Introduction The systemic inflammatory response syndrome (SIRS) exacerbates hepatic encephalopathy (HE) in patients with cirrhosis. SIRS is a proinflammatory response tasked with killing infectious organisms through activation of the immune system, whereas CARS is a global deactivation of the immune system aimed at restoring homeostasis. The timing and magnitude of CARS may impact on patient outcomes. This study aimed to characterise the relationship between neutrophil oxidative stress, plasma cytokine profile and ammonia in a cohort of patients with advanced cirrhosis undergoing assessment for liver transplantation (LT). Patients specifically referred for LT with chronic HE (n=7) were compared to those who had no history of overt HE (n=17) and healthy controls (HC) (n=8).
Methods Neutrophils were isolated at the time of LT assessment and 72 h following LT (n=6/24). Quantification of spontaneous oxidative burst (OB) was determined by measuring the percentage of neutrophils producing reactive oxidants at rest. Formation of oxidative reactants was monitored by oxidation of dihydrorhodamine (DHR 123) to rhodamine. To identify neutrophils, cells were stained with anti- CD16-PE IgG1 and analysed by flow cytometry. Clinical data, blood biochemistry, arterial ammonia and a full set of microbial cultures were collected. Cytokine analysis for TNF-α, IL-1ß, IL-6, IL-8, IL-10 and IL-17 were performed by ELISA.
Results There were no differences in MELD score, neutrophil count, ammonia (p=0.85) or empirical antibiotic use between those with chronic HE and those without. Neutrophil spontaneous OB was elevated in those with HE (30% (9–77) vs 13% (9–41), p=0.04) compared to those without. Patients with chronic HE had markedly decreased proinflammatory cytokines (TNF-α, p=0.02; IL-6, p=0.009 and IL-17, p=0.01) compared to those without HE but not the neutrophil-specific cytokine IL-8, upregulated in response to oxidative stress. The anti-inflammatory cytokine IL-10 was low in patients with HE compared to those without HE (6 (5–65) vs 207 (34–369) pg/ml, p=0.02) and HCs. Cirrhotic cytokine profiles and elevated spontaneous OB returned to HC levels post-LT.
Conclusion These data suggest that patients with advanced cirrhosis and chronic HE have neutrophil-induced oxidative stress which triggers CARS rather than SIRS with time. IL-10 may protect against chronic HE and oxidative stress.
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