Epigenetic biomarkers for cholangiocarcinoma (CCA) can be detected in bile samples of patients with primary sclerosing cholangitis (PSC). European researchers found that droplet digital polymerase chain reaction (ddPCR) could accurately detect promotor methylation of the CDO1, CNRIP1, SEPT9, and VIM genes linked to CCA.

“CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis,” the authors wrote.

In the study, published in Hepatology, 344 bile samples were analyzed from 273 patients with either sporadic or PSC-associated CCA, PSC, or other nonmalignant liver diseases. Analysis of the area under the receiver operating characteristics (ROC) curve revealed high areas for all 4 biomarkers (ranging from 0.77 to 0.87) in the detection of CCA among patients with PSC.

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When the samples were limited to just PSC patients who were diagnosed with CCA within 12 months after bile collection, the sensitivity increased to 100% with a specificity of 90%. All patients in this group were positive for the biomarkers, had CCA ranging from early- to late-stage, and had different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels, highlighting the usefulness of this new diagnostic technique.

The ROC specificity could be increased higher to 93% if only PSC patients with a follow-up time of more than 36 months were used as controls. The specificity stayed high (83%) if the control group was reduced to only the 23 PSC patients with dysplasia.

“The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC,” the authors concluded.

Patients with PSC are at an increased risk of developing CCA, and CCA is usually not detected in these patients until it has reached the advanced stages of malignancy. New diagnostic tools such as ddPCR that can detect CCA in PSC patients early and accurately can help to meet this clinical need.


Vedeld HM, Grimsrud MM, Andresen K, et al. Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology. Published online August 26, 2021. doi:10.1002/hep.32125