Brain lactate in hepatic encephalopathy: Friend or foe?

Liver Failure Group, UCL Institute for Liver and Digestive Health, The Royal Free Hospital, Pond Street, London NW3 2PF, United KingdomSee Article, pages 554–560Pathogenesis of intracranial hypertension in acute liver failure(ALF) has been a subject of intense investigation and debate overa number of years. Hyperammonemia, systemic and braininflammation, and alterations in cerebral blood flow have all beensuggested as interrelated pathogenic mechanisms [1]. Theprevailing hypothesis is that increased brain ammonia resultsin cytotoxic brain edema due to an increase in astrocytic gluta-mine, which acts as an osmolyte producing accumulation ofwater in the cell [2]. Cerebral hyperlactatemia has been sug-gested to be associated with increased ICP in patients with ALF.In fact, close correlation between increased brain lactate andincreased ICP was shown in humans with ALF [3]. The pathophys-iological mechanism of this increase in brain lactate is not fullyunderstood but has been suggested to occur due to relative cere-bral hypoperfusion, reduced cerebral oxygenation and an ammo-nia induced inhibition of a key enzyme in the tricarboxylic acidcycle, alpha-ketoglutarate dehydrogenase driving anaerobicmetabolism [4,5]. Arguments countering this contention are theobservations that cerebral blood flow is indeed increased in latestages of ALF, which correlates with the severity of intracranialhypertension, a maintained lactate/pyruvate ratio, undisturbedcerebral alpha-ketoglutarate dehydrogenase in ALF animals andno significant differences in brain mitochondrial complex activi-ties [6,7]. Taken together, the studies favour the hypothesis thatthe increase in brain lactate is a consequence of pathophysiologicmechanisms rather than its cause and therefore a marker ratherthan a therapeutic target. The study by Bosoi et al. questions thishypothesis [8]. Data about brain lactate metabolism in chronicliver disease is scarce and therefore the paper in the present issueof the Journal adds further to the literature.The authors of the study interpret their data to suggest thatbrain lactate and not brain glutamine acts as a pivotal osmolytein the pathogenesis of brain edema in a chronic liver failureanimal model and therefore is a potential target for therapy.The study was performed in 6-weeks bile duct ligated rats(BDL) rats. BDL rats demonstrated a significant increase in brainlactate (p <0.001), and brain glutamine (p <0.001 and p <0.01respectively) and de novo synthesis of brain lactate and glutaminefrom 13C-labelled glucose compared with Sham rats. Toinvestigate the role of lactate in the physiopathology of the brainedema, the authors administered to dichloroacetate (DCA) intra-peritoneally, a drug that decreases lactate synthesis by shiftinglactate dehydrogenase activity from lactate to pyruvate produc-tion. The results demonstrate that DCA treatment normalizedbrain lactate levels and reduced brain water content in BDL rats(p <0.05). Cerebral glutamine, ammonia, and liver enzymes werenot significantly different between groups. They also used asecond intervention, a synthetic carbon, AST-120, which theyhave shown in the past, reduces ammonia in a similar model. Thisintervention reduced the arterial ammonia and also reducedbrain water measured by gravimetry method. Here again theyobserved a diminution in the brain lactate with no changes inthe brain glutamine levels. They conclude that reduction in brainlactate may be a potential therapeutic target.This suggestion is provocative and requires discussionconsidering the role that lactate plays as an important energyresource for the brain [9,10]. Lactate is produced by astrocytesas a final product of glycolysis and is transported into the extra-cellular space. The neurons take up this lactate via transporters[11] and can use the lactate obtained from the astrocytes asenergy converting the lactate to pyruvate by lactate dehydroge-nase, which then enters the tricarboxylic acid cycle [12]. Theexistence of this lactate shuttle between astrocytes and neuronsis supported by a number of experimental studies [13] and hasbeen demonstrated in patients with traumatic brain injury [14].During the recent past, several human and animal studies pointto the importance of brain lactate in maintaining homeostasis[13] that require consideration to put into context the results ofBosoi et al. [8]. Suzuki et al. [15] demonstrated the importanceof lactate in long-term memory formation and long-term poten-tiation showing that long-term memory was impaired after theadministration of 1,4-dideoxy-1,4-imino-darabinitol [DAB], apotent inhibitor of astrocytic glycogen phosphorylase and theimprovement by the administration of exogenous lactate.Smith et al. showed that exogenous sodium lactate administra-tion during exercise leads to a reduction in the glucose consump-tion rate [16] and that the brain could use this to provide energyas an alternative source. In an animal model of traumatic braininjury, Chen et al. demonstrated that lactate could be used byan injured area of the brain as energy source [17] and thecognitive impairment during traumatic brain injury could beimproved by the administration of lactate [18]. Ichai et al.demonstrated that the acute infusion of sodium lactate was moreeffective treating the intracranial hypertension than MannitolJournal of Hepatology 2014 vol. 60