NAC supplementation decreased lipid peroxidation and restored the activity of antioxidant enzymes as well as structural deficits observed in the cortex and cerebellum. Chatauret N., Zwingmann C., Rose C., Leibfritz D., Butterworth R.F. Before This extravasation of IgG was accompanied by significant up-regulation of matrix metalloproteinase-9 (MMP-9), an endopeptidase known to modulate opening of the BBB in a wide range of neurological disorders.82, In ALF, astrocytes exposed to ammonia develop signs of oxidative stress. Weissenborn K., Ennen J., Schomerus H., Ruckert N., Hecker H. Neuropsychological characterization of hepatic encephalopathy. Bernal W., Donaldson N., Wyncoll D., Wendon J. Liaw S.H., Kuo I., Eisenberg D. Discovery of the ammonium substrate site on glutamine synthetase, a third cation binding site. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. There are no data in human ALF but the recognized hepatotoxicity of the drug may well limit clinical trials. Rose C., Ytrebo L.M., Davies N.A. In those who developed ICH, mortality fell from 95% to 55% (P<0.0001). Glutamine, the Trojan horse, thereby acts as a carrier of ammonia into mitochondria, where its accumulation can lead to oxidative stress and ultimately, astrocyte swelling. Accordingly, treatment of HE with pure ammonia lowering strategies is becoming obsolete as novel strategies which target systemic inflammation gather a greater evidence base including rifaximin- which is quickly becoming the new mainstay in the treatment of HE whilst other anti-inflammatory therapies are undergoing scrutiny. Broadly speaking, those patients who were experiencing significant neurological disturbances had elevated blood ammonia levels16,17 but whilst blood ammonia levels were generally higher in cirrhotic patients with either past or present neurological disturbances, blood ammonia concentration was not predictive or consistent with severity HE.18,19 This finding has been replicated with one such study showing that 69% of individuals with no overt signs of HE had elevated blood ammonia levels, whilst a number of patients with more significant grade 3 or 4 HE had either normal or only slightly elevated levels of ammonia in their blood.20, This is in contrast to ALF whereby the relationship between blood ammonia levels and the clinical severity of HE is more clear-cut. Shawcross D.L., Sharifi Y., Canavan J.B. The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. Harrison P.M., Keays R., Bray G.P., Alexander G.J., Williams R. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver dysfunction. A figure summarizing how ammonia and immune dysfunction contribute to the propensity to develop hepatic encephalopathy and brain edema in the context of acute and chronic liver failure. Vaquero J., Polson J., Chung C. Infection and the progression of hepatic encephalopathy in acute liver failure. Jalan R., Schnurr K., Mookerjee R. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Invitro studies have shown that the BBB can become compromised by the presence of IL-1 via intracellular endothelial cell cyclooxygenase and TNF- activity, which induces endothelin-1 production promoting cerebral inflammation and disrupting the permeability of brain micro-vascular endothelial cells.80,81 Chastre and colleagues have shown that endotoxin administration in an ALF mouse model led to a rapid precipitation of hepatic coma and BBB permeability to the 25-kDa protein immunoglobulin G (IgG). Keiding S., Sorensen M., Munk O.L., Bender D. Human (13)N-ammonia PET studies: the importance of measuring (13)N-ammonia metabolites in blood. Rifaximin- is a broad-spectrum antibiotic which has minimal systemic absorption. Furthermore, in stable cirrhotic patients undergoing neuropsychological testing, there was a significant deterioration in scores following induced hyperammonemia in the inflammatory state, but not after its resolution, suggesting inflammation and its mediators may be important in modulating the cerebral effect of ammonia.70 This observation applies equally to patients with cirrhosis that develop advanced HE with infection and systemic inflammation, but not ammonia, being implicated in the development of advanced HE.19, In an animal model of MHE, Cauli and colleagues demonstrated an improved learning ability following the administration of the NSAID, ibuprofen.71 This may act by reducing the inducible nitric oxide activity within the cerebral cortex. Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Unexpectedly however, mRNA and protein expression of iNOS and COX-2 and mRNA expression of proinflammatory cytokines and the chemokine monocyte chemoattractive protein-1 (MCP-1) in the cerebral cortex from deceased patients with liver cirrhosis and HE did not differ compared to patients without HE and non-cirrhotic controls.73 However, D'Mello and colleagues have elegantly shown in a bile duct-ligated resection mouse model that there is significant infiltration of activated monocytes into the brain accompanying microglial activation. Antoniades C., Berry P., Wendon J., Vergani D. The importance of immune dysfunction in determining outcome in acute liver failure. Sepsis and inflammation are terms often used synonymously, however they are not equivalent clinical entities. Bethesda, MD 20894, Web Policies This, combined with altered neurotransmission, increased oxidative/nitrosative stress and immune dysfunction are thought to underpin the development of HE. The occurrence of hyperammonaemia is not specific to liver dysfunction, and can also be observed in various other disease states including, but not limited to, inborn errors of the urea cycle, Reye's syndrome and valproate poisoning.24 In the context of liver failure, the brain, and more specifically, astrocytes, act as an alternative metabolic pathway for ammonia; but not without a toll. Taylor N.J., Nishtala A., Manakkat Vijay G.K. Shawcross D.L., Wendon J.A. Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Whilst the BBB has been shown to remain anatomically intact in HE,28 PET studies utilizing 13N-ammonia have demonstrated an increased uptake and trapping of ammonia in the brains of individuals with CLF, with controversy prevailing over the respective roles that alterations in the permeability of the BBB, and blood ammonia levels, may have in this observation.2932, From the neuropathological standpoint, significant astrocyte swelling and cytotoxic brain edema are cardinal features of human ALF. Phear E., Sherlock S., Summerskill W. Blood ammonium levels in liver disease and hepatic coma. Glutamine synthetase: glial localization in brain. The https:// ensures that you are connecting to the Phillips G., Schwartz R., Gabuzda G., Davidson C. The syndrome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. Bajaj J.S., Cordoba J., Mullen K.D. While the full mechanism is yet to be elucidated, there is a large body of evidence implicating ammonia in both direct and indirect toxic effects on the brain culminating in metabolic disarray, astrocyte dysfunction and cerebral edema. about navigating our updated article layout. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Septic encephalopathy or delirium, which will be discussed in an accompanying review in this journal, is well documented and can present similarly to HE with altered consciousness and motor activity, in the absence of cerebral infection. The site is secure. SIRS is the clinical manifestation of the systemic release of pro-inflammatory cytokines and mediators including, but not limited to TNF-, IL-1, IL-6, IL-8 and IL-12. Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Rolando N., Wade J., Davalos M., Wendon J., Philpott-Howard J., Williams R. The systemic inflammatory response syndrome in acute liver failure. Jiang W., Desjardins P., Butterworth R. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. Definition of the Systemic Inflammatory Response Syndrome.58. Keiding S., Sorensen M., Bender D., Munk O.L., Ott P., Vilstrup H. Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography. Larsen F.S., Hansen B.A., Ejlersen E. Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant hepatic failure. de Vries H.E., Blom-Roosemalen M.C., van Oosten M. The influence of cytokines on the integrity of the blood-brain barrier invitro. Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. However, novel strategies that target ammonia-induced neutrophil dysfunction would be of particular interest to explore such as modulators of p38-Mitogen Activated Phosphokinase95 and TLR-9.97. It has been proposed that low-grade astrocyte swelling, as may be seen in CLF,46 could have significant functional consequences despite the absence of clinically overt ICH, and impairment of the cross-talk between swollen astrocytes and neurones has also been suggested to alter cerebral function.47, Evidence suggests that the neuropsychological effects of induced hyperammonaemia, and the subsequent elevation of astrocyte glutamine levels, are determined by the intrinsic ability of the brain to buffer these changes by losing key osmolytes such as myo-inositol48; a process which may in itself be modulated by other factors such as hyponatraemia, a major risk factor for the development of overt HE in patients with CLF.49,50, In states of hyperammonaemia, ammonia detoxification within astrocytes leads to an intracellular accumulation of glutamine which, it is widely postulated, generates an osmotic stress and causes astrocytes to swell in HE; this is known as the osmotic gliopathy theory, and the reader is directed to a review by Brusilow and colleagues for a more detailed account.51. Shawcross D., Davies N., Williams R., Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. Bass N.M., Mullen K.D., Sanyal A. Rifaximin treatment in hepatic encephalopathy. Abbreviations: CBF: cerebral blood flow; NAC: N-acetyl cysteine; NSAID: Non-steroidal anti-inflammatory drug. Rao K.V., Panickar K.S., Jayakumar A.R., Norenberg M.D. Shawcross D.L., Shabbir S.S., Taylor N.J., Hughes R.D. Guevara M., Baccaro M.E., Torre A. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Cooper A.J., Lai J.C. Cerebral ammonia metabolism in normal and hyperammonemic rats. Aquantitative evaluation of the permeability of the blood brain barrier of portacaval shunted rats. Although the mechanisms are discreet, it is possible that infection can factor into the precipitation of an encephalopathic state, whether the patient has underlying liver disease, or not. Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Bajaj J.S., Saeian K., Christensen K.M. High volume plasmapheresis can alleviate brain edema in ALF and improves systemic hemodynamics despite increasing CBF.105 Plasmapheresis is likely to have a positive impact on systemic immune and endothelial dysfunction by reducing the proinflammatory milieu and thus SIRS. Ammonia derived from the gut is absorbed into the hepatic portal circulation and transported to the liver where, under normal physiological conditions, it enters the urea cycle and is metabolized. Ammonia that bypasses this primary fate is subsequently picked up and detoxified by glutamine synthetase (GS), an enzyme found in the hepatocytes surrounding the hepatic vein (as well as in muscle and astroglial cells), which catalyses the conversion of ammonia and glutamate to glutamine.23 Whilst the liver is critical in the homeostatic control of blood ammonia levels, other organs such as the brain, muscle and kidney are also known to play a role in regulating them. Fine structural localization of glutamine synthetase in astrocytes of rat brain. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleepwake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia. NAC has a potential therapeutic role as both an antioxidant and anti-inflammatory agent. The .gov means its official. The neurological manifestations of acute liver failure. Norenberg M. Hepatic encephalopathy: studies with astrocyte cultures. In chronic liver disease experimental models, portal vein ligated animals have not been found to exhibit microglial activation, however, feeding rats an ammonium-containing diet or performing bile duct ligation (BDL) was sufficient to induce microglial activation and neuroinflammation which was reduced by administering ibuprofen.72 Zemtsova and colleagues have demonstrated up-regulation of the microglial activation marker ionized calcium-binding adaptor molecule-1 in the cerebral cortex from acutely ammonia-intoxicated rats and in the cerebral cortex from patients with cirrhosis who had HE, but not from patients with cirrhosis who did not have HE. Bernal W., Hyyrylainen A., Gera A. Manakkat Vijay G.K., Abeles R.D., Ramage S. Neutrophil intracellular toll-like receptor (TLR9) expression serves as a biomarker that determines presence and severity of encephalopathy in acute liver failure and cirrhosis. ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease.1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure.2 Patients presenting with ALF are at risk of developing its cardinal, life-threatening feature, cerebral edema. Patients became drowsy, apathetic, weak, confused and disorientated to time and place, and exhibited various inappropriate behaviors. Kendall B.E., Kingsley D.P., Leonard J.V., Lingam S., Oberholzer V.G. Traber P.G., Dal C.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. The impact of ammonia is significantly greater on pure populations of neurones, as compared to populations of neurones co-cultured with astrocytes, highlighting a neuroprotective role for astrocytes.27, The strategic positioning of astrocytes within the neurovascular unit (composed of the cerebral microvascular endothelium, astrocytes, pericytes and extracellular matrix) is thought to facilitate the efficiency with which astroglial cells can detoxify ammonia and trap it in the brain. In a chronic portocaval-shunted rat model, Cauli and colleagues showed that the NSAID ibuprofen restored the ability of the rats to learn the Y-task maze, in addition to normalization of the function of the glutamate-nitric oxide cyclic guanosine monophosphate enzyme pathway in the cerebral cortex.71 Unfortunately, NSAID drugs can only have a limited role in the treatment of HE in patients with cirrhosis as they have adverse cardiovascular and renal toxicities which impact upon the protective role of prostaglandins in cellular metabolism. The severity of the HE did not however correlate with the arterial ammonia level, serum biochemistry or the underlying disease severity as measured by the MELD score.19. IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. In acetaminophen-induced ALF, early administration of intravenous NAC can prevent hepatic necrosis by increasing hepatic stores of glutathione.98 NAC has been shown to increase oxygen delivery to the tissues and increases oxygen consumption, concurrent with increased arterial blood pressure and cerebral perfusion pressure.99 It has been shown that these effects are mediated through increased nitric oxide/guanylate cyclase enzyme activity.100, In a BDL model of CLF, animals administered NAC for two weeks had improved spatial memory and reduced motor deficits. When ammonia combines with glutamate in the astrocytes to form glutamine, there is a reduction in the amount of glutamate in the cell. Circulating neutrophil dysfunction in acute liver failure. Moderate hypothermia (33C) has been extensively investigated as a therapeutic modality in patients presenting with ALF and uncontrolled ICH.106108 It has been postulated to improve outcomes through a variety of mechanisms including reducing CBF, brain ammonia uptake, systemic inflammation, ROS production and oxidative stress which helps to lower ICH.64 The use of mild hypothermia (cooling patients to <35C) has now become standard of care in many tertiary liver centers109 but its role in patients unsuitable for liver transplantation remains debatable. Blei A.T. Medical therapy of brain edema in fulminant hepatic failure. Gabuzda G.J., Phillips G., Davidson C. Reversible toxic manifestations in patients with cirrhosis of the liver given cation-exchange resins. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. However, brain capillary endothelial cells and their tight junctions appeared intact.34,39 Nguyen has also described physically intact tight junctions in ALF, but these were lengthened and tortuous in shape.40, In CLF, astrocytes typically exhibit morphological features of Alzheimer type II astrocytosis, which include a large swollen nucleus, prominent nucleolus, margination of the chromatin pattern and significant enlargement of the cytoplasm. Jover R., Rodrigo R., Felipo V. Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: a model of hepatic encephalopathy in cirrhosis. Some years later, Gabuzda and colleagues14 performed a therapeutic trial in 12 cirrhotic subjects which aimed to assess the efficacy of three different cation-exchange resins in the treatment of ascites; this followed reports that cation-exchange resins were effective in treating the fluid overload state associated with congestive cardiac failure. These substances precipitated the development of a syndrome identical to that of impending hepatic coma and lay the foundations of our understanding that ammonia is central in the pathogenesis of HE. These strategies will now be discussed [Figure3]. Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Llovet J.M., Bartoli R., March F. Translocated intestinal bacteria cause spontaneous bacterial peritonitis in cirrhotic rats: molecular epidemiologic evidence. Careers, Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Norenberg M. Alight and electron microscopic study of experimental portal-systemic (ammonia) encephalopathy. Insult to the liver, whether acute or chronic in nature, reduces its capacity to metabolize ammonia and this exerts an ammonia burden on extrahepatic tissues which can result in hyperammonaemia up to five times that of normal blood ammonia levels. Chung C., Gottstein J., Blei A.T. Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Liu Q., Duan Z.P., Ha dK., Bengmark S., Kurtovic J., Riordan S.M. The dynamics of ammonia metabolism in man. Measurement of cytotoxic and interstitial components of cerebral edema in acute hepatic failure by diffusion tensor imaging. Hahn and colleagues demonstrated the induction of an encephalopathic state in dogs following the formation of a surgical shunt, known as Eck's fistula, which served to divert nitrogen-rich blood from the portal vein directly to the inferior vena cava, therein bypassing the liver. Joshi D., O'Grady J., Patel A. Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. Takada Y., Ishiguro S., Fukunaga K. Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin. Shawcross D., Wright G., Stadlbauer V. Ammonia impairs neutrophil phagocytic function in liver disease. However, ammonia cannot be responsible alone because protein nitrosation was not demonstrated in ammonia-fed sham-operated and ammonia-fed BDL rats in the absence of an inflammatory stimulus. Phenotypically, AoCLF may be indistinct from ALF, and in some cases patients may even develop cerebral edema, although this is generally considered to be rare.5 Great emphasis is put on actively seeking out and treating any precipitating factors in patients with cirrhosis presenting with overt HE, so as to minimize their risk of developing potentially fatal complications.6, Minimal hepatic encephalopathy (MHE) cannot, by definition, be detected by the clinician alone, and its diagnosis therefore hinges on detailed assessment of the patient's history and comprehensive examination of the neurologic system, as well as formal psychometric testing.7 It has therefore recently been redefined as covert HE.8 The prevalence of MHE in patients with cirrhosis has been estimated to lie between 30% and 84%, with variations in the diagnostic criteria thought to be responsible for this wide range.9, Ammonia was first implicated in the pathogenesis of HE by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. Glutamine: a Trojan horse in ammonia neurotoxicity. Die Eck'sche fistel zwischen der unteren hohlvene und der pfortader und ihre folgen fur den organismus. Discrepancies in the direct correlation between ammonia concentration and the severity of HE in patients with cirrhosis, have contributed to the general consensus that whilst ammonia has an irrefutable, and key role in the pathogenesis of HE, it may not be solely responsible for the neurocognitive sequelae and other factors might be contributing. Bjerring P.N., Eefsen M., Hansen B.A., Larsen F.S. However, ammonia had no impact on microglial glutamate release, prostaglandin synthesis, and messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and the proinflammatory cytokines IL-1/, TNF-, or IL-6. Rajkovic I.A., Williams R. Mechanisms of abnormalities in host defences against bacterial infection in liver disease. Antoniades C.G., Berry P.A., Wendon J.A., Vergani D. The importance of immune dysfunction in determining outcome in acute liver failure. Jalan R., Olde Damink S., Deutz N., Hayes P., Lee A. Stadlbauer V., Mookerjee R., Hodges S., Wright G., Davies N., Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. Gibson G., Zimber A., Krook L., Richardson E.J., Visek W. Brain histology and behaviour of mice injected with urease. Moreover, as functional immunoparesis is a consistent finding in patients with ALF and CLF,94,118,119 this could be detrimental rendering patients susceptible to bacterial and fungal infection. National Library of Medicine Cordoba J., Gottstein J., Blei A. Nencki M., Pawlow J., Zaleski J. Ueber den ammoniakgehalt des blutes under der organe und die harnstoffbildung bei den saugethieren. Accessibility Marini J.C., Broussard S.R. Simon-Talero M., Garcia-Martinez R., Torrens M. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. Astrocytes are the most abundant cells of the central nervous system (CNS) and are the cells most commonly found to be affected in patients with HE owing to the exclusive localization of GS within the CNS to astrocytes.25,26, Astrocytes are involved in numerous functions in the brain, such as the provision of nutrients and mechanical support to surrounding neurones, the regulation of ion transport and neurotransmitter uptake in the brain, as well as being key components of the bloodbrain barrier (BBB). Nitrosation of proteins in the frontal cortex of BDL and endotoxin-treated animals can be demonstrated. Rodrigo R., Cauli O., Gomez-Pinedo U. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Both ammonia-fed and control BDL animals have evidence of active inflammation but the rats fed ammonia had a significant rise in brain edema, glutamine, and reduction in myo-inositol and on co-ordination testing, had impaired motor function suggesting either an additive, or possibly synergistic effect of these two factors.79 Further supporting evidence can be gleaned when endotoxin is administered to BDL rats exacerbating cytotoxic brain edema with the induction of pre-coma, despite a preserved BBB. In MHE, patients have elevated plasma levels of inflammatory markers including IL-6 and IL-18 which correlates with the presence and the severity of HE69 but is not determined by the severity of underlying liver disease or ammonia levels per se. The systemic inflammatory response syndrome in the outcome of hepatic encephalopathy in acute liver failure adapted from Rolando etal.60. Using electron microscopy, Kato and colleagues observed marked swelling of astroglial foot processes in samples of cerebral cortex obtained from patients succombing from ALF.33 Similar results have been gathered from animal models of ALF,34 as well as from CT studies of the brains of children with ornithine carbamoyl transferase deficiency, a congenital disorder of the urea cycle associated with acute episodes of hyperammonaemia35 and cultured astrocytes exposed to pathophysiologically relevant concentrations of ammonia.36 Recent MRI studies of patients with ALF demonstrate evidence of interstitial brain edema as well as cytotoxic edema, implying there may be a vasogenic component to the cerebral edema in ALF.37,38 In an animal model of ALF, astrocyte swelling, extravascular and interstitial edema has been described. Kimelberg H.K. Vorobioff J., Bredfeldt J.E., Groszmann R.J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. There are striking similarities between the clinical presentation of septic shock and ALF with them sharing the common cardinal features of encephalopathy, coagulopathy and cardiovascular collapse. It has been shown that increasing inflammation has a direct correlation with increasing CBF64 which in turn is known to raise intracranial pressure.65 This has been further demonstrated by studies which have examined therapeutic strategies that reduce systemic inflammation and cerebral hyperemia. Cirera I., Bauer T.M., Navasa M. Bacterial translocation of enteric organisms in patients with cirrhosis. This mirrored a fall in the markers of disease severity on intensive care admission reflecting earlier recognition, improved care, and use of salvage emergency liver transplantation.4, In patients with CLF, the symptoms of HE tend to be far less severe and occur insidiously in keeping with the chronic nature of this disease. Rai V., Nath K., Saraswat V.A., Purwar A., Rathore R.K., Gupta R.K. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Zoratti M., Szabo I., De M.U. Nguyen J.H. Received 2013 Dec 9; Accepted 2014 Jun 5. hepatic encephalopathy, ammonia, inflammation, infection, systemic inflammatory response syndrome, HE, hepatic encephalopathy; ICH, intracranial hypertension; AoCLF, acute-on-chronic liver failure; MHE, minimal hepatic encephalopathy; GS, glutamine synthetase; CNS, central nervous system; BBB, bloodbrain barrier; PAG, phosphate-activated glutaminase; CBF, cerebral blood flow; iNOS, inducible nitric oxide synthase; PTP, permeability transition pore; MPT, mitochondrial permeability transition; ATP, adenosine triphosphate; TLR, toll-like receptor. The In: Norenberg M., Hertz L., Schousboe A., editors. Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study.