Genotype correlates with the natural history of severe bile salt export pump deficiency

JOURNAL OF HEPATOLOGY

卷:73

Article

van Wessel, Daan B. E.¹  Thompson, Richard J.²  Gonzales, Emmanuel^3,5  Jankowska, Irena^5,6  Sokal, Etienne^5,7  Grammatikopoulos, Tassos²  Kadaristiana, Agustina²  Jacquemin, Emmanuel³  Spraul, Anne⁴  Lipinski, Patryk^5,6  Czubkowski, Piotr^5,6  Rock, Nathalie⁷  Shagrani, Mohammad^8,9  Broering, Dieter⁸  Algoufi, Talal⁸  Mazhar, Nejat⁸  Nicastro, Emanuele¹⁰  Kelly, Deirdre A.^5,11  Nebbia, Gabriella¹²  Arnell, Henrik^5,13  Fischler, Bjoern^5,13  Hulscher, Jan B. F.^5,14  Serranti, Daniele¹⁵  Arikan, Cigdem¹⁶  Polat, Esra¹⁷  Debray, Dominique¹⁸  Lacaille, Florence¹⁸  Goncalves, Cristina^5,19  Hierro, Loreto^5,20  Bartolo, Gema Munoz^5,20  Mozer-Glassberg, Yael²¹  Azaz, Amer²²  Brecelj, Jernej^23,24  Dezsofi, Antal²⁵  Calvo, Pier Luigi²⁶  Grabhorn, Enke²⁷  Sturm, Ekkehard^5,28  van der Woerd, Wendy J.²⁹  Kamath, Binita M.^30,31  Wang, Jian-She³²  Li, Liting³²  Durmaz, Oezlem³³  Onal, Zerrin³³  Bunt, Ton M. G.¹  Hansen, Bettina E.^34,35  Verkade, Henkjan J.^1,5 

[1] Univ Groningen, Univ Med Ctr Groningen, Pediat Gastroenterol & Hepatol, Groningen, Netherlands

[2] Kings Coll London, London, England

[3] Univ Paris Sud, Bicetre Hosp, AP HP,Serv Hepatol & Transplantat Hepat Pediat, Paris Saclay,Inserm UMR S 1174, Orsay, France

[4] Univ Paris Sud, Bicetre Hosp, AP HP, Paris Saclay,Inserm UMR S 1174,Serv Biochem, Orsay, France

[5] European Reference Network Hepatol Dis ERN RARE L, Hamburg, Germany

[6] Childrens Mem Hlth Inst, Gastroenterol Hepatol Nutr Disorders & Paediat, Warsaw, Poland

[7] Catholic Univ Louvain, Clin St Luc, Brussels, Belgium

[8] King Faisal Specialist Hosp & Res Ctr, Liver & SB Transplant & Hepatobiliary Pancreat Su, Riyadh, Saudi Arabia

[9] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia

[10] Osped Papa Giovanni XXIII, Pediat Hepatol Gastroenterol & Transplantat, Bergamo, Italy

[11] Birmingham Womens & Childrens Hosp, Liver Unit, Birmingham, W Midlands, England

[12] Fdn Irccs Ca Granda Osped Maggiore Policlin, Serv Epatol & Nutr Pediat, Milan, Italy

[13] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Karolinska Inst, Pediat Digest Dis, Stockholm, Sweden

[14] Univ Med Ctr Groningen, Paediat Surg, Groningen, Netherlands

[15] Meyer Childrens Univ Hosp Florence, Paediat & Liver Unit, Florence, Italy

[16] Koc Univ, Paediat GI & Hepatol Liver Transplantat Ctr, Sch Med, Kuttam Syst Liver Med, Istanbul, Turkey

[17] Hosp Umraniye Training & Res Hosp, Istanbul, Turkey

[18] Hop Necker Enfants Malad, Unite Hepatol Pediat & Transplantat, Paris, France

[19] Coimbra Univ, Hosp Ctr, Coimbra, Portugal

[20] La Paz Univ Hosp, Pediat Liver Serv, Madrid, Spain

[21] Schneider Childrens Med Ctr Israel, Inst Gastroenterol Nutr & Liver Dis, Petah Tiqwa, Israel

[22] Sheikh Khalifa Med City, Abu Dhabi, U Arab Emirates

[23] Univ Ljubljana, Univ Childrens Hosp Ljubljana, Dept Gastroenterol Hepatol & Nutr, Ljubljana, Slovenia

[24] Univ Ljubljana, Fac Med, Dept Paediat, Ljubljana, Slovenia

[25] Semmelweis Univ, Dept Paediat 1, Budapest, Hungary

[26] Azienda Osped Citta Salute & Sci Univ Hosp, Regina Margherita Childrens Hosp, Pediat Gastroenterol Unit, Turin, Italy

[27] Univ Klinikum Hamburg Eppendorf, Klin Kinder & Jugendmed, Hamburg, Germany

[28] Univ Childrens Hosp Tubingen, Tubingen, Germany

[29] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Paediat Gastroenterol Hepatol & Nutr, Utrecht, Netherlands

[30] Hosp Sick Children, Toronto, ON, Canada

[31] Univ Toronto, Toronto, ON, Canada

[32] Fudan Univ, Childrens Hosp, Shanghai, Peoples R China

[33] Istanbul Univ, Istanbul Fac Med, Istanbul, Turkey

[34] Univ Hlth Network, Toronto Ctr Liver Dis, Toronto, ON, Canada

[35] Univ Toronto, IHPME, Toronto, ON, Canada

关键词: Severe BSEP deficiency;    PFIC2;    ABCB11;    Natural history;    Surgical biliary diversion;   

DOI  :  10.1016/j.jhep.2020.02.007

来源: Elsevier

【 摘 要 】

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 mu mol/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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free