Interlobular Bile Duct Loss in Pediatric Cholestatic Disease is Associated with Aberrant Cytokeratin 7 Expression by Hepatocytes

Abstract

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.

The use of Yes-associated protein expression in the diagnosis of persistent neonatal cholestatic liver disease

“…We also saw increased nuclear YAP expression in periportal hepatocytes. Periportal hepatocytes are candidates for a putative reserve pool of pleuripotent precursors for biliary epithelium/proliferating bile ductules 32 . This pool is likely to be activated in context of adaptive/reparative change such as BA, and manipulation of the process, perhaps via YAP, may hold future therapeutic potential.…”

Hepatocyte Cytokeratin 7 Expression in Chronic Allograft Rejection

“…17,18 In addition, several pediatric cholestatic conditions including Alagille syndrome (ductopenic), progressive familial intrahepatic cholestasis (often ductopenic), extrahepatic biliary atresia and PSC (variably ductopenic), and inborn errors of bile acid synthesis (not ductopenic) have been shown to demonstrate aberrant CK7 expression, with expression most prominent in ductopenic cases. 15,19 This study demonstrates frequent aberrant expression of CK7 by hepatocytes in CR across a spectrum of native diseases. The relative specificity of staining irrespective of age, sex, and posttransplantation interval links the aberrant staining to CR (ie, aberrant staining is not merely a transplant-related phenomenon).…”

“…[12][13][14] Aberrant expression of CK7 by hepatocytes has been noted in several conditions characterized by ductopenia and/or cholestasis, including primary biliary cirrhosis (PBC), Alagille syndrome, and progressive familial intrahepatic cholestasis. [15][16][17][18][19] This expression is believed to reflect a metaplastic change in the setting of cholestasis and loss of hepatocyte contact with the biliary tree. While a previous keratin immunohistochemical study in hepatic allograft rejection examined the usefulness of keratin AE1 in counting bile ducts, to our knowledge, the expression of CK7 by hepatocytes in CR, another ductopenic, cholestatic condition, has not been systematically studied.…”

Liver Pathology in Infantile Mitochondrial DNA Depletion Syndrome

“…The aberrant expression under reactive conditions suggests a reversion to the pluripotent hepatic progenitor cell. This aberrant hepatocyte CK7 expression has been documented in a variety of disorders affecting the liver, including extrahepatic biliary obstruction, infection, progressive familial intrahepatic cholestasis, inborn errors of bile acid synthesis, bile duct paucity, chronic liver graft rejection, and primary biliary cirrhosis [20][21][22]. In this study, aberrant CK7 expression in hepatocytes was noted in the livers of patient 1 at 2 months (autopsy), patient 2 at 2 months and 9 months (autopsy), and patient 3 at 2 months.…”

“…Syndromic bile duct paucity in children has classically been associated with Alagille [23] and Williams [24,25] syndromes; however, numerous nonsyndromic causes have also been identified. Nonsyndromic causes of bile duct paucity include, but are not limited to, progressive familial intrahepatic cholestasis, infection, chi-onic allograft rejection, graft-versus-host disease, and biliary atresia [20,22,25,26]. It should be noted that few portal tracts were available for review due to the small size of the needle core biopsy from patient 3.…”