Features of hepatocellular and biliary senescence in pediatric autoimmune and primary sclerosing cholangitis
DOI:
https://doi.org/10.15574/SP.2025.5(149).2026Keywords:
pediatric autoimmune liver disease, primary sclerosing cholangitis, autoimmune sclerosing cholangitis, hepatocellular senescence, biliary senescence, cholangiocytes, p16^INK4a, p21^WAF1/Cip1Abstract
Cellular senescence is considered one of the key mechanisms driving fibrosis progression in immune-mediated cholangiopathies. The markers p16^INK4a and p21^WAF1/Cip1 reflect the senescent phenotype; however, data on their expression in children with autoimmune sclerosing cholangitis (ASC) and primary sclerosing cholangitis (PSC) are lacking.
Aim - to evaluate the expression of p16^INK4a and p21^WAF1/Cip1 in liver biopsies of children with ASC and PSC and to determine their pathogenetic and diagnostic significance.
Materials and methods. Twenty-seven liver biopsies from children aged 4-18 years (18 with ASC, 9 with PSC) were analyzed. Morphological changes and fibrosis stage were assessed according to the Nakanuma classification. Immunohistochemistry for p16^INK4a and p21^WAF1/Cip1 was performed in cholangiocytes and hepatocytes to detect cellular senescence.
Results. p16^INK4a expression in cholangiocytes was frequent in both ASC (77.8%) and PSC (88.9%). Senescent cholangiocytes with p16^INK4a expression were already present at early disease stages, confirming the early development of the biliary senescence phenotype. p21^WAF1/Cip1 expression in cholangiocytes was rare (16.7% and 11.1%, respectively). In hepatocytes, expression of p16^INK4a (83.3% vs 22.2%) and p21^WAF1/Cip1 (66.7% vs 11.1%) was significantly more frequent in ASC than in PSC.
Conclusions. In most children with ASC and PSC, p16^INK4a-positive cholangiocytes were detected, confirming the biliary senescence phenotype as a key pathogenetic feature. ASC was additionally characterized by the coexistence of hepatocellular and biliary senescence phenotypes, which may contribute to faster fibrosis progression. Expression of p16^INK4a and p21^WAF1/Cip1 in hepatocytes and cholangiocytes may serve as a potential morphological biomarker of severe disease course and as a promising target for novel therapeutic strategies.
The study complied with the principles of the Declaration of Helsinki and was approved by the institutional ethics committee. Informed consent was obtained from the patients prior to participation.
The authors declare no conflict of interest.
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