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.