Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02545309 |
| Other study ID # |
26-569 ex 13/14 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 21, 2015 |
| Est. completion date |
January 2026 |
Study information
| Verified date |
March 2024 |
| Source |
Medical University of Graz |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
SSC-CIP is increasing in patients after critical illness. Pathogenesis is still largely
unclear. The investigators hypothesize that genetic variants of biliary transporter genes are
frequent in patients with SSC-CIP. In approximately 140 patients and controls the rate of
genetic variants in biliary transporter genes, gut permeability and gut microbiome as well as
bone health will be studied.
Description:
SSC is a process of fibroobliteration of intra- and extrahepatic bile ducts due to the fact
that the bile ducts receive their blood supply exclusively through the hepatic artery and
therefore are more prone to ischemia than other parts of the liver. Several factors, such as
intraductal stone disease, surgical or blunt abdominal trauma, intra-arterial chemotherapy,
and recurrent pancreatitis can lead to SSC. A relatively new entity is SSC occurring after
critical illness (SSC-CIP). So far 97 cases have been reported in literature. All these
patients recovered from critical illness, where they received ventilation with positive
end-expiratory pressure and vasopressors. A rapid increase in cholestasis and irregular
strictures of the intrahepatic bile ducts were observed within weeks after the onset of the
critical illness. On endoscopic retrograde cholangiography typically biliary casts can be
found. Patients with SSC-CIP furthermore have a distinct microbial profile in bile with
frequent detection of difficult to treat organisms. To date, only liver transplantation (in
selected patients) provides a curative treatment. Prognosis of SSC-CIP is poor with a
mortality rate of 36% after 18 months and the need for liver transplantation in 23%.
To date not much is known about potential risk factors for the development of SSC-CIP. Since
not all patients receiving high pressure ventilation and vasopressors develop SSC-CIP, it can
be hypothesized that other, patient-specific, factors may play a role in the development of
SSC-CIP. Since it is a disease of bile ducts, genetic variants in biliary transporters might
play a role. Genetic variants of bile acid transporters, such as BSEP (Bile salt export pump)
or MDR3 (multidrug resistance protein 3) have been described as inducers and modifiers of
liver disease, such as intrahepatic cholestasis of pregnancy, drug induced cholestasis or
treatment success of hepatitis C.
Another potentially important but underreported problem in SSC-CIP is impaired bone health.
It is well known, that chronic liver disease, often results in metabolic bone disease:
reduced bone mineral density is found in up to 60% and atraumatic fractures in 20% of
patients. Specifically chronic cholestatic liver disease is associated with increased
fracture risk. This can result in spontaneous or low-impact fractures in such patients,
adversely affecting quality of life and survival.
However, no data on bone mineral density and bone mineral metabolism in SSC-CIP are available
yet.
The investigators therefore aim to analyse a panel of potentially relevant genes in bile acid
transport and bile composition in patients with SSC-CIP to identify potential genetic
variants associated with the development of SSC-CIP. Serum markers of bone mineral metabolism
and osteodensitometry data will be obtained too. Furthermore, since the microbial profile in
bile of SSC-CIP patients shows a predominance of difficult to treat pathogens, changes in gut
microbiome composition and/or gut permeability with consecutive translocation of bacterial
products into the circulation might be of relevance. From a clinical point of view mortality
in SSC-CIP is often related to multi-organ failure. Since infections play an important role
in the development of multi-organ failure, the investigators also hypothesize, that SSC-CIP
leads to an impairment of innate immune responses.
