Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
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.
Knisely
A S
AS
Institute of Liver Studies, King's College Hospital, London, UK. alex.knisely@kcl.ac.uk
Strautnieks
Sandra S
SS
Meier
Yvonne
Y
Stieger
Bruno
B
Byrne
Jane A
JA
Portmann
Bernard C
BC
Bull
Laura N
LN
Pawlikowska
Ludmila
L
Bilezikçi
Banu
B
Ozçay
Figen
F
László
Aranka
A
Tiszlavicz
László
L
Moore
Lynette
L
Raftos
Jeremy
J
Arnell
Henrik
H
Fischler
Björn
B
Németh
Antal
A
Papadogiannakis
Nikos
N
Cielecka-Kuszyk
Joanna
J
Jankowska
Irena
I
Pawłowska
Joanna
J
Melín-Aldana
Hector
H
Emerick
Karan M
KM
Whitington
Peter F
PF
Mieli-Vergani
Giorgina
G
Thompson
Richard J
RJ
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
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004273:DNA, Neoplasm