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Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome: Results from The GALA Study |
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Hepatology. 2022 Aug 29. doi: 10.1002/hep.32761. Online ahead of print.
Shannon M Vandriel 1, Li-Ting Li 2, Huiyu She 2, Jian-She Wang 2, Melissa A Gilbert 3, Irena Jankowska 4, Piotr Czubkowski 4, Dorota Gliwicz-Miedzinska 4, Emmanuel M Gonzales 5, Emmanuel Jacquemin 5, Jérôme Bouligand 6, Nancy B Spinner 3, Kathleen M Loomes, David A Piccoli, Lorenzo D'Antiga 7, Emanuele Nicastro 7, Étienne Sokal 8, Tanguy Demaret 8, Noelle H Ebel 9, Jeffrey A Feinstein 10, Rima Fawaz 11, Silvia Nastasio 12, Florence Lacaille 13, Dominique Debray 14, Henrik Arnell 15, Björn Fischler 16, Susan Siew 17, Michael Stormon 17, Saul J Karpen 18, Rene Romero 18, Kyung Mo Kim 19, Woo Yim Baek 19, Winita Hardikar 20, Sahana Shankar 21, Amin J Roberts 22, Helen M Evans 22, M Kyle Jensen 23, Marianne Kavan 23, Shikha S Sundaram 24, Alexander Chaidez 24, Palaniswamy Karthikeyan 25, Maria Camila Sanchez 26, Maria Lorena Cavalieri 26, Henkjan J Verkade 27, Way Seah Lee 28, James E Squires 29, Christina Hajinicolaou 30, Chatmanee Lertudomphonwanit 31, Ryan T Fischer 32, Catherine Larson-Nath 33, Yael Mozer-Glassberg 34, Cigdem Arikan 35, Henry C Lin 36, Jesus Quintero Bernabeu 37, Seema Alam 38, Deirdre Kelly 39, Elisa Carvalho 40, Cristina Targa Ferreira 41, Giuseppe Indolfi 42, Ruben E Quiros-Tejeira 43, Pinar Bulut 44, Pier Luigi Calvo 45, Zerrin Önal 46, Pamela L Valentino 11, Dev M Desai 47, John Eshun 48, Maria Rogalidou 49, Antal Dezsofi 50, Sabina Wiecek 51, Gabriella Nebbia 52, Raquel Borges Pinto 53, Victorien M Wolters 54, María Legarda Tamara 55, Andréanne N Zizzo 56, Jennifer Garcia 57< |
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Author information
- 1The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, Canada.
- 2Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China.
- 3The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania, United States.
- 4The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland.
- 5Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Bicêtre Hospital, AP-HP. Université Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hepatinov, University of Paris-Saclay, Orsay, France.
- 6Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France, 7The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Philadelphia, Pennsylvania, United States.
- 7Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy.
- 8Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium.
- 9Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, United States.
- 10Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California, United States.
- 11Yale University School of Medicine, Department of Pediatrics, New Haven, United States.
- 12Boston Children's Hospital and Harvard Medical School, Division of Gastroenterology, Hepatology, & Nutrition, Boston, United States.
- 13Department of Pediatric Gastroenterology, and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
- 14Pediatric liver unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
- 15Astrid Lindgren Children's Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
- 16Astrid Lindgren Children's Hospital, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Paediatric Digestive Diseases, Stockholm, Sweden.
- 17The Children's Hospital at Westmead, Department of Gastroenterology, Sydney, Australia.
- 18Children's Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, United States.
- 19Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea, Republic of.
- 20Royal Children's Hospital, Department of Gastroenterology and Clinical Nutrition, Melbourne, Australia.
- 21Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India.
- 22Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand.
- 23University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Salt Lake City, United States.
- 24Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado and University of Colorado School of Medicine, Aurora, United States.
- 25Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, United Kingdom.
- 26Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina.
- 27University Medical Center Groningen, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen, Netherlands.
- 28Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.
- 29University of Pittsburgh School of Medicine, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Pittsburgh, United States.
- 30Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa.
- 31Ramathibodi Hospital Mahidol University, Division of Gastroenterology, Department of Pediatrics, Bangkok, Thailand.
- 32Children's Mercy Kansas City, Department of Gastroenterology, Section of Hepatology, Kansas City, United States.
- 33University of Minnesota, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Minneapolis, United States.
- 34Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel.
- 35Koc University School of Medicine, Department of Pediatric Gastroenterology and Organ Transplant, Istanbul, Turkey.
- 36Oregon Health and Science University, Division of Pediatric Gastroenterology, Department of Pediatrics, Portland, United States.
- 37Hospital Universitari Vall d'Hebron, Pediatric Hepatology and Liver Transplant Department, Barcelona, Spain.
- 38Institute of Liver and Biliary Sciences, Department of Pediatric Hepatology, New Delhi, India.
- 39Liver Unit, Birmingham Women's & Children's Hospital NHS Trust and University of Birmingham, Birmingham, United Kingdom.
- 40Pediatric Gastroenterology Department, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brazil.
- 41Pediatric Gastroenterology Service, Hospital da Criança Santo Antônio, Universidade Federal de Ciências da Saúde de Porto Alegre, Complexo Hospitalar Santa Casa, Porto Alegre, RS, Brazil.
- 42Department Neurofarba, University of Florence and Meyer Children's University Hospital, Paediatric and Liver Unit, Florence, Italy.
- 43Children's Hospital & Medical Center and University of Nebraska Medical Center, Department of Pediatrics, Omaha, United States.
- 44Phoenix Children's Hospital, Division of Pediatric Gastroenterology and Hepatology, Phoenix, United States.
- 45Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy.
- 46Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey.
- 47Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, United States.
- 48Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital and The University of Tennessee Health Science Center, Memphis, United States.
- 49Division of Gastroenterology & Hepatology,"Agia Sofia" Children's Hospital, First Department of Pediatrics, University of Athens, Athens, Greece.
- 50First Department of Paediatrics, Semmelweis University, Budapest, Hungary.
- 51Medical University of Silesia in Katowice, Department of Pediatrics, Katowice, Poland.
- 52Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy.
- 53Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil.
- 54Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands.
- 55Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain.
- 56Children's Hospital, London Health Sciences Centre, Division of Paediatric Gastroenterology and Hepatology, Western University, London, Ontario, Canada.
- 57Division of Pediatric Gastroenterology, Hepatology and Nutrition/ Miami Transplant Institute, University of Miami, Miami, United States.
- 58University of California San Diego, Rady Children's Hospital San Diego, Division of Pediatric Gastroenterology, San Diego, United States.
- 59Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa.
- 60Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
- 61Children's Hospital of Eastern Ontario, Division of Gastroenterology, Hepatology and Nutrition, Ottawa, Canada.
- 62University of Rochester Medical Center, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rochester, New York, United States.
- 63University Medical Center Ljubljana, Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, Ljubljana, Slovenia.
- 64University of Manitoba, Section of Pediatric Gastroenterology, Department of Pediatrics, Winnipeg, Canada.
- 65Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
- 66Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
- 67Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, United States.
- 68Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
- 69CentroHospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal.
- 70Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, United States.
- 71Department of Hepatology and Gastroenterology, Bioodonostia Health Research Institute - Donostia University Hospital, Universidad del País Vasco (UPV/EHU), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastián, Spain.
- 72Harvard Medical School, Massachusetts General Hospital for Children, Boston, United States.
- 73Institute of Liver Studies, King's College London, London, United Kingdom.
- 74Toronto General Hospital University Health Network, Toronto, Canada.
- 75Institute of Health Policy, Management and Evaluation, Toronto, Canada.
Abstract
Background: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.
Methods: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.
Results: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those <5.0 mg/dL. Median TB levels between ≥5.0 and <10.0 mg/dL and >10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to <5.0 mg/dL. Median TB <5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p<0.001).
Conclusions: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.
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