The concept of "the inflamed brain" in acute liver failure: mechanisms and new therapeutic opportunities.
The presence and severity of a systemic inflammatory response is a major predictor of brain edema and encephalopathy in acute liver failure (ALF) and polymorphisms of the gene coding for the proinflammatory cytokine TNF-alpha are known to influence the clinical outcome in ALF. Recent reports provide robust evidence for a role of neuroinflammation(inflammation of the brain per se) in ALF with the cardinal features of neuroinflammation including activation of microglial cells and increased production in situ of pro-inflammatory cytokines such as TNF-alpha and interleukins IL-1beta and IL-6. Multiple liver-brain signalling pathways have been proposed to explain the phenomenon of neuroinflammation in liver failure and these include direct effects of systemically-derived cytokines, recruitment of monocytes relating to microglial activation as well as effects of liver failure-derived toxins and altered permeability of the blood-brain barrier. Synergistic mechanisms involving ammonia and cytokines have been proposed. Currently-available strategies aimed at lowering of blood ammonia such as lactulose, probiotics and rifaximin have the potential to dampen systemic inflammation as does the anti-oxidant N-acetyl cysteine, mild hypothermia and albumin dialysis. Experimental studies demonstrate that deletion of genes coding for TNF-alpha or IL-1 leads to attenuation of the CNS consequences of ALF and administration of the TNF-alpha receptor antagonist etanercept has comparable beneficial effects in experimental ALF. Together, these findings confirm a major role for central neuroinflammatory mechanisms in general and mechanisms involving TNF-alpha in particular in the pathogenesis of the cerebral consequences of ALF and open the door to novel therapeutic interventions in this often fatal disorder.
Department of Medicine, University of Montreal, Montreal, QC, Canada. roger.butterworth@umontreal.ca.
Roger F
RF
Butterworth
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D001929:Brain Edema / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015316:Genetic Therapy / Q000639:trends*; D006501:Hepatic Encephalopathy / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000235:genetics / Q000378:metabolism / Q000628:therapy
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators
Acute liver failure; Ammonia; Encephalopathy; Microglia; Minocycline; Neuroinflammation; Proinflammatory cytokines