Hepatitis B virus (HBV) infection may cause the development of intrahepatic cholangiocarcinoma (iCCA) from hepatocytes in some patients, according to a study published in the journal Hepatology International.

Immunofluorescence and immunohistochemistry results found that HBV does not infect normal bile duct epithelial cells, in contrast to the generally accepted theory that iCCA is derived from these cells.

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In the study, hepatitis B surface antigens (HBsAg) were only detected in intrahepatic CCA tissues and organoids collected from HBV-infected patients with iCCA. DNA from HBV was also only detected in iCCA samples from HBV-infected patients with intrahepatic CCA. 

Hemotoxylin and eosin staining also showed a difference in the distributions of tumor cell growth between patients with and without HBV. Patients without HBV had tumor cell growth that was vascular-shaped and grew along the bile duct while HBV-positive patients had a relatively scattered distribution without a vascular shape. The staining differences suggest that the 2 types of iCCA may have different origins.

This information, combined with previous evidence that mature hepatocytes retain phenotypic plasticity and can differentiate into bile duct cells, provides support for the theory that HBV infection could lead to the conversion of hepatocytes into intrahepatic CCA cells.

“These results give us a strong proof that HBV can lead to the transdifferentiation of hepatocytes into ICC cells. There is a causal relationship between HBV infection and ICC formation,” the authors wrote.

Roughly 40% (n=74) of the 182 patients included in the study were positive for HBsAg. This subset of patients had significantly shorter disease-free survival (DFS) than patients who were negative for HBsAg (P =0.0137; median 4 months versus 7 months, respectively). The overall survival (OS) also tended to be lower in the HBsAg-positive patients, although the difference did not reach significance (P =0.1121).

No difference was observed between the HBsAg-positive and negative groups in regard to age, sex, liver cirrhosis, and other clinical baseline data. No differences in pathological characteristics were observed between the groups either. The HBsAg-positive patients did have significantly higher neutrophil levels, however (5.586 ± 2.167 × 109/L versus 4.680 ± 1.843 × 109/L; P =0.005).


Song Z, Lin S, Wu X, et al. Hepatitis B virus-related intrahepatic cholangiocarcinoma originates from hepatocytes. Hepatol Int. Published online June 27, 2023. doi:10.1007/s12072-023-10556-3