Serum extracellular vesicles (EVs) appear to contain proteins that could serve as potential biomarkers and aid in the early diagnosis and prognosis of cholangiocarcinoma (CCA), according to a recently published study in the Journal of Hepatology.

Although the incidence of CCA has risen significantly in recent decades, most patients have a poor prognosis, mainly because many cases are diagnosed at advanced stages where surgical resection is no longer an option.

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Currently, CCA diagnosis requires advanced imaging techniques as well as histological confirmation. However, in many cases, obtaining histological confirmation can be difficult due to the risk associated with liver biopsy. Thus, noninvasive techniques are needed that have the capability to make an early CCA diagnosis. 

Serum EVs play an important role in cell communication and contain a varied array of biomolecules, which makes them a potential source of biomarkers. Therefore, the authors aimed to compare the serum EV protein profiles of patients with CCA secondary to primary sclerosing cholangitis (PSC) with those of patients with nonPSC-related CCA and healthy controls.

Samples were analyzed using transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting, revealing clear protein profiles when comparing samples from healthy controls with those from patients with PSC-related CCA and nonPSC-related CCA. 

The authors distinguished proteins specific to PSC-CCA and nonPSC CCA, as well as common proteins between the two (pan-CCA-EV biomarkers), using mass spectrometry. Those pan-CCA-EV biomarkers could later be detected in total serum using enzyme-linked immunosorbent assay (ELISA) and immunoblotting, facilitating diagnosis. 

Further analyses using ELISA showed that serum EVs could differentiate between intrahepatic CCA and hepatocellular carcinoma and estimate the prognosis of patients with CCA.

“In conclusion, we here demonstrated that serum EVs contain protein biomarkers for the prediction of CCA development in PSC, as well as for the early tumor detection in individuals with PSC, in individuals without PSC and also for CCAs regardless of disease etiology, which are amenable to be detected using total serum,” the authors concluded.


Lapitz A, Azkargorta M, Milkiewicz P, et al. Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis and prognostication of cholangiocarcinoma. J Hepatol. Published online February 28, 2023. doi:10.1016/j.jhep.2023.02.027