Abstract
Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn’s disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.
Highlights
Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections
Parameter Age Gender Cause of intensive care unit (ICU) admission Myocardial infarction Cardiothoracic surgery Polytrauma Pneumonia Acute pancreatitis Ruptured abdominal aortic aneurysm Major bleeding after thyroid surgery ICU features ICU days Ventilation days Vasopressors (%) Renal replacement therapy (%) Endoscopic features* Time from ICU admission to endoscopic retrograde cholangiopancreaticography (ERCP), days Intrahepatic strictures and rarefications Extrahepatic stricture Biliary casts Endoscopic interventions** Nasobiliary drainage Infectious complications*** Sepsis Cholangitis Pneumonia Wound infection Abscess of the liver Colitis Clinical course Progression to liver cirrhosis Liver transplantation Death Laboratory values**** ALT (U/l) Alkaline phosphatase (U/l) y-GT (U/l) Bilirubin Creatinine INR CRP model of end-stage liver disease (MELD) score (UNOS modified) Follow-up
We hypothesize that ICU patients carrying Nucleotide-binding oligomerization domain containing 2 (NOD2) variants might be predisposed to infectious complications, and may have an increased risk for the development of sclerosing cholangitis (SSC) in the setting of bile duct ischemia
Summary
Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. We hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn’s disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease. Bile secretion is maintained by hepatocanalicular transport proteins, including the bile salt export pump (ABCB11), the phosphatidylcholine floppase ABCB4, and the phosphatidylserine flippase ATP8B1 Mutations in these genes cause progressive familial intrahepatic cholestasis, and transporter polymorphisms might potentially increase the risk for the development of other cholestatic liver diseases including SC-CIP. Genetic studies have not been carried out in SC-CIP
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
