Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03566797 |
| Other study ID # |
SC_prospective |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 20, 2018 |
| Est. completion date |
December 2027 |
Study information
| Verified date |
August 2023 |
| Source |
Medical University of Graz |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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.
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.
