ReviewMetabolic brain disease2014
Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy-therapeutic perspectives.
Review in Metabolic brain disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 2 of them syntheses that pooled it.
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
37 citing papers in PubMed, 2 syntheses or guidelines pooled it, 71 citations in OpenAlex.
- Branched-chain amino acids for people with cirrhosis and hepatic encephalopathy.The Cochrane database of systematic reviews · 2026Pooled it
- Branched-chain amino acids for people with hepatic encephalopathy.The Cochrane database of systematic reviews · 2017Pooled it
- Trial
- Proline promotes prolyl 4-hydroxylase subunit alpha 1 via transforming growth factor beta 1 to increase the synthesis and deposition of collagen in grass carp (Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2026Article
- Novel roles of ammonia in physiology and cancer.Journal of molecular cell biology · 2025Review
- Liver as a nexus of daily metabolic cross talk.International review of cell and molecular biology · 2025Review
- Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFκB.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Microbiota-gut-liver-brain axis and hepatic encephalopathy.Microbiome research reports · 2024Review
- Ammonia scavenger and glutamine synthetase inhibitors cocktail in targeting mTOR/β-catenin and MMP-14 for nitrogen homeostasis and liver cancer.Medical oncology (Northwood, London, England) · 2023Article
- The pathogenesis of gut microbiota in hepatic encephalopathy by the gut-liver-brain axis.Bioscience reports · 2023Article
- Muscle Amino Acid and Adenine Nucleotide Metabolism during Exercise and in Liver Cirrhosis: Speculations on How to Reduce the Harmful Effects of Ammonia.Metabolites · 2022Review
- Serum Amino Acids Imbalance in Canine Chronic Hepatitis: Results in 16 Dogs.Veterinary sciences · 2022Article
- Metabolomic serum abnormalities in dogs with hepatopathies.Scientific reports · 2022Article
- Side effects of amino acid supplements.Physiological research · 2022Article
- Paeoniae Radix Rubra can enhance fatty acid β-oxidation and alleviate gut microbiota disorder in α-naphthyl isothiocyanate induced cholestatic model rats.Frontiers in pharmacology · 2022Article
- Fifteen years of urea cycle disorders brain research: Looking back, looking forward.Analytical biochemistry · 2022Review
- The Prophylactic Effects of Glutamine on Muscle Protein Synthesis and Degradation in Rats with Ethanol-Induced Liver Damage.Nutrients · 2021Article
- The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases.Physiological research · 2021Review
- An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia.International journal of molecular sciences · 2021Review
- A Comprehensive Review Evaluating the Impact of Protein Source (Vegetarian vs. Meat Based) in Hepatic Encephalopathy.Nutrients · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.
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Registered trials
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