Increased Availability of Central Benzodiazepine Receptors in Patients with Chronic Hepatic Encephalopathy and Alcohol Related Cirrhosis

Overview

Journal Gut

Specialty Gastroenterology

Date 2000 Mar 15

PMID 10716686

Citations 16

Authors

R Jalan

N Turjanski

S D Taylor-Robinson

M J Koepp

M P Richardson

J A Wilson

J D Bell

D J Brooks

Affiliations

Soon will be listed here.

Abstract

Background/aims: To measure cerebral benzodiazepine receptor binding using (11)C-flumazenil positron emission tomography in patients with stable chronic hepatic encephalopathy, who were also characterised by proton magnetic resonance spectroscopy.

Methods: Six abstinent patients of mean age 61 years with alcohol related cirrhosis and grade I-II hepatic encephalopathy and 11 matched healthy volunteers were studied. Each patient's encephalopathy was defined according to clinical, psychometric, electroencephalographic, and magnetic resonance spectroscopy criteria. Using positron emission tomography, the brain volume of distribution of (11)C-flumazenil was obtained; this reflects benzodiazepine receptor availability. Proton magnetic resonance spectra were acquired at 1.5 T using a multivoxel technique; peak area ratios were calculated for choline, glutamine/glutamate, N-acetylaspartate, and creatine resonances.

Results: The mean volume of distribution of (11)C-flumazenil was significantly higher in the cortex, cerebellum, and the basal ganglia in the patients compared with controls (p<0.001). In the patient group, the mean glutamine/glutamate to creatine ratio was significantly increased and the mean choline to creatine ratio was significantly decreased in all brain areas, compared with healthy volunteers. However, the N-acetylaspartate to creatine ratio was unchanged compared with controls.

Conclusions: The spectroscopy results reflect the cerebral metabolic derangement associated with hepatic encephalopathy. Stable grade I-II chronic hepatic encephalopathy in alcohol related cirrhosis may be associated with increased cerebral benzodiazepine receptor availability. However, a direct effect of previous chronic exposure to alcohol cannot be excluded.

Citing Articles

Changing Epidemiology of Cirrhosis and Hepatic Encephalopathy.

Louissaint J, Deutsch-Link S, Tapper E Clin Gastroenterol Hepatol. 2022; 20(8S):S1-S8.

PMID: 35940729 PMC: 9531320. DOI: 10.1016/j.cgh.2022.04.036.

Gut Microbiota at the Intersection of Alcohol, Brain, and the Liver.

Gupta H, Suk K, Kim D J Clin Med. 2021; 10(3).

PMID: 33540624 PMC: 7867253. DOI: 10.3390/jcm10030541.

Protective effects of synbiotic soymilk fortified with whey protein concentrate and zinc sulfate against bile duct ligated-induced hepatic encephalopathy.

Jalilpiran Y, Tanideh N, Rahmdel S, Azarpira N, Mokhtari M, Mazloom Z Gastroenterol Hepatol Bed Bench. 2020; 13(1):64-76.

PMID: 32190227 PMC: 7069541.

Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity.

Moeller S, London E, Northoff G Neurosci Biobehav Rev. 2015; 61:35-52.

PMID: 26657968 PMC: 4731270. DOI: 10.1016/j.neubiorev.2015.11.010.

Quantification of glutamate and glutamine using constant-time point-resolved spectroscopy at 3 T.

Gu M, Zahr N, Spielman D, Sullivan E, Pfefferbaum A, Mayer D NMR Biomed. 2012; 26(2):164-72.

PMID: 22761057 PMC: 3742105. DOI: 10.1002/nbm.2831.

References

Ross B, Jacobson S, Villamil F, Korula J, Kreis R, Ernst T . Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities. Radiology. 1994; 193(2):457-63. DOI: 10.1148/radiology.193.2.7972763. View

Lassen N, Bartenstein P, Lammertsma A, Prevett M, Turton D, Luthra S . Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle. J Cereb Blood Flow Metab. 1995; 15(1):152-65. DOI: 10.1038/jcbfm.1995.17. View

Taylor-Robinson S, Sargentoni J, Marcus C, Morgan M, Bryant D . Regional variations in cerebral proton spectroscopy in patients with chronic hepatic encephalopathy. Metab Brain Dis. 1994; 9(4):347-59. DOI: 10.1007/BF02098881. View

Ferenci P, Herneth A, Puspok A, Steindl P . Neuropharmacologic modulation of hepatic encephalopathy: experimental and clinical data. Adv Exp Med Biol. 1994; 368:103-12. DOI: 10.1007/978-1-4615-1989-8_10. View

Taylor-Robinson S, Sargentoni J, Oatridge A, Bryant D, Hajnal J, Marcus C . MR imaging and spectroscopy of the basal ganglia in chronic liver disease: correlation of T1-weighted contrast measurements with abnormalities in proton and phosphorus-31 MR spectra. Metab Brain Dis. 1996; 11(3):249-68. DOI: 10.1007/BF02237962. View

Ross B, Danielsen E, Bluml S . Proton magnetic resonance spectroscopy: the new gold standard for diagnosis of clinical and subclinical hepatic encephalopathy?. Dig Dis. 1996; 14 Suppl 1:30-9. DOI: 10.1159/000171581. View

Ferenci P, Herneth A, Steindl P . Newer approaches to therapy of hepatic encephalopathy. Semin Liver Dis. 1996; 16(3):329-38. DOI: 10.1055/s-2007-1007245. View

Taylor-Robinson S, Buckley C, Changani K, Hodgson H, Bell J . Cerebral proton and phosphorus-31 magnetic resonance spectroscopy in patients with subclinical hepatic encephalopathy. Liver. 1999; 19(5):389-98. DOI: 10.1111/j.1478-3231.1999.tb00067.x. View

Pugh R, Murray-Lyon I, Dawson J, Pietroni M, Williams R . Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973; 60(8):646-9. DOI: 10.1002/bjs.1800600817. View

10.

CONN H, Leevy C, VLAHCEVIC Z, Rodgers J, Maddrey W, Seeff L . Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977; 72(4 Pt 1):573-83. View

11.

KENDRICK D, Gibson A, Moyes I . The Revised Kendrick Battery: clinical studies. Br J Soc Clin Psychol. 1979; 18(3):329-40. DOI: 10.1111/j.2044-8260.1979.tb00343.x. View

12.

Maziere M, Hantraye P, Prenant C, Sastre J, Comar D . Synthesis of ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine-3-carboxylate (RO 15.1788-11C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography. Int J Appl Radiat Isot. 1984; 35(10):973-6. DOI: 10.1016/0020-708x(84)90215-1. View

13.

Samson Y, Hantraye P, Baron J, Soussaline F, Comar D, Maziere M . Kinetics and displacement of [11C]RO 15-1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography. Eur J Pharmacol. 1985; 110(2):247-51. DOI: 10.1016/0014-2999(85)90218-3. View

14.

Gitlin N, Lewis D, Hinkley L . The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambulant, non-shunted patients with cirrhosis. J Hepatol. 1986; 3(1):75-82. DOI: 10.1016/s0168-8278(86)80149-0. View

15.

Bakti G, Fisch H, Karlaganis G, Minder C, BIRCHER J . Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology. 1987; 7(4):629-38. DOI: 10.1002/hep.1840070403. View

16.

Butterworth R, Giguere J, Michaud J, Lavoie J, Layrargues G . Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol. 1987; 6(1-2):1-12. DOI: 10.1007/BF02833598. View

17.

Mhatre M, Mehta A, Ticku M . Chronic ethanol administration increases the binding of the benzodiazepine inverse agonist and alcohol antagonist [3H]RO15-4513 in rat brain. Eur J Pharmacol. 1988; 153(1):141-5. DOI: 10.1016/0014-2999(88)90599-7. View

18.

Olsen R, Tobin A . Molecular biology of GABAA receptors. FASEB J. 1990; 4(5):1469-80. DOI: 10.1096/fasebj.4.5.2155149. View

19.

Basile A, PANNELL L, Jaouni T, Gammal S, Fales H, Jones E . Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proc Natl Acad Sci U S A. 1990; 87(14):5263-7. PMC: 54303. DOI: 10.1073/pnas.87.14.5263. View

20.

Mullen K, Szauter K . "Endogenous" benzodiazepine activity in body fluids of patients with hepatic encephalopathy. Lancet. 1990; 336(8707):81-3. DOI: 10.1016/0140-6736(90)91594-z. View