Abstract
Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. 26 patients with alcoholic cirrhosis and variceal haemorrhage were studied prior to and 1-hour after TIPSS insertion. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). Significantly higher LPS concentrations and neutrophil reactive oxidant species (ROS) production were observed in PV vs HV blood. Cross-incubation of HV plasma with PV neutrophils resulted in reduced ROS production. Insertion of TIPSS was associated with a significant increase in arterial LPS concentrations and deterioration in neutrophil phagocytosis. Number of organ failures and arterial IL-6 concentrations at presentation were associated with increased mortality. The portal circulation has a distinct immunological milieu characterised by a pathological neutrophil phenotype and an anti-inflammatory cytokine profile associated with heightened LPS levels. TIPSS insertion renders this neutrophil functional defect systemic, associated with an increase in arterial LPS and a susceptibility to sepsis.
Highlights
Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised
The central role of inflammation-driven portal hypertension is further demonstrated by the observed decrease in hepatic venous pressure gradient (HVPG) in patients with severe alcoholic hepatitis treated with anti-TNF (Tumour Necrosis Factor) αtherapy[6]
This study provides direct evidence for portal endotoxaemia in refractory variceal haemorrhage and describes the magnitude of bacterial translocation in this context
Summary
Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). A previous study from this group[12] described a significant deterioration in neutrophil ROS production following TIPSS insertion for refractory variceal haemorrhage suggestive of a differential portal and systemic immunological milieu. The primary objective of this study was to characterise the differential nature of the innate immune response and LPS concentrations within the splanchnic vascular beds to determine to what extent they are compartmentalised within the portal circulation and rendered systemic by TIPSS insertion. We sought to determine the associations of pro-inflammatory indices and organ failure with 30, 60 and 90-day mortality in this patient cohort to ascertain the prognostic significance of these factors
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