title: Covert hepatic encephalopathy: elevated total glutathione and absence of brain water content changes.
abstract: Recent pathophysiological models suggest that oxidative stress and hyperammonemia lead to a mild brain oedema in hepatic encephalopathy (HE). Glutathione (GSx) is a major cellular antioxidant and known to be involved in the interception of both. The aim of this work was to study total glutathione levels in covert HE (minimal HE and HE grade 1) and to investigate their relationship with local brain water content, levels of glutamine (Gln), myo-inositol (mI), neurotransmitter levels, critical flicker frequency (CFF), and blood ammonia. Proton magnetic resonance spectroscopy ((1)H MRS) data were analysed from visual and sensorimotor cortices of thirty patients with covert HE and 16 age-matched healthy controls. Total glutathione levels (GSx/Cr) were quantified with respect to creatine. Furthermore, quantitative MRI brain water content measures were evaluated. Data were tested for links with the CFF and blood ammonia. GSx/Cr was elevated in the visual (mHE) and sensorimotor (mHE, HE 1) MRS volumes and correlated with blood ammonia levels (both P < 0.001). It was further linked to Gln/Cr and mI/Cr (P < 0.01 in visual, P < 0.001 in sensorimotor) and to GABA/Cr (P < 0.01 in visual). Visual GSx/Cr correlated with brain water content in the thalamus, nucleus caudatus, and visual cortex (P < 0.01). Brain water measures did neither show group effects nor correlations with CFF or blood ammonia. Elevated total glutathione levels in covert HE (< HE 2) correlate with blood ammonia and may be a regional-specific reaction to hyperammonemia and oxidative stress. Brain water content is locally linked to visual glutathione levels, but appears not to be associated with changes of clinical parameters. This might suggest that cerebral oedema is only marginally responsible for the symptoms of covert HE.
authors.affiliation: Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany. georg.oeltzschner@med.uni-duesseldorf.de.|Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany. georg.oeltzschner@med.uni-duesseldorf.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Oeltzschner
authors.affiliation: Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Butz
authors.affiliation: Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany.
authors.forename: Frithjof
authors.initials: F
authors.lastname: Wickrath
authors.affiliation: Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Wittsack
authors.affiliation: Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany.
authors.forename: Alfons
authors.initials: A
authors.lastname: Schnitzler
mesh_terms: D000368:Aged; D000641:Ammonia / Q000097:blood; D001921:Brain / Q000378:metabolism*; D001929:Brain Edema / Q000097:blood / Q000378:metabolism*; D003401:Creatine / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000097:blood / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D014867:Water
chemical_list: D014867:Water; D000641:Ammonia; D005978:Glutathione; D003401:Creatine
keywords: Ammonia; Brain water content; Glutathione; Hepatic encephalopathy; MR spectroscopy