title: Identification of Bile Duct Paucity in Alagille Syndrome: Using CK7 and EMA Immunohistochemistry as a Reliable Panel for Accurate Diagnosis.
abstract: Bile duct paucity is the absence or marked reduction in the number of interlobular bile ducts (ILBD) within portal tracts. Its syndromic variant, Alagille syndrome (ALGS), is a multisystem disorder with effects on the liver, cardiovascular system, skeleton, face, and eyes. It is inherited as an autosomal dominant trait due to defects in NOTCH signaling pathway. ALGS is characterized by vanishing ILBD with subsequent chronic obstructive cholestasis in approximately 89% of cases. Cholestasis stimulates formation of new bile ductules through a process of neoductular reaction, making it difficult to evaluate the presence or absence of ILBD. Therefore, finding a method to differentiate clearly between ILBD and the ductular proliferation is essential for accurate diagnosis. A database search identified 28 patients with confirmed diagnosis of ALGS between 1992 and 2014. Additionally, 7 controls were used. A panel of two immunostains, cytokeratin 7 (CK7) and epithelial membrane antigen (EMA), was performed. CK7 highlighted the bile duct epithelium of ILBD and ductular proliferation, while EMA stained only the brush border of ILBD. In our ALGS group, the ratio of EMA-positive ILBD to identified portal tracts was 12.6% (range, 0%-41%). However, this same ratio was 95.0% (range, 90%-100%) among control cases (P < 0.001). We propose a panel of two immunostains, CK7 and EMA, to differentiate ILBD from ductular proliferation in patients with cholestasis. With this panel, identification of bile duct paucity can be achieved. Additional studies, including molecular confirmation and clinical correlation, would provide a definitive diagnosis of ALGS.
authors.affiliation: 1 Department of Pediatric Pathology, Emory University School of Medicine, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA, 30322-1101, USA.
authors.forename: Haley K
authors.initials: HK
authors.lastname: Herman
authors.affiliation: 1 Department of Pediatric Pathology, Emory University School of Medicine, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA, 30322-1101, USA.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Abramowsky
authors.affiliation: 1 Department of Pediatric Pathology, Emory University School of Medicine, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA, 30322-1101, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Caltharp
authors.affiliation: 1 Department of Pediatric Pathology, Emory University School of Medicine, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA, 30322-1101, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Metry
authors.affiliation: 1 Department of Pediatric Pathology, Emory University School of Medicine, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA, 30322-1101, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Cundiff
authors.affiliation: 2 Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA, 30322-1101, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Romero
authors.affiliation: 2 Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA, 30322-1101, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Gillespie
authors.affiliation: 1 Department of Pediatric Pathology, Emory University School of Medicine, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA, 30322-1101, USA.
authors.forename: Bahig M
authors.initials: BM
authors.lastname: Shehata
mesh_terms: D000293:Adolescent; D016738:Alagille Syndrome / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000002:abnormalities / Q000737:chemistry*; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000378:metabolism / Q000473:pathology; D016208:Databases, Factual; D003937:Diagnosis, Differential; D004847:Epithelial Cells / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D053552:Keratin-7 / Q000032:analysis*; D008297:Male; D018396:Mucin-1 / Q000032:analysis*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; C507497:KRT7 protein, human; D053552:Keratin-7; C060192:MUC1 protein, human; D018396:Mucin-1
keywords: Alagille syndrome; CK7; EMA; bile duct paucity