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01-12-2014 | Research Article

Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy

Authors: Cristina R. Bosoi, Christopher F. Rose

Published in: Metabolic Brain Disease | Issue 4/2014

Abstract

Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome, is a frequent complication of liver failure/disease. Increased concentrations of lactate are commonly observed in HE patients, in the systemic circulation, but also in the brain. Traditionally, increased cerebral lactate is considered a marker of energy failure/impairment however alterations in lactate homeostasis may also lead to a rise in brain lactate and result in neuronal dysfunction. The latter may involve the development of brain edema. This review will target the significance of increased cerebral lactate in the pathogenesis of HE.

Throughout the text, “lactate” will represent L-lactate.

Throughout the text, “LDH” will represent L-LDH.

Abdelmalak M, Lew A, Ramezani R et al (2013) Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab 109:139–143. doi:10.1016/j.ymgme.2013.03.019 PubMedCentralPubMedCrossRef

Amodio P, Biancardi A, Montagnese S et al (2007) Neurological complications after orthotopic liver transplantation. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver 39:740–747. doi:10.1016/j.dld.2007.05.004

Atluri DK, Asgeri M, Mullen KD (2010) Reversibility of hepatic encephalopathy after liver transplantation. Metab Brain Dis 25:111–113. doi:10.1007/s11011-010-9178-x PubMedCrossRef

Bajaj JS, Saeian K, Verber MD et al (2007) Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gastroenterol 102:754–760. doi:10.1111/j.1572-0241.2007.01048.x PubMedCrossRef

Baron J-C, Yamauchi H, Fujioka M, Endres M (2014) Selective neuronal loss in ischemic stroke and cerebrovascular disease. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 34:2–18. doi:10.1038/jcbfm.2013.188 CrossRef

Bélanger M, Yang J, Petit J-M et al (2011) Role of the glyoxalase system in astrocyte-mediated neuroprotection. J Neurosci Off J Soc Neurosci 31:18338–18352. doi:10.1523/JNEUROSCI.1249-11.2011 CrossRef

Bernal W, Donaldson N, Wyncoll D, Wendon J (2002) Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 359:558–563. doi:10.1016/S0140-6736(02)07743-7 PubMedCrossRef

Bittar PG, Charnay Y, Pellerin L et al (1996) Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 16:1079–1089. doi:10.1097/00004647-199611000-00001 CrossRef

Bjerring PN, Hauerberg J, Frederiksen H-J et al (2008) Cerebral glutamine concentration and lactate-pyruvate ratio in patients with acute liver failure. Neurocrit Care 9:3–7. doi:10.1007/s12028-008-9060-4 PubMedCrossRef

Bjerring PN, Hauerberg J, Jørgensen L et al (2010) Brain hypoxanthine concentration correlates to lactate/pyruvate ratio but not intracranial pressure in patients with acute liver failure. J Hepatol 53:1054–1058. doi:10.1016/j.jhep.2010.05.032 PubMedCrossRef

Bo J, Li W, Chen Z et al (2013) D-lactate: a novel contributor to metabolic acidosis and high anion gap in diabetic ketoacidosis. Clin Chem 59:1406–1407. doi:10.1373/clinchem.2013.208777 PubMedCrossRef

Bosman DK, Deutz NE, De Graaf AA et al (1990) Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatol Baltim Md 12:281–290CrossRef

Bosoi CR, Rose CF (2013) Brain edema in acute liver failure and chronic liver disease: similarities and differences. Neurochem Int 62:446–457. doi:10.1016/j.neuint.2013.01.015 PubMedCrossRef

Bosoi CR, Yang X, Huynh J et al (2012) Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 52:1228–1235. doi:10.1016/j.freeradbiomed.2012.01.006 PubMedCrossRef

Bosoi CR, Zwingmann C, Marin H et al (2014) Increased brain lactate is central to the development of brain edema in rats with chronic liver disease. J Hepatol 60:554–560. doi:10.1016/j.jhep.2013.10.011 PubMedCrossRef

Butterworth RF (2007) Neuronal cell death in hepatic encephalopathy. Metab Brain Dis 22:309–320. doi:10.1007/s11011-007-9072-3 PubMedCrossRef

Butterworth RF, Kril JJ, Harper CG (1993) Thiamine-dependent enzyme changes in the brains of alcoholics: relationship to the Wernicke-Korsakoff syndrome. Alcohol Clin Exp Res 17:1084–1088PubMedCrossRef

Calvert LD, Shelley R, Singh SJ et al (2008) Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:1090–1094. doi:10.1164/rccm.200707-1032OC PubMedCrossRef

Cauli O, López-Larrubia P, Rodrigo R et al (2011) Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats. Gastroenterology 140:638–645. doi:10.1053/j.gastro.2010.10.043 PubMedCrossRef

Chatauret N, Zwingmann C, Rose C et al (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterology 125:815–824PubMedCrossRef

Chavarria L, Oria M, Romero-Gimenez J et al (2010) Diffusion tensor imaging supports the cytotoxic origin of brain edema in a rat model of acute liver failure. Gastroenterology 138:1566–1573. doi:10.1053/j.gastro.2009.10.003 PubMedCrossRef

Chen F, Ohashi N, Li W et al (2009) Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure. Hepatol Baltim Md 50:1914–1923. doi:10.1002/hep.23203 CrossRef

Ciancio A, Marchet A, Saracco G et al (2002) Spectral electroencephalogram analysis in hepatic encephalopathy and liver transplantation. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc 8:630–635. doi:10.1053/jlts.2002.33971

Clemmesen JO, Høy CE, Kondrup J, Ott P (2000) Splanchnic metabolism of fuel substrates in acute liver failure. J Hepatol 33:941–948PubMedCrossRef

Fitzpatrick SM, Hetherington HP, Behar KL, Shulman RG (1989) Effects of acute hyperammonemia on cerebral amino acid metabolism and pHi in vivo, measured by 1H and 31P nuclear magnetic resonance. J Neurochem 52:741–749PubMedCrossRef

Gorman AM (2008) Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12:2263–2280. doi:10.1111/j.1582-4934.2008.00402.x PubMedCrossRef

Hartmann IJ, Groeneweg M, Quero JC et al (2000) The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 95:2029–2034. doi:10.1111/j.1572-0241.2000.02265.x PubMedCrossRef

Hertz L, Dienel GA (2002) Energy metabolism in the brain. Int Rev Neurobiol 51:1–102PubMedCrossRef

Hindfelt B, Plum F, Duffy TE (1977) Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest 59:386–396. doi:10.1172/JCI108651 PubMedCentralPubMedCrossRef

Jeppesen JB, Mortensen C, Bendtsen F, Møller S (2013) Lactate metabolism in chronic liver disease. Scand J Clin Lab Invest. doi:10.3109/00365513.2013.773591 PubMed

Kaila K, Ransom BR (1998) pH and brain function. Wiley-Liss, New York

Kim WR, Brown RS Jr, Terrault NA, El-Serag H (2002) Burden of liver disease in the United States: summary of a workshop. Hepatol Baltim Md 36:227–242. doi:10.1053/jhep.2002.34734 CrossRef

Krautwald M, Münch G (2010) Advanced glycation end products as biomarkers and gerontotoxins - a basis to explore methylglyoxal-lowering agents for Alzheimer’s disease? Exp Gerontol 45:744–751. doi:10.1016/j.exger.2010.03.001 PubMedCrossRef

Kumar A, Kant S, Singh SM (2013) Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: a role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation. Toxicol Appl Pharmacol 273:196–208. doi:10.1016/j.taap.2013.09.005 PubMedCrossRef

Lai JC, Cooper AJ (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–1386PubMedCrossRef

Languren G, Montiel T, Julio-Amilpas A, Massieu L (2013) Neuronal damage and cognitive impairment associated with hypoglycemia: an integrated view. Neurochem Int 63:331–343. doi:10.1016/j.neuint.2013.06.018 PubMedCrossRef

Lee WM (1993) Acute liver failure. N Engl J Med 329:1862–1872. doi:10.1056/NEJM199312163292508 PubMedCrossRef

Levraut J, Ciebiera JP, Chave S et al (1998) Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med 157:1021–1026. doi:10.1164/ajrccm.157.4.9705037 PubMedCrossRef

Lin S, Raabe W (1985) Ammonia intoxication: effects on cerebral cortex and spinal cord. J Neurochem 44:1252–1258PubMedCrossRef

Lowry OH, Passonneau JV (1966) Kinetic evidence for multiple binding sites on phosphofructokinase. J Biol Chem 241:2268–2279PubMed

Mans AM, DeJoseph MR, Hawkins RA (1994) Metabolic abnormalities and grade of encephalopathy in acute hepatic failure. J Neurochem 63:1829–1838PubMedCrossRef

Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 32:1152–1166. doi:10.1038/jcbfm.2011.149 CrossRef

Pellerin L, Bouzier-Sore A-K, Aubert A et al (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55:1251–1262. doi:10.1002/glia.20528 PubMedCrossRef

Perazzo JC (2012) Hepatic encephalopathy: an approach to its multiple pathophysiological features. World J Hepatol 4:50. doi:10.4254/wjh.v4.i3.50 PubMedCentralPubMedCrossRef

Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14. doi:10.1111/j.1471-4159.2005.03168.x PubMedCrossRef

Preuss M (2012) An energy-failure based brain edema concept. Med Hypotheses 79:259–260. doi:10.1016/j.mehy.2012.05.003 PubMedCrossRef

Rose C (2012) Ammonia-lowering strategies for the treatment of hepatic encephalopathy. Clin Pharmacol Ther 92(3):321–31. doi:10.1038/clpt.2012.112 PubMedCrossRef

Rose C, Kresse W, Kettenmann H (2005) Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J Biol Chem 3(280(22)):20937–44CrossRef

Rose C, Ytrebø LM, Davies NA et al (2007) Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure. Hepatol Baltim Md 46:1883–1892. doi:10.1002/hep.21877 CrossRef

Sawara K, Desjardins P, Chatauret N et al (2009) Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure. Neurochem Int 55:119–123. doi:10.1016/j.neuint.2009.01.023 PubMedCrossRef

Schurr A (2006) Lactate: the ultimate cerebral oxidative energy substrate? J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 26:142–152. doi:10.1038/sj.jcbfm.9600174 CrossRef

Sen S, Rose C, Ytrebø LM et al (2006) Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study. Crit Care Med 34:158–164PubMedCrossRef

Shih MT, Singh AK, Wang A-M, Patel S (2004) Brain lesions with elevated lactic acid peaks on magnetic resonance spectroscopy. Curr Probl Diagn Radiol 33:85–95. doi:10.1016/j.cpradiol.2003.11.002 PubMedCrossRef

Sotil EU, Gottstein J, Ayala E et al (2009) Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc 15:184–192. doi:10.1002/lt.21593

Stacpoole PW, Henderson GN, Yan Z, James MO (1998) Clinical pharmacology and toxicology of dichloroacetate. Environ Health Perspect 106(4):989–994PubMedCentralPubMedCrossRef

Stadtman ER, Levine RL (2000) Protein oxidation. Ann N Y Acad Sci 899:191–208PubMedCrossRef

Staub F, Baethmann A, Peters J et al (1990) Effects of lactacidosis on glial cell volume and viability. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 10:866–876CrossRef

Tas A, Akbal E, Beyazit Y, Kocak E (2012) Serum lactate level predict mortality in elderly patients with cirrhosis. Wien Klin Wochenschr 124:520–525. doi:10.1007/s00508-012-0208-z PubMedCrossRef

Therrien G, Rose C, Butterworth J, Butterworth RF (1997) Protective effect of L-carnitine in ammonia-precipitated encephalopathy in the portacaval shunted rat. Hepatol Baltim Md 25:551–556. doi:10.1002/hep.510250310 CrossRef

Tofteng F, Jorgensen L, Hansen BA et al (2002) Cerebral microdialysis in patients with fulminant hepatic failure. Hepatol Baltim Md 36:1333–1340. doi:10.1053/jhep.2002.36944 CrossRef

Vogels BA, Karlsen OT, Mass MA et al (1997) L-ornithine vs. L-ornithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats. J Hepatol 26:174–182PubMedCrossRef

Woll PJ, Record CO (1979) Lactate elimination in man: effects of lactate concentration and hepatic dysfunction. Eur J Clin Invest 9:397–404PubMedCrossRef

Wright G, Davies NA, Shawcross DL et al (2007) Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatol Baltim Md 45:1517–1526. doi:10.1002/hep.21599 CrossRef

Yamamoto S, Nguyen JH (2006) TIMP-1/MMP-9 imbalance in brain edema in rats with fulminant hepatic failure. J Surg Res 134:307–314. doi:10.1016/j.jss.2005.11.588 PubMedCentralPubMedCrossRef

Yao H, Sadoshima S, Fujii K et al (1987) Cerebrospinal fluid lactate in patients with hepatic encephalopathy. Eur Neurol 27:182–187PubMedCrossRef

Zauner C, Schneeweiss B, Schneider B et al (2000) Short-term prognosis in critically ill patients with liver cirrhosis: an evaluation of a new scoring system. Eur J Gastroenterol Hepatol 12:517–522PubMedCrossRef

Zosel A, Egelhoff E, Heard K (2010) Severe lactic acidosis after an iatrogenic propylene glycol overdose. Pharmacotherapy 30:219. doi:10.1592/phco.30.2.219 PubMedCentralPubMedCrossRef

Zwingmann C (2007) Nuclear magnetic resonance studies of energy metabolism and glutamine shunt in hepatic encephalopathy and hyperammonemia. J Neurosci Res 85:3429–3442. doi:10.1002/jnr.21445 PubMedCrossRef

Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. Hepatol Baltim Md 37:420–428. doi:10.1053/jhep.2003.50052 CrossRef

Title: Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy
Authors: Cristina R. Bosoi
Christopher F. Rose
Publication date: 01-12-2014
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 4/2014
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-014-9573-9

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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