Secondary Sclerosis Cholangitis Prospective (SSCpro)
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|ClinicalTrials.gov Identifier: NCT03566797|
Recruitment Status : Recruiting
First Posted : June 25, 2018
Last Update Posted : August 8, 2019
|Condition or disease|
|Secondary Sclerosis Cholangitis in Critically Ill Patients|
Secondary sclerosing cholangitis in critically ill patients (SC-CIP) is a rare, quickly progressive, cholestatic liver disease which is observed in patients suffering from a severe illness with the need for long term treatment on an intensive care unit (ICU). Invasive ventilation, polytrauma, hypotension, systemic inflammatory response syndrome, burns, complex operations and severe (co-) morbidities such as obesity have been discussed as risk factors. Patients suffering from SC-CIP do not have any underlying liver disease. Usually, long- term ICU treatment is described as the trigger mechanism for the development of this disease, although also rapid development of SC-CIP after an ICU stay as short as nine days is described in a single case.
The pathogenesis of SC-CIP is not fully understood yet: Ischemic injury of the intrahepatic biliary system, bile cast formation and recurrent biliary infections are discussed as major factors. The disease leads to a progressive destruction of the intra- and extrahepatic biliary tree with the development of strictures resulting in liver fibrosis with in some cases rapid progression to cirrhosis with the need for liver transplantation within months. The gold standard for diagnosis is endoscopic retrograde cholangiopancreaticography (ERCP), although magnetic resonance cholangiopancreatography (MRCP) as non-invasive alternative can lead to the diagnosis in most cases. Prognosis is poor and transplant-free survival has been found to be 40 months in average. Liver transplantation is the only curative treatment, which shows excellent outcome and quality of life comparable to other indication for liver transplantation.
Microbiological analysis of bile from patients with SC-CIP and primary sclerosing cholangitis (PSC) show a significant different microbiological profile in these two cohorts with dominance of drug resistant organisms in the bile of SC-CIP. No data on the gut microbiome in SC-CIP are available so far. Other chronic liver diseases show distinct changes in microbiome composition with potential influence on the inflammation process in these liver diseases (non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, PSC and liver cirrhosis). In general a decrease in diversity, a higher abundance of potentially pathogenic species and a lower abundance of beneficial species has been observed.
Dysbiosis is thought to increase intestinal permeability. Increased gut permeability is most frequently observed in liver cirrhosis but was also found in alcohol-induced injury, NAFLD and hepatitis C-mediated liver injury. With an impaired gut permeability bacteria from the intestinal lumen can be translocated into extraintestinal parts of the body (lymph nodes, blood) and prompt inflammatory responses. Genetic polymorphisms in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene, a known risk factor for bacterial translocation, increases the odds of developing SC-CIP.
It is hypothesized that the gut microbiome composition is altered in SC-CIP and that this is associated with increased gut permeability and markers of inflammation. Reasons for this might lie in gene polymorphisms influencing bacterial translocation or bile acid composition.
The aim of this study is to prospectively assess the incidence of SC-CIP in a cohort of patients at risk for developing SC-CIP (ICU treatment with the need for mechanical ventilation or extracorporeal membrane oxygenation >/= 5 days) and study differences in gut microbiome composition, gut permeability, bacterial translocation, inflammation as well as genetic polymorphisms in patients developing SC-CIP and patients with comparable disease severity who did not develop SC-CIP.
|Study Type :||Observational|
|Estimated Enrollment :||380 participants|
|Official Title:||Secondary Sclerosing Cholangitis in Critically Ill Patients (SC-CIP): A Prospective Cohort Study|
|Actual Study Start Date :||July 20, 2018|
|Estimated Primary Completion Date :||June 1, 2021|
|Estimated Study Completion Date :||June 1, 2022|
Patients developing SC-CIP
Patients with similar severity of critical illness not developing SC-CIP
- Incidence of SC-CIP in patients at risk [ Time Frame: during hospital stay, on average 4 weeks ]risk is defined as need for mechanical ventilation or extracorporeal membrane oxygenation >/= 5 days
- Gut microbiome composition [ Time Frame: at inclusion ]16S rRNA sequencing
- Stool zonulin [ Time Frame: at inclusion ]gut permeability marker, ELISA
- Stool calprotectin [ Time Frame: at inclusion ]gut inflammation marker, ELISA
- Serum endotoxin [ Time Frame: at inclusion ]bacterial translocation marker, cell-based assay
- Serum lipopolysaccharide binding protein [ Time Frame: at inclusion ]bacterial translocation marker, ELISA
- soluble cluster of differentiation 14 (sCD14) [ Time Frame: at inclusion ]bacterial translocation marker, ELISA
- bile acid transporter polymorphisms [ Time Frame: at inclusion ]sequencing of bile acid transporter genes
- NOD2 polymorphisms [ Time Frame: at inclusion ]sequencing of the NOD2 gene
Biospecimen Retention: Samples With DNA
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03566797
|Medical University Graz||Recruiting|
|Contact: Vanessa Stadlbauer-Köllner, MD 0043 316 385 ext 82282 firstname.lastname@example.org|