Pathogenetic mechanisms of hepatic encephalopathy.
Hepatic encephalopathy (HE) in liver cirrhosis is a clinical manifestation of a low-grade cerebral oedema, which is exacerbated in response to ammonia and other precipitating factors. This low-grade cerebral oedema is accompanied by an increased production of reactive oxygen and nitrogen oxide species (ROS/RNOS), which trigger multiple protein and RNA modifications, thereby affecting brain function. The action of ammonia, inflammatory cytokines, benzodiazepines and hyponatraemia integrates at the level of astrocyte swelling and oxidative stress. This explains why heterogenous clinical conditions can precipitate HE episodes. Oxidised RNA species, which are formed in response to oxidative stress, also participate in local postsynaptic protein synthesis in neurons, which is required for memory formation. Although the functional consequences of RNA oxidation in this context remain to be established, these findings bear a potential biochemical explanation for the multiple alterations of neurotransmitter receptor systems and of synaptic plasticity. Such changes may in part also underlie the pathologically altered oscillatory networks in the brain of HE patients in vivo, as detected by magnetencephalography. These disturbances of oscillatory networks, which in part are triggered by hypothalamic structures, can explain the motor and cognitive deficits in patients with HE. Current therapeutic strategies aim at the elimination of precipitating factors. The potential of therapies targeting downstream pathophysiological events in HE has not yet been explored, but offers novel potential sites of therapeutic intervention.
Häussinger
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Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. haeussin@uni-duesseldorf.de
Schliess
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F
D001253:Astrocytes / Q000473:pathology; D001929:Brain Edema / Q000150:complications*; D006501:Hepatic Encephalopathy / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012313:RNA / Q000378:metabolism; D012720:Severity of Illness Index
D012313:RNA