Introduction Bacterial translocation and endotoxaemia are important in the pathogenesis of neutrophil dysfunction in cirrhosis. At present, it is not clear whether systemic endotoxaemia occurs as a consequence of a defect at the gut barrier interface or diminished hepatic function and associated portosystemic shunting.
Aim The aims of this study were (1) to quantify the degree of portal endotoxaemia and the contribution of the liver in the regulation of systemic endotoxin (ET) levels, (2) to determine intestinal production of cytokines and adhesion molecules and (3) to determine whether the portal and hepatic milieu modulates neutrophil function.
Method 12 patients with cirrhosis (54±3.2 yr, Pugh 10.2±1.0, eight male, four female) were studied prior to and 1-h after TIPSS insertion. Blood was sampled from the artery, hepatic vein (HV), portal vein (PV) and its tributaries. PV blood was sampled before insertion of the TIPSS. Endotoxin (ET) (LAL assay), LBP, BPI, IL-6, IL-10, TNFR55, TNFR75, sICAM and sELAM (using ELISA) were measured. Neutrophil respiratory burst and phagocytosis was measured using FACS in neutrophils derived from the HV and PV, prior to and following cross-incubation with PV and HV plasma, respectively.
Results TIPSS insertion resulted in a significant increase in arterial ET levels from 0.08±0.02 to 0.19±0.02 EU/ml (p=0.0001). Mean ET levels in the PV and HV pre-TIPSS insertion were 0.22±0.02 and 0.04±0.02 EU/ml respectively. Transintestinal (TI) and transhepatic (TH) ET fractional extraction (FE) rates were 2.7±0.7 and −0.5±0.06, respectively. HV neutrophil resting burst was significantly increased from 52±5.3 to 78±4.5% after incubation with PV plasma (p<0.0001). Conversely PV neutrophil resting burst was significantly reduced from 85±3.5 to 60±5.3% (p<0.0001) after incubation with HV plasma. Positive intestinal FE rates were observed most markedly with BPI, IL-6 and IL-10. Neutrophil phagocytosis was reduced post-TIPSS from 66±7.5 to 42±6.5% (p=0.0004) and resting burst increased from 62±5.6 to 87±2.8% (p=0.0001).
Conclusion This study provides direct evidence for portal endotoxaemia in cirrhosis. The data suggest that the liver is responsible for compartmentalising ET and associated neutrophil dysfunction within the portal circulation. Intestinal production of IL-6 and IL-10 was also demonstrated. TIPSS insertion disturbs this compartmentalisation and exposes the systemic circulation to portal endotoxaemia. Strategies to diminish portal endotoxaemia or enhance hepatic ET clearance capacity are important therapeutic targets to minimise neutrophil dysfunction in cirrhosis.
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