Glutamine in the pathogenesis of hepatic encephalopathy: The Trojan horse hypothesis revisited

Kakulavarapu V. Rama Rao, Michael D. Norenberg

Research output: Contribution to journalReview articlepeer-review

63 Scopus citations


Hepatic encephalopathy (HE) is major neuropsychiatric disorder occurring in patients with severe liver disease and ammonia is generally considered to represent the major toxin responsible for this condition. Ammonia in brain is chiefly metabolized ("detoxified") to glutamine in astrocytes due to predominant localization of glutamine synthetase in these cells. While glutamine has long been considered innocuous, a deleterious role more recently has been attributed to this amino acid. This article reviews the mechanisms by which glutamine contributes to the pathogenesis of HE, how glutamine is transported into mitochondria and subsequently hydrolyzed leading to high levels of ammonia, the latter triggering oxidative and nitrative stress, the mitochondrial permeability transition and mitochondrial injury, a sequence of events we have collectively termed as the Trojan horse hypothesis of hepatic encephalopathy.

Original languageEnglish (US)
Pages (from-to)593-598
Number of pages6
JournalNeurochemical Research
Issue number3
StatePublished - Mar 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience


  • 6-Diazo-5-oxo-l-norleucine (DON)
  • Ammonia
  • Astrocytes
  • Glutaminase
  • Glutamine
  • Hepatic encephalopathy
  • Mitochondrial permeability transition
  • Oxidative stress
  • l-Histidine


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