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Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

Vandriel SM 1 , Li LT 2 , She H 2 , Wang JS 2 , Gilbert MA 3 , Jankowska I 4 Show all authors , Czubkowski P 4 , Gliwicz-Miedzińska D 4 , Gonzales EM 5 , Jacquemin E 5 , Bouligand J 6 , Spinner NB 3 , Loomes KM 7 , Piccoli DA 7 , D'Antiga L 8 , Nicastro E 8 , Sokal É 9 , Demaret T 9 , Ebel NH 10 , Feinstein JA 11 , Fawaz R 12 , Nastasio S 13 , Lacaille F 14 , Debray D 15 , Arnell H 16 , Fischler B 16 , Siew S 17 , Stormon M 17 , Karpen SJ 18 , Romero R 18 , Kim KM 19 , Baek WY 19 , Hardikar W 20 , Shankar S 21 , Roberts AJ 22 , Evans HM 22 , Jensen MK 23 , Kavan M 23 , Sundaram SS 24 , Chaidez A 24 , Karthikeyan P 25 , Sanchez MC 26 , Cavalieri ML 26 , Verkade HJ 27 , Lee WS 28 , Squires JE 29 , Hajinicolaou C 30 , Lertudomphonwanit C 31 , Fischer RT 32 , Larson-Nath C 33 , Mozer-Glassberg Y 34 , Arikan C 35 , Lin HC 36 , Bernabeu JQ 37 , Alam S 38 , Kelly DA 39 , Carvalho E 40 , Ferreira CT 41 , Indolfi G 42 , Quiros-Tejeira RE 43 , Bulut P 44 , Calvo PL 45 , Önal Z 46 , Valentino PL 12 , Desai DM 47 , Eshun J 48 , Rogalidou M 49 , Dezsőfi A 50 , Wiecek S 51 , Nebbia G 52 , Pinto RB 53 , Wolters VM 54 , Tamara ML 55 , Zizzo AN 56 , Garcia J 57 , Schwarz K 58 , Beretta M 59 , Sandahl TD 60 , Jimenez-Rivera C 61 , Kerkar N 62 , Brecelj J 63 , Mujawar Q 64 , Rock N 65 , Busoms CM 66 , Karnsakul W 67 , Lurz E 68 , Santos-Silva E 69 , Blondet N 70 , Bujanda L 71 , Shah U 72 , Thompson RJ 73 , Hansen BE 74 , Kamath BM 1 , Global ALagille Alliance (GALA) Study Group

Affiliations 

  • 1 Division of Gastroenterology, Hepatology and Nutrition , The Hospital for Sick Children and the University of Toronto , Toronto , Canada
  • 2 The Center for Pediatric Liver Diseases , Children's Hospital of Fudan University , Shanghai , China
  • 3 Division of Genomic Diagnostics , Department of Pathology and Laboratory Medicine , The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine , Philadelphia , Pennsylvania , USA
  • 4 Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics , The Children's Memorial Health Institute , Warsaw , Poland
  • 5 Pediatric 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 and Inserm U1193, Hepatinov, Université Paris-Saclay , Le Kremlin-Bicêtre , France
  • 6 Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris-Saclay , Assistance Publique-Hôpitaux de Paris , Centre Hospitalier Universitaire de Bicêtre , Le Kremlin-Bicêtre , France
  • 7 Division of Gastroenterology, Hepatology and Nutrition , The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine , Philadelphia , Pennsylvania , USA
  • 8 Pediatric Hepatology, Gastroenterology and Transplantation , Ospedale Papa Giovanni XXIII , Bergamo , Italy
  • 9 Service De Gastroentérologie & Hépatologie Pédiatrique , Cliniques Universitaires Saint-Luc , Brussels , Belgium
  • 10 Division of Gastroenterology , Department of Pediatrics , Stanford University School of Medicine , Palo Alto , California , USA
  • 11 Department of Pediatrics (Cardiology) , Stanford University School of Medicine , Lucile Packard Children's Hospital , Palo Alto , California , USA
  • 12 Department of Pediatrics , Yale University School of Medicine , New Haven , Connecticut , USA
  • 13 Division of Gastroenterology, Hepatology, & Nutrition , Boston Children's Hospital and Harvard Medical School , Boston , Massachusetts , USA
  • 14 Department of Pediatric Gastroenterology, and Nutrition , Necker-Enfants Malades Hospital , University of Paris , Paris , France
  • 15 Pediatric 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
  • 16 Department of Paediatric Gastroenterology, Hepatology and Nutrition , Astrid Lindgren Children's Hospital, Karolinska University Hospital , Stockholm , Sweden
  • 17 Department of Gastroenterology , The Children's Hospital at Westmead , Sydney , Australia
  • 18 Division of Pediatric Gastroenterology, Hepatology & Nutrition , Children's Healthcare of Atlanta & Emory University School of Medicine , Atlanta , Georgia , USA
  • 19 Department of Pediatrics , University of Ulsan College of Medicine , Asan Medical Center Children's Hospital , Seoul , Republic of Korea
  • 20 Department of Gastroenterology and Clinical Nutrition , Royal Children's Hospital , Melbourne , Australia
  • 21 Mazumdar Shaw Medical Center , Narayana Health , Bangalore , India
  • 22 Department of Paediatric Gastroenterology , Starship Child Health , Auckland , New Zealand
  • 23 Division of Pediatric Gastroenterology, Hepatology and Nutrition , University of Utah , Salt Lake City , Utah , USA
  • 24 Section 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 , Colorado , USA
  • 25 Leeds Teaching Hospitals NHS Trust , Leeds Children's Hospital , Leeds , UK
  • 26 Pediatric Gastroenterology and Hepatology Division , Hospital Italiano Buenos Aires , Buenos Aires , Argentina
  • 27 Department of Pediatrics , Center for Liver, Digestive, and Metabolic Diseases , University Medical Center Groningen , Groningen , The Netherlands
  • 28 Faculty of Medicine, Department of Paediatrics , University of Malaya , Kuala Lumpur , Malaysia
  • 29 Division of Pediatric Gastroenterology and Hepatology , Department of Pediatrics , University of Pittsburgh School of Medicine , Pittsburgh , Pennsylvania , USA
  • 30 Division of Paediatric Gastroenterology , Department of Paediatrics and Child Health , Chris Hani Baragwanath Academic Hospital , University of the Witwatersrand , Johannesburg , South Africa
  • 31 Division of Gastroenterology , Department of Pediatrics , Ramathibodi Hospital Mahidol University , Bangkok , Thailand
  • 32 Department of Gastroenterology, Section of Hepatology , Children's Mercy Kansas City , Kansas City , Missouri , USA
  • 33 Division of Pediatric Gastroenterology, Hepatology, and Nutrition , University of Minnesota , Minneapolis , Minnesota , USA
  • 34 Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petah Tikva , Israel
  • 35 Department of Pediatric Gastroenterology and Organ Transplant , Koc University School of Medicine , Istanbul , Turkey
  • 36 Division of Pediatric Gastroenterology , Department of Pediatrics , Oregon Health and Science University , Portland , Oregon , USA
  • 37 Pediatric Hepatology and Liver Transplant Department , Hospital Universitari Vall d'Hebron , Barcelona , Spain
  • 38 Department of Pediatric Hepatology , Institute of Liver and Biliary Sciences , New Delhi , India
  • 39 Liver Unit , Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham , Birmingham , UK
  • 40 Pediatric Gastroenterology Department , Hospital da Criança de Brasília , Centro Universitário de Brasília , Brasília , Brazil
  • 41 Pediatric Gastroenterology Service , Hospital da Criança Santo Antôni, Universidade Federal de Ciências da Saúde de Porto Alegre , Complexo Hospitalar Santa Casa , Porto Alegre , RS , Brazil
  • 42 Paediatric and Liver Unit , Department Neurofarba , University of Florence and Meyer Children's University Hospital , Florence , Italy
  • 43 Department of Pediatrics , Children's Hospital & Medical Center and University of Nebraska Medical Center , Omaha , Nebraska , USA
  • 44 Division of Pediatric Gastroenterology and Hepatology , Phoenix Children's Hospital , Phoenix , USA
  • 45 Pediatric Gastroenterology Unit , Regina Margherita Children's Hospital , Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza , Turin , Italy
  • 46 Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul Medical Faculty , Istanbul University , Istanbul , Turkey
  • 47 Solid Organ Transplant Department , Children's Health - Children's Medical Center , Dallas , Texas , USA
  • 48 Department of Pediatric Gastroenterology , Le Bonheur Children's Hospital, The University of Tennessee Health Science Center , Memphis , Texas , USA
  • 49 Division of Gastroenterology & Hepatology, First Department of Pediatrics , "Agia Sofia" Children's Hospital , University of Athens , Athens , Greece
  • 50 First Department of Paediatrics , Semmelweis University , Budapest , Hungary
  • 51 Department of Pediatrics , Medical University of Silesia in Katowice , Katowice , Poland
  • 52 Servizio di Epatologia Pediatrica , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
  • 53 Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição , Porto Alegre , RS , Brazil
  • 54 Department of Pediatric Gastroenterology , University Medical Center Utrecht , Utrecht , The Netherlands
  • 55 Paediatric Gastroenterology Unit , Cruces University Hospital , Bilbao , Spain
  • 56 Division of Paediatric Gastroenterology and Hepatology , London Health Sciences Centre, Children's Hospital , Western University , London , Ontario , Canada
  • 57 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Miami Transplant Institute , University of Miami , Miami , Florida , USA
  • 58 Division of Pediatric Gastroenterology , University of California San Diego, Rady Children's Hospital San Diego , San Diego , California , USA
  • 59 Faculty of Health Sciences, Wits Donald Gordon Medical Centre , University of the Witwatersrand , Johannesburg , South Africa
  • 60 Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus , Denmark
  • 61 Division of Gastroenterology, Hepatology and Nutrition , Children's Hospital of Eastern Ontario , Ottawa , Canada
  • 62 Division of Pediatric Gastroenterology, Hepatology and Nutrition , Department of Pediatrics , University of Rochester Medical Center , Rochester , New York , USA
  • 63 Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Faculty of Medicine , University Medical Center Ljubljana , Ljubljana , Slovenia
  • 64 Section of Pediatric Gastroenterology , Department of Pediatrics , University of Manitoba , Winnipeg , Canada
  • 65 Department of Paediatrics, Gynaecology and Obstetrics , Geneva University Hospitals, University of Geneva , Geneva , Switzerland
  • 66 Pediatric Gastroenterology Hepatology and Nutrition Unit , Hospital Sant Joan de Déu , Esplugues de Llobregat , Spain
  • 67 Department of Pediatrics , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
  • 68 Department of Pediatrics , Dr. von Hauner Children's Hospital , University Hospital , LMU Munich , Munich , Germany
  • 69 Pediatric Gastroenterology Unit , Centro Hospitalar Universitário Do Porto , Porto , Portugal
  • 70 Gastroenterology and Hepatology , Seattle Children's Hospital , Seattle , Washington , USA
  • 71 Department of Hepatology and Gastroenterology , Biodonostia 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
  • 72 Harvard Medical School , Massachusetts General Hospital for Children , Boston , Massachusetts , USA
  • 73 Institute of Liver Studies , King's College London , London , UK
  • 74 Toronto General Hospital University Health Network , Toronto , Ontario , Canada
Hepatology, 2023 Feb 01;77(2):512-529.
PMID: 36036223 DOI: 10.1002/hep.32761

Abstract

BACKGROUND AND AIMS: 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.

APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 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. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS 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% confidence interval [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

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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