Biliary atresia (BA) is characterized by the occlusion of extrahepatic bile ducts due to sclerosing inflammation. Necroptosis is a recently characterized form of programmed cell death but has not been examined in BA. We, therefore, explored the potential involvement of necroptosis in the pathogenesis of BA by evaluating the correlation between necroptosis-related factors and clinicopathological features of BA patients. We studied liver biopsy specimens of 59 patients with BA and 30 with congenital biliary dilatation (CBD). We also evaluated 14 surgical BA cases, who eventually underwent liver transplantation and 9 normal liver from neonates and infants obtained at autopsy. Necroptosis-related factors including toll-like receptor 3 (TLR3), receptor-interacting protein kinase1 (RIP1), receptor-interacting protein kinase3 (RIP3), mixed lineage kinase domain-like (MLKL), and phosphorylated mixed lineage kinase domain-like (pMLKL) in these liver specimens were immunolocalized. TLR3, RIP1, MLKL in the intrahepatic cholangiocytes was significantly higher in BA than CBD. pMLKL immunoreactivity was significantly greater at an earlier age of BA patients. The native liver survival period was significantly prolonged in the high RIP3 group. The low RIP3 status could serve as an adverse clinical prognostic factor for the native liver survival among the necroptosis-related factors examined in this study.
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Congenital biliary dilation
Receptor-interacting protein kinase1
Receptor-interacting protein kinase3
Mixed lineage kinase domain-like
Phosphorylated mixed lineage kinase domain-like
Danger-associated molecular patterns
TIR domain-containing adapter protein interferon-β
- H score:
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We appreciate the skillful technical assistance of Ms. Yayoi Aoyama (Department of Pathology, Tohoku University Hospital, Sendai, Japan). We would like to thank Enago (www.enago.jp) for the English language review.
Conflicts of interest
The authors have no conflicts of interest.
Ethics approval and consent to participate
The study protocol was approved by the Ethics Committee of the Tohoku University School of Medicine (Accession No. 2019-1-470). Written informed consent was obtained from all patients prior to surgery.
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Supplementary file1 (DOCX 2164 KB) The receiver operating characteristics (ROC) curve against the native liver survival of the H-score and LI
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Hashimoto, M., Fujishima, F., Lomphithak, T. et al. Necroptosis in biliary atresia of the liver. Med Mol Morphol 54, 305–315 (2021). https://doi.org/10.1007/s00795-021-00289-3
- Biliary atresia
- Congenital biliary dilation
- Phosphorylated mixed lineage kinase domain-like
- Cell death