ReviewMetabolic brain disease2016
Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited.
Review in Metabolic brain disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 45 citations in OpenAlex.
- Guanosine Attenuates Astrocyte-Associated Glutamatergic Dysregulation and Improves Survival in Acute Liver Failure-Induced Hepatic Encephalopathy.Metabolites · 2026Article
- Gut microbiome and bile acid metabolism in liver disease: Mechanisms, clinical implications, and therapeutic opportunities.Pharmacological reviews · 2026Review
- Glutamine and Albumin Levels in Cerebrospinal Fluid Are Correlated with Neurological Severity in an Experimental Model of Acute Hepatic Encephalopathy.Metabolites · 2025Article
- Case Report: Posterior reversible encephalopathy syndrome after lenvatinib treatment for hepatocellular carcinoma.Frontiers in pharmacology · 2025Article
- Trace Element Imbalances in Acquired Hepatocerebral Degeneration and Changes after Liver Transplant.Biology · 2023Article
- Hyperammonemia and Hepatic Encephalopathy in Pediatric and Adult Liver Intensive Care Unit.Sisli Etfal Hastanesi tip bulteni · 2023Article
- Bile acid receptors and signaling crosstalk in the liver, gut and brain.Liver research (Beijing, China) · 2021Review
- Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.International journal of molecular sciences · 2021Review
- Chronic Liver Diseases and the Microbiome-Translating Our Knowledge of Gut Microbiota to Management of Chronic Liver Disease.Gastroenterology · 2021Review
- The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure.International journal of molecular sciences · 2020Article
- Mesoporous silica SBA-15 decreases hyperammonemia and affects the gene expression of mitogen-activated protein kinases in the prefrontal cortex of rats with bile duct ligation.Iranian journal of basic medical sciences · 2020Article
- Triphasic waves in electroencephalogram as a possible early marker of carcinomatous meningitis: a case report.Medicine · 2020Article
- Atypical neuroimaging findings in patients with acquired hepatocerebral degeneration.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2020Article
- Effects of a high protein diet and liver disease in an in silico model of human ammonia metabolism.Theoretical biology & medical modelling · 2019Article
- Alcohol, liver disease and the gut microbiota.Nature reviews. Gastroenterology & hepatology · 2019Review
- Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment.Expert review of neurotherapeutics · 2019Review
- Reduced Liver Lipid Peroxidation in Subcellular Fractions Is Associated with a Hypometabolic State in Rats with Portacaval Anastomosis.Oxidative medicine and cellular longevity · 2019Article
- Cognitive impairment after liver transplantation: residual hepatic encephalopathy or posttransplant encephalopathy?Hepatic medicine : evidence and research · 2019Article
- Practical Issues in the Management of Overt Hepatic Encephalopathy.Gastroenterology & hepatology · 2017Article
- Globus pallidus MR signal abnormalities in children with chronic liver disease and/or porto-systemic shunting.European radiology · 2017Article
Corrections and comments
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Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The concept of synergistic mechanisms as the pathophysiologic basis of hepatic encephalopathy started with the pioneering work of Les Zieve in Minneapolis some 60 years ago where synergistic actions of the liver-derived toxins ammonia, methanethiol, and octanoic acid were described. More recently, synergistic actions of ammonia and manganese, a toxic metal that is normally eliminated via the hepatobiliary route and shown to accumulate in brain in liver failure, on the glutamatergic neurotransmitter system were described. The current upsurge of interest in brain inflammation (neuroinflammation) in relation to the CNS complications of liver failure has added a third dimension to the synergy debate. The combined actions of ammonia, manganese and pro-inflammatory cytokines in brain in liver failure result in oxidative/nitrosative stress resulting from activation of glutamate (NMDA) receptors and consequent nitration of key brain proteins. One such protein, glutamine synthetase, the sole enzyme responsible for brain ammonia removal is nitrated and inactivated in brain in liver failure. Consequently, brain ammonia levels increase disproportionately resulting in alterations of brain excitability, impaired brain energy metabolism, encephalopathy and brain swelling. Experimental therapeutic approaches for which proof-of-principle has been established include the NMDA receptor antagonist memantine, N-acetyl cysteine (recently shown to have antioxidant properties at both hepatic and cerebral levels) and probiotics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.