Secondary Sclerosing Cholangitis in Critically Ill Patients (SSC-CIP)

Secondary Sclerosing Cholangitis in Critically Ill Patients (SSC-CIP): A Pilot Study on the Possible Genetic Basis of the Disease

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Secondary Sclerosing Cholangitis

Detailed 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.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8010
    • Department of Internal Medicine, Medical University of Graz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients with no liver disease in the past, who develop secondary sclerosing cholangitis during/after a critical illness

Description

Inclusion Criteria:

• informed consent
• Age above 18 years
• secondary sclerosing cholangitis in critically ill patients

Exclusion Criteria:

• mechanical cholestasis
• primary sclerosing cholangitis
• primary biliary cirrhosis
• Immune globulin G4 associated cholangitis
• toxic cholestasis

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
SSC-CIP; Patients with secondary sclerosing cholangitis in critically ill patients
control; Patients with similar degree of critical illness who do not develop secondary sclerosing cholangitis in critically ill patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
bile acid transporter genes	Rate of genetic variants in biliary transporter genes	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
gut permeability	degree of increase in gut permeability	Day 1
bile acids	changes in bile acid composition	Day 1
bone health	Lumbar spine Z-Scores	Day 1
upper gastrointestinal bleeding episodes	gastrointestinal bleeding on upper gastrointestinal endoscopy	through study completion, an average of 3 years (from date of inclusion through end of observation/death)

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Investigators: Principal Investigator: Vanessa Stadlbauer, MD, Medical University of Graz

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2015
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: July 29, 2015
• First Submitted That Met QC Criteria: September 7, 2015
• First Posted (Estimated): September 9, 2015

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplastic Processes; Biliary Tract Diseases; Bile Duct Diseases; Neoplasm Metastasis; Cholangitis; Cholangitis, Sclerosing
• Other Study ID Numbers: 26-569 ex 13/14