Quick Search:

uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive

Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-5485

Strautnieks, S S; Byrne, J A; Pawlikowska, L; Cebecauerova, D; Rayner, A; Dutton, L; Meier, Y; Antoniou, A; Stieger, B; Arnell, H; Ozcay, F; Al-Hussaini, H F; Bassas, A F; Verkade, H J; Fischler, B; Nemeth, A; Kotalova, R; Shneider, B L; Cielecka-Kuszyk, J; McClean, P; Whitington, P F; Sokal, E; Jirsa, M; Wali, S H; Jankowska, I; Pawlowska, J; Mieli-Vergani, G; Knisely, A S; Buli, L N; Thompson, R J (2008). Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology, 134(4):1203-1214.

[img]
Preview
Accepted Version (Creative Commons: Attribution 3.0 Unported (cc-by))
PDF
1MB

View at publisher

Abstract

BACKGROUND & AIMS: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

Citations

110 citations in Web of Science®
133 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

150 downloads since deposited on 14 Nov 2008
29 downloads since 12 months

Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
DDC:610 Medicine & health
Language:English
Date:April 2008
Deposited On:14 Nov 2008 09:54
Last Modified:23 Nov 2012 16:31
Publisher:Elsevier
ISSN:0016-5085
Publisher DOI:doi:10.1053/j.gastro.2008.01.038
PubMed ID:18395098

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page