Skip to main content
NCBI home page
Journal of Psychiatry & Neuroscience: JPN logoLink to Journal of Psychiatry & Neuroscience: JPN
. 1998 Sep;23(4):217–222.

Plasma concentrations of endogenous benzodiazepine-receptor ligands in patients with hepatic encephalopathy: a comparative study.

C A Hernández-Avila 1, W J Shoemaker 1, H A Ortega-Soto 1
PMCID: PMC1188937  PMID: 9785700

Abstract

OBJECTIVE: Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder secondary to acute or chronic liver failure. Although the exact causes of HE have not been clarified, enhanced central nervous system inhibition at the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, mediated by increased levels of endogenous benzodiazepine-receptor ligands (BZRL), has been proposed. Research exploring this hypothesis has yielded contradictory findings. This study evaluated the presence and levels of BZRL in plasma from patients with HE and 3 comparison groups. DESIGN: Cross-sectional study. PATIENTS: Twenty-four patients with HE, 10 patients with liver cirrhosis without encephalopathy (LC), 4 patients with uremic encephalopathy (UE), and 9 healthy subjects. INTERVENTIONS: Radio-receptor assay of plasma samples from patients and controls. MAIN OUTCOME MEASURES: Plasma levels of BZRL. RESULTS: The patients in the HE group had significantly higher plasma BZRL levels than the patients with UE and the healthy subjects, but not than those with LC, in whom these compounds were also detected in significant concentrations. When patients were classified according to the severity of HE, plasma of BZRL showed a modest correlation with stage of severity (r = 0.37). Interestingly, approximately one-third of the patients with HE did not have detectable levels of BZRL. CONCLUSION: Endogenous BZRL may play a role in the pathogenesis of HE, although neuropsychiatric symptoms in HE are difficult to explain in terms of these compounds alone.

Full text

PDF
217

Images in this article

221Fig. 1
on p.221

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Basile A. S., Harrison P. M., Hughes R. D., Gu Z. Q., Pannell L., McKinney A., Jones E. A., Williams R. Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy. Hepatology. 1994 Jan;19(1):112–121. [PubMed] [Google Scholar]
  2. Basile A. S., Hughes R. D., Harrison P. M., Murata Y., Pannell L., Jones E. A., Williams R., Skolnick P. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med. 1991 Aug 15;325(7):473–478. doi: 10.1056/NEJM199108153250705. [DOI] [PubMed] [Google Scholar]
  3. Basile A. S., Pannell L., Jaouni T., Gammal S. H., Fales H. M., Jones E. A., Skolnick P. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5263–5267. doi: 10.1073/pnas.87.14.5263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bassett M. L., Mullen K. D., Skolnick P., Jones E. A. Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology. 1987 Nov;93(5):1069–1077. doi: 10.1016/0016-5085(87)90571-3. [DOI] [PubMed] [Google Scholar]
  5. Devlin T., Shoemaker W. J. Characterization of kappa opioid binding using dynorphin A1-13 and U69,593 in the rat brain. J Pharmacol Exp Ther. 1990 May;253(2):749–759. [PubMed] [Google Scholar]
  6. Faull R. L., Villiger J. W. Multiple benzodiazepine receptors in the human basal ganglia: a detailed pharmacological and anatomical study. Neuroscience. 1988 Feb;24(2):433–451. doi: 10.1016/0306-4522(88)90340-5. [DOI] [PubMed] [Google Scholar]
  7. Mullen K. D., Basile A. S. Benzodiazepine-receptor antagonists and hepatic encephalopathy: where do we stand? Gastroenterology. 1993 Sep;105(3):937–940. doi: 10.1016/0016-5085(93)90916-z. [DOI] [PubMed] [Google Scholar]
  8. Olasmaa M., Guidotti A., Costa E., Rothstein J. D., Goldman M. E., Weber R. J., Paul S. M. Endogenous benzodiazepines in hepatic encephalopathy. Lancet. 1989 Mar 4;1(8636):491–492. doi: 10.1016/s0140-6736(89)91384-6. [DOI] [PubMed] [Google Scholar]
  9. Olasmaa M., Rothstein J. D., Guidotti A., Weber R. J., Paul S. M., Spector S., Zeneroli M. L., Baraldi M., Costa E. Endogenous benzodiazepine receptor ligands in human and animal hepatic encephalopathy. J Neurochem. 1990 Dec;55(6):2015–2023. doi: 10.1111/j.1471-4159.1990.tb05790.x. [DOI] [PubMed] [Google Scholar]
  10. Pomier-Layrargues G., Giguère J. F., Lavoie J., Perney P., Gagnon S., D'Amour M., Wells J., Butterworth R. F. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology. 1994 Jan;19(1):32–37. [PubMed] [Google Scholar]
  11. Pritchett D. B., Sontheimer H., Shivers B. D., Ymer S., Kettenmann H., Schofield P. R., Seeburg P. H. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature. 1989 Apr 13;338(6216):582–585. doi: 10.1038/338582a0. [DOI] [PubMed] [Google Scholar]
  12. Rao V. L., Murthy C. R., Butterworth R. F. Glutamatergic synaptic dysfunction in hyperammonemic syndromes. Metab Brain Dis. 1992 Mar;7(1):1–20. doi: 10.1007/BF01000437. [DOI] [PubMed] [Google Scholar]
  13. Rothstein J. D. Benzodiazepine-receptor ligands and hepatic encephalopathy: a causal relationship? Hepatology. 1994 Jan;19(1):248–250. [PubMed] [Google Scholar]
  14. Samson Y., Bernuau J., Pappata S., Chavoix C., Baron J. C., Maziere M. A. Cerebral uptake of benzodiazepine measured by positron emission tomography in hepatic encephalopathy. N Engl J Med. 1987 Feb 12;316(7):414–415. doi: 10.1056/NEJM198702123160716. [DOI] [PubMed] [Google Scholar]
  15. Schafer D. F., Pappas S. C., Brody L. E., Jacobs R., Jones E. A. Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas. Gastroenterology. 1984 Mar;86(3):540–545. [PubMed] [Google Scholar]
  16. Widler P., Fisch H. U., Schoch P., Zimmermann A., Schläpfer T. E., Reichen J. Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat. Hepatology. 1993 Dec;18(6):1459–1464. [PubMed] [Google Scholar]
  17. Yurdaydin C., Walsh T. J., Engler H. D., Ha J. H., Li Y., Jones E. A., Basile A. S. Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res. 1995 May 8;679(1):42–48. doi: 10.1016/0006-8993(95)00241-h. [DOI] [PubMed] [Google Scholar]
  18. Zieve L., Ferenci P., Rzepczynski D., Ebner J., Zimmermann C. A benzodiazepine antagonist does not alter the course of hepatic encephalopathy or neural gamma-aminobutyric acid (GABA) binding. Metab Brain Dis. 1987 Sep;2(3):201–205. doi: 10.1007/BF00999611. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Psychiatry and Neuroscience are provided here courtesy of Canadian Science Publishing

RESOURCES