Immune Function in Patients With Obstructive Jaundice

Study Overview
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Brief Summary
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Patients with obstructive jaundice (OJ) often require surgical, endoscopic or radiological interventions to facilitate biliary drainage and relieve jaundice. However it is known that patients with OJ have increased surgical risks than non-jaundiced patients undergoing the same procedures. Surgery for severe OJ is associated with a significant post-operative mortality (10-15%) and morbidity (30-65%). The commonest complications are related to sepsis but the pathophysiological mechanisms behind this susceptibility to bacterial infection are not clear. Recent work has shown a pivotal role of bile in the maintenance of enterocyte tight junctions and the expression of tight junction-associated proteins which could account for the translocation of enteric bacteria and bacterial products to mesenteric lymph node complexes, the portal circulation and subsequently the liver. Some of these bacterial products, such as endotoxin and quorum sensing signalling molecules (QSSMs), have immunomodulatory properties which may dampen normal immune responses to infection resulting in life-threatening organ dysfunction. Bacterial endotoxin and quorum sensing signalling molecules (QSSMs) represent good candidates for the mediators of this immune suppression and although there is a compelling case for their involvement in the pathogenesis of sepsis, evidence to support their involvement in the aetiology of infection in OJ is currently lacking.

Detailed Description
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Obstructive jaundice (OJ) is a condition where a blockage of flow of bile from the liver leads to the accumulation of bile products in the blood resulting in yellowing and itching of the skin. Common causes of OJ include gallstones and also tumours of the pancreas or bile duct. Relieving this type of jaundice and treating the underlying cause can include endoscopic or surgical procedures. It is known however, that patients with OJ have increased surgical risks than non-jaundiced patients who undergo the same operations. Studies have shown that surgery for severe OJ is associated with a postoperative mortality in the region of 10-15% and morbidity rates of 30-65%. Complications related to bacterial infection are common and patients developing severe infections may require treatment with broad spectrum antibiotics with care in intensive or high dependency units. Although antibiotics have proved invaluable in treating postoperative infections they carry the potential for adverse effects. Antibiotics can suppress normal gut bacteria and allow disease causing bacteria to proliferate, such as Clostridium difficile. This usually manifests as mild-to-moderate diarrhoea but can occasionally cause life-threatening bowel inflammation. The widespread use of antibiotics is also central to the development of bacterial strains with antibiotic resistance. This clinical problem also has economic, political and environmental implications for the National Health Service. Adherence to measures of infection control, education and antibiotic policy can minimise antibiotic resistance; however the limits surrounding such approaches have led to a demand for novel or alternative strategies. It has recently been discovered that bacteria are able to communicate by producing specialised molecules known as quorum sensing signalling molecules (QSSMs). An accumulation of QSSMs in their surrounding environment allow for the bacteria to quantify the size of colonies. At specific colony sizes the concentration of QSSMs reaches a critical threshold leading to the activation of genes that cause an infection. Disruption of quorum sensing has been shown to reduce the severity of infection in animal studies and this has led to the development of inhibitors of quorum sensing as a possible strategy in antibacterial therapy. Previous work conducted at the University of Nottingham has demonstrated that QSSMs also influence the number and function of a specific type of immune cell known as 'antigen presenting cells'. These cells are pivotal in allowing the immune system to recognise components of bacteria as foreign and thereby mount the appropriate response. It was found that large numbers of these types of cells underwent programmed cell death (cell suicide) in the presence of QSSMs compared to when QSSMs were absent. This mirrors the situation in blood sampled from patients with severe infections where there is a greater proportion of cell deaths among antigen presenting cells than other types of immune cell. It is likely that the susceptibility to infectious complications in patients with obstructive jaundice is due to the interplay of various factors. The absence of intestinal bile has implications for the integrity of the bowel wall as a barrier, changes in gut microflora flora and translocation of both bacteria and their products. In addition, it is clear that a form of immune dysfunction occurs, which dampens the normal response following exposure to bacterial products. This immune dysfunction may avert powerful inflammatory cascades resulting in life-threatening multi organ dysfunction but at the expense of conditions that favour bacterial survival. QSSMs represent good candidates for the mediators of this immune dysfunction and although there is a compelling case for their involvement in the pathogenesis of sepsis, definitive evidence to support their role in infective processes in OJ is currently lacking.

Official Title
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Quorum Sensing Signal Molecules (QSSMs) and Immune Dysfunction in Patients Undergoing Endoscopic Retrograde Cholangiopancreatography (ERCP) for Obstructive Jaundice

Conditions
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Obstructive Jaundice, Disease as Reason for ERCP, Immune Dysfunction, Immune Tolerance

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obstructive jaundice Willing to participate and able to give informed consent Alcohol abstinence during study Exclusion Criteria: Acute Physiology and Chronic Health Evaluation (APACHE) II Score ≥8 Severe neutropaenia Smokers/substance abuse Diabetes Mellitus Oral/IV Steroids On regular antibiotics Patients with active cholangitis Patients who have a history liver transplantation or chronic liver disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with obstructive jaundice<br>Patients with obstructive jaundice | |
| Healthy volunteers<br>Healthy volunteers | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in monocyte cytokine responses to endotoxin stimulation | Evaluation of monocyte cytokine responses to endotoxin stimulation at specified time points | Baseline (pre ERCP) and post ERCP days 1, 7, 14 and 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in concentration of systemic quorum sensing signaling molecules | Evaluation of the presence of quorum sensing signalling molecules in the systemic circulation at specified time points | Baseline (pre ERCP) and post ERCP days 1, 7, 14 and 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obstructive jaundice, ERCP, Immune dysfunction, Endotoxin tolerance, Quorum sensing