Daan B E van Wessel1, Richard J Thompson2, Emmanuel Gonzales3, Irena Jankowska4, Etienne Sokal5, Tassos Grammatikopoulos2, Agustina Kadaristiana2, Emmanuel Jacquemin6, Anne Spraul7, Patryk Lipiński4, Piotr Czubkowski4, Nathalie Rock8, Mohammad Shagrani9, Dieter Broering10, Talal Algoufi10, Nejat Mazhar10, Emanuele Nicastro11, Deirdre A Kelly12, Gabriella Nebbia13, Henrik Arnell14, Jan B F Hulscher15, Daniele Serranti16, Cigdem Arikan17, Esra Polat18, Dominique Debray19, Florence Lacaille19, Cristina Goncalves20, Loreto Hierro21, Gema Muñoz Bartolo21, Yael Mozer-Glassberg22, Amer Azaz23, Jernej Brecelj24, Antal Dezsőfi25, Pier Luigi Calvo26, Enke Grabhorn27, Ekkehard Sturm28, Wendy J van der Woerd29, Binita M Kamath30, Jian-She Wang31, Liting Li31, Özlem Durmaz32, Zerrin Onal32, Ton M G Bunt1, Bettina E Hansen33, Henkjan J Verkade34. 1. Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands. 2. King's College London, United Kingdom. 3. Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER). 4. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland. 5. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Université; Catholique de Louvain, Cliniques St Luc, Brussels, Belgium. 6. Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France. 7. Service de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France. 8. Université; Catholique de Louvain, Cliniques St Luc, Brussels, Belgium. 9. Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; Alfaisal University, College of Medicine, Riyadh, Saudi Arabia. 10. Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. 11. Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy. 12. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom. 13. Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. 14. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 15. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Paediatric Surgery, University Medical Centre Groningen, Groningen, The Netherlands. 16. Paediatric and Liver Unit, Meyer Children's University Hospital of Florence. 17. Koc University School of Medicine, Paediatric GI and Hepatology Liver Transplantation Centre, Kuttam System in Liver Medicine, Istanbul, Turkey. 18. Hospital Umraniye Training and Research Hospital, Istanbul, Turkey. 19. Unité; d'hépatologie Pédiatrique et Transplantation, Hôpital Necker, Paris, France. 20. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Coimbra University Hospital Center, Coimbra, Portugal. 21. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Liver Service, La Paz University Hospital, Madrid, Spain. 22. Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Centre of Israel. 23. Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates. 24. Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Paediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 25. 1st Department of Paediatrics, Semmelweis University, Budapest, Hungary. 26. Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Torino, Italy. 27. Klinik Für Kinder- Und Jugendmedizin, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany. 28. European Reference Network on Hepatological Diseases (ERN RARE-LIVER); University Children's Hospital Tübingen, Tübingen, Germany. 29. Wilhelmina Children's Hospital, University Medical Centre Utrecht, Paediatric Gastroenterology, Hepatology and Nutrition, Utrecht, The Netherlands. 30. The Hospital for Sick Children and the University of Toronto, Toronto, Canada. 31. Children's Hospital of Fudan University, Shanghai, China. 32. Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey. 33. Toronto Centre for Liver Disease, University Health Network, Canada; IHPME, University of Toronto, Canada. 34. Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Electronic address: h.j.verkade@umcg.nl.
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.
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.
Authors: Kathleen M Loomes; Robert H Squires; Deirdre Kelly; Sanjay Rajwal; Nisreen Soufi; Alain Lachaux; Irena Jankowska; Cara Mack; Kenneth D R Setchell; Palaniswamy Karthikeyan; Ciara Kennedy; Alejandro Dorenbaum; Nirav K Desai; Will Garner; Thomas Jaecklin; Pamela Vig; Alexander Miethke; Richard J Thompson Journal: Hepatol Commun Date: 2022-05-04
Authors: Daan B E van Wessel; Richard J Thompson; Emmanuel Gonzales; Irena Jankowska; Benjamin L Shneider; Etienne Sokal; Tassos Grammatikopoulos; Agustina Kadaristiana; Emmanuel Jacquemin; Anne Spraul; Patryk Lipiński; Piotr Czubkowski; Nathalie Rock; Mohammad Shagrani; Dieter Broering; Talal Algoufi; Nejat Mazhar; Emanuele Nicastro; Deirdre Kelly; Gabriella Nebbia; Henrik Arnell; Björn Fischler; Jan B F Hulscher; Daniele Serranti; Cigdem Arikan; Dominique Debray; Florence Lacaille; Cristina Goncalves; Loreto Hierro; Gema Muñoz Bartolo; Yael Mozer-Glassberg; Amer Azaz; Jernej Brecelj; Antal Dezsőfi; Pier Luigi Calvo; Dorothee Krebs-Schmitt; Steffen Hartleif; Wendy L van der Woerd; Jian-She Wang; Li-Ting Li; Özlem Durmaz; Nanda Kerkar; Marianne Hørby Jørgensen; Ryan Fischer; Carolina Jimenez-Rivera; Seema Alam; Mara Cananzi; Noémie Laverdure; Cristina Targa Ferreira; Felipe Ordonez; Heng Wang; Valerie Sency; Kyung Mo Kim; Huey-Ling Chen; Elisa Carvalho; Alexandre Fabre; Jesus Quintero Bernabeu; Estella M Alonso; Ronald J Sokol; Frederick J Suchy; Kathleen M Loomes; Patrick J McKiernan; Philip Rosenthal; Yumirle Turmelle; Girish S Rao; Simon Horslen; Binita M Kamath; Maria Rogalidou; Wikrom W Karnsakul; Bettina Hansen; Henkjan J Verkade Journal: Hepatology Date: 2021-07-13 Impact factor: 17.425