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ALTERATIONS OF BRAIN LEVELS OF NEUROACTIVE STEROIDS ALLOPREGNANOLONE AND DEHYDROEPIANDROSTERONE SULFATE IN PATIENTS WHO DIED IN HEPATIC COMA: FURTHER EVIDENCE FOR THE NOTION OF “INCREASED GABAergic TONE” IN HEPATIC ENCEPHALOPATHY
S Ahboucha1,2, G Baker2, G Pomier-Layrargues3, RF Butterworth1
1Neuroscience Research Unit, CHUM (Hôpital Saint-Luc) Montreal; 2Neurochemical Research Unit, University of Alberta, Edmonton; 3Liver Unit, CHUM (Hôpital Saint-Luc), Montreal
Several studies have suggested that “increased GABAergic tone” is one of the mechanisms in the pathogenesis of hepatic encephalopathy (HE). Recently, neuroinhibitory steroids were demonstrated to be major candidates to explain the phenomenon of “increased GABAergic tone” in human HE. As part of a series of studies on neuroactive steroids in relation to human HE, concentrations of dehydroepiandrosterone sulfate (DHEAS), a GABA-A receptor (GR) negative allosteric modulator, 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5alpha-tetrahydeoxycorticosterone (THDOC), two positive allosteric modulators of the GR, as well as allopregnanolone isomers 3alpha,5beta-THP and 3beta,5alpha-THP (positive and negative modulators of GR receptors respectively) were measured by either gas chromatography/mass spectrometry or radioimmunoassay in samples of frontal cortex obtained at autopsy from 11 cirrhotic patients who died in hepatic coma compared to an equal number of control subjects free of hepatic or neurological diseases at the time of death matched for age, gender, and autopsy delay intervals. Patient material showed a significant reduction of DHEAS (5.81±0.88 µg /g tissue) compared to controls (9.70±0.79µg /g, p<0.01) and a significant increase of 3alpha,5alpha-THP in HE (patients: 4.1 ±1.4ng/g; controls: 0.38 ± 0.51ng/g). Brain levels of DHEAS and allopregnanolone in four patients with liver disease who died without HE, and in a patient who died in uremic coma were in the control range. Brain levels of 3alpha,5beta-THP and 3beta,5alpha-THP were not changed in any of the groups studied. Alterations of allopregnanolone and DHEAS were also observed in plasma of 16 patients with primary biliary cirrhosis compared to 11 controls. However, 12 patients with chronic hepatitis C showed only increased levels of allopregnanolone but no change in plasma DHEAS. Brain reduction of DHEAS, a negative GR modulator, together with an increase of allopregnanolone a positive GR modulator would induce further stimulation of these receptors in patients with HE. These findings support the notion of “increased GABAergic tone” in human HE.
This work has been funded by CIHR.