Secondary Sclerosis Cholangitis Prospective (SSCpro)

• ClinicalTrials.gov Identifier: NCT03566797
• Recruitment Status: Recruiting
• First Posted: June 25, 2018
• Last Update Posted: September 1, 2021
• Sponsor: Medical University of Graz
• Information provided by (Responsible Party): Medical University of Graz

Study Description

Brief Summary:

SC-CIP is increasing in patients after critical illness. Pathogenesis is still largely unclear. Gut microbiome composition, gut permeability, bacterial translocation, inflammation and/or genetic variants contribute to the pathogenesis The aim of this project is to study gut microbiome composition, gut permeability, bacterial translocation, inflammation, bile acid composition and genetic polymorphisms by conducting a prospective cohort study in patients with a high risk to develop SC-CIP.

Condition or disease
Secondary Sclerosis Cholangitis in Critically Ill Patients

Detailed Description:

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 Design

• Study Type: Observational
• Estimated Enrollment: 380 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• 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, 2023
• Estimated Study Completion Date: June 1, 2024

Groups and Cohorts

Group/Cohort
SC-CIP; Patients developing SC-CIP
noSC-CIP; Patients with similar severity of critical illness not developing SC-CIP

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. Gut microbiome composition [ Time Frame: at inclusion ]
   16S rRNA sequencing
2. Stool zonulin [ Time Frame: at inclusion ]
   gut permeability marker, ELISA
3. Stool calprotectin [ Time Frame: at inclusion ]
   gut inflammation marker, ELISA
4. Serum endotoxin [ Time Frame: at inclusion ]
   bacterial translocation marker, cell-based assay
5. Serum lipopolysaccharide binding protein [ Time Frame: at inclusion ]
   bacterial translocation marker, ELISA
6. soluble cluster of differentiation 14 (sCD14) [ Time Frame: at inclusion ]
   bacterial translocation marker, ELISA
7. bile acid transporter polymorphisms [ Time Frame: at inclusion ]
   sequencing of bile acid transporter genes
8. NOD2 polymorphisms [ Time Frame: at inclusion ]
   sequencing of the NOD2 gene

Biospecimen Retention:   Samples With DNA

DNA, serum, plasma, stool urine

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Patients admitted to Intensive Care Units at the University Hospital Graz

Criteria

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the study OR "surrogate consent" by the institutional review board.
• Age above 18 years
• Mechanical ventilation or extracorporeal membrane oxygenation >/= 5 days

Exclusion Criteria:

• Primary or secondary sclerosing cholangitis diagnosed before current ICU admission

Contacts and Locations

Locations

Austria

Medical University Graz; Recruiting

Graz, Austria

Contact: Vanessa Stadlbauer-Köllner, MD 0043 316 385 ext 82282 vanessa.stadlbauer@medunigraz.at

Sponsors and Collaborators

Medical University of Graz

More Information

• Responsible Party: Medical University of Graz
• ClinicalTrials.gov Identifier: NCT03566797
• Other Study ID Numbers: SC_prospective
• First Posted: June 25, 2018
• Last Update Posted: September 1, 2021
• Last Verified: August 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasm Metastasis; Cholangitis; Sclerosis; Critical Illness; Pathologic Processes; Neoplastic Processes; Neoplasms; Disease Attributes; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases