Invited Editorials
Editorial: neutrophil dysfunction in patients with cirrhosis – authors’ reply N. J. Taylor, Y. Ma & D. L. Shawcross Institute of Liver Studies and Transplantation, King’s College London School of Medicine at King’s College Hospital, London, UK. E-mail: [email protected] doi:10.1111/apt.12935
We thank Asrani and Kamath for their insightful editorial on our study which adds to the growing evidence that neutrophil dysfunction in cirrhosis mirrors worsening severity of disease and predicts poor outcome.1, 2 Neutrophils show divergent responses in terms of phagocytosis of microorganisms and production of reactive oxygen species, thus neutrophils contribute both to susceptibility to infection and endothelial activation which is a prerequisite to the development of organ dysfunction.3 The difficulty, however, is determining whether this dysfunction is merely a surrogate marker of advancing disease or a consequence of chronic endotoxaemia and immune exhaustion. The supposition being that chronic low-grade endotoxaemia resulting from bacterial translocation across a leaky gut induces a pro-inflammatory plasma milieu leading to changes in neutrophil behaviour.4 Our study aimed to characterise the impact of cirrhosis on neutrophil function by prospectively monitoring function indices, but due to the heterogeneity of the cirrhotic population, low number of septic events and the number of subjects who underwent transplantation during follow-up, this led to confounders prohibitive to performing instructive sub-group analysis. Studying a highly selected group not listed for transplantation will thus give clues to the natural history of immune dysfunction in advancing cirrhosis. In addition, interventional studies interrogating the effect of therapies such as albumin,
Editorial: healing of refractory reflux oesophagitis – an ongoing unmet clinical need R. H. Hunt*, Y. Yuan* & C. Scarpignato† *Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada. Aliment Pharmacol Ther 2014; 40: 982-989 ª 2014 John Wiley & Sons Ltd
antibiotics modulating gut microbiota, immunosuppression and plasmapheresis are warranted. The exact causality of neutrophil dysfunction remains unclear, and while there is association with pro-inflammatory cytokine levels, there is no consistency. Neutrophil malfunction following exposure to ammonia in vivo and ex vivo does however, seem to be a consistent finding and may explain why neutrophil function deteriorates with advancing disease.5–7 Nevertheless, determining the cellular changes and role of inflammosome proteins and pathways appears likely to identify novel targets to modulate neutrophil function and may offer a potential strategy to improve outcomes in patients with cirrhosis.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
REFERENCES 1. Asrani SK, Kamath PS. Editorial: neutrophil dysfunction in patients with cirrhosis. Aliment Pharmacol Ther 2014; 40: 986. 2. Taylor NJ, Manakkat Vijay GK, Abeles RD, et al. The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality. Aliment Pharmacol Ther 2014; 40: 705–15. 3. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157–69. 4. Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010; 52: 2044–52. 5. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010; 51: 1062–9. 6. Shawcross D, Wright G, Stadlbauer V, et al. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 2008; 48: 1202–12. 7. Taylor NJ, Nishtala A, Manakkat Vijay GK, et al. Circulating neutrophil dysfunction in acute liver failure. Hepatology 2013; 57: 1142–52.
†
Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, Italy. E-mail: [email protected] doi:10.1111/apt.12933
987
Editorial: neutrophil dysfunction in patients with cirrhosis – authors’ reply N. J. Taylor, Y. Ma & D. L. Shawcross Institute of Liver Studies and Transplantation, King’s College London School of Medicine at King’s College Hospital, London, UK. E-mail: [email protected] doi:10.1111/apt.12935
We thank Asrani and Kamath for their insightful editorial on our study which adds to the growing evidence that neutrophil dysfunction in cirrhosis mirrors worsening severity of disease and predicts poor outcome.1, 2 Neutrophils show divergent responses in terms of phagocytosis of microorganisms and production of reactive oxygen species, thus neutrophils contribute both to susceptibility to infection and endothelial activation which is a prerequisite to the development of organ dysfunction.3 The difficulty, however, is determining whether this dysfunction is merely a surrogate marker of advancing disease or a consequence of chronic endotoxaemia and immune exhaustion. The supposition being that chronic low-grade endotoxaemia resulting from bacterial translocation across a leaky gut induces a pro-inflammatory plasma milieu leading to changes in neutrophil behaviour.4 Our study aimed to characterise the impact of cirrhosis on neutrophil function by prospectively monitoring function indices, but due to the heterogeneity of the cirrhotic population, low number of septic events and the number of subjects who underwent transplantation during follow-up, this led to confounders prohibitive to performing instructive sub-group analysis. Studying a highly selected group not listed for transplantation will thus give clues to the natural history of immune dysfunction in advancing cirrhosis. In addition, interventional studies interrogating the effect of therapies such as albumin,
Editorial: healing of refractory reflux oesophagitis – an ongoing unmet clinical need R. H. Hunt*, Y. Yuan* & C. Scarpignato† *Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada. Aliment Pharmacol Ther 2014; 40: 982-989 ª 2014 John Wiley & Sons Ltd
antibiotics modulating gut microbiota, immunosuppression and plasmapheresis are warranted. The exact causality of neutrophil dysfunction remains unclear, and while there is association with pro-inflammatory cytokine levels, there is no consistency. Neutrophil malfunction following exposure to ammonia in vivo and ex vivo does however, seem to be a consistent finding and may explain why neutrophil function deteriorates with advancing disease.5–7 Nevertheless, determining the cellular changes and role of inflammosome proteins and pathways appears likely to identify novel targets to modulate neutrophil function and may offer a potential strategy to improve outcomes in patients with cirrhosis.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
REFERENCES 1. Asrani SK, Kamath PS. Editorial: neutrophil dysfunction in patients with cirrhosis. Aliment Pharmacol Ther 2014; 40: 986. 2. Taylor NJ, Manakkat Vijay GK, Abeles RD, et al. The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality. Aliment Pharmacol Ther 2014; 40: 705–15. 3. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157–69. 4. Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010; 52: 2044–52. 5. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010; 51: 1062–9. 6. Shawcross D, Wright G, Stadlbauer V, et al. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 2008; 48: 1202–12. 7. Taylor NJ, Nishtala A, Manakkat Vijay GK, et al. Circulating neutrophil dysfunction in acute liver failure. Hepatology 2013; 57: 1142–52.
†
Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, Italy. E-mail: [email protected] doi:10.1111/apt.12933
987
