Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure

N Engl J Med. 1991 Aug 15;325(7):473-8. doi: 10.1056/NEJM199108153250705.


Background: Increased gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathogenesis of hepatic encephalopathy. The mechanism by which GABA-ergic activity is increased in hepatic failure is unclear, but recent studies in animals with encephalopathy due to fulminant hepatic failure suggest that GABA-ergic neurotransmission may be increased by the presence of elevated concentrations of benzodiazepine agonists such as diazepam and N-desmethyldiazepam.

Methods and results: Samples of frontal cortex were obtained at autopsy from 11 patients with hepatic encephalopathy who died of acetaminophen-induced fulminant hepatic failure and 8 patients who died of cardiovascular disease or trauma. None of the 19 patients had received benzodiazepines while hospitalized. Chromatographic analyses of extracts of these samples revealed 4 to 19 peaks representing substances that inhibited the binding of a radiolabeled imidazobenzodiazepine ([3H]flumazenil) to its receptors. Several of these peaks had retention times corresponding to those of known 1,4-benzodiazepines. Ultraviolet- and mass-spectroscopic analysis confirmed that two of these peaks represented diazepam and N-desmethyldiazepam. The patients who died of fulminant hepatic failure could be divided into two groups: six who had had significantly elevated brain concentrations (2-fold to 10-fold higher than normal) of substances inhibiting the binding of [3H]flumazenil and five who had normal concentrations.

Conclusions: Brain concentrations of substances inhibiting the binding of [3H]flumazenil to its receptors are increased in some patients with hepatic encephalopathy due to fulminant hepatic failure. The origin of these substances is unknown, but these findings provide a rational basis for trials of benzodiazepine-receptor antagonists in the management of this disorder.

MeSH terms

  • Adult
  • Aged
  • Benzodiazepines / analysis*
  • Brain Chemistry*
  • Chromatography
  • Diazepam / analysis
  • Flumazenil / metabolism
  • Frontal Lobe / chemistry
  • Hepatic Encephalopathy / metabolism*
  • Hepatic Encephalopathy / physiopathology
  • Humans
  • Mass Spectrometry
  • Middle Aged
  • Nordazepam / analysis
  • Receptors, GABA-A / drug effects
  • Synaptic Transmission
  • gamma-Aminobutyric Acid / metabolism


  • Receptors, GABA-A
  • Benzodiazepines
  • Flumazenil
  • gamma-Aminobutyric Acid
  • Nordazepam
  • Diazepam