2003, Number 1
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Ann Hepatol 2003; 2 (1)
Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy
Vaquero J, Chung C, Blei AT
Language: English
References: 132
Page: 12-22
PDF size: 207.84 Kb.
Text Extraction
Hepatic encephalopathy and brain edema are important complications in the course of a patient with acute liver failure. Presumed unrelated for many years, increasing evidence suggests that an increase in brain water is seen in all forms of hepatic encephalopathy. Ammonia, traditionally linked to the pathogenesis of hepatic encephalopathy, plays an important role in the increase in brain water. In acute liver failure, an osmotic disturbance in the astrocyte, in combination with an alteration of cerebral blood flow results in overt brain edema and intracranial hypertension. In cirrhosis, magnetic resonance techniques indicate the presence of a brain osmotic disturbance. Several clinical factors modulate the development of brain swelling.
REFERENCES
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35: 716-721.
Ware AJ, D’Agostino AN, Combes B. Cerebral edema: a major complication of massive hepatic necrosis. Gastroenterology 1971; 61: 877-884.
Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodes J. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30: 890-895.
O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439-445.
Bernuau J, Goudeau A, Poynard T, Dubois F, Lesage G, Yvonnet B, Degott C, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986; 6: 648-651.
Castells A, Salmeron JM, Navasa M, Rimola A, Salo J, Andreu H, Mas A, et al. Liver transplantation for acute liver failure: analysis of applicability. Gastroenterology 1993; 105: 532-538.
Hoofnagle JH, Carithers RL, Jr., Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology 1995; 21: 240-252.
O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993; 342: 273-275.
Cordoba J, Blei AT. Brain edema and hepatic encephalopathy. Semin Liver Dis 1996; 16: 271-280.
Kato M, Hughes RD, Keays RT, Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 1992; 15: 1060-1066.
Traber PG, Dal Canto M, Ganger DR, Blei AT. 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: 1272-1277.
Traber P, DalCanto M, Ganger D, Blei AT. Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization. Gastroenterology 1989; 96: 885-891.
Matkowskyj KA, Marrero JA, Carroll RE, Danilkovich AV, Green RM, Benya RV. Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model. Am J Physiol 1999; 277: G455-462.
Gove CD, Hughes RD, Ede RJ, Williams R. Regional cerebral edema and chloride space in galactosamine-induced liver failure in rats. Hepatology 1997; 25: 295-301.
Dixit V, Chang TM. Brain edema and the blood brain barrier in galactosamine-induced fulminant hepatic failure rats. An animal model for evaluation of liver support systems. ASAIO Trans 1990; 36: 21-27.
Zaki AE, Ede RJ, Davis M, Williams R. Experimental studies of blood brain barrier permeability in acute hepatic failure. Hepatology 1984; 4: 359-363.
Horowitz ME, Schafer DF, Molnar P, Jones EA, Blasberg RG, Patlak CS, Waggoner J, et al. Increased blood-brain transfer in a rabbit model of acute liver failure. Gastroenterology 1983; 84: 1003-1011.
Bassett ML, Mullen KD, Scholz B, Fenstermacher JD, Jones EA. Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy. Gastroenterology 1990; 98: 747-757.
Livingstone AS, Potvin M, Goresky CA, Finlayson MH, Hinchey EJ. Changes in the blood-brain barrier in hepatic coma after hepatectomy in the rat. Gastroenterology 1977; 73: 697-704.
Alexander B, Li X, Benjamin IS, Segal MB, Sherwood R, Preston JE. A quantitative evaluation of the permeability of the blood brain barrier of portacaval shunted rats. Metab Brain Dis 2000; 15: 93-103.
Brusilow SW: Inborn errors of urea synthesis. In: Lloyd J, Scriver C, eds. Genetic and metabolic diseases in pediatrics. London: Butterworths, 1985; 140-165.
Takahashi H, Koehler RC, Brusilow SW, Traystman RJ. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 1991; 261: H825-829.
Blei AT, Olafsson S, Therrien G, Butterworth RF. Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology 1994; 19: 1437-1444.
Norenberg MD, Bender AS. Astrocyte swelling in liver failure: role of glutamine and benzodiazepines. Acta Neurochir Suppl (Wien) 1994; 60: 24-27.
Ganz R, Swain M, Traber P, DalCanto M, Butterworth RF, Blei AT. Ammonia-induced swelling of rat cerebral cortical slices: implications for the pathogenesis of brain edema in acute hepatic failure. Metab Brain Dis 1989; 4: 213-223.
Swain M, Butterworth RF, Blei AT. Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats. Hepatology 1992; 15: 449-453.
Mans AM, DeJoseph MR, Hawkins RA. Metabolic abnormalities and grade of encephalopathy in acute hepatic failure. J Neurochem 1994; 63: 1829-1838.
Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999; 29: 648-653.
Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol 2002; 67: 259-279.
Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science 1977; 195: 1356-1358.
Cordoba J, Gottstein J, Blei AT. Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema. Hepatology 1996; 24: 919-923.
Cordoba J, Crespin J, Gottstein J, Blei AT. Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis. Gastroenterology 1999; 116: 686-693.
Olafsson S, Gottstein J, Blei AT. Brain edema and intracranial hypertension in rats after total hepatectomy. Gastroenterology 1995; 108: 1097-1103.
McConnell JR, Antonson DL, Ong CS, Chu WK, Fox IJ, Heffron TG, Langnas AN, et al. Proton spectroscopy of brain glutamine in acute liver failure. Hepatology 1995; 22: 69-74.
Haussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, Gerok W, et al. Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 1994; 107: 1475-1480.
Bates TE, Williams SR, Kauppinen RA, Gadian DG. Observation of cerebral metabolites in an animal model of acute liver failure in vivo: a 1H and 31P nuclear magnetic resonance study. J Neurochem 1989; 53: 102-110.
Bosman DK, Deutz NE, De Graaf AA, vd Hulst RW, Van Eijk HM, Bovee WM, Maas MA, et al. Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 1990; 12: 281-290.
Strauss GI, Knudsen GM, Kondrup J, Moller K, Larsen FS. Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Gastroenterology 2001; 121: 1109-1119.
Chung C, Gottstein J, Blei AT. Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 2001; 34: 249-254.
Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF. Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [H-C] nuclear magnetic resonance study. Hepatology 2003; 37: 420-428.
Michalak A, Rose C, Butterworth J, Butterworth RF. Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 1996; 24: 908-913.
Peeling J, Shoemaker L, Gauthier T, Benarroch A, Sutherland GR, Minuk GY. Cerebral metabolic and histological effects of thioacetamide-induced liver failure. Am J Physiol 1993; 265: G572-578.
Zimmermann C, Ferenci P, Pifl C, Yurdaydin C, Ebner J, Lassmann H, Roth E, 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.
Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982; 23: 625-629.
Tofteng F, Jorgensen L, Hansen BA, Ott P, Kondrup J, Larsen FS. Cerebral microdialysis in patients with fulminant hepatic failure. Hepatology 2002; 36: 1333-1340.
Tofteng F, Larsen FS. Monitoring extracellular concentrations of lactate, glutamate, and glycerol by in vivo microdialysis in the brain during liver transplantation in acute liver failure. Liver Transpl 2002;8:302-305.
Bosman DK, Deutz NE, Maas MA, van Eijk HM, Smit JJ, de Haan JG, Chamuleau RA. Amino acid release from cerebral cortex in experimental acute liver failure, studied by in vivo cerebral cortex microdialysis. J Neurochem 1992; 59: 591-599.
Rose C, Michalak A, Pannunzio M, Chatauret N, Rambaldi A, Butterworth RF. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure. Hepatology 2000; 31: 872-877.
de Knegt RJ, Schalm SW, van der Rijt CC, Fekkes D, Dalm E, Hekking-Weyma I. Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure: an experimental study based on in vivo brain dialysis. J Hepatol 1994; 20: 19-26.
Tossman U, Delin A, Eriksson LS, Ungerstedt U. Brain cortical amino acids measured by intracerebral dialysis in portacaval shunted rats. Neurochem Res 1987; 12: 265-269.
Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 1997; 229: 201-203.
Chan H, Butterworth RF. Evidence for an astrocytic glutamate transporter deficit in hepatic encephalopathy. Neurochem Res 1999; 24: 1397-1401.
Chan H, Hazell AS, Desjardins P, Butterworth RF. Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes. Neurochem Int 2000; 37: 243-248.
Mena EE, Cotman CW. Pathologic concentrations of ammonium ions block L-glutamate uptake. Exp Neurol 1985; 89: 259-263.
Bender AS, Norenberg MD. Effects of ammonia on L-glutamate uptake in cultured astrocytes. Neurochem Res 1996; 21: 567-573.
Oppong KN, Bartlett K, Record CO, al Mardini H. Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat. Hepatology 1995; 22: 553-558.
Moroni F, Lombardi G, Moneti G, Cortesini C. The release and neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy. J Neurochem 1983; 40: 850-854.
Erecinska M, Pastuszko A, Wilson DF, Nelson D. Ammonia-induced release of neurotransmitters from rat brain synaptosomes: differences between the effects on amines and amino acids. J Neurochem 1987; 49: 1258-1265.
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.
Van Harreveld A. Swelling of the Muller fibers in the chicken retina. J Neurobiol 1982; 13: 519-536.
Noble LJ, Hall JJ, Chen S, Chan PH. Morphologic changes in cultured astrocytes after exposure to glutamate. J Neurotrauma 1992; 9: 255-267.
Hermenegildo C, Marcaida G, Montoliu C, Grisolia S, Minana MD, Felipo V. NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochem Res 1996; 21: 1237-1244.
Vogels BA, Maas MA, Daalhuisen J, Quack G, Chamuleau RA. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 1997; 25: 820-827.
Wendon JA, Harrison PM, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 1994; 19: 1407-1413.
Vaquero J, Gottstein J, Cahill ME, Blei AT. N-acetylcysteine prevents ammonia-induced brain edema in rats after portacaval anastomosis. The 11th International Symposium on Hepatic Encephalopathy and Nitrogen Metabolism. Abstract book 2002: p31 [Abstract].
Kosenko E, Kaminsky Y, Kaminsky A, Valencia M, Lee L, Hermenegildo C, Felipo V. Superoxide production and antioxidant enzymes in ammonia intoxication in rats. Free Radic Res 1997; 27: 637-644.
Kosenko E, Felipo V, Montoliu C, Grisolia S, Kaminsky Y. Effects of acute hyperammonemia in vivo on oxidative metabolism in nonsynaptic rat brain mitochondria. Metab Brain Dis 1996; 12: 69-82.
Murthy CR, Rama Rao KV, Bai G, Norenberg MD. Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 2001; 66: 282-288.
Warskulat U, Gorg B, Bidmon HJ, Muller HW, Schliess F, Haussinger D. Ammonia-induced heme oxygenase-1 expression in cultured rat astrocytes and rat brain in vivo. Glia 2002; 40: 324-336.
Song G, Dhodda VK, Blei AT, Dempsey RJ, Rao VL. GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of portacaval shunted rats. J Neurosci Res 2002; 68: 730-737.
Rao VL, Audet RM, Butterworth RF. Increased neuronal nitric oxide synthase expression in brain following portacaval anastomosis. Brain Res 1997; 765: 169-172.
Master S, Gottstein J, Blei AT. Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 1999; 30: 876-880.
Schliess F, Gorg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A, Butterworth RF, et al. Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. Faseb J 2002; 16: 739-741.
Seda HW, Hughes RD, Gove CD, Williams R. Inhibition of rat brain Na+,K+-ATPase activity by serum from patients with fulminant hepatic failure. Hepatology 1984; 4: 74-79.
Ede RJ, Gove CD, Hughes RD, Marshall W, Williams R. Reduced brain Na+, K+-ATPase activity in rats with galactosamine-induced hepatic failure: relationship to encephalopathy and cerebral oedema. Clin Sci (Lond) 1987; 72: 365-371.
Holmin T, Agardh CD, Alinder G, Herlin P, Hultberg B. 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.
Bates TE, Williams SR, Busza AL, Gadian DG, Proctor E. A 31P nuclear magnetic resonance study in vivo of metabolic abnormalities in rats with acute liver failure. NMR Biomed 1988; 1: 67-73.
Larsen FS, Pott F, Hansen BA, Ejlersen E, Knudsen GM, Clemmesen JD, Secher NH. Transcranial Doppler sonography may predict brain death in patients with fulminant hepatic failure. Transplant Proc 1995; 27: 3510-3511.
Aggarwal S, Kramer D, Yonas H, Obrist W, Kang Y, Martin M, Policare R. Cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study. Hepatology 1994; 19: 80-87.
Larsen FS. Cerebral circulation in liver failure: Ohm’s law in force. Semin Liver Dis 1996; 16: 281-292.
Larsen FS, Ejlersen E, Clemmesen JO, Kirkegaard P, Hansen BA. Preservation of cerebral oxidative metabolism in fulminant hepatic failure: an autoregulation study. Liver Transpl Surg 1996; 2: 348-353.
Larsen FS, Knudsen GM, Hansen BA. Pathophysiological changes in cerebral circulation, oxidative metabolism and blood-brain barrier in patients with acute liver failure. Tailored cerebral oxygen utilization. J Hepatol 1997; 27: 231-238.
Magistretti PJ, Pellerin L, Rothman DL, Shulman RG. Energy on demand. Science 1999; 283: 496-497.
Larsen FS, Ejlersen E, Hansen BA, Knudsen GM, Tygstrup N, Secher NH. Functional loss of cerebral blood flow autoregulation in patients with fulminant hepatic failure. J Hepatol 1995; 23: 212-217.
Strauss G, Hansen BA, Kirkegaard P, Rasmussen A, Hjortrup A, Larsen FS. Liver function, cerebral blood flow autoregulation, and hepatic encephalopathy in fulminant hepatic failure. Hepatology 1997; 25: 837-839.
Larsen FS, Adel Hansen B, Pott F, Ejlersen E, Secher NH, Paulson OB, Knudsen GM. Dissociated cerebral vasoparalysis in acute liver failure. A hypothesis of gradual cerebral hyperaemia. J Hepatol 1996; 25: 145-151.
Strauss G, Hansen BA, Knudsen GM, Larsen FS. Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure. J Hepatol 1998; 28: 199-203.
Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia. Hepatology 2001; 34: 50-54.
Aggarwal S, Yonas H, Kang Y, Martin M, Kramer D, Obrist WD, Darby J. Relationship of cerebral blood flow and cerebral swelling to outcome in patients with acute fulminant hepatic failure. Transplant Proc 1991; 23: 1978-1979.
Jalan R, Damink SW, Deutz NE, Lee A, Hayes PC. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999; 354: 1164-1168.
Clemmesen JO, Hansen BA, Larsen FS. Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin. Hepatology 1997; 26: 1423-1425.
Larsen FS, Gottstein J, Blei AT. Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J Hepatol 2001; 34: 548-554.
Larsen FS, Wendon J. Brain edema in liver failure: basic physiologic principles and management. Liver Transpl 2002; 8: 983-989.
Hudetz AG. Blood flow in the cerebral capillary network: a review emphasizing observations with intravital microscopy. Microcirculation 1997; 4: 233-252.
Strauss E, da Costa MF. The importance of bacterial infections as precipating factors of chronic hepatic encephalopathy in cirrhosis. Hepatogastroenterology 1998; 45: 900-904.
Rolando N, Harvey F, Brahm J, Philpott-Howard J, Alexander G, Gimson A, Casewell M, et al. Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients. Hepatology 1990; 11: 49-53.
de la Mata M, Meager A, Rolando N, Daniels HM, Nouri-Aria KT, Goka AK, Eddleston AL, et al. Tumour necrosis factor production in fulminant hepatic failure: relation to aetiology and superimposed microbial infection. Clin Exp Immunol 1990; 82: 479-484.
Rolando N, Ellis A, de Groote D, Wendon J, Williams R. Correlation of serial cytokine levels with progression to coma (grade IV) in patients with acute liver failure (ALF). Hepatology 1995; 22: 366A.
Muto Y, Nouri-Aria KT, Meager A, Alexander GJ, Eddleston AL, Williams R. Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure. Lancet 1988; 2: 72-74.
Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32: 734-739.
Vaquero J, Schiodt F, Chung C, Rademaker AW, Lee WM, Blei AT. Predictors of progression to deep hepatic encephalopathy in acute liver failure: results of the US Acute Liver Failure Study Group. Hepatology 2002; 36: 222A.
Wong ML, Bongiorno PB, al-Shekhlee A, Esposito A, Khatri P, Licinio J. IL-1 beta, IL-1 receptor type I and iNOS gene expression in rat brain vasculature and perivascular areas. Neuroreport 1996; 7: 2445-2448.
Jalan R, Pollok A, Shah S, Madhavan K, Simpson K. Liver derived pro-inflammatory cytokines may be important in producing intracranial hypertension in acute liver failure. J Hepatol 2002; 37: 536.
Rozga J, Podesta L, LePage E, Hoffman A, Morsiani E, Sher L, Woolf GM, et al. Control of cerebral oedema by total hepatectomy and extracorporeal liver support in fulminant hepatic failure. Lancet 1993; 342: 898-899.
Jalan R, Williams R. The inflammatory basis of intracranial hypertension in acute liver failure. J Hepatol 2001; 34: 940-942.
Munoz SJ, Moritz MJ, Bell R, Northrup B, Martin P, Radomski J. Factors associated with severe intracranial hypertension in candidates for emergency liver transplantation. Transplantation 1993; 55: 1071-1074.
Kodakat SK, Gopal PB, Wendon J. Intracranial pressure is related to body temperature in acute liver failure. Liver Transpl 2001; 7: C87.
Katsumura H, Kabuto M, Hosotani K, Handa Y, Kobayashi H, Kubota T. The influence of total body hyperthermia on brain haemodynamics and blood-brain barrier in dogs. Acta Neurochir (Wien) 1995; 135: 62-69.
Mueller SM. Increased blood-brain barrier permeability during hyperthermia in the awake rat. Trans Am Neurol Assoc 1979; 104: 81-83.
Kodakat SK, Gopal PB, Wendon JA. Hyperglycaemia is associated with intracranial hypertension in patients with acute liver failure [abstract]. Liver Transpl 2001; 7: C21.
Nakakimura K, Fleischer JE, Drummond JC, Scheller MS, Zornow MH, Grafe MR, Shapiro HM. Glucose administration before cardiac arrest worsens neurologic outcome in cats. Anesthesiology 1990; 72: 1005-1011.
Lam AM, Winn HR, Cullen BF, Sundling N. Hyperglycemia and neurological outcome in patients with head injury. J Neurosurg 1991; 75: 545-551.
Shah V, Webster S, Gottstein J, Blei AT. Reduction of cerebral perfusion precedes rise of intracranial pressure in rats with ischemic fulminant liver failure. Hepatology 1993; 17: 1117-1122.
Bihari D, Gimson AE, Lindridge J, Williams R. Lactic acidosis in fulminant hepatic failure. Some aspects of pathogenesis and prognosis. J Hepatol 1985; 1: 405-416.
Ellis A, Wendon J. Circulatory, respiratory, cerebral, and renal derangements in acute liver failure: pathophysiology and management. Semin Liver Dis 1996; 16: 379-388.
Abbasoglu O, Goldstein RM, Vodapally MS, Jennings LW, Levy MF, Husberg BS, Klintmalm GB. Liver transplantation in hyponatremic patients with emphasis on central pontine myelinolysis. Clin Transplant 1998; 12: 263-269.
Bluml S, Zuckerman E, Tan J, Ross BD. Proton-decoupled 31P magnetic resonance spectroscopy reveals osmotic and metabolic disturbances in human hepatic encephalopathy. J Neurochem 1998; 71: 1564-1576.
Cordoba J, Gottstein J, Blei AT. Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis. J Hepatol 1998; 29: 589-594.
Tizianello A, Garibotto G, Robaudo C, Saffioti S, Pontremoli R, Bruzzone M, Deferrari G. Renal ammoniagenesis in humans with chronic potassium depletion. Kidney Int 1991; 40: 772-778.
Olde Damink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R. Interorgan ammonia metabolism in liver failure. Neurochem Int 2002; 41: 177-188.
Clemmesen JO, Kondrup J, Ott P. Splanchnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology 2000; 118: 1131-1139.
Sugarbaker SP, Revhaug A, Wilmore DW. The role of the small intestine in ammonia production after gastric blood administration. Ann Surg 1987; 206: 5-17.
Olde Damink SW, Dejong CH, Deutz NE, Soeters PB. Effects of simulated upper gastrointestinal hemorrhage on ammonia and related amino acids in blood and brain of chronic portacaval-shunted rats. Metab Brain Dis 1997; 12: 121-135.
Cooper AJ, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev 1987; 67: 440-519.
Haussinger D, Steeb R, Gerok W. Metabolic alkalosis as driving force for urea synthesis in liver disease: pathogenetic model and therapeutic implications. Clin Investig 1992; 70: 411-415.
Tannen RL, Goyal M. Response of ammoniagenesis to acute alkalosis. Am J Physiol 1984; 247: F827-836.
DuBose TD, Jr., Good DW. Effects of chronic Cl depletion alkalosis on proximal tubule transport and renal production of ammonium. Am J Physiol 1995; 269: F508-514.
Fine A. Effects of acute metabolic acidosis on renal, gut, liver, and muscle metabolism of glutamine and ammonia in the dog. Kidney Int 1982; 21: 439-444.
Welbourne TC. Effect of metabolic acidosis on hindquarter glutamine and alanine release. Metabolism 1986; 35: 614-618.
Gorg B, Foster N, Reinehr R, Bidmon HJ, Hongen A, Haussinger D, Schliess F. Benzodiazepine-induced protein tyrosine nitration in rat astrocytes. Hepatology 2003; 37: 334-342.
Jayakumar AR, Panickar KS, Norenberg MD. Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. J Neurochem 2002; 83: 1226-1234.
Bender AS, Norenberg MD. Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J Neurosci Res 1998; 54: 673-680.