Interlobular bile duct loss in pediatric cholestatic disease is associated with aberrant cytokeratin 7 expression by hepatocytes.

The objective of this study was to determine whether aberrant hepatic expression of cytokeratin 7 (CK7) and/or other putative stem cell markers is seen in pediatric cholestatic diseases. Eighteen liver biopsies and 14 liver explants from pediatric patients with extrahepatic biliary atresia (EHBA), Alagille syndrome (AGS), primary sclerosing cholangitis (PSC), inborn errors of bile acid synthesis, and progressive familial intrahepatic cholestasis (PFIC) were examined along with 5 histologically normal control liver biopsies. Immumohistochemical stains (CK7, CD56, and OV6) were performed on paraffin-embedded tissue. Staining of interlobular bile ducts (ILBD), proliferating bile ductules, and hepatocytes was scored using a semiquantitative scale. There were significant differences in CK7 staining of hepatocytes among the cholestatic diseases (P < 0.006). All cases with AGS showed CK7 hepatocyte staining, while EHBA and PSC had variable hepatocyte staining. Patients with PFIC had prominent CK7 hepatocyte staining, while those with inborn errors of bile acid synthesis had little. Control biopsies showed rare hepatocyte staining. Analysis based on the presence or absence of ILBD revealed significantly more CK7 hepatocyte staining in cases with loss of ILBD (P < 0.001). CD56 staining of hepatocytes was also present more frequently in cases with absent or reduced ILBD. Regardless of underlying disease, loss of ILBD is a major determinant of aberrant expression of CK7 by hepatocytes. Aberrant CK7 expression may reflect a metaplastic change to a "stem cell" phenotype induced by loss of contact with the more distal biliary tree.