Pathophysiology of hepatic encephalopathy: The concept of synergism.
Hepatic encephalopathy (HE) remains a severe neuropsychiatric complication of liver failure. Neuropathological evaluation of material from patients who died in hepatic coma reveals morphologic changes primarily to astrocytes (cytotoxic edema, Alzheimer Type II astrocytosis) accompanied by discreet neuronal changes. Liver failure results in the accumulation in brain of neurotoxic compounds (ammonia, manganese, proinflammatory cytokines, mercaptans, octanoic acid) that may act synergistically to impair neuropsychiatric function. Ammonia and manganese act synergistically to activate mitochondrial benzodiazepine receptors leading to increased production of neuroactive steroids, many of which (allopregnanolone, THDOC) have potent neuroinhibitory properties resulting from activation of a neuromodulatory site on the GABA-A receptor ("increased GABAergic tone"). New evidence demonstrates that proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and the interleukins (IL-1beta, and IL-6) are produced not only by the liver but also by the brain in liver failure. Ammonia and proinflammatory cytokines generated either by intercurrent infection or from hepatocyte necrosis in liver failure act synergistically to decrease the capacity of astrocytes to remove glutamate from the brain extracellular space leading to the activation of glutamate (NMDA) receptors that in turn results in alterations of cell-cell signalling and hyperexcitability. Therapy for HE continues to rely heavily on strategies aimed at reduction of gut ammonia production, increased ammonia removal and, ultimately, liver transplantation. A more complete understanding of pathophysiologic mechanisms has led to novel potential strategies aimed at decreasing both GABAergic tone, glutamate (NMDA) receptor activation and proinflammatory cytokines. Such strategies hold promise for new therapies for HE in the near future.
Butterworth
Roger F
RF
Neuroscience Research Unit (CHUM), University of Montreal, Montreal, QC, Canada.