The Role of Neuroinflammation in the Pathogenesis of Hepatic Encephalopathy

Covert Hepatic Encephalopathy: Not as Minimal as You Might Think

HE liver plays a key role in the synthesis of proteins, metabolism of toxins and drugs, and in modulation of immunity. In critically ill patients, hypoxic, toxic, and inflammatory insults can affect hepatic excretory, synthetic, and/or purification functions, leading to systemic complications such as coagulopathy, increased risk of infection, hypoglycemia, and acute kidney injury. In severe cases, hepatic encephalopathyorbraindysfunction(acuteliverfailure)may occur. Because of the lack of specificity of standard laboratory investigations, identifying liver injury or dysfunction in critically ill patients remains a significant challenge. In addition, the great heterogeneity of criteria used to define the consequences of liver insults increases the difficulties for the clinician to properly interpret hepatic biochemical abnormalities. In this review, we choose to defineliver injuryas an elevation in serum concentrations of routinely measured hepatic enzymes, including aminotransferases (aspartate aminotransferase [AST]; alanine aminotransferase, [ALT]), alkaline phosphatase (ALP), or!-glutamyl transpeptidase. Hepatic dysfunctionrefers to derangement of pathways related to synthetic or clearance function, including international normalized ratio (INR) and bilirubin.Hepatotoxicity refers to hepatic injury and dysfunction caused by a drug or another noninfectious agent. 1 Acute liver failuredesignates

Measurement of Serum Acetaminophen–Protein Adducts in Patients With Acute Liver Failure

Serum Apoptosis Markers in Acute Liver Failure: A Pilot Study

Preface E.A. Jones, A.J. Meijer, R.A.F.M. Chamuleau. Acknowledgements. Part 1: Nitrogen metabolism in relation to liver disease. 1. Novel aspects of nitrogen metabolism in liver disease D. Haussinger, et al. 2. The interorgan exchange of amino acids and ammonia and the effect of plasmapheresis in acute liver failure J.O. Clemmesen, et al. 3. Metabolic consequences of an upper gastro-intestinal bleed in patients with cirrhosis S.W.M. Olde Damink, et al. 4. Citrin deficiency T. Saheki, et al. Part 2: Assessment of overt and minimal hepatic encephalopathy. 5. Assessment of hepatic encephalopathy K. Weissenborn. 6. Evaluation of mental state in a clinical trial of MARS for patients with acute hepatic encephalopathy: comparison of two scales J. Vaquero, et al. 7. Relationship between minimal hepatic encephalopathy and extrapyramidal signs in cirrhotic patients R. Jover, et al. 8. Evaluation of visual focus in cirrhotic patients S. Schiff, et al. 9. Detection of minimal hepatic encephalopathy: EEG spectral analysis vs. cognitive evoked potentials P. Valenti, et al. 10. Analysis of critical flicker frequency threshold in hepatic encephalopathy: dynamics and cortical activations G. Kircheis, et al. 11. Cortical origin of mini-asterixis in hepatic encephalopathy L. Timmermann, et al. 12. Imaging studies in hepatic encephalopathy B. Ahl, et al. 13. Subclinical and overt hepatic encephalopathy - etection and treatment control by proton magnetic resonance spectroscopy (1H-MRS) H.G. Hass, et al. Part 3: Animal models of acute liver failure.14. Long-term observations on rats with thioacetamide-induced hepatic failure W. Hilgier, et al. 15. Reversal of Fischer's ratio in an anaesthetised porcine model of acute liver failure K.J. Dabos, et al. Part 4: Neuropsychiatric dysfunction in chronic liver disease. 16. Experience with neuropsychiatric complications of interferon-based therapy for chronic viral hepatitis K.D. Mullen. 17. Cognitive effects of long-term interferon treatment for chronic viral hepatitis E. De Toni, et al. 18. Is fatigue of cholestasis mediated by altered central serotoninergic neurotransmission? T. Celik, et al. 19. Reduced pallidal magnetisation transfer ratios are associated with fatigue in pre-cirrhotic patients with primary biliary cirrhosis D.M. Forton, et al. Part 5: Pathophysiology of hepatic encephalopathy. 20. Pathogenesis of hepatic encephalopathy K.D. Mullen. 21. Effect of blood plasma components from patients with hepatic encephalopathy on electrophysiological activity of primary frontal cortex networks in vitro J. Loock, et al. 22. Hyperammonemia and liver failure alter signal transduction associated with glutamate receptors and modulation of guanylate cyclase by nitric oxide R. Corbalan, et al. 23. Increased cerebral and peripheral vasodilation, and whole body nitric oxide production after insertion of a transjugular intrahepatic portal-systemic stent in patients with cirrhosis R. Jalan, et al. 24. Concomitant changes in melatonin metabolism and in hypothalamic histamine in rats with a portacaval anastomosis V. Lozeva-Thomas, et al. 25. Brain energy metabolism in acute liver failure: studies using NMR spectroscopy

Approach to the patient with acute severe autoimmune hepatitis.

IMPAIRED CEREBRAL AUTOREGULATION IN PATIENTS WITH ADVANCED LIVER FAILURE: AN UNDER-RECOGNIZED PHENOMENON

Preface.- Foundation of the 'International Society of Hepatic Encephalopathy and Nitrogen Metabolism' (ISHEN).- I. Physiology and pathophysiology of astrocytes.- Water transport in the brain: basic concepts and astrocyte swelling.- Osmotic and Oxidative stress in hepatic encephalopathy.- NADPH oxidase is a major source of swelling-induced generation of reactive oxygen species in rat astrocytes.- Detoxification of hydrogen peroxide by astrocytes.- Glutamate release from astrocytes, impact on neuronal function.- Hepatic stellate cells and astrocytes both star-shaped but not next of kin.- Localization and function of the ATP -binding cassette C (ABCC/MRP) efflux pumps in human brain.- Glial mechanism of axomal growth protection from ammonia.- Selenoprotein P: a link between liver and brain.- II Pathogenesis of HE.- The peripheral benzodiazepine receptor and neurosteroids in the pathogenesis of hepatic encephalopathy and ammonia neurotoxicity.- Glutamatergic synaptic regulation deficit in liver failture: A review of molecular mechanisms.- Synaptic plasticity in animal models relevant for hepatic encephalopathy.- NMDA receptors in hyperammonemia and hepatic encephalopathy.- Prehepatic portal hypertension and mitochondrial dysfunction in brain hipppo-campus.- Nuclear magnetic resonance studies in experimental animal models of hepatic encephalopathy.- The role of inflammation in hepatic encephalopathy.- III. Brain imging in HE research.- Altered neural oscillations and synchronization: a pathophysiological hallmark of hepatic encephalopathy.- Neurotransmitter receptor alterations in hepatic encephalopathy.- Quantitiative T1 and water content mapping in hepatic encephalopathy.- Central nervous system involvement in Hepatitis C virus infection: what to measure?.- Localized MR-correlated spectroscopy using two spectral dimensions: Theoretical description and pilot investigation in hepatic encephalopathy.- IV. New aspects of nitrogen metabolism.- Urea cycle disorders.-The pathophysiology of citrin deficiency.- Hepatic encephalopathy in organic acidurias - Hyperammonemia and energy failure.- Glutamine synthetase deficiency in the human.- Hepatic dysfunction and encephalopathy in inborn errors of metabolism.- Amino acids and mTOR-dependent signalling.- Ceramide is a negative regulator of insulin action, nutrient uptake and protein synthesis in cultured rat skeletal muscle cells.- Ammonia transport in aquaporins - Molecular mechanicsm and clinical relevance.- Glutamine synthetase as a target of ss-catenin: New insights into hepatic heterogeneity.- Ammonia metabolism in liver cirrhosis.- V. Clinical assissment of HE.- Definition and assessment of low grade hepatic encephalopathy.- Hepatic encephalopathy in acute liver failure.- Quality of life in chronic liver diseases and in hepatic encephalopathy.- Hyponatremia: A risk factor of hepatic encephalopathy in cirrhosis.- Neuropsychological dysfunction in minimal hepatic encephalopathy: a review compared with own experience.- Computerised or paper and pencil psychometric tests for the assessment of hepatic encephalopathy?.- Neuropsychological basis of critical flicker frequency analysis (CFF).- Critical assessment of the PHES-test in patients with low grade hepatic encephalopathy.- VI. Treatment.- Evidence-based medicine and treatment of hepatic encephalopathy.- Brain acute liver failure edema in: Mechanisms and therapeutical options.- Hepatic encephalopathy and artificial liver support.- Prometheus(R) - A new extracorporeal system for the treatment of liver failure.- Modulation of intestinal flora for the treatment of hepatic encephalopahty in cirrhosis.- Prevention of post-TIPS hepatic encephalopathy.- Milestones in HE research.- Group picture.- Index

Toward an Improved Definition of Acute-on-Chronic Liver Failure

Correction

Indication of Liver Transplantation in the Treatment of Newly Categorized Acute-on-Chronic Liver Failure In Japan

Although ammonia is considered the main factor involved in the pathogenesis of hepatic encephalopathy (HE), it correlates well with the severity of HE in acute liver failure, but not in chronic liver disease. Oxidative stress is another factor believed to play a role in the pathogenesis of this syndrome; it represents an imbalance between the production and neutralization of reactive oxygen species, which leads to cellular dysfunction. In the setting of liver disease, oxidative stress represents a systemic phenomenon induced by several mechanisms: decreased antioxidant synthesis, increased systemic release of oxidant enzymes, generation of reactive oxygen species, and impaired neutrophil function. High ammonia concentrations induce cerebral oxidative stress, thus contributing to severe hepatic encephalopathy, as observed in acute liver failure. In chronic liver disease, significantly lower degrees of hyperammonemia (<500 μM) do not induce cerebral nor systemic oxidative stress. Data from both animal and human studies sustain that there is a synergistic effect between systemic oxidative stress, and ammonia that is implicated in the pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver disease. Several hypotheses have emerged following the development of appropriate animal models of HE and following studies using postmortem brain tissue from HE patients. It was originally suggested that primary energy failure was responsible for HE; however, there is now mounting evidence that the pathogenetic defect involves neurotransmission failure. Specific neurotransmitter systems implicated in the pathogenesis of portal-systemic encephalopathy (PSE) include the excitatory amino acid glutamate as well as neuroactive and/or neurotoxic biogenic amine metabolites. Although it has been proposed that alterations in the gamma-aminobutyric acid (GABA) system may play a pathogenic role in HE associated with both chronic and acute liver failure, there is now overwhelming evidence to the contrary. On the other hand, there is evidence to suggest that a subgroup of patients with HE have increased blood and CSF concentrations of substances that bind to GABA-related benzodiazepine receptors in brain. Alterations of both the glutamatergic and serotoninergic neurotransmitter systems in PSE likely result from the metabolic consequences of chronic exposure of brain to toxic levels of ammonia. In addition to its effects on glutamatergic and serotoninergic systems during chronic liver disease, ammonia has been intimately associated with the brain edema invariably observed in acute liver failure. It is evident that, regardless of the type of liver failure, effective reductions of ammonia levels remains the strategy of choice in the prevention of encephalopathy. The further elucidation of neurotransmitter alterations in HE could result in novel "downstream" neuropharmacologic approaches to its prevention and treatment.

Reply

Hepatic encephalopathy (HE) is a major complication for acute and chronic liver failure. Despite several decades of intensive clinical and basic research, the pathogenesis of HE is still incompletely understood, and the precise mechanisms causing brain dysfunction in liver failure are still not fully established. Several theories concerning the pathogenesis of HE have been previously suggested, including the ammonia theory, which received the most attention. These theories are not mutually exclusive and the validity of none of them has been definitely proved experimentally. In this review article, an attractive theory concerning the pathogenesis of HE, the tumour necrosis factor-alpha (TNF) theory, is presented and comprehensively discussed after accumulation of sufficient data which indicate that the pro-inflammatory cytokine, TNF, is strongly involved in the pathogenesis of HE associated with both acute and chronic liver failure. This theory seems to be superior to all other previous theories in the pathogenesis of HE, and may induce development of other beneficial therapeutical modalities for HE directed towards inhibition of TNF production and/or action, and towards enhancement of its degradation.