1. Genotype correlates with the natural history of severe bile salt export pump deficiency.
- Author
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van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly DA, Nebbia G, Arnell H, Björn Fischler, Hulscher JBF, Serranti D, Arikan C, Polat E, Debray D, Lacaille F, Goncalves C, Hierro L, Muñoz Bartolo G, Mozer-Glassberg Y, Azaz A, Brecelj J, Dezsőfi A, Calvo PL, Grabhorn E, Sturm E, van der Woerd WJ, Kamath BM, Wang JS, Li L, Durmaz Ö, Onal Z, Bunt TMG, Hansen BE, and Verkade HJ
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 11 genetics, Adult, Biliary Tract Surgical Procedures statistics & numerical data, Child, Preschool, Female, Genetic Testing methods, Humans, Liver Neoplasms diagnosis, Liver Neoplasms prevention & control, Male, Mutation, Predictive Value of Tests, Prognosis, Retrospective Studies, Severity of Illness Index, Survival Analysis, Time, ATP Binding Cassette Transporter, Subfamily B, Member 11 deficiency, Bile Acids and Salts blood, Bile Acids and Salts metabolism, Biliary Tract Surgical Procedures methods, Carcinoma, Hepatocellular diagnosis, Carcinoma, Hepatocellular prevention & control, Cholestasis, Intrahepatic diagnosis, Cholestasis, Intrahepatic genetics, Cholestasis, Intrahepatic physiopathology, Cholestasis, Intrahepatic surgery
- Abstract
Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date., Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category., Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001)., Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS., Lay Summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease., Competing Interests: Conflicts of interest Daan B.E. van Wessel: [nothing to disclose], Richard J. Thompson [consultancy for Shire, Albireo, Mirum, Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics], Emmanuel M. Gonzales [Consultant for CTRS and Mirum Pharmaceuticals], Irena Jankowska [nothing to disclose], Tassos Grammatikopoulos [nothing to disclose], Agustina Kadaristiana [nothing to disclose], Patryk Lipiński [nothing to disclose], Piotr Czubkowski [nothing to disclose], Nathalie Rock [nothing to disclose] Emmanuel Jacquemin [nothing to disclose], Anne Spraul [nothing to disclose], Etienne M. Sokal [founder and CSMO of Promethera Biosciences], Mohammad Shagrani [nothing to disclose], Dieter Broering [nothing to disclose], Talal Algoufi [nothing to disclose], Nejat Mazhar [nothing to disclose], Emanuele Nicastro [nothing to disclose] Deirdre Kelly [Consultant for Albireo], Gabriela Nebbia [nothing to disclose], Henrik Arnell [consultant for Albireo and Mirum Pharmaceuticals], Björn Fischler [has attended one advisory board meeting with Albireo in 2016], Jan Hulscher [nothing to disclose], Daniele Serranti [nothing to disclose], Cigdem Arikan [nothing to disclose], Esra Polat [nothing to disclose], Dominique Debray [consultant for Alexion pharmaceuticals], Florence Lacaille [nothing to disclose], Cristina Goncalves [nothing to disclose], Loreto Hierro [nothing to disclose], Gema Muñoz Bartolo [nothing to disclose], Yael Mozer-Glassberg [nothing to disclose], Amer Azaz [nothing to disclose], Jernej Brecelj [nothing to disclose], Antal Dezsőfi [nothing to disclose], Pier Luigi Calvo [nothing to disclose], Enke Grabhorn [nothing to disclose], Ekkehard Sturm [nothing to disclose] Wendy van der Woerd [nothing to disclose], Binita Kamath [consultant for Mirum Pharmaceuticals, Shire and DCI], Jian-She Wang [nothing to disclose], Liting Li [nothing to disclose], Özlem Durmaz [nothing to disclose], Zerrin Onal [nothing to disclose], Ton Bunt [nothing to disclose], Bettina Hansen [consultant for Mirum Pharmaceuticals, Albireo AB, Chemomab, Calliditas, Intercept, Cyma Bay, unrestricted grants from Cyma bay, Intercept, Mirum and Albireo], Henkjan J. Verkade [Consultant for Danone/Nutricia Research, Ausnutria BV, Albireo AB, GMP+Orphan, Mirum Pharmaceuticals, Intercept and Vivet]. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. All rights reserved.)
- Published
- 2020
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