This causally implicated the inability of the bypassed liver to convert the neurotoxic ammonia into urea and its subsequent accumulation in the brain, in the syndrome which was later termed HE.12,13. 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.
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.
Chronic hyponatremia exacerbates ammonia-induced brain oedema in rats after portacaval anastomosis. The protein albumin has antioxidant properties and is an endotoxin scavenger. 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. Stahl J. However, IL-1 and TNF- gene deletions significantly delayed the onset of HE and brain edema. The impact of organ dysfunction in cirrhosis: survival at a cost?
Studies have also shown that inflammation may exert its effects in part through alterations of cerebral blood flow (CBF).
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.L., Balata S., Olde Damink S.W. 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. Clemmesen J., Larsen F., Kondrup J., Hansen B., Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.
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.
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. Ytrebo L.M., Korvald C., Nedredal G.I., Elvenes O.P., Nielsen Grymyr O.J., Revhaug A. N-acetylcysteine increases cerebral perfusion pressure in pigs with fulminant hepatic failure. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. The systemic inflammatory response syndrome. de Vries H.E., Blom-Roosemalen M.C., van Oosten M. The influence of cytokines on the integrity of the blood-brain barrier invitro.
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. 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.
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.
Blood-brain barrier in acute liver failure.
Cordoba J., Gottstein J., Blei A.
Hahn M., Massen O., Nencki M., Pavlov I.
A large double-blinded randomized controlled trial of 299 patients, demonstrated an improvement in maintained remission from HE and a reduction in hospitalizations due to HE over a six month period in patients with cirrhosis who were administered rifaximin versus placebo.120 Increased levels of the anti-inflammatory cytokine IL-10 have been found in rifaximin-treated groups which may allude to its mechanism of action being an anti-inflammatory rather than ammonia-lowering in nature.121 Furthermore, a recent observational study demonstrated that rifaximin- intriguingly reduced systemic endotoxin levels and disease severity score122 and may therefore have a therapeutic role in HE by reducing systemic inflammation rather than lowering blood ammonia levels. This indiscriminate production of ROS would almost certainly induce endothelial dysfunction and bystander tissue damage which could contribute to the promotion of systemic inflammation and SIRS.94,95 Bajaj J.S., Saeian K., Christensen K.M.
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. Bajaj J.S., Cordoba J., Mullen K.D. Invivo supportive evidence of neutrophil malfunction including spontaneous over-production of ROS and impaired phagocytic activity has also been derived from neutrophils isolated from ammonia-fed rats and also from patients with cirrhosis given an oral ammonia load.95 Thus hyperammonaemia is thought to induce dysfunction in one of the key cells of the inflammatory response. 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. 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. Rao K.V., Panickar K.S., Jayakumar A.R., Norenberg M.D. Joshi D., O'Grady J., Patel A. Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. 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. 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.
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. 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. Didier N., Romero I.A., Creminon C., Wijkhuisen A., Grassi J., Mabondzo A. Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability.
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). Whilst results from this study indicated that the resins were indeed effective diuretics, significantly reducing ascites and edema, almost all of the cirrhotic subjects receiving the ammonium-containing cation-exchange resins developed marked neurological and behavioral disturbances. Weissenborn K., Ennen J., Schomerus H., Ruckert N., Hecker H. Neuropsychological characterization of hepatic encephalopathy. Vaquero J., Polson J., Chung C. Infection and the progression of hepatic encephalopathy in acute liver failure.
Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. Nencki M., Zaleski J. Ueber die Bestimmung des Ammoniaks in Thierischen Fluessigkeiten und Geweben. Jalan R., Schnurr K., Mookerjee R. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Rodrigo R., Cauli O., Gomez-Pinedo U. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy.
Vorobioff J., Bredfeldt J.E., Groszmann R.J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Zwingmann C., Chatauret N., Leibfritz D., Butterworth R.F. The neurological manifestations of acute liver failure.
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. Phear E., Sherlock S., Summerskill W. Blood ammonium levels in liver disease and hepatic coma. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver dysfunction.
Felipo V., Urios A., Montesinos E. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. 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. 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).
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.
Chronic hyponatremia exacerbates ammonia-induced brain oedema in rats after portacaval anastomosis. The protein albumin has antioxidant properties and is an endotoxin scavenger. 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. Stahl J. However, IL-1 and TNF- gene deletions significantly delayed the onset of HE and brain edema. The impact of organ dysfunction in cirrhosis: survival at a cost?
Studies have also shown that inflammation may exert its effects in part through alterations of cerebral blood flow (CBF).
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.L., Balata S., Olde Damink S.W. 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. Clemmesen J., Larsen F., Kondrup J., Hansen B., Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.
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.
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. Ytrebo L.M., Korvald C., Nedredal G.I., Elvenes O.P., Nielsen Grymyr O.J., Revhaug A. N-acetylcysteine increases cerebral perfusion pressure in pigs with fulminant hepatic failure. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. The systemic inflammatory response syndrome. de Vries H.E., Blom-Roosemalen M.C., van Oosten M. The influence of cytokines on the integrity of the blood-brain barrier invitro.
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. 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.
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.
Blood-brain barrier in acute liver failure.
Cordoba J., Gottstein J., Blei A.
Hahn M., Massen O., Nencki M., Pavlov I.
A large double-blinded randomized controlled trial of 299 patients, demonstrated an improvement in maintained remission from HE and a reduction in hospitalizations due to HE over a six month period in patients with cirrhosis who were administered rifaximin versus placebo.120 Increased levels of the anti-inflammatory cytokine IL-10 have been found in rifaximin-treated groups which may allude to its mechanism of action being an anti-inflammatory rather than ammonia-lowering in nature.121 Furthermore, a recent observational study demonstrated that rifaximin- intriguingly reduced systemic endotoxin levels and disease severity score122 and may therefore have a therapeutic role in HE by reducing systemic inflammation rather than lowering blood ammonia levels. This indiscriminate production of ROS would almost certainly induce endothelial dysfunction and bystander tissue damage which could contribute to the promotion of systemic inflammation and SIRS.94,95 Bajaj J.S., Saeian K., Christensen K.M.
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. Bajaj J.S., Cordoba J., Mullen K.D. Invivo supportive evidence of neutrophil malfunction including spontaneous over-production of ROS and impaired phagocytic activity has also been derived from neutrophils isolated from ammonia-fed rats and also from patients with cirrhosis given an oral ammonia load.95 Thus hyperammonaemia is thought to induce dysfunction in one of the key cells of the inflammatory response. 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. 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. Rao K.V., Panickar K.S., Jayakumar A.R., Norenberg M.D. Joshi D., O'Grady J., Patel A. Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. 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. 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.
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. 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. Didier N., Romero I.A., Creminon C., Wijkhuisen A., Grassi J., Mabondzo A. Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability.
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). Whilst results from this study indicated that the resins were indeed effective diuretics, significantly reducing ascites and edema, almost all of the cirrhotic subjects receiving the ammonium-containing cation-exchange resins developed marked neurological and behavioral disturbances. Weissenborn K., Ennen J., Schomerus H., Ruckert N., Hecker H. Neuropsychological characterization of hepatic encephalopathy. Vaquero J., Polson J., Chung C. Infection and the progression of hepatic encephalopathy in acute liver failure.
Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. Nencki M., Zaleski J. Ueber die Bestimmung des Ammoniaks in Thierischen Fluessigkeiten und Geweben. Jalan R., Schnurr K., Mookerjee R. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Rodrigo R., Cauli O., Gomez-Pinedo U. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy.
Vorobioff J., Bredfeldt J.E., Groszmann R.J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Zwingmann C., Chatauret N., Leibfritz D., Butterworth R.F. The neurological manifestations of acute liver failure.
Felipo V., Urios A., Montesinos E. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. 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. 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).