The neurological manifestations of acute liver failure

Acute liver failure is a disorder which impacts on multiple organ systems and results from hepatocellular necrosis in a patient with no previous history of chronic liver disease. It typically culminates in the development of liver dysfunction, coagulopathy and encephalopathy, and is associated with high mortality in poor prognostic groups. In acute liver failure, some patients may develop cerebral edema and increased intracranial pressure although recent data suggest that intracranial hypertension is less frequent than previously described, complicating 29% of acute cases who have proceeded to grade 3/4 coma. Neurological manifestations are primarily underpinned by the development of brain edema. The onset of encephalopathy can be rapid and dramatic with the development of asterixis, delirium, hyperreflexia, clonus, seizures, extensor posturing and coma. Ammonia plays a definitive role in the development of cytotoxic brain edema. Patients with acute liver failure have a marked propensity to develop renal insufficiency and hence impaired ammonia excretion. The incidence of both bacterial and fungal infection occurs in approximately one third of patients. The relationship between inflammation, as opposed to infection, and progression of encephalopathy is similar to that observed in chronic liver disease. Intracranial pressure monitoring is valuable in identifying surges in intracranial hypertension requiring intervention. Insertion of an intracranial bolt should be considered only in the subgroup of patients who have progressed to grade 4 coma. Risk factors for developing intracranial hypertension are those with hyperacute and acute etiologies, progression to grade 3/4 hepatic encephalopathy, those who develop pupillary abnormalities (dilated pupils, sluggishly responsive to light) or seizures, have systemic inflammation, an arterial ammonia >150 μmol/L, hyponatremia, and those in receipt of vasopressor support. Strategies employed in patients with established encephalopathy (grade 3/4) aim to maintain freedom from infection/inflammatory milieu, provide adequate sedation, and correct hypo-osmolality.     

Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.     

Reprint of: Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.     

Glutamine in the pathogenesis of acute hepatic encephalopathy

Hepatic encephalopathy (HE) is the major neurological disorder associated with liver disease. It presents in chronic and acute forms, and astrocytes are the major neural cells involved. While the principal etiological factor in the pathogenesis of HE is increased levels of blood and brain ammonia, glutamine, a byproduct of ammonia metabolism, has also been implicated in its pathogenesis. This article reviews the current status of glutamine in the pathogenesis of HE, particularly its involvement in some of the events triggered by ammonia, including mitochondrial dysfunction, generation of oxidative stress, and alterations in signaling mechanisms, including activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-κB). Mechanisms by which glutamine contributes to astrocyte swelling/brain edema associated with acute liver failure (ALF) will also be described.     

GABAergic neurosteroids: the "endogenous benzodiazepines" of acute liver failure

Acute liver failure (ALF) or fulminant hepatic failure represents a serious life-threatening condition. ALF is characterized by a significant liver injury that leads to a rapid onset of hepatic encephalopathy (HE). In ALF, patients manifest rapid deterioration in consciousness leading to hepatic coma together with an onset of brain edema which induces high intracranial pressure that frequently leads to herniation and death. It is well accepted that hyperammonemia is a cardinal, but not the sole, mediator in the pathophysiology of ALF. There is increasing evidence that neurosteroids, including the parent neurosteroid pregnenolone, and the progesterone metabolites tetrahydroprogesterone (allopregnanolone) and tetrahydrodeoxycorticosterone (THDOC) accumulate in brain in experimental models of ALF. Neurosteroids in ALF represent good candidates to explain the phenomenon of "increased GABAergic tone" in chronic and ALF, and the beneficial effects of benzodiazepine drugs. The mechanisms that trigger brain neurosteroid changes in ALF are not yet well known, but could involve partially de novo neurosteroidogenesis following activation of the translocator protein (TSPO). The factors that contribute to TSPO changes in ALF may include ammonia and cytokines. It is possible that increases in brain levels of neurosteroids in ALF may result in auto-regulatory mechanisms where hypothermia may play a significant role. Possible mechanisms that may involve neurosteroids in the pathophysiology of HE, and more speculatively in brain edema, and inflammatory processes in ALF are suggested.     

Neuropathology of acute liver failure

Cerebral edema has been identified in all forms of liver disease and is closely related to the development of hepatic encephalopathy. Cerebral edema is most readily recognized in acute liver failure (ALF), while the main cause of death in patients with ALF is multi-organ failure; brain herniation as a result of intracranial hypertension does remain a major cause of mortality. The mechanisms responsible for cerebral edema in ALF suggest both cytotoxic and vasogenic injury. This article reviews the gross and ultrastructural changes associated with cerebral edema in ALF. The primary cause of cerebral edema is associated with astrocyte swelling, mainly perivascular edema and ammonia still remains the primary neurotoxin involved in its pathogenesis. The astrocytic changes were confined to the gray matter. The other organelles involved in the pathogenesis of ALF include mitochondria, basement membrane, pericytes, microglial cells, blood-brain barrier (BBB) etc. Discrete neuronal changes have recently been reported. Recent studies in animal and humans have demonstrated the microglial changes which have the potential to cause neuronal dysfunction in ALF. The alterations in BBB still remain unclear though few studies have showed disruption of tight junction proteins indicating the involvement of BBB in cellular swelling.     

Neurological complications of acute liver failure: pathophysiological basis of current management and emerging therapies

One of the major causes of mortality in patients with acute liver failure (ALF) is the development of hepatic encephalopathy (HE) which is associated with increased intracranial pressure (ICP). High ammonia levels, increased cerebral blood flow and increased inflammatory response have been identified as major contributors to the development of HE and the related brain swelling. The general principles of the management of patients with ALF are straightforward. They include identifying the insult causing hepatic injury, providing organ systems support to optimize the patient's physical condition, anticipation and prevention of development of complications. Increasing insights into the pathophysiological mechanisms of ALF are contributing to better therapies. For instance, the evident role of cerebral hyperemia in the pathogenesis of increased ICP has led to a re-evaluation of established therapies such as hyperventilation, N-acetylcysteine, thiopentone sodium and propofol. The role of systemic inflammatory response in the pathogenesis of increased ICP has also gained importance supporting the concept that antibiotics given prophylactically reduce the risk of developing sepsis during the course of illness. Moderate hypothermia has also been established as a therapy able to reduce ICP in patients with uncontrolled intracranial hypertension and to prevent increases in ICP during orthopic liver transplantation. Ornithine phenylacetate, a new drug in the treatment of liver failure, and liver replacement therapies are still being investigated both experimentally and clinically. Despite many advances in the understanding of the pathophysiological basis and the management of intracranial hypertension in ALF, more clinical trials should be conducted to determine the best therapeutic management for this difficult clinical event.     

Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline

Encephalopathy and brain edema are serious complications of acute liver failure (ALF). The precise pathophysiologic mechanisms responsible have not been fully elucidated but it has been recently proposed that microglia‐derived proinflammatory cytokines are involved. In the present study we evaluated the role of microglial activation and the protective effect of the anti‐inflammatory drug minocycline in the pathogenesis of hepatic encephalopathy and brain edema in rats with ALF resulting from hepatic devascularisation. ALF rats were killed 6 h after hepatic artery ligation before the onset of neurological symptoms and at coma stages of encephalopathy along with their appropriate sham‐operated controls and in parallel with minocycline‐treated ALF rats. Increased OX‐42 and OX‐6 immunoreactivities confirming microglial activation were accompanied by increased expression of interleukins (IL‐1β, IL‐6) and tumor necrosis factor‐alpha (TNF‐α) in the frontal cortex at coma stage of encephalopathy in ALF rats compared with sham‐operated controls. Minocycline treatment prevented both microglial activation as well as the up‐regulation of IL‐1β, ΙL‐6 and TNF‐α mRNA and protein expression with a concomitant attenuation of the progression of encephalopathy and brain edema. These results offer the first direct evidence for central proinflammatory mechanisms in the pathogenesis of brain edema and its complications in ALF and suggest that anti‐inflammatory agents may be beneficial in these patients.     

Therapeutic hypothermia in the management of acute liver failure

A large body of experimental data and preliminary clinical studies point to the induction of mild hypothermia (32-35 °C) as a valuable approach to control the development of brain edema and intracranial hypertension in acute liver failure (ALF). The ability of hypothermia to affect multiple processes probably explains its efficacy to prevent these cerebral complications. Remarkably, mild hypothermia has been shown to prevent or attenuate most of the major alterations involved in the pathogenesis of the cerebral complications of ALF, including the accumulation of ammonia in the brain and the circulation, the alterations of brain glucose metabolism, the brain osmotic disturbances, the accumulation of glutamate and lactate in brain extracellular space, the development of inflammation and oxidative/nitrosative stress, and others. Limited information suggests that the systemic effects of hypothermia may also be beneficial for some peripheral complications of ALF. Translation of the beneficial effects of therapeutic hypothermia into standard clinical practice, however, needs to be confirmed in adequately designed clinical trials. Such trials will be important to determine the safety of therapeutic hypothermia, to identify which patients might benefit from it, and to provide the optimal guidelines for its use in patients with ALF.     

Evidence for an Astrocytic Glutamate Transporter Deficit in Hepatic Encephalopathy

There is increasing evidence to suggest that hepatic encephalopathy in acute liver failure is the result of altered glutamatergic function. In particular, the high affinity uptake of glutamate is decreased in brain slices and synaptosomes from rats with acute liver failure as well as by exposure of cultured astrocytes to concentrations of ammonia equivalent to those reported in brain in acute liver failure. Both protein and gene expression of the recently cloned and sequenced astrocytic glutamate transporter GLT-1 are significantly reduced in the brains of rats with acute liver failure. Decreased expression of GLT-1 in brain in acute liver failure results in increased extracellular brain glutamate concentrations which correlates with arterial ammonia concentrations and with the appearance of severe encephalopathy and brain edema in these animals. Ammonia-induced reductions in expression of GLT-1 resulting in increased extracellular glutamate concentrations could explain some of the symptoms (hyperexcitability, cerebral edema) characteristic of hepatic encephalopathy in acute liver failure.     

The brain glutamate system in liver failure

Liver failure results in significant alterations of the brain glutamate system. Ammonia and the astrocyte play major roles in such alterations, which affect several components of the brain glutamate system, namely its synthesis, intercellular transport (uptake and release), and function. In addition to the neurological symptoms of hepatic encephalopathy, modified glutamatergic regulation may contribute to other cerebral complications of liver failure, such as brain edema, intracranial hypertension and changes in cerebral blood flow. A better understanding of the cause and precise nature of the alterations of the brain glutamate system in liver failure could lead to new therapeutic avenues for the cerebral complications of liver disease.     

Changes in free radicals,trace elements,and neurophysiological function in rats with liver damage induced byD-galactosamine

The changes in trace elements, free radicals, and neurophysiological function were investigated in rats with liver damage induced byd-galactosamine (GalN). The elevated results showed that all the parameters related to free radical metabolism changed after administration of GalN. Relative free radical concentration, malonaldehyde (MDA), and oxidized glutathione (GSSG) elevated, but reduced glutathione (GSH) decreased. Concurrently, zinc, copper, manganese, and selenium contents in liver were significantly reduced, whereas iron was elevated. In rats with hepatic encephalopathy (HE) owing to fulminant hepatic failure (FHF) induced by a high dosage of GalN, the latencies of VEPs were delayed. Moreover, there is a correlation between Zn content of brain and the latencies of VEPs. The results of this study suggested that lipid peroxidation by free radicals might be responsible for GalN-induced liver damage in which trace elements were involved, and that change in brain Zn might play a role in the neural inhibition of HE owing to FHF.     

Hepatic encephalopathy: An update of pathophysiologic mechanisms

Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in both acute and chronic liver failure. Although the precise pathophysiologic mechanisms responsible for HE are not completely understood, a deficit in neurotransmission rather than a primary deficit in cerebral energy metabolism appears to be involved. The neural cell most vulnerable to liver failure is the astrocyte. In acute liver failure, the astrocyte undergoes swelling resulting in increased intracranial pressure; in chronic liver failure, the astrocyte undergoes characteristic changes known as Alzheimer type II astrocytosis. In portal-systemic encephalopathy resulting from chronic liver failure, astrocytes manifest altered expression of several key proteins and enzymes including monoamine oxidase B, glutamine synthetase, and the so-called peripheral-type benzodiazepine receptors. In addition, expression of some neuronal proteins such as monoamine oxidase A and neuronal nitric oxide synthase are modified. In acute liver failure, expression of the astrocytic glutamate transporter GLT-1 is reduced, leading to increased extracellular concentrations of glutamate. Many of these changes have been attributed to a toxic effect of ammonia and/or manganese, two substances that are normally removed by the hepatobiliary route and that in liver failure accumulate in the brain. Manganese deposition in the globus pallidus in chronic liver failure results in signal hyperintensity on T1-weighted Magnetic Resonance Imaging and may be responsible for the extrapyramidal symptoms characteristic of portal-systemic encephalopathy. Other neurotransmitter systems implicated in the pathogenesis of hepatic encephalopathy include the serotonin system, where a synaptic deficit has been suggested, as well as the catecholaminergic and opioid systems. Further elucidation of the precise nature of these alterations could result in the design of novel pharmacotherapies for the prevention and treatment of hepatic encephalopathy.     

Neuroimaging in acute liver failure

Acute liver failure (ALF) is frequently complicated by the development of brain edema that can lead to intracranial hypertension and severe brain injury. Neuroimaging techniques allow a none-invasive assessment of brain tissue and cerebral hemodynamics by means of transcranial Doppler ultrasonography, magnetic resonance and nuclear imaging with radioligands. These methods have been very helpful to unravel the pathogenesis of this process and have been applied to patients and experimental models. They allow monitoring the outcome of patients with ALF and neurological manifestations. The increase in brain water can be detected by observing changes in brain volume and disturbances in diffusion weighted imaging. Neurometabolic changes are detected by magnetic resonance spectroscopy, which provides a pattern of abnormalities characterized by an increase in glutamine and a decrease in myo-inositol. Disturbances in cerebral blood flow are depicted by SPECT or PET and can be monitored and the bedside by assessing the characteristics of the waveform provided by transcranial Doppler ultrasonography. Neuroimaging methods, which are rapidly evolving, will undoubtedly lead to future diagnostic and therapeutic progress that could be very helpful for patients with ALF.     

Reprint of: Neuroimaging in acute liver failure

Acute liver failure (ALF) is frequently complicated by the development of brain edema that can lead to intracranial hypertension and severe brain injury. Neuroimaging techniques allow a none-invasive assessment of brain tissue and cerebral hemodynamics by means of transcranial Doppler ultrasonography, magnetic resonance and nuclear imaging with radioligands. These methods have been very helpful to unravel the pathogenesis of this process and have been applied to patients and experimental models. They allow monitoring the outcome of patients with ALF and neurological manifestations. The increase in brain water can be detected by observing changes in brain volume and disturbances in diffusion weighted imaging. Neurometabolic changes are detected by magnetic resonance spectroscopy, which provides a pattern of abnormalities characterized by an increase in glutamine and a decrease in myo-inositol. Disturbances in cerebral blood flow are depicted by SPECT or PET and can be monitored and the bedside by assessing the characteristics of the waveform provided by transcranial Doppler ultrasonography. Neuroimaging methods, which are rapidly evolving, will undoubtedly lead to future diagnostic and therapeutic progress that could be very helpful for patients with ALF.     

Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined

Acute liver failure (ALF) is characterized neuropathologically by cytotoxic brain edema and biochemically by increased brain ammonia and its detoxification product, glutamine. The osmotic actions of increased glutamine synthesis in astrocytes are considered to be causally related to brain edema and its complications (intracranial hypertension, brain herniation) in ALF. However studies using multinuclear (1)H- and (13)C-NMR spectroscopy demonstrate that neither brain glutamine concentrations per se nor brain glutamine synthesis rates correlate with encephalopathy grade or the presence of brain edema in ALF. An alternative mechanism is now proposed whereby the newly synthesized glutamine is trapped within the astrocyte as a consequence of down-regulation of its high affinity glutamine transporter SNAT5 in ALF. Restricted transfer out of the cell rather than increased synthesis within the cell could potentially explain the cell swelling/brain edema in ALF. Moreover, the restricted transfer of glutamine from the astrocyte to the adjacent glutamatergic nerve terminal (where glutamine serves as immediate precursor for the releasable/transmitter pool of glutamate) could result in decreased excitatory transmission and excessive neuroinhibition that is characteristic of encephalopathy in ALF. Paradoxically, in spite of renewed interest in arterial ammonia as a predictor of raised intracranial pressure and brain herniation in ALF, ammonia-lowering agents aimed at reduction of ammonia production in the gut have so far been shown to be of limited value in the prevention of these cerebral consequences. Mild hypothermia, shown to prevent brain edema and intracranial hypertension in both experimental and human ALF, does so independent of effects on brain glutamine synthesis; whether or not hypothermia restores expression levels of SNAT5 in ALF awaits further studies. While inhibitors of brain glutamine synthesis such as methionine sulfoximine, have been proposed for the prevention of brain edema in ALF, potential adverse effects have so far limited their applicability.     

The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy

Hepatic encephalopathy (HE) is a serious cerebral complication of both acute and chronic liver failure. In acute liver failure, astrocytes undergo swelling which results in increased intracranial pressure and may lead to brain herniation and death. In chronic liver failure, Alzheimer-type II astrocytosis is the characteristic neuropathologic finding. Patients with liver failure manifest severe alterations of their quality of life including sleep disorders as well as memory, learning, and locomotor abnormalities. Neurosteroids (NS) are synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads) and are suggested to play a role in the pathogenesis of HE. NS bind and modulate different types of neural receptors; effects on the gamma amino butyric acid (GABA)-A receptor complex are the most extensively studied. For example, the NS tetrahydroprogesterone (allopregnanolone), and tetrahydrodeoxycorticosterone (THDOC) are potent positive allosteric modulators of the GABA-A receptor. As a consequence of modulation of these receptors, NS stimulate inhibitory neurotransmission in the CNS, and neuroinhibitory changes including "increased GABA-ergic tone" have been suggested as pathophysiological mechanisms in HE. Moreover, some NS bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins are altered in HE. This review summarizes findings consistent with the involvement of NS in human and experimental HE.     

An update on the role of brain glutamine synthesis and its relation to cell-specific energy metabolism in the hyperammonemic brain: further studies using NMR spectroscopy

Ammonia is a neurotoxin that is implicated in the pathogenesis of hepatic encephalopathy due to acute and chronic liver failure. However, its relation to neurological damage and brain edema is poorly understood. During the last decades, it has been the prevailing hypothesis that an osmotic disturbance induced by the astrocytic accumulation of glutamine leads to brain edema. However, various findings are at variance with this hypothesis. The present review will discuss: (a) correlation of ammonia with encephalopathy and brain edema in HE; (b) glutamine synthesis and astrocyte swelling; (c) glutamine synthesis and the glutamine-cycle: relation to brain energy metabolism; (d) glutamine synthesis and the glutamate-glutamine cycle and its relation to anaplerotic activity; (e) evidence favouring the "glutamine hypothesis"; (f) evidence contradicting the "glutamine hypothesis"; (g) glutamine synthesis and osmoregulation; (h) glutamine synthesis in chronic liver failure; (i) impaired brain energy metabolism in acute liver failure (ALF) and its relation to astrocytic glutamine synthesis. Taken together, the precise role of glutamine in the development of brain edema in ALF remains unclear. Astrocytic changes due to glutamine accumulation may lead secondarily to effects on brain energy metabolism. However, the relation between impaired energy metabolism and glutamine accumulation has not been well established. It is noteworthy that no single biochemical factor appears to be responsible for the many symptoms of HE. For example, brain glutamine accumulation and low-grade brain edema occur in chronic liver failure (CLF) suggesting common mechanisms are responsible for the neurological dysfunction in CLF and ALF. Recent NMR spectroscopic studies have provided considerably new information in this area. Future NMR studies using the stable isotope 13C may be useful in the study of the dynamics of brain metabolism in patients with ALF so as to better elucidate the precise role of glutamine accumulation and of glutamine-independent components to brain edema in ALF.     

The molecular pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE) incorporates a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction with a potential for full reversibility. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of HE in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. For over a 100 years ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. The present review focuses upon the molecular mechanisms involved in the pathogenesis of HE. Therapy of HE is directed primarily at reducing ammonia generation and increasing its detoxification.     

Asymmetric Dimethylarginine and Hepatic Encephalopathy: Cause,Effect or Association?

The methylated derivative of l-arginine, asymmetric dimethylarginine (ADMA) is synthesized in different mammalian tissues including the brain. ADMA acts as an endogenous, nonselective, competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) and may limit l-arginine supply from the plasma to the enzyme via reducing its transport by cationic amino acid transporters. Hepatic encephalopathy (HE) is a relatively frequently diagnosed complex neuropsychiatric syndrome associated with acute or chronic liver failure, characterized by symptoms linked with impaired brain function leading to neurological disabilities. The l-arginine—nitric oxide (NO) pathway is crucially involved in the pathomechanism of HE via modulating important cerebral processes that are thought to contribute to the major HE symptoms. Specifically, activation of this pathway in acute HE leads to an increase in NO production and free radical formation, thus, contributing to astrocytic swelling and cerebral edema. Moreover, the NO-cGMP pathway seems to be involved in cerebral blood flow (CBF) regulation, altered in HE. For this reason, depressed NO-cGMP signaling accompanying chronic HE and ensuing cGMP deficit contributes to the cognitive and motor failure. However, it should be remembered that ADMA, a relatively little known element limiting NO synthesis in HE, may also influence the NO-cGMP pathway regulation. In this review, we will discuss the contribution of ADMA to the regulation of the NO-cGMP pathway in the brain, correlation of ADMA level with CBF and cognitive alterations observed during HE progression in patients and/or animal models of HE.