hepatic encephalopathy and contributes to neurological decline.Hepatology. 2012; 56: 958AGoogle Scholar, 40Thrane V.R. Thrane A.S. Chanag J. et al.Real-time analysis of microglial activation and motility in hepatic and hyperammonemic encephalopathy.Neuroscience. 2012; 220: 247-255Crossref PubMed Scopus (46) Google Scholar Onset of coma/edema stages of encephalopathy resulted in increased expression of a range of markers of microglial activation and, in this model, deletion of the genes coding for TNF-alpha or IL-1beta delayed the onset of encephalopathy and attenuated the level of brain edema in these animals.41Bemeur C. Qu H. Desjardins P. Butterworth R.F. 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Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia.J Cereb Blood Flow Metab. 2009; 29: 944-952Crossref PubMed Scopus (96) Google Scholar (Figure 3). These increased brain concentrations of pro-inflammatory cytokines were accompanied by increases in expression of the genes for which they encode suggesting their synthesis in situ, in the brain. Evidence for increased cytokine synthesis in the brain was also reported in patients with ALF due primarily to acetaminophen overdose using the technique of arterio-venous differences.44Wright G. Shawcross D. Olde Daminck S.W. Jalan R. Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension.Metab Brain Dis. 2007; 22: 375-388Crossref PubMed Scopus (96) Google ScholarSystemic inflammation had already been well established prior to these reports of the presence of neuroinflammation in ALF. 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