These alterations to astrocyte morphology can be seen in the brains of patients with chronic hyperammonaemia due to congenital disorders of the urea cycle enzymes, as well as in various experimental animal models of hyperammonaemia,41,42 and in astrocyte cultures chronically exposed to hyperammonaemia.43 Experimental models of CLF in rats have consistently shown no evidence of BBB breakdown,28,44 however Chavarria and colleagues45 have recently provided evidence for the presence of both cytotoxic and vasogenic edema in cirrhotic patients awaiting liver transplantation. 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. D'Mello C., Le T., Swain M.G. This may correlate with the parallel observation of early cerebral microglial activation in animal models of ALF which increases as HE and brain edema ensues.67,68, As with ALF, there is direct evidence for the role of inflammation in exacerbating the severity of HE in patients with cirrhosis. Cerebral recruitment of monocytes was abolished in MCP-1/CCL2 or CCR2 knockout mice. Studies have also shown that inflammation may exert its effects in part through alterations of cerebral blood flow (CBF). The dynamics of ammonia metabolism in man. 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). 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. They show that in the presence of hepatic inflammation, mice demonstrate elevated cerebral MCP-1 levels, as well as increased numbers of circulating CCR2-expressing monocytes. Rolando N., Wade J., Davalos M., Wendon J., Philpott-Howard J., Williams R. The systemic inflammatory response syndrome in acute liver failure. Vaquero J., Polson J., Chung C. Infection and the progression of hepatic encephalopathy in acute liver failure. Thiel K., Proven A., Davies N. The development and testing of the University College London Liver Support Device (ARSENEL): improvement in survival in paracetamol-induced acute liver failure pigs. Rodrigo R., Cauli O., Gomez-Pinedo U. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. encephalopathy hepatic precipitants Systemic and local brain inflammation is observed in these animals which increases further in those given endotoxin. Sepsis and inflammation are terms often used synonymously, however they are not equivalent clinical entities. Six weeks post-operatively, the dogs began to exhibit increased levels of aggression, irritability, ataxia, as well as experiencing seizures and eventually lapsing into coma especially following ingestion of an ammonia-rich meal.10 Two years later, in another canine study with surgical portocaval fistulas, it was discovered that the urinary concentration of ammonia salts was elevated, leading to the logical first suggestion that ammonia may be key in the development of this neurobehavioural syndrome.11 The ingestion of ammonium salts was subsequently shown to exacerbate the neurobehavioural symptoms in these dogs, causing them to become comatose and die. Patients became drowsy, apathetic, weak, confused and disorientated to time and place, and exhibited various inappropriate behaviors. 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. Liaw S.H., Kuo I., Eisenberg D. Discovery of the ammonium substrate site on glutamine synthetase, a third cation binding site. 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 views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Hyperammonemia increases sensitivity to LPS. Ammonia interferes with mitochondrial energy metabolism and studies have reported depletion of ATP invitro and invivo models of ammonia neurotoxicity.53 The implications of energy failure in ALF have largely been disregarded despite the presence of higher lactate levels in patients with ALF, which is a consequence of energy failure.54 In an experimental rodent model of ALF,55 in the early (pre-coma) stages of HE there was a significant 24.5-fold increase in total brain glutamine and lactate but in the severe (coma) stages of HE and brain edema, there was a further significant increase in brain lactate but no such increase in glutamine implying that impaired glucose oxidative pathways rather than intracellular glutamine accumulation per se may play a more dominant role.56,57. 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. Gregorios J.B., Mozes L.W., Norenberg M.D. Dhanda S., Kaur S., Sandhir R. Preventive effect of N-acetyl-. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. Sorensen M., Keiding S. New findings on cerebral ammonia uptake in HE using functional (13)N-ammonia PET. 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. Gibson G., Zimber A., Krook L., Richardson E.J., Visek W. Brain histology and behaviour of mice injected with urease. 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). 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. Bjerring P.N., Eefsen M., Hansen B.A., Larsen F.S. Jalan R., Olde Damink S.W., Hayes P.C., Deutz N.E., Lee A. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. 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. Nguyen J.H. 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.
The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. Circulating neutrophil dysfunction in acute liver failure. Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Marini J.C., Broussard S.R. 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. Felipo V., Urios A., Montesinos E. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Rifaximin- is a broad-spectrum antibiotic which has minimal systemic absorption. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver dysfunction. 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. Bass N.M., Mullen K.D., Sanyal A. Rifaximin treatment in hepatic encephalopathy. 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. 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.
NAC has a potential therapeutic role as both an antioxidant and anti-inflammatory agent. PMC legacy view
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. National Library of Medicine 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. This was observed in a recent study where healthy controls with keloid scars were found to subsequently have a degree of hyperammonemic encephalopathy with raised ammonia and inflammatory markers, but without any evidence of liver impairment.78. Bethesda, MD 20894, Web Policies Shawcross D., Wright G., Stadlbauer V. Ammonia impairs neutrophil phagocytic function in liver disease. Shawcross D., Davies N., Williams R., Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. Particular insults that can induce SIRS include injury direct to hepatocytes, such as acetaminophen-induced toxicity or acute alcoholic hepatitis, or may develop in the periphery in response to sterile injury such as pancreatitis, burns, surgery or trauma.58 SIRS can culminate in the development of tissue injury following activation of neutrophils and microvascular dysfunction which induces vasodilatation, capillary leak, mitochondrial dysfunction and disseminated intravascular coagulation which lead to impaired tissue oxygenation, cell death and multiorgan failure akin to that observed in patients with septic shock or ALF. This review was supported by the Medical Research Council (MRC) Centre for Transplantation, King's College London, UKMRC grant no. Accessibility Perez del P.S., Pizcueta P., Engel P., Bosch J. 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. Abbreviations: CBF: cerebral blood flow; NAC: N-acetyl cysteine; NSAID: Non-steroidal anti-inflammatory drug. de Vries H.E., Blom-Roosemalen M.C., van Oosten M. The influence of cytokines on the integrity of the blood-brain barrier invitro. 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. Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension. Gorg B., Bidmon H.J., Haussinger D. Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy. 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. Definition of the Systemic Inflammatory Response Syndrome.58. These cytokines are produced in response to inflammation and can affect the BBB with TNF- being released early and subsequently promoting IL-1 and IL-6 release. Tofteng F., Larsen F.S. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure. Martinez-Hernandez A., Bell K.P., Norenberg M.D. Before Gove C.D., Hughes R.D., Ede R.J., Williams R. Regional cerebral edema and chloride space in galactosamine-induced liver failure in rats. 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 https:// ensures that you are connecting to the 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. The systemic inflammatory response syndrome.
Joshi D., O'Grady J., Patel A. Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. A single centre experience of 3300 patients. Brusilow S.W., Koehler R.C., Traystman R.J., Cooper A.J. ammonia levels serum clinical severity evaluation encephalopathy hepatic patients liver disease correlation its Jiang W., Desjardins P., Butterworth R. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline.