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

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.