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Cited by 209Liver Disease and TransplantationAmino Acid Enzymes and MetabolismMetabolism and Genetic Disorders

Astrocyte Glutamine Synthetase: Importance in Hyperammonemic Syndromes and Potential Target for Therapy

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Brusilow, Saul W., Koehler, Raymond C., Traystman, Richard J., Cooper, Arthur J.L.·2010·Neurotherapeutics
DOI 10.1016/j.nurt.2010.05.015PMC PMC2975543
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Abstract

Many theories have been advanced to explain the encephalopathy associated with chronic liver disease and with the less common acute form. A major factor contributing to hepatic encephalopathy is hyperammonemia resulting from portacaval shunting and/or liver damage. However, an increasing number of causes of hyperammonemic encephalopathy have been discovered that present with the same clinical and laboratory features found in acute liver failure, but without liver failure. Here, we critically review the physiology, pathology, and biochemistry of ammonia (i.e., NH3 plus NH4+) and show how these elements interact to constitute a syndrome that clinicians refer to as hyperammonemic encephalopathy (i.e., acute liver failure, fulminant hepatic failure, chronic liver disease). Included will be a brief history of the status of ammonia and the centrality of the astrocyte in brain nitrogen metabolism. Ammonia is normally detoxified in the liver and extrahepatic tissues by conversion to urea and glutamine, respectively. In the brain, glutamine synthesis is largely confined to astrocytes, and it is generally accepted that in hyperammonemia excess glutamine compromises astrocyte morphology and function. Mechanisms postulated to account for this toxicity will be examined with emphasis on the osmotic effects of excess glutamine (the osmotic gliopathy theory). Because hyperammonemia causes osmotic stress and encephalopathy in patients with normal or abnormal liver function alike, the term "hyperammonemic encephalopathy" can be broadly applied to encephalopathy resulting from liver disease and from various other diseases that produce hyperammonemia. Finally, the possibility that a brain glutamine synthetase inhibitor may be of therapeutic benefit, especially in the acute form of liver disease, is discussed.

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  • Astrocytes can exhibit cell-autonomous disturbances, as in astrocytopathies caused by mutated astrocytic genes such as GFAP in Alexander disease, direct viral infections, or toxic substances that specifically damage astrocytes such as ammonium in hepatic encephalopathy.

    “Astrocytes may also exhibit cell-autonomous disturbances8, as happens in astrocytopathies resulting from mutated alleles of astrocytic genes (for example, GFAP in Alexander disease)9, as well as from direct viral infections or exposure to toxic substances that specifically damage astrocytes (for example, ammonium in hepatic encephalopathy)10.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [10]

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  1. [28]Conn HO Bircher J Hepatic encephalopathy Bloomington, IL Medi-Ed Press 1994 43 61
  2. [104]Bruton CJ Corsellis JAN Russell A Hereditary hyperammonaemia Brain 1970 93 423 34 5310321
  3. [109]Sørensen M Keiding S New findings on cerebral ammonia uptake in HE using functional 13N-ammonia PET Metab Brain Dis 2007 22 277 84 17828586
  4. [118]Albrecht J Norenberg MD Glutamine: a Trojan horse in ammonia neurotoxicity Hepatology 2006 44 788 94 17006913
  5. [174]Sonnewald U Therrien G Butterworth RF Portacaval anastomosis results in altered neuron-astrocytic metabolic trafficking of amino acids J Neurochem 1996 67 1711 7 8858957
  6. [177]Stravitz RT Kramer AH Davern T the Acute Liver Failure Study Group Crit Care Med 2007 35 2498 508 17901832

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Authors
Brusilow, S. W., Koehler, R. C., Traystman, R. J., & Cooper, A. J. L.
Affiliations
  • Johns Hopkins University (US)
  • University of Colorado Denver (US)
  • New York Medical College (US)
Corresponding author
  • Brusilow, Saul W.
  • Cooper, Arthur J.L.
ORCID
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2010-10
Volume
7
Issue
4
Pages
452-470
ISSN
1878-7479 (ISSN-L)
DOI
10.1016/j.nurt.2010.05.015
PMC
PMC2975543
OpenAlex
W2104703549
Cited by
209
References
215
Citations by year
2026: 9 · 2025: 13 · 2024: 10 · 2023: 10 · 2022: 16 · 2021: 17 · 2020: 7 · 2019: 11 · 2018: 14 · 2017: 11 · 2016: 14 · 2015: 13 · 2014: 23 · 2013: 16 · 2012: 16
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotherapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ns025275-14)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 16739, R01DK016739)
  • National Institute of Neurological Disorders and Stroke (R01NS046072, NS 25275)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
hyperammonemic encephalopathy, glutamine synthetase, astrocytes, hyperammonemia, chronic liver disease, acute liver failure, ammonia detoxification, glutamine synthetase inhibitors, portacaval shunt
MeSH terms
Animals, Astrocytes, Enzyme Inhibitors, Glutamate-Ammonia Ligase, Hepatic Encephalopathy, Humans, Hyperammonemia

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