Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis

Jansen, Plm; Strautnieks, S.S.; Jacquemin, Emmanuel; Hadchouel, Michelle; Sokal, Étienne; Hooiveld, Guido; Koning, JH; Jager-Krikken, Alie de; Kuipers, Folkert; Stellaard, Frans; Bijleveld, Cma; Gouw, Annette; Goor, van Harry; Rj, Thompson; Müller, Michael

doi:10.1016/s0016-5085(99)70287-8

Cited by 414 publications

(298 citation statements)

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“…For 6 families immunohistochemical protocols used were as described 2 . BSEP marking was classified as normal, not detected or abnormal, where abnormal refers to either reduced intensity or focal absence.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Bile salt export pump (BSEP) deficiency is caused by mutations in ABCB11 1,2 . The severity of BSEP deficiency varies from progressive early-onset 1 to remitting and late-onset phenotypes [3][4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

“…In 5 families only parental DNA was analysed. We have previously reported single mutations in 8 families 1,2,32 ; the second mutant allele is now identified in each. Clinical observations in 21 families have been reported previously 28,29,33 .…”

mentioning

confidence: 96%

“…Where possible, BSEP immunohistochemical analysis (30%) 2,28,29 and/or microsatellite-based haplotype analysis 13,30,31 were used. The resultant subgroup was analysed for ABCB11 mutations.…”

mentioning

confidence: 99%

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Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

et al. 2008

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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. Abbreviations:ABC, ATP-binding cassette; AFP, α-fetoprotein; BSEP, bile salt export pump; CpG, cytosine-guanine; CC, cholangiocarcinoma; FIC1, familial intrahepatic cholestasis 1; γ-GT, γ-glutamyl transferase; HCC, hepatocellular carcinoma; IC, intracellular loop; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NBF, nucleotide-binding fold; OLT, orthotopic liver transplantation; PEBD, partial external biliary diversion; PFIC, progressive familial intrahepatic cholestasis; PCR, polymerase chain reaction; RE, restriction endonuclease; SSCP, single-strand conformation polymorphism; TM, transmembrane domain; UDCA, ursodeoxycholic acid Acknowledgements We thank the families and the Children's Liver Disease Foundation for support and encouragement, and those who referred families for analysis, including Drs U Baumann, W Berquist, M de Vree, K Emerick, G Ferry, M Finegold, W Hardikar, S Horslen, R Houwen, R Jaffe, L Klomp, F Lacaille, K Mann, P McKiernan, H Sharp, R Sokol, E Sturm, L Szönyi, J Taminou, and J Watkins. We also thank Dr R Garcia-Kennedy for access...

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Section: Immunohistochemistrymentioning

confidence: 99%