Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.
Gastroenterology
; 134(4): 1203-14, 2008 Apr.
Article
en En
| MEDLINE
| ID: mdl-18395098
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
ADN de Neoplasias
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Familia
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Colestasis Intrahepática
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Transportadoras de Casetes de Unión a ATP
Tipo de estudio:
Etiology_studies
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Incidence_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Female
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Humans
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Male
País/Región como asunto:
America do norte
Idioma:
En
Revista:
Gastroenterology
Año:
2008
Tipo del documento:
Article
País de afiliación:
Reino Unido