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Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency |
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Hepatology. 2021 Mar 5. doi: 10.1002/hep.31787. Online ahead of print.
Daan B E van Wessel 1, Richard J Thompson 2, Emmanuel Gonzales 3 4, Irena Jankowska 4 5, Benjamin L Shneider 6 7, Etienne Sokal 4 8, Tassos Grammatikopoulos 2, Agustina Kadaristiana 2, Emmanuel Jacquemin 3 9, Anne Spraul 9 10, Patryk Lipinski 4 5, Piotr Czubkowski 4 5, Nathalie Rock 8, Mohammad Shagrani 11 12, Dieter Broering 11, Talal Algoufi 11, Nejat Mazhar 11, Emanuele Nicastro 13, Deirdre Kelly 4 14, Gabriella Nebbia 15, Henrik Arnell 4 16, Björn Fischler 4 16, Jan B F Hulscher 4 17, Daniele Serranti 18, Cigdem Arikan 19, Dominique Debray 20, Florence Lacaille 20, Cristina Goncalves 4 21, Loreto Hierro 4 22, Gema Muñoz Bartolo 4 22, Yael Mozer-Glassberg 23, Amer Azaz 24, Jernej Brecelj 25, Antal Dezsofi 26, Pier Luigi Calvo 27, Dorothee Krebs-Schmitt 28, Steffen Hartleif 4 29, Wendy L van der Woerd 30, Jian-She Wang 31, Li-Ting Li 31, Özlem Durmaz 32, Nanda Kerkar 33, Marianne Hørby Jørgensen 4 34, Ryan Fischer 35, Carolina Jimenez-Rivera 36, Seema Alam 37, Mara Cananzi 4 38, Noémie Laverdure 4 39, Cristina Targa Ferreira 40, Felipe Ordonez 41, Heng Wang 42, Valerie Sency 42, Kyung Mo Kim 43, Huey-Ling Chen 44, Elisa Carvalho 45, Alexandre Fabre 46, Jesus Quintero Bernabeu 4 47, Estella M Alonso 7 48, Ronald J Sokol 7 49, Frederick J Suchy 7 50, Kathleen M Loomes 7 51, Patrick J McKiernan 7 52, Philip Rosenthal 7 53, Yumirle Turmelle 7 54, Girish S Rao 7 55, Simon Horslen 7 56, Binita M Kamath 7 57, Maria Rogalidou 58, Wikrom W Karnsakul 59, Bettina Hansen 60 61, Henkjan J Verkade 1 4
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Author information
- 1Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
- 2Institute of Liver Studies, King's College Hospital, Denmark Hill, London, United Kingdom.
- 3Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques (AVB-CG), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), European Reference Network RARE-LIVER, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, Paris, France.
- 4European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
- 5Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
- 6Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
- 7Childhood Liver Disease Research Network (ChiLDReN).
- 8Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium.
- 9Université Paris-Saclay, INSERM, UMR-S 1193, Hepatinov, Orsay, France.
- 10Biochemistry Unit, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques (AVB-CG), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), European Reference Network RARE-LIVER, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, Paris, France.
- 11Department of Liver &, SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
- 12Alfaisal University, College of Medicine, Riyadh, Saudi Arabia.
- 13Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
- 14Liver Unit, Birmingham Women's and Children's Hospital, University of Birmingham, Birmingham, United Kingdom.
- 15Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
- 16Pediatric Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
- 17Pediatric Surgery, University Medical Center Groningen, Groningen, the Netherlands.
- 18Pediatric and Liver Unit, Meyer Children's University Hospital of Florence, Florence, Italy.
- 19Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Kuttam System in Liver Medicine, Istanbul, Turkey.
- 20Pediatric Hepatology unit, Reference center for Biliary atresia and genetic cholestatic diseases (AVB-CG), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), European Reference Network RARE-LIVER, APHP-Neckler Enfants malades university hospital, Faculté de Médecine Paris-Centre, Paris, France.
- 21Coimbra University Hospital Center, Coimbra, Portugal.
- 22Pediatric Liver Service, La Paz University Hospital, Madrid, Spain.
- 23Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel.
- 24Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
- 25Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
- 261st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
- 27Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Torino, Italy.
- 28Klinik Für Kinder-Und Jugendmedizin, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.
- 29University Children's Hospital T?bingen, T?bingen, Germany.
- 30Wilhelmina Children's Hospital, University Medical Center Utrecht, Pediatric Gastroenterology, Hepatology and Nutrition, Utrecht, the Netherlands.
- 31Children's Hospital of Fudan University, Shanghai, China.
- 32Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.
- 33Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, NY, USA.
- 34Pediatric and adolescent department Rigshospitalet Copenhagen University Hospital, Department of Pediatrics and Adolescent Medicine, Copenhagen, Denmark.
- 35Children's Mercy Hospital, Section of Hepatology and Transplant Medicine, Kansas City, MO, USA.
- 36Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, Canada.
- 37Institute of Liver and Biliary Sciences, Pediatric Hepatology, New Delhi, India.
- 38University Hospital of Padova, Pediatric Gastroenterology and Hepatology, Padova, Italy.
- 39Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de gastroentérologie, hépatologie et nutrition pédiatriques, Lyon, France.
- 40Hospital da Criança Santo Antônio, Pediatric Gastroenterology, Porto Allegre, Brazil.
- 41Fundación Cardioinfantil Instituto de Cardiologia, Pediatric Gastroenterology and Hepatology, Bogotá, Colombia.
- 42DDC Clinic Center for Special Needs Children, Middlefield, OH, USA.
- 43Asan Medical Center Children's Hospital, Department of Pediatrics, Seoul, South Korea.
- 44National Taiwan University Children's Hospital, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Taipei, Taiwan.
- 45Brasília Children's Hospital, Pediatric Gastroenterology and Hepatology, Brasilia, Brazil.
- 46Aix Marseille University, INSERM, MMG, Marseille, France, and APHM, Timone Enfant, serveice de pédiatrie multidisciplinaire, Marseille, France.
- 47Pediatric Hepatology and Liver Transplant Unit, Barcelona, Spain.
- 48Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
- 49Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
- 50Mount Sinai Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
- 51Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- 52Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- 53Department of Pediatrics and Surgery, UCSF Benioff Children's Hospital, UCSF School of Medicine, San Francisco, CA, USA.
- 54Section of Hepatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO, USA.
- 55Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
- 56Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
- 57The Hospital for Sick Children, University of Toronto, Toronto, Canada.
- 58Division of Pediatric Gastroenterology & Hepatology, 1st Pediatrics Department, University of Athens, Agia Sofia Children's Hospital, Athens, Greece.
- 59Division of Pediatric Gastroenterology, Nutrition, and Hepatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 60Toronto Center for Liver Disease, University Health Network, Canada.
61IHPME, University of Toronto, NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) consortium, Canada.
Abstract
Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs <194 µmol/L: 49% versus sBAs ≥194 µmol/L: 15%; P=0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P=0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P=0.06) and post-SBD sBA concentrations <65μmol/L (P=0.05) tended to be associated with improved NLS. Conclusion: Less than half of FIC1 deficiency patients reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.
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