• Manakkat VijayGodhev KGK1Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, United Kingdom.2Liver Intensive Care Unit, King's College London School of Medicine at King's College Hos, Jennifer M Ryan, Robin D Abeles, Stephen Ramage, Vishal Patel, Christine Bernsmeier, Antonio Riva, Mark J W McPhail, Thomas H Tranah, Lee J L Markwick, Nicholas J Taylor, William Bernal, Georg Auzinger, Chris Willars, Shilpa Chokshi, Julia A Wendon, Yun Ma, and Debbie L Shawcross.
• 1Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, United Kingdom.2Liver Intensive Care Unit, King's College London School of Medicine at King's College Hospital, London, United Kingdom.3Foundation for Liver Research, London, United Kingdom.4Hepatology and Gastroenterology, Liver and Antiviral Unit, St. Marys Hospital, Imperial College London, London, United Kingdom.
• Crit. Care Med. 2016 Jan 1; 44 (1): 43-53.

ObjectivesThere is a marked propensity for patients with acetaminophen-induced acute liver failure to develop sepsis, which may culminate in multiple organ failure and death. Toll-like receptors sense pathogens and induce inflammatory responses, but whether this is protective or detrimental in acetaminophen-induced acute liver failure remains unknown.Design, Setting, And PatientsWe assessed Toll-like receptor expression on circulating neutrophils and their function in 24 patients with acetaminophen-induced acute liver failure and compared with 10 healthy controls.InterventionsNeutrophil Toll-like receptor 2, -4, and -9 expression and cytokine production and function were studied ex vivo at baseline and following stimulation with lipopolysaccharide, oligodeoxynucleotides, ammonium chloride, and interleukin-8. To examine the influence of acetaminophen-induced acute liver failure plasma and endogenous DNA on Toll-like receptors-9 expression, healthy neutrophils were incubated with acetaminophen-induced acute liver failure plasma with and without deoxyribonuclease-I.Measurements And Main ResultsCirculating neutrophil Toll-like receptor 9 expression was increased in acetaminophen-induced acute liver failure on day 1 compared with healthy controls (p = 0.0002), whereas Toll-like receptor 4 expression was decreased compared with healthy controls (p < 0.0001). Toll-like receptor 2 expression was unchanged. Neutrophil phagocytic activity was decreased, and spontaneous oxidative burst increased in all patients with acetaminophen-induced acute liver failure compared with healthy controls (p < 0.0001). Neutrophil Toll-like receptor 9 expression correlated with plasma interleukin-8 and peak ammonia concentration (r = 0.6; p < 0.05) and increased with severity of hepatic encephalopathy (grade 0-2 vs 3/4) and systemic inflammatory response syndrome score (0-1 vs 2-4) (p < 0.05). Those patients with advanced hepatic encephalopathy (grade 3/4) or high systemic inflammatory response syndrome score (2-4) on day 1 had higher neutrophil Toll-like receptor 9 expression, arterial ammonia concentration, and plasma interleukin-8 associated with neutrophil exhaustion. Healthy neutrophil Toll-like receptor 9 expression increased upon stimulation with acetaminophen-induced acute liver failure plasma, which was abrogated by preincubation with deoxyribonuclease-I. Intracellular Toll-like receptor 9 was induced by costimulation with interleukin-8 and ammonia.ConclusionThese data point to neutrophil Toll-like receptor 9 expression in acetaminophen-induced acute liver failure being mediated both by circulating endogenous DNA as well as ammonia and interleukin-8 in a synergistic manner inducing systemic inflammation, neutrophil exhaustion, and exacerbating hepatic encephalopathy.

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