title: Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
abstract: Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational-analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)--or "neonatal hepatitis" suggesting PFIC--that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or "neonatal hepatitis" suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13-52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11.
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK. alex.knisely@kcl.ac.uk
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Strautnieks
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Meier
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Jane A
authors.initials: JA
authors.lastname: Byrne
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Portmann
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Banu
authors.initials: B
authors.lastname: Bilezikçi
authors.forename: Figen
authors.initials: F
authors.lastname: Ozçay
authors.forename: Aranka
authors.initials: A
authors.lastname: László
authors.forename: László
authors.initials: L
authors.lastname: Tiszlavicz
authors.forename: Lynette
authors.initials: L
authors.lastname: Moore
authors.forename: Jeremy
authors.initials: J
authors.lastname: Raftos
authors.forename: Henrik
authors.initials: H
authors.lastname: Arnell
authors.forename: Björn
authors.initials: B
authors.lastname: Fischler
authors.forename: Antal
authors.initials: A
authors.lastname: Németh
authors.forename: Nikos
authors.initials: N
authors.lastname: Papadogiannakis
authors.forename: Joanna
authors.initials: J
authors.lastname: Cielecka-Kuszyk
authors.forename: Irena
authors.initials: I
authors.lastname: Jankowska
authors.forename: Joanna
authors.initials: J
authors.lastname: Pawłowska
authors.forename: Hector
authors.initials: H
authors.lastname: Melín-Aldana
authors.forename: Karan M
authors.initials: KM
authors.lastname: Emerick
authors.forename: Peter F
authors.initials: PF
authors.lastname: Whitington
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Thompson
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009154:Mutation; D011379:Prognosis
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004273:DNA, Neoplasm