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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. 2023 Feb 1;77(2):512-529. doi: 10.1002/hep.32761.Epub 2022 Oct 13.
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 7, David A Piccoli 7, Lorenzo D'Antiga 8, Emanuele Nicastro 8, Étienne Sokal 9, Tanguy Demaret 9, Noelle H Ebel 10, Jeffrey A Feinstein 11, Rima Fawaz 12, Silvia Nastasio 13, Florence Lacaille 14, Dominique Debray 15, Henrik Arnell 16 17, Björn Fischler 16 18, Susan Siew 19, Michael Stormon 19, Saul J Karpen 20, Rene Romero 20, Kyung Mo Kim 21, Woo Yim Baek 21, Winita Hardikar 22, Sahana Shankar 23, Amin J Roberts 24, Helen M Evans 24, M Kyle Jensen 25, Marianne Kavan 25, Shikha S Sundaram 26, Alexander Chaidez 26, Palaniswamy Karthikeyan 27, Maria Camila Sanchez 28, Maria Lorena Cavalieri 28, Henkjan J Verkade 29, Way Seah Lee 30, James E Squires 31, Christina Hajinicolaou 32, Chatmanee Lertudomphonwanit 33, Ryan T Fischer 34, Catherine Larson-Nath 35, Yael Mozer-Glassberg 36, Cigdem Arikan 37, Henry C Lin 38, Jesus Quintero Bernabeu 39, Seema Alam 40, Deirdre A Kelly 41, Elisa Carvalho 42, Cristina Targa Ferreira 43, Giuseppe Indolfi 44, Ruben E Quiros-Tejeira 45, Pinar Bulut 46, Pier Luigi Calvo 47, Zerrin Önal 48, Pamela L Valentino
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Author information
- 1Division of Gastroenterology, Hepatology and Nutrition , The Hospital for Sick Children and the University of Toronto , Toronto , Canada.
- 2The Center for Pediatric Liver Diseases , Children's Hospital of Fudan University , Shanghai , China.
- 3Division 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.
- 4Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics , The Children's Memorial Health Institute , 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 and Inserm U1193, Hepatinov, Université Paris-Saclay , Le Kremlin-Bicêtre , 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.
- 7Division of Gastroenterology, Hepatology and Nutrition , The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine , Philadelphia , Pennsylvania , USA.
- 8Pediatric Hepatology, Gastroenterology and Transplantation , Ospedale Papa Giovanni XXIII , Bergamo , Italy.
- 9Service De Gastroentérologie & Hépatologie Pédiatrique , Cliniques Universitaires Saint-Luc , Brussels , Belgium.
- 10Division of Gastroenterology , Department of Pediatrics , Stanford University School of Medicine , Palo Alto , California , USA.
- 11Department of Pediatrics (Cardiology) , Stanford University School of Medicine , Lucile Packard Children's Hospital , Palo Alto , California , USA.
- 12Department of Pediatrics , Yale University School of Medicine , New Haven , Connecticut , USA.
- 13Division of Gastroenterology, Hepatology, & Nutrition , Boston Children's Hospital and Harvard Medical School , Boston , Massachusetts , USA.
- 14Department of Pediatric Gastroenterology, and Nutrition , Necker-Enfants Malades Hospital , University of Paris , Paris , France.
- 15Pediatric 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.
- 16Department of Paediatric Gastroenterology, Hepatology and Nutrition , Astrid Lindgren Children's Hospital, Karolinska University Hospital , Stockholm , Sweden.
- 17Department of Women's and Children's Health , Karolinska Institutet , Stockholm , Sweden.
- 18CLINTEC , Karolinska Institutet , Stockholm , Sweden.
- 19Department of Gastroenterology , The Children's Hospital at Westmead , Sydney , Australia.
- 20Division of Pediatric Gastroenterology, Hepatology & Nutrition , Children's Healthcare of Atlanta & Emory University School of Medicine , Atlanta , Georgia , USA.
- 21Department of Pediatrics , University of Ulsan College of Medicine , Asan Medical Center Children's Hospital , Seoul , Republic of Korea.
- 22Department of Gastroenterology and Clinical Nutrition , Royal Children's Hospital , Melbourne , Australia.
- 23Mazumdar Shaw Medical Center , Narayana Health , Bangalore , India.
- 24Department of Paediatric Gastroenterology , Starship Child Health , Auckland , New Zealand.
- 25Division of Pediatric Gastroenterology, Hepatology and Nutrition , University of Utah , Salt Lake City , Utah , USA.
- 26Section 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.
- 27Leeds Teaching Hospitals NHS Trust , Leeds Children's Hospital , Leeds , UK.
- 28Pediatric Gastroenterology and Hepatology Division , Hospital Italiano Buenos Aires , Buenos Aires , Argentina.
- 29Department of Pediatrics , Center for Liver, Digestive, and Metabolic Diseases , University Medical Center Groningen , Groningen , The Netherlands.
- 30Faculty of Medicine, Department of Paediatrics , University of Malaya , Kuala Lumpur , Malaysia.
- 31Division of Pediatric Gastroenterology and Hepatology , Department of Pediatrics , University of Pittsburgh School of Medicine , Pittsburgh , Pennsylvania , USA.
- 32Division of Paediatric Gastroenterology , Department of Paediatrics and Child Health , Chris Hani Baragwanath Academic Hospital , University of the Witwatersrand , Johannesburg , South Africa.
- 33Division of Gastroenterology , Department of Pediatrics , Ramathibodi Hospital Mahidol University , Bangkok , Thailand.
- 34Department of Gastroenterology, Section of Hepatology , Children's Mercy Kansas City , Kansas City , Missouri , USA.
- 35Division of Pediatric Gastroenterology, Hepatology, and Nutrition , University of Minnesota , Minneapolis , Minnesota , USA.
- 36Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petah Tikva , Israel.
- 37Department of Pediatric Gastroenterology and Organ Transplant , Koc University School of Medicine , Istanbul , Turkey.
- 38Division of Pediatric Gastroenterology , Department of Pediatrics , Oregon Health and Science University , Portland , Oregon , USA.
- 39Pediatric Hepatology and Liver Transplant Department , Hospital Universitari Vall d'Hebron , Barcelona , Spain.
- 40Department of Pediatric Hepatology , Institute of Liver and Biliary Sciences , New Delhi , India.
- 41Liver Unit , Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham , Birmingham , UK.
- 42Pediatric Gastroenterology Department , Hospital da Criança de Brasília , Centro Universitário de Brasília , Brasília , Brazil.
- 43Pediatric Gastroenterology Service , Hospital da Criança Santo Antôni, Universidade Federal de Ciências da Saúde de Porto Alegre , Complexo Hospitalar Santa Casa , Porto Alegre , RS , Brazil.
- 44Paediatric and Liver Unit , Department Neurofarba , University of Florence and Meyer Children's University Hospital , Florence , Italy.
- 45Department of Pediatrics , Children's Hospital & Medical Center and University of Nebraska Medical Center , Omaha , Nebraska , USA.
- 46Division of Pediatric Gastroenterology and Hepatology , Phoenix Children's Hospital , Phoenix , USA.
- 47Pediatric Gastroenterology Unit , Regina Margherita Children's Hospital , Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza , Turin , Italy.
- 48Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul Medical Faculty , Istanbul University , Istanbul , Turkey.
- 49Solid Organ Transplant Department , Children's Health - Children's Medical Center , Dallas , Texas , USA.
- 50Department of Pediatric Gastroenterology , Le Bonheur Children's Hospital, The University of Tennessee Health Science Center , Memphis , Texas , USA.
- 51Division of Gastroenterology & Hepatology, First Department of Pediatrics , "Agia Sofia" Children's Hospital , University of Athens , Athens , Greece.
- 52First Department of Paediatrics , Semmelweis University , Budapest , Hungary.
- 53Department of Pediatrics , Medical University of Silesia in Katowice , Katowice , Poland.
- 54Servizio di Epatologia Pediatrica , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy.
- 55Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição , Porto Alegre , RS , Brazil.
- 56Department of Pediatric Gastroenterology , University Medical Center Utrecht , Utrecht , The Netherlands.
- 57Paediatric Gastroenterology Unit , Cruces University Hospital , Bilbao , Spain.
- 58Division of Paediatric Gastroenterology and Hepatology , London Health Sciences Centre, Children's Hospital , Western University , London , Ontario , Canada.
- 59Division of Pediatric Gastroenterology, Hepatology and Nutrition, Miami Transplant Institute , University of Miami , Miami , Florida , USA.
- 60Division of Pediatric Gastroenterology , University of California San Diego, Rady Children's Hospital San Diego , San Diego , California , USA.
- 61Faculty of Health Sciences, Wits Donald Gordon Medical Centre , University of the Witwatersrand , Johannesburg , South Africa.
- 62Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus , Denmark.
- 63Division of Gastroenterology, Hepatology and Nutrition , Children's Hospital of Eastern Ontario , Ottawa , Canada.
- 64Division of Pediatric Gastroenterology, Hepatology and Nutrition , Department of Pediatrics , University of Rochester Medical Center , Rochester , New York , USA.
- 65Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Faculty of Medicine , University Medical Center Ljubljana , Ljubljana , Slovenia.
- 66Section of Pediatric Gastroenterology , Department of Pediatrics , University of Manitoba , Winnipeg , Canada.
- 67Department of Paediatrics, Gynaecology and Obstetrics , Geneva University Hospitals, University of Geneva , Geneva , Switzerland.
- 68Pediatric Gastroenterology Hepatology and Nutrition Unit , Hospital Sant Joan de Déu , Esplugues de Llobregat , Spain.
- 69Department of Pediatrics , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA.
- 70Department of Pediatrics , Dr. von Hauner Children's Hospital , University Hospital , LMU Munich , Munich , Germany.
- 71Pediatric Gastroenterology Unit , Centro Hospitalar Universitário Do Porto , Porto , Portugal.
- 72Gastroenterology and Hepatology , Seattle Children's Hospital , Seattle , Washington , USA.
- 73Department 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.
- 74Harvard Medical School , Massachusetts General Hospital for Children , Boston , Massachusetts , USA.
- 75Institute of Liver Studies , King's College London , London , UK.
- 76Toronto General Hospital University Health Network , Toronto , Ontario , Canada.
- 77Institute of Health Policy, Management and Evaluation , Toronto , Ontario , Canada.
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 < 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 therapies.
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 < 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 therapies.
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