Immune dysfunction in patients with obstructive jaundice before and after endoscopic retrograde cholangiopancreatography

Abstract

This prospective observational study investigated monocyte cytokine responses to lipopolysaccharide (LPS) in patients with obstructive jaundice (OJ) before and after endoscopic biliary drainage. Dendritic cell (DC) subsets and their expression of co-stimulatory molecules were also studied. Forty patients with OJ and ten non-jaundiced patients with normal gastroscopy findings were recruited. Ten healthy volunteers provided control blood samples for immunological assays. Patients with OJ had blood and duodenal mucosa sampled at the time of endoscopic retrograde cholangiopancreatography (ERCP) and further blood sampled during the recovery phase. Monocyte cytokine responses to LPS, DC subsets and co-stimulatory molecule expression were compared with controls. Duodenal morphology and occludin expression were also assessed. Monocytes obtained before ERCP from jaundiced patients demonstrated reduced cytokine responses to endotoxin compared with controls (IL-1β: 2678 compared with 4631 pg/ml, P=0.04 and IL-6: 3442 compared with 6157 pg/ml, P=0.002). Monocytes from patients with malignancy had poorer responses to endotoxin than from those with benign OJ (IL-1β: 2025 compared with 3332 pg/ml, P=0.001). After ERCP, the secretion of inflammatory cytokines by monocytes obtained from jaundiced patients increased (IL-1β: 2150 compared with 2520 pg/ml, P=0.03 and IL-6: 2488 compared with 3250 pg/ml, P=0.01). Occludin expression (85 compared with 95%, P=0.004) and mean duodenal villus height (334 compared with 404 μm, P=0.03) were lower in jaundiced patients. Before biliary drainage, patients with OJ had a higher percentage of myeloid dendritic cells (mDCs) and greater mDC expression of CD40 (P=0.04) and CD86 (P=0.04). Monocytes from patients with OJ had lower proinflammatory cytokine secretion in response to LPS, an effect reversed following biliary drainage.

Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

“…Under cholestatic conditions, when bile acid levels are highly increased, patients suffer from an impaired immune cell function associated with increased morbidity and mortality 7 , 10 – 12 . To determine the influence of bile acids on immune induction in LPS-stimulated human macrophages, a microarray-based transcriptome analysis was performed.…”

“…2 ) 55 , 56 . The effects of bile acids could be associated with the described reduced pathogen clearance in BDL mice and cholestatic patients 9 – 12 .…”

“…Under cholestatic conditions, patients exhibit higher morbidity and mortality rates as a consequence of bacterial and viral infection 9 – 12 . Previous studies have shown that bile acids affect the pro-inflammatory cytokine expression in human blood derived macrophages and Kupffer cells, while the expression of the anti-inflammatory mediator IL-10 is constant 7 , 19 .…”

“…This impairment is accompanied by reduced pro-inflammatory responses of immune cells, such as monocytes, macrophages, NK cells and T cells 6 – 8 , associated with higher morbidity and mortality rates in cholestatic patients. Moreover, these patients exhibit higher susceptibility to bacterial and viral infections compared to healthy donors 9 – 12 .…”

Does Pre-operative Biliary Drainage Influence Long-Term Survival in Patients With Obstructive Jaundice With Resectable Pancreatic Head Cancer?

“…This result may be explained by the fact that tumor aggressiveness in patients with high TB levels was stronger than patients with low TB levels. Another possible explanation for this is that severe obstructive jaundice may relate to immunosuppression, causing micrometastasis formation of tumors before intervention ( 21 – 23 ). Further experimental studies are needed to identify the relationship between the TB level and nature of pancreatic cancer.…”