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. Learn more However, IL-1 and TNF- gene deletions significantly delayed the onset of HE and brain edema. 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. This observation led to the concept of effective albumin concentration,110 which represents the fact that plasma albumin concentration per se does not reflect its functional capacity.111 Infusion of albumin has benefits above that of simple volume expansion and can reduce the severity of HE.112 Stadlbauer and colleagues have demonstrated that albumin prevented the deleterious effect of patients' plasma on neutrophil phagocytosis, spontaneous oxidative burst and TLR expression.113 In a recently published double blind randomized controlled trial, 56 cirrhotic patients with an acute episode of HE (grade II-IV) were randomized to receive albumin (1.5g/kg on day 1 and 1.0g/kg on day 3) or isotonic saline. Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Takada Y., Ishiguro S., Fukunaga K. Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin. The preliminary analysis of a recent trial of high volume plasmpheresis in 120 patients suggests that it may improve survival in patients unsuitable for liver transplantation (verbal communicationDr Finn Stolze Larsen). Gabuzda G.J., Phillips G., Davidson C. Reversible toxic manifestations in patients with cirrhosis of the liver given cation-exchange resins. Vorobioff J., Bredfeldt J.E., Groszmann R.J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. Despite an up-regulation of genes associated with microglia activation, proinflammatory cytokine mRNA profiles remained unchanged in the brain of patients with liver cirrhosis and HE as compared to controls supporting the previous findings of the Zemtsova study.75 Perhaps the most interesting observation of this study however was that many anti-inflammatory genes were up-regulated in the cerebral cortex suggesting that the brain is able to induce appropriate compensatory anti-inflammatory responses in HE.76, As inflammation, infection and ammonia have all been shown to be important interdependent factors in the pathogenesis of HE, the next question that demands to be answered is as to whether infection and inflammation have a synergistic relationship with ammonia. Therefore both ammonia and an additional inflammatory insult need to be present for nitrosation of brain proteins to occur.28 These studies clearly demonstrate that the neurocognitive manifestations of hyperammonaemia can be exacerbated in an inflammatory environment. This prompted further investigation by Phillips and colleagues later on in the same year.15 In this study, patients with advanced cirrhosis were administered ammonium chloride, urea, protein or di-ammonium citrate, and observed. Hassanein T.I., Tofteng F., Brown R.S., Jr. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Garcia-Martinez R., Caraceni P., Bernardi M., Gines P., Arroyo V., Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. These neurocognitive changes presented within a few days of the administration of the ammonium-containing cation-exchange resins and resolved soon after their discontinuation, therein illustrating the generally reversible nature of HE. Blei A.T. Medical therapy of brain edema in fulminant hepatic failure. 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. Kumar R., Shalimar, Sharma H. Persistent hyperammonemia is associated with complications and poor outcomes in patients with acute liver failure. Gorg B., Bidmon H.J., Haussinger D. Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy. MR/J006742/1 and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. A shortage of glutamate is partly avoided by amination of -ketoglutarate to produce glutamate.83 This removal of a substrate in the Tricarboxylic Acid Cycle (TCA), as well as ammonia being an inhibitor to enzymes required for TCA cycle activity (such as pyruvate dehydrogenase and -ketoglutarate dehydrogenase), is likely to explain the high levels of pyruvate and lactate seen in brains of HE patients.55, One critical consequence of oxidative and nitrosative stress is the induction of mitochondrial permeability transition (MPT).84 The MPT usually develops in response to an increase in mitochondrial calcium levels and results in a sudden opening of the permeability transition pore (PTP), a large non-selective permeability pore in the inner mitochondrial membrane. will also be available for a limited time. Norenberg M. Alight and electron microscopic study of experimental portal-systemic (ammonia) encephalopathy. Effects of liver disease and hyperammonemia. Liu Q., Duan Z.P., Ha dK., Bengmark S., Kurtovic J., Riordan S.M. 
Minocycline is a broad-spectrum tetracycline antibiotic which has been shown to attenuate endotoxin-induced neuroinflammation.104 Jiang and colleagues have explored its use in an experimental model of ALF and found that it delayed the progression of HE and brain edema.67 It is postulated to exert a potent inhibitory action on microglial activation independently of its antimicrobial properties. Bajaj J.S., Saeian K., Christensen K.M. Etanercept also decreased IL-6 levels in the brain, attenuated microglial activation as assessed by OX-42 immunoreactivity, and increased brain glutathione concentrations.63 Together, these studies support the role of inflammation, whether caused by infection or as a consequence of ALF itself, as being manifest in determining the severity, progression and outcome of HE in ALF.
The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. 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. Gregorios J.B., Mozes L.W., Norenberg M.D. It is perhaps therefore not a surprise to observe that in those patients with ALF in whom there is concurrent inflammation (SIRS), have more advanced manifestations of HE and a poorer prognosis.
Jalan R., Schnurr K., Mookerjee R. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. However, significant differences in survival were found at day 90 (albumin 69.2% versus saline 40.0%; P=0.02) suggesting that the development of HE may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.114, Albumin dialysis has also been studied in a randomized controlled trial in patients with HE and advanced cirrhosis, and found to be effective for the treatment of HE,115 however the benefits of albumin dialysis appear to be independent of changes in ammonia level or cytokines.116, An albumin replacement system with a novel endotoxin ligation (ARSeNEL) component has been developed and tested in a porcine ALF model. An integral role of the neurosupportive astroglial cells is to form the BBB, determining cerebrovascular tone and with the capacity to secrete an array of different neurotrophic factors and cytokines such as IL-1, IL-6 and TNF-. Shawcross D., Wright G., Olde Damink S., Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. 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. Systemic inflammation, also commonly referred to as SIRS (systemic inflammatory response syndrome) can present as a consequence of many pathologies in both sterile and non-sterile environments[Figure1].58 It is not contingent on the presence of infection and may occur purely as a consequence of liver inflammation and necrosis. sharing sensitive information, make sure youre on a federal PMC legacy view 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. Rajkovic I.A., Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Norenberg M. Hepatic encephalopathy: studies with astrocyte cultures. Nguyen J.H. 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. The impact of organ dysfunction in cirrhosis: survival at a cost? 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. Harrison P., Wendon J., Williams R. Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure. Shawcross D.L., Shabbir S.S., Taylor N.J., Hughes R.D. Cirera I., Bauer T.M., Navasa M. Bacterial translocation of enteric organisms in patients with cirrhosis. National Library of Medicine The Trojan horse hypothesis has recently been proposed as an alternative theory to explain the development of astrocyte swelling and implicates an important role for both ammonia and glutamine.52 The excess glutamine synthesized within astrocytes is transported into mitochondria where it is metabolised by phosphate-activated glutaminase (PAG) to ammonia and glutamate.
The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. 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. Gregorios J.B., Mozes L.W., Norenberg M.D. It is perhaps therefore not a surprise to observe that in those patients with ALF in whom there is concurrent inflammation (SIRS), have more advanced manifestations of HE and a poorer prognosis.
Jalan R., Schnurr K., Mookerjee R. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. However, significant differences in survival were found at day 90 (albumin 69.2% versus saline 40.0%; P=0.02) suggesting that the development of HE may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.114, Albumin dialysis has also been studied in a randomized controlled trial in patients with HE and advanced cirrhosis, and found to be effective for the treatment of HE,115 however the benefits of albumin dialysis appear to be independent of changes in ammonia level or cytokines.116, An albumin replacement system with a novel endotoxin ligation (ARSeNEL) component has been developed and tested in a porcine ALF model. An integral role of the neurosupportive astroglial cells is to form the BBB, determining cerebrovascular tone and with the capacity to secrete an array of different neurotrophic factors and cytokines such as IL-1, IL-6 and TNF-. Shawcross D., Wright G., Olde Damink S., Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. 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. Systemic inflammation, also commonly referred to as SIRS (systemic inflammatory response syndrome) can present as a consequence of many pathologies in both sterile and non-sterile environments[Figure1].58 It is not contingent on the presence of infection and may occur purely as a consequence of liver inflammation and necrosis. sharing sensitive information, make sure youre on a federal PMC legacy view 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. Rajkovic I.A., Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Norenberg M. Hepatic encephalopathy: studies with astrocyte cultures. Nguyen J.H. 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. The impact of organ dysfunction in cirrhosis: survival at a cost? 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. Harrison P., Wendon J., Williams R. Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure. Shawcross D.L., Shabbir S.S., Taylor N.J., Hughes R.D. Cirera I., Bauer T.M., Navasa M. Bacterial translocation of enteric organisms in patients with cirrhosis. National Library of Medicine The Trojan horse hypothesis has recently been proposed as an alternative theory to explain the development of astrocyte swelling and implicates an important role for both ammonia and glutamine.52 The excess glutamine synthesized within astrocytes is transported into mitochondria where it is metabolised by phosphate-activated glutaminase (PAG) to ammonia and glutamate.