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Semin Liver Dis 2003; 23(3): 251-258
DOI: 10.1055/s-2003-42643
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Molecular Neurobiology of Acute Liver Failure

Roger F. Butterworth
  • Director, Neuroscience Research Unit Hôpital Saint-Luc (CHUM) Montreal, Québec Canada
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Publication History

Publication Date:
02 October 2003 (online)

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ABSTRACT

Acute liver failure results in encephalopathy and brain edema that is characterized by astrocytic cell swelling. Molecular biological techniques have led to the identification of alterations in expression of several genes coding for key astrocytic proteins in acute liver failure. Such proteins include amino acid transporters, structural proteins, the endothelial cell glucose transporter GLUT-1, the mitochondrial “peripheral-type” benzodiazepine receptor, and the water channel protein aquaporin IV. Magnetic resonance spectroscopic studies reveal increased brain lactate concentrations that are positively correlated with severity of encephalopathy and brain edema in acute liver failure, suggesting a deficit of cellular oxidative capacity and impending brain energy failure. Mild hypothermia prevents brain edema in acute liver failure, and mechanisms responsible for this beneficial effect include reduced blood-brain ammonia transfer as well as normalization of astrocytic amino acid transport and brain energy metabolism. Further elucidation of the molecular mechanisms responsible for brain edema and encephalopathy in acute liver failure will undoubtedly lead to novel treatment strategies for these complications.

KEYWORDS

Acute liver failure - brain edema - gene expression - ammonia - brain energy metabolism - astrocytes - transporters - osmoregulation - hypothermia

REFERENCES

  • 1 Kato 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 1060-1066
    PubMedGoogle Scholar
  • 2 Traber P G, DalCanto M, Ganger D R, Blei A T. Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier.  Hepatology . 1987;  7 1273-1277
    PubMedGoogle Scholar
  • 3 Potvin M, Morrison H F, Hinchey E J. et al . Cerebral abnormalities in hepatectomized rats with acute hepatic coma.  Lab Invest . 1984;  50 560-564
    PubMedGoogle Scholar
  • 4 Desjardins P, Michalak A, Therrien G. et al . Increased expression of the astrocytic/endothelial cell glucose transporter (and water channel) protein GLUT-1 in relation to brain glucose metabolism and edema in acute liver failure (Abst 254).  Hepatology . 2001;  34 237
    PubMedGoogle Scholar
  • 5 Desjardins P, Bélanger M, Butterworth R F. Alterations in expression of genes coding for key astrocytic proteins in acute liver failure.  J Neurosci Res . 2001;  66 967-971
    CrossrefPubMedGoogle Scholar
  • 6 Holmin T, Agardh C D, Alinder G. et al . The influence of total hepatectomy on cerebral energy state, ammonia-related amino acids of the brain and plasma amino acids in the rat.  Eur J Clin Invest . 1983;  13 215-220
    PubMedGoogle Scholar
  • 7 Swain M, Butterworth R F, Blei A T. Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats.  Hepatology . 1992;  15 449-453
    PubMedGoogle Scholar
  • 8 Mans A M, DeJoseph M R, Hawkins R A. Metabolic abnormalities and grade of encephalopathy in acute hepatic failure.  J Neurochem . 1994;  63 1829-1838
    PubMedGoogle Scholar
  • 9 Swain M S, Bergeron M, Audet R. et al . Monitoring of neurotransmitter amino acids by means of an indwelling cisterna magna catheter: a comparison of two rodent models of fulminant liver failure.  Hepatology . 1992;  16 1028-1035
    PubMedGoogle Scholar
  • 10 Peeling J, Shoemaker L, Gauthier T. et al . Cerebral metabolic and histological effects of thioacetamide-induced liver failure.  Am J Physiol . 1993;  265 G572-G578
    PubMedGoogle Scholar
  • 11 Clemmesen J O, Larsen F S, Kondrup J. et al . Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.  Hepatology . 1999;  29 648-653
    CrossrefPubMedGoogle Scholar
  • 12 Cooper A J, Plum F. Biochemistry and physiology of brain ammonia.  Physiol Rev . 1987;  67 440-519
    PubMedGoogle Scholar
  • 13 Butterworth R F. Pathophysiology of hepatic encephalopathy: a new look at ammonia.  Metab Brain Dis . 2002;  17 221-227
    CrossrefPubMedGoogle Scholar
  • 14 Dejong C HC, Kampman M T, Deutz N EP, Soeters P B. Cerebral cortex ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.  J Neurochem . 1992;  59 1071-1079
    PubMedGoogle Scholar
  • 15 Jalan R, Dalmink S WM, Lee O. et al . Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure.  Lancet . 1999;  354 1164-1168
    CrossrefPubMedGoogle Scholar
  • 16 Record 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;  6 387-394
    CrossrefPubMedGoogle Scholar
  • 17 McConnell J R, Antonson D L, Ong C S. et al . Proton spectroscopy of brain glutamine in acute liver failure.  Hepatology . 1995;  22 69-74
    CrossrefPubMedGoogle Scholar
  • 18 Gupta R K, Saraswat V A, Poptani H. et al . Magnetic resonance imaging and localized in vivo proton spectroscopy in patients with fulminant hepatic failure.  Am J Gastroenterol . 1993;  88 670-674
    PubMedGoogle Scholar
  • 19 Zwingmann C, Chatauret N, Leibfritz D, Butterworth R F. Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [1H-13C] NMR study.  Hepatology . 2003;  37 420-428
    CrossrefPubMedGoogle Scholar
  • 20 Tyce G M, Ogg J, Owen Jr A C. Metabolism of acetate to amino acids in brains of rats after complete hepatectomy.  J Neurochem . 1981;  36 640-650
    PubMedGoogle Scholar
  • 21 Zimmermann C, Ferenci P, Pifl C. et al . Hepatic encephalopathy in thioacetamide-induced acute liver failure in rats: characterization of an improved model and study of amino acid-ergic neurotransmission.  Hepatology . 1989;  9 594-601
    PubMedGoogle Scholar
  • 22 Hertz L, Murthy C R, Lai J C, Fitzpatrick S M, Cooper A J. Some metabolic effects of ammonia on astrocytes and neurons in primary cultures.  Neurochem Pathol . 1987;  6 97-129
    PubMedGoogle Scholar
  • 23 Bosman D K, Deutz N EP, Maas M AW. et al . Amino acid release from cerebral cortex in experimental acute liver failure, studied by in vivo cerebral cortex microdialysis.  J Neurochem . 1992;  59 591-599
    PubMedGoogle Scholar
  • 24 Deutz N EP, DeGraaf A A, De Haan G J. et al .In vivo brain 1H-NMR spectroscopy (IH-NMRS) during acute hepatic encephalopathy (HE). In: Soeters PB Wilson JHP Meijer AJ Holm E eds. Advances in Ammonia Metabolism and Hepatic Encephalopathy Amsterdam: Excerpta Medica 1988: 439-446
    Google Scholar
  • 25 Chatauret 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 95-102
    CrossrefPubMedGoogle Scholar
  • 26 Tofteng F, Jorgensen L, Hansen B A. et al . Cerebral microdialysis in patients with fulminant hepatic failure, Hepatology .  2002;  36 1333-1340
    CrossrefPubMedGoogle Scholar
  • 27 Nyberg S L, Cerra F B, Gruetter R. Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog.  Liver Transpl Surg . 1998;  4 158-165
    CrossrefPubMedGoogle Scholar
  • 28 Staub F, Baethmann A, Peters J. et al . Effects of lactacidosis on glial cell volume and viability.  J Cereb Blood Flow Metab . 1990;  10 866-876
    PubMedGoogle Scholar
  • 29 Lai J CK, Cooper A JL. α-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution and effects of inhibitors.  J Neurochem . 1986;  47 1376-1386
    CrossrefPubMedGoogle Scholar
  • 30 Lowry O H, Passonneau J V. Kinetic evidence for multiple binding sites on phosphofructokinase.  J Biol Chem . 1966;  241 2268-2279
    PubMedGoogle Scholar
  • 31 Eng L F, Ghirnikar R S, Lee Y L. Glial fibrillary acidic protein: GFAP-31 years (1969-2000).  Neurochem Res . 2000;  25 1439-1451
    Google Scholar
  • 32 Bélanger M, Desjardins P, Chatauret N, Butterworth R F. Loss of expression of glial fibrillary acidic protein in acute hyperammonemia.  Neurochem Int . 2002;  41 155-160
    CrossrefPubMedGoogle Scholar
  • 33 Norenberg M D, Neary J T, Norenberg L O, McCarthy M. Ammonia induced decreased in glial fibrillary acidic protein in cultured astrocytes.  J Neuropathol Exp Neurol . 1990;  49 399-405
    PubMedGoogle Scholar
  • 34 Ding M, Eliasson C, Betsholtz C. et al . Altered taurine release following hypotonic stress in astrocytes from mice deficient for GFAP and vimentin.  Mol Brain Res . 1998;  62 77-81
    CrossrefPubMedGoogle Scholar
  • 35 Tanaka K, Watase K, Manabe T. et al . Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.  Science . 1997;  276 1699-1702
    CrossrefPubMedGoogle Scholar
  • 36 Michalak 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;  24 908-913
    PubMedGoogle Scholar
  • 37 Ellis A J, Wendon J A, Williams R. Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.  Hepatology . 2000;  32 536-541
    CrossrefPubMedGoogle Scholar
  • 38 Knecht K, Michalak A, Rose C. et al . Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure.  Neurosci Lett . 1997;  229 201-203
    CrossrefPubMedGoogle Scholar
  • 39 Butterworth R F. Glutamate transporters in hyperammonemia.  Neurochem Int . 2002;  41 81-85
    PubMedGoogle Scholar
  • 40 Van Harreveld A, Fifkova E. Light- and electron-microscopic changes in central nervous tissue after electrophoretic injection of glutamate.  Exp Mol Pathol . 1971;  15 61-81
    CrossrefPubMedGoogle Scholar
  • 41 Zafra F, Aragon C, Olivares L. et al . Glycine transporters are differentially expressed among CNS cells.  J Neurosci . 1995;  15 3952-3969
    PubMedGoogle Scholar
  • 42 Zwingmann C, Desjardins P, Hazell A. et al . Reduced expression of astrocytic glycine transporter (GLYT-1) in acute liver failure.  Metab Brain Dis . 2002;  17 263-273
    CrossrefPubMedGoogle Scholar
  • 43 Michalak A, Chatauret N, Butterworth R F. Evidence for a serotonin transporter deficit in experimental acute liver failure.  Neurochem Int . 2001;  38 163-168
    PubMedGoogle Scholar
  • 44 Michalak A, Rose C, Butterworth R F. Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure.  Neurochem Int . 2001;  38 25-30
    CrossrefPubMedGoogle Scholar
  • 45 Fischbarq J, Kuang K Y, Vera J C. et al . Glucose transporters serve as water channels.  Proc Natl Acad Sci USA . 1990;  87 3244-3247
    PubMedGoogle Scholar
  • 46 Margulies J E, Thompson R C, Demetriou A A. Aquaporin-4 water channel is up-regulated in the brain in fulminant hepatic failure (Abst).  Hepatology . 1999;  30 395A
    CrossrefPubMedGoogle Scholar
  • 47 Itzhak Y, Roig-Cantisano A, Dombro R S. et al . Acute liver failure and hyperammonemia increase peripheral-type receptor binding and pregnenolone synthesis in mouse brain.  Brain Res . 1995;  705 345-348
    CrossrefPubMedGoogle Scholar
  • 48 Takahashi H, Koehler R C, Brusilow S W, Traystman R J. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats.  Am J Physiol . 1991;  261 H825-H829
    PubMedGoogle Scholar
  • 49 Blei A T, Olafsson S, Therrien G, Butterworth R F. Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis.  Hepatology . 1994;  19 1437-1444
    CrossrefPubMedGoogle Scholar
  • 50 Rose C, Michalak A, Rama Rao V K. et al . L-ornithine L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure.  Hepatology . 1999;  30 636-640
    CrossrefPubMedGoogle Scholar
  • 51 Rose C, Michalak A, Pannunzio M. et al . Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure.  Hepatology . 2000;  3 872-877
    PubMedGoogle Scholar
  • 52 Traber P, DalCanto M, Ganger D, Blei A T. Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization.  Gastroenterology . 1989;  96 885-891
    PubMedGoogle Scholar
  • 53 Schenker S, Warren K S. Effect of temperature variation on toxicity and metabolism of ammonia in mice.  J Lab Clin Med . 1962;  60 291-301
    PubMedGoogle Scholar
  • 54 Basile A S, Hughes R D, Harrison P M. et al . Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure.  N Engl J Med . 1991;  325 473-478
    PubMedGoogle Scholar
  • 55 Basile A S, Pannell L, Jaouni T. et al . Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.  Proc Natl Acad Sci USA . 1990;  87 5263-5267
    PubMedGoogle Scholar
  • 56 Widler P, Fisch H U, Schoch P. et al . Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopthy in the thioacetamide-treated rat.  Hepatology . 1993;  18 1459-1464
    CrossrefPubMedGoogle Scholar
  • 57 Ferenci P, Grimm G. Treatment of hepatic encephalopathy with the benzodiazepine antagonist flumazenil. In: Butterworth RF, Pomier Layrargues G, eds. Hepatic Encephalopathy: Pathophysiology and Treatment Clifton, NJ 1989: 597-612
    Google Scholar
  • 58 Van der Rijt C C, de Knegt J R, Schalm S W. et al . Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit.  Metab Brain Dis   1990;  5 131-141
    PubMedGoogle Scholar
  • 59 Vogels B A, Maas M A, Daalhuisen J. et al . Memantine, a non-competitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats.  Hepatology . 1997;  25 820-827
    CrossrefPubMedGoogle Scholar