Introduction Neutrophil phagocytic dysfunction is associated with increased risk of infection and mortality in patients with cirrhosis. The p38-mitogen-activated protein kinase (MAPK) signalling pathway is a critical step in neutrophil activation and is modulated by chemokines, ammonia and endotoxaemia.
Aim This longitudinal study aims to characterise the relationship between neutrophil function and volume, plasma cytokine profile and ammonia, in order to assess neutrophil function as a biomarker of susceptibility to infection and contributor to the development of hepatic encephalopathy (HE) in cirrhosis.
Method Neutrophils were isolated at baseline, following the development of HE, and post-LT, from a cohort of 75 patients with cirrhosis and controls during an 18-month follow-up period. Phagocytosis was analysed by flow cytometry using FITC-labelled E. coli and oxidative burst (OB) was determined by the percentage of neutrophils producing reactive oxygen species (ROS) at rest and after stimulation with opsonised E. coli. Neutrophil volume was measured using flow cytometry and transmission electron microscopy. Clinical data, blood biochemistry, arterial ammonia and microbial cultures were collected prospectively. Analysis of stimulated neutrophil intracellular cytokine production, plasma cytokine profile and neutrophil basal levels of phosphorylated P38-MAPK were performed.
Results At baseline patients had a median age of 54 (44–62), 31% were female, 43% were on antibiotics. Median MELD score was 17 (12–22). During follow-up nine patients developed overt grade 2–4 HE, 12 patients underwent LT and nine died. Neutrophil phagocytic capacity was significantly impaired in patients with advanced cirrhosis (p=0.001) and was associated with a 20% increase in neutrophil volume. In those who underwent uncomplicated LT, neutrophil phagocytic capacity improved by 15% within 72 h. Phagocytic impairment correlated with increasing plasma concentrations of CRP*, ammonia*, IgG**, proinflammatory cytokines TNF-*, IL-6* and the anti-inflammatory cytokine IL-10* (*p<0.05, **p<0.1). Resting neutrophil production of ROS as a measure of neutrophil activation was significantly increased in patients with cirrhosis with further elevation following the development of HE.
Conclusion Phagocytic dysfunction is universal in patients with cirrhosis and is related in part to the development of ammonia-induced neutrophil swelling, which is reversible following LT. Increasing levels of endotoxin and/or ammonia leading to neutrophil activation via the p38-MAPK pathway and resultant generation of ROS may prove the link between neutrophils, ammonia and infection in the development of HE in cirrhosis.
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