Multicenter Study

. 2023 Feb 1;77(2):512-529.

doi: 10.1002/hep.32761. Epub 2022 Oct 13.

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

Shannon M Vandriel¹, Li-Ting Li², Huiyu She², Jian-She Wang², Melissa A Gilbert³, Irena Jankowska⁴, Piotr Czubkowski⁴, Dorota Gliwicz-Miedzińska⁴, Emmanuel M Gonzales⁵, Emmanuel Jacquemin⁵, Jérôme Bouligand⁶, Nancy B Spinner³, Kathleen M Loomes⁷, David A Piccoli⁷, Lorenzo D'Antiga⁸, Emanuele Nicastro⁸, Étienne Sokal⁹, Tanguy Demaret⁹, Noelle H Ebel¹⁰, Jeffrey A Feinstein¹¹, Rima Fawaz¹², Silvia Nastasio¹³, Florence Lacaille¹⁴, Dominique Debray¹⁵, Henrik Arnell^{16

17}, Björn Fischler^{16

18}, Susan Siew¹⁹, Michael Stormon¹⁹, Saul J Karpen²⁰, Rene Romero²⁰, Kyung Mo Kim²¹, Woo Yim Baek²¹, Winita Hardikar²², Sahana Shankar²³, Amin J Roberts²⁴, Helen M Evans²⁴, M Kyle Jensen²⁵, Marianne Kavan²⁵, Shikha S Sundaram²⁶, Alexander Chaidez²⁶, Palaniswamy Karthikeyan²⁷, Maria Camila Sanchez²⁸, Maria Lorena Cavalieri²⁸, Henkjan J Verkade²⁹, Way Seah Lee³⁰, James E Squires³¹, Christina Hajinicolaou³², Chatmanee Lertudomphonwanit³³, Ryan T Fischer³⁴, Catherine Larson-Nath³⁵, Yael Mozer-Glassberg³⁶, Cigdem Arikan³⁷, Henry C Lin³⁸, Jesus Quintero Bernabeu³⁹, Seema Alam⁴⁰, Deirdre A Kelly⁴¹, Elisa Carvalho⁴², Cristina Targa Ferreira⁴³, Giuseppe Indolfi⁴⁴, Ruben E Quiros-Tejeira⁴⁵, Pinar Bulut⁴⁶, Pier Luigi Calvo⁴⁷, Zerrin Önal⁴⁸, Pamela L Valentino¹², Dev M Desai⁴⁹, John Eshun⁵⁰, Maria Rogalidou⁵¹, Antal Dezsőfi⁵², Sabina Wiecek⁵³, Gabriella Nebbia⁵⁴, Raquel Borges Pinto⁵⁵, Victorien M Wolters⁵⁶, María Legarda Tamara⁵⁷, Andréanne N Zizzo⁵⁸, Jennifer Garcia⁵⁹, Kathleen Schwarz⁶⁰, Marisa Beretta⁶¹, Thomas Damgaard Sandahl⁶², Carolina Jimenez-Rivera⁶³, Nanda Kerkar⁶⁴, Jernej Brecelj⁶⁵, Quais Mujawar⁶⁶, Nathalie Rock⁶⁷, Cristina Molera Busoms⁶⁸, Wikrom Karnsakul⁶⁹, Eberhard Lurz⁷⁰, Ermelinda Santos-Silva⁷¹, Niviann Blondet⁷², Luis Bujanda⁷³, Uzma Shah⁷⁴, Richard J Thompson⁷⁵, Bettina E Hansen^{76

77}, Binita M Kamath¹; 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 Women's and Children's Health , Karolinska Institutet , Stockholm , Sweden.
¹⁸ CLINTEC , Karolinska Institutet , Stockholm , Sweden.
¹⁹ Department of Gastroenterology , The Children's Hospital at Westmead , Sydney , Australia.
²⁰ Division of Pediatric Gastroenterology, Hepatology & Nutrition , Children's Healthcare of Atlanta & Emory University School of Medicine , Atlanta , Georgia , USA.
²¹ Department of Pediatrics , University of Ulsan College of Medicine , Asan Medical Center Children's Hospital , Seoul , Republic of Korea.
²² Department of Gastroenterology and Clinical Nutrition , Royal Children's Hospital , Melbourne , Australia.
²³ Mazumdar Shaw Medical Center , Narayana Health , Bangalore , India.
²⁴ Department of Paediatric Gastroenterology , Starship Child Health , Auckland , New Zealand.
²⁵ Division of Pediatric Gastroenterology, Hepatology and Nutrition , University of Utah , Salt Lake City , Utah , USA.
²⁶ 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.
²⁷ Leeds Teaching Hospitals NHS Trust , Leeds Children's Hospital , Leeds , UK.
²⁸ Pediatric Gastroenterology and Hepatology Division , Hospital Italiano Buenos Aires , Buenos Aires , Argentina.
²⁹ Department of Pediatrics , Center for Liver, Digestive, and Metabolic Diseases , University Medical Center Groningen , Groningen , The Netherlands.
³⁰ Faculty of Medicine, Department of Paediatrics , University of Malaya , Kuala Lumpur , Malaysia.
³¹ Division of Pediatric Gastroenterology and Hepatology , Department of Pediatrics , University of Pittsburgh School of Medicine , Pittsburgh , Pennsylvania , USA.
³² Division of Paediatric Gastroenterology , Department of Paediatrics and Child Health , Chris Hani Baragwanath Academic Hospital , University of the Witwatersrand , Johannesburg , South Africa.
³³ Division of Gastroenterology , Department of Pediatrics , Ramathibodi Hospital Mahidol University , Bangkok , Thailand.
³⁴ Department of Gastroenterology, Section of Hepatology , Children's Mercy Kansas City , Kansas City , Missouri , USA.
³⁵ Division of Pediatric Gastroenterology, Hepatology, and Nutrition , University of Minnesota , Minneapolis , Minnesota , USA.
³⁶ Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petah Tikva , Israel.
³⁷ Department of Pediatric Gastroenterology and Organ Transplant , Koc University School of Medicine , Istanbul , Turkey.
³⁸ Division of Pediatric Gastroenterology , Department of Pediatrics , Oregon Health and Science University , Portland , Oregon , USA.
³⁹ Pediatric Hepatology and Liver Transplant Department , Hospital Universitari Vall d'Hebron , Barcelona , Spain.
⁴⁰ Department of Pediatric Hepatology , Institute of Liver and Biliary Sciences , New Delhi , India.
⁴¹ Liver Unit , Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham , Birmingham , UK.
⁴² Pediatric Gastroenterology Department , Hospital da Criança de Brasília , Centro Universitário de Brasília , Brasília , Brazil.
⁴³ 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.
⁴⁴ Paediatric and Liver Unit , Department Neurofarba , University of Florence and Meyer Children's University Hospital , Florence , Italy.
⁴⁵ Department of Pediatrics , Children's Hospital & Medical Center and University of Nebraska Medical Center , Omaha , Nebraska , USA.
⁴⁶ Division of Pediatric Gastroenterology and Hepatology , Phoenix Children's Hospital , Phoenix , USA.
⁴⁷ Pediatric Gastroenterology Unit , Regina Margherita Children's Hospital , Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza , Turin , Italy.
⁴⁸ Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul Medical Faculty , Istanbul University , Istanbul , Turkey.
⁴⁹ Solid Organ Transplant Department , Children's Health - Children's Medical Center , Dallas , Texas , USA.
⁵⁰ Department of Pediatric Gastroenterology , Le Bonheur Children's Hospital, The University of Tennessee Health Science Center , Memphis , Texas , USA.
⁵¹ Division of Gastroenterology & Hepatology, First Department of Pediatrics , "Agia Sofia" Children's Hospital , University of Athens , Athens , Greece.
⁵² First Department of Paediatrics , Semmelweis University , Budapest , Hungary.
⁵³ Department of Pediatrics , Medical University of Silesia in Katowice , Katowice , Poland.
⁵⁴ Servizio di Epatologia Pediatrica , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy.
⁵⁵ Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição , Porto Alegre , RS , Brazil.
⁵⁶ Department of Pediatric Gastroenterology , University Medical Center Utrecht , Utrecht , The Netherlands.
⁵⁷ Paediatric Gastroenterology Unit , Cruces University Hospital , Bilbao , Spain.
⁵⁸ Division of Paediatric Gastroenterology and Hepatology , London Health Sciences Centre, Children's Hospital , Western University , London , Ontario , Canada.
⁵⁹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Miami Transplant Institute , University of Miami , Miami , Florida , USA.
⁶⁰ Division of Pediatric Gastroenterology , University of California San Diego, Rady Children's Hospital San Diego , San Diego , California , USA.
⁶¹ Faculty of Health Sciences, Wits Donald Gordon Medical Centre , University of the Witwatersrand , Johannesburg , South Africa.
⁶² Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus , Denmark.
⁶³ Division of Gastroenterology, Hepatology and Nutrition , Children's Hospital of Eastern Ontario , Ottawa , Canada.
⁶⁴ Division of Pediatric Gastroenterology, Hepatology and Nutrition , Department of Pediatrics , University of Rochester Medical Center , Rochester , New York , USA.
⁶⁵ Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Faculty of Medicine , University Medical Center Ljubljana , Ljubljana , Slovenia.
⁶⁶ Section of Pediatric Gastroenterology , Department of Pediatrics , University of Manitoba , Winnipeg , Canada.
⁶⁷ Department of Paediatrics, Gynaecology and Obstetrics , Geneva University Hospitals, University of Geneva , Geneva , Switzerland.
⁶⁸ Pediatric Gastroenterology Hepatology and Nutrition Unit , Hospital Sant Joan de Déu , Esplugues de Llobregat , Spain.
⁶⁹ Department of Pediatrics , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA.
⁷⁰ Department of Pediatrics , Dr. von Hauner Children's Hospital , University Hospital , LMU Munich , Munich , Germany.
⁷¹ Pediatric Gastroenterology Unit , Centro Hospitalar Universitário Do Porto , Porto , Portugal.
⁷² Gastroenterology and Hepatology , Seattle Children's Hospital , Seattle , Washington , USA.
⁷³ 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.
⁷⁴ Harvard Medical School , Massachusetts General Hospital for Children , Boston , Massachusetts , USA.
⁷⁵ Institute of Liver Studies , King's College London , London , UK.
⁷⁶ Toronto General Hospital University Health Network , Toronto , Ontario , Canada.
⁷⁷ Institute of Health Policy, Management and Evaluation , Toronto , Ontario , Canada.

PMID: 36036223
PMCID: PMC9869940
DOI: 10.1002/hep.32761

Multicenter Study

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

Shannon M Vandriel et al. Hepatology. 2023.

. 2023 Feb 1;77(2):512-529.

doi: 10.1002/hep.32761. Epub 2022 Oct 13.

Authors

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 Women's and Children's Health , Karolinska Institutet , Stockholm , Sweden.
¹⁸ CLINTEC , Karolinska Institutet , Stockholm , Sweden.
¹⁹ Department of Gastroenterology , The Children's Hospital at Westmead , Sydney , Australia.
²⁰ Division of Pediatric Gastroenterology, Hepatology & Nutrition , Children's Healthcare of Atlanta & Emory University School of Medicine , Atlanta , Georgia , USA.
²¹ Department of Pediatrics , University of Ulsan College of Medicine , Asan Medical Center Children's Hospital , Seoul , Republic of Korea.
²² Department of Gastroenterology and Clinical Nutrition , Royal Children's Hospital , Melbourne , Australia.
²³ Mazumdar Shaw Medical Center , Narayana Health , Bangalore , India.
²⁴ Department of Paediatric Gastroenterology , Starship Child Health , Auckland , New Zealand.
²⁵ Division of Pediatric Gastroenterology, Hepatology and Nutrition , University of Utah , Salt Lake City , Utah , USA.
²⁶ 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.
²⁷ Leeds Teaching Hospitals NHS Trust , Leeds Children's Hospital , Leeds , UK.
²⁸ Pediatric Gastroenterology and Hepatology Division , Hospital Italiano Buenos Aires , Buenos Aires , Argentina.
²⁹ Department of Pediatrics , Center for Liver, Digestive, and Metabolic Diseases , University Medical Center Groningen , Groningen , The Netherlands.
³⁰ Faculty of Medicine, Department of Paediatrics , University of Malaya , Kuala Lumpur , Malaysia.
³¹ Division of Pediatric Gastroenterology and Hepatology , Department of Pediatrics , University of Pittsburgh School of Medicine , Pittsburgh , Pennsylvania , USA.
³² Division of Paediatric Gastroenterology , Department of Paediatrics and Child Health , Chris Hani Baragwanath Academic Hospital , University of the Witwatersrand , Johannesburg , South Africa.
³³ Division of Gastroenterology , Department of Pediatrics , Ramathibodi Hospital Mahidol University , Bangkok , Thailand.
³⁴ Department of Gastroenterology, Section of Hepatology , Children's Mercy Kansas City , Kansas City , Missouri , USA.
³⁵ Division of Pediatric Gastroenterology, Hepatology, and Nutrition , University of Minnesota , Minneapolis , Minnesota , USA.
³⁶ Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petah Tikva , Israel.
³⁷ Department of Pediatric Gastroenterology and Organ Transplant , Koc University School of Medicine , Istanbul , Turkey.
³⁸ Division of Pediatric Gastroenterology , Department of Pediatrics , Oregon Health and Science University , Portland , Oregon , USA.
³⁹ Pediatric Hepatology and Liver Transplant Department , Hospital Universitari Vall d'Hebron , Barcelona , Spain.
⁴⁰ Department of Pediatric Hepatology , Institute of Liver and Biliary Sciences , New Delhi , India.
⁴¹ Liver Unit , Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham , Birmingham , UK.
⁴² Pediatric Gastroenterology Department , Hospital da Criança de Brasília , Centro Universitário de Brasília , Brasília , Brazil.
⁴³ 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.
⁴⁴ Paediatric and Liver Unit , Department Neurofarba , University of Florence and Meyer Children's University Hospital , Florence , Italy.
⁴⁵ Department of Pediatrics , Children's Hospital & Medical Center and University of Nebraska Medical Center , Omaha , Nebraska , USA.
⁴⁶ Division of Pediatric Gastroenterology and Hepatology , Phoenix Children's Hospital , Phoenix , USA.
⁴⁷ Pediatric Gastroenterology Unit , Regina Margherita Children's Hospital , Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza , Turin , Italy.
⁴⁸ Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul Medical Faculty , Istanbul University , Istanbul , Turkey.
⁴⁹ Solid Organ Transplant Department , Children's Health - Children's Medical Center , Dallas , Texas , USA.
⁵⁰ Department of Pediatric Gastroenterology , Le Bonheur Children's Hospital, The University of Tennessee Health Science Center , Memphis , Texas , USA.
⁵¹ Division of Gastroenterology & Hepatology, First Department of Pediatrics , "Agia Sofia" Children's Hospital , University of Athens , Athens , Greece.
⁵² First Department of Paediatrics , Semmelweis University , Budapest , Hungary.
⁵³ Department of Pediatrics , Medical University of Silesia in Katowice , Katowice , Poland.
⁵⁴ Servizio di Epatologia Pediatrica , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy.
⁵⁵ Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição , Porto Alegre , RS , Brazil.
⁵⁶ Department of Pediatric Gastroenterology , University Medical Center Utrecht , Utrecht , The Netherlands.
⁵⁷ Paediatric Gastroenterology Unit , Cruces University Hospital , Bilbao , Spain.
⁵⁸ Division of Paediatric Gastroenterology and Hepatology , London Health Sciences Centre, Children's Hospital , Western University , London , Ontario , Canada.
⁵⁹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Miami Transplant Institute , University of Miami , Miami , Florida , USA.
⁶⁰ Division of Pediatric Gastroenterology , University of California San Diego, Rady Children's Hospital San Diego , San Diego , California , USA.
⁶¹ Faculty of Health Sciences, Wits Donald Gordon Medical Centre , University of the Witwatersrand , Johannesburg , South Africa.
⁶² Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus , Denmark.
⁶³ Division of Gastroenterology, Hepatology and Nutrition , Children's Hospital of Eastern Ontario , Ottawa , Canada.
⁶⁴ Division of Pediatric Gastroenterology, Hepatology and Nutrition , Department of Pediatrics , University of Rochester Medical Center , Rochester , New York , USA.
⁶⁵ Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Faculty of Medicine , University Medical Center Ljubljana , Ljubljana , Slovenia.
⁶⁶ Section of Pediatric Gastroenterology , Department of Pediatrics , University of Manitoba , Winnipeg , Canada.
⁶⁷ Department of Paediatrics, Gynaecology and Obstetrics , Geneva University Hospitals, University of Geneva , Geneva , Switzerland.
⁶⁸ Pediatric Gastroenterology Hepatology and Nutrition Unit , Hospital Sant Joan de Déu , Esplugues de Llobregat , Spain.
⁶⁹ Department of Pediatrics , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA.
⁷⁰ Department of Pediatrics , Dr. von Hauner Children's Hospital , University Hospital , LMU Munich , Munich , Germany.
⁷¹ Pediatric Gastroenterology Unit , Centro Hospitalar Universitário Do Porto , Porto , Portugal.
⁷² Gastroenterology and Hepatology , Seattle Children's Hospital , Seattle , Washington , USA.
⁷³ 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.
⁷⁴ Harvard Medical School , Massachusetts General Hospital for Children , Boston , Massachusetts , USA.
⁷⁵ Institute of Liver Studies , King's College London , London , UK.
⁷⁶ Toronto General Hospital University Health Network , Toronto , Ontario , Canada.
⁷⁷ Institute of Health Policy, Management and Evaluation , Toronto , Ontario , Canada.

PMID: 36036223
PMCID: PMC9869940
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 < 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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Conflict of interest statement

Binita M. Kamath consults for and received grants from Mirum and Albireo. She consults for Audentes Therapeutics and Third Rock Ventures. Bettina E. Hansen consults for Mirum, Albireo, Chemomab, Calliditas, Intercept and Cyma Bay. She received grants from Mirum, Albireo, Intercept and Cyma Bay. Deirdre A. Kelly consults for, advises, and received grants from Mirum and Albireo. Emmanuel M. Gonzales consults for Albireo, CTRS, Mirum, and Vivet. Henrik Arnell consults for Albireo and Baxter. Henry C. Lin advises Albireo. Emmanuel Jacquemin consults for Laboratoire CTRS France and Vivet Therapeutics France. Kathleen Schwarz consults for and received grants from Gilead. She consults for Mirum. She received grants from Albireo. Kathleen M. Loomes consults for and received grants from Albireo and Mirum. She consults for Travere Therapeutics. Lorenzo D'Antiga consults for Albireo and Mirum. M. Kyle Jensen consults for Albireo and Guidepoint Global. Nanda Kerkar advises Albireo and Mirum. Emanuele Nicastro advises and received grants from Mirum Pharmaceuticals. Noelle H. Ebel consults for Mirum Pharmaceuticals. Rene Romero consults for Albireo and Mirum. He received grants from Gilead. Richard J. Thompson owns stock in, consults for, and advises Generation Bio and Rectify. He consults for, advises, and is on the speakers' bureau for Albireo and Mirum. Rima Fawaz consults for Mirum. She advises Albireo. Ryan T. Fischer is on the speakers' bureau for Albireo and Mirum. Saul J. Karpen consults for Albireo, Intercept, and Mirum. Nancy B. Spinner consults for Mirum and Travere. Wikrom Karnsakul consults for and received grants from Albireo and Gilead. He consults for Mirum.

Figures

**FIGURE 1**
Ascertainment of the GALA Study cohort stratified by patients with Alagille syndrome (ALGS) with and without a history of neonatal cholestasis. Abbreviations: GALA, The Global ALagille Alliance (GALA) Study; *JAG1*, *JAGGED1*; VUS, variant of uncertain significance.

**FIGURE 2**
Cumulative incidence of native liver survival (NLS) in the presence of competing events (liver transplantation [LT] or risk of death without LT; n = 1184) in children with Alagille syndrome (ALGS) who presented with neonatal cholestasis. At 5, 10, and 18 years, the rate of NLS was 66.8%, 54.4%, and 40.3%.

**FIGURE 3**
Patient and graft survival following isolated liver transplantation (LT) in 345 children with Alagille syndrome (ALGS). Patient and graft survival following LT is calculated from the date of LT until retransplantation, death or the date of last known clinical follow‐up. (A) After LT, 10‐ and 20‐year patient survival rates were 91.0% and 88.0%, respectively. (B) After LT, 10‐ and 20‐year graft survival rates were 86.3% and 83.4%, respectively.

**FIGURE 4**
Time to first adverse liver‐related event in 1184 children with Alagille syndrome (ALGS). A Kaplan–Meier analysis revealed by 5, 10, and 18 years, 36.3%, 51.5%, and 66.0% of children with ALGS will experience at least one adverse liver‐related event, respectively.

**FIGURE 5**
Cumulative incidence of clinically evident portal hypertension in an international cohort of children with Alagille syndrome (ALGS). (A) Ultrasound‐confirmed splenomegaly and PLT <150 × 10⁹/L; (B) ascites requiring treatment with diuretics; (C) gastrointestinal varices requiring intervention; (D) clinically evident portal hypertension. Abbreviation: PLT, platelet count.

**FIGURE 6**
Early biochemical predictors for native liver survival in children with Alagille syndrome (ALGS). (A) Median serum total bilirubin levels between >6 and ≤12 months; (B) Median serum total bilirubin levels from the first 12 months of life; (C) Median serum aspartate aminotransferase (AST) levels between >6 and ≤12 months; (D) Median serum AST levels from the first 12 months of life.

See this image and copyright information in PMC

Comment in

The Global Alagille Alliance study: Redefining the natural history of Alagille syndrome.
Habash N, Ibrahim SH. Habash N, et al. Hepatology. 2023 Feb 1;77(2):347-349. doi: 10.1002/hep.32760. Epub 2022 Sep 17. Hepatology. 2023. PMID: 36036191 No abstract available.
Letter to the Editor: Much more needed in natural history of Alagille syndrome.
Singh SP, Mondia N. Singh SP, et al. Hepatology. 2023 Apr 1;77(4):E78. doi: 10.1097/HEP.0000000000000006. Epub 2023 Feb 3. Hepatology. 2023. PMID: 36626631 No abstract available.

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

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