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

Shannon M Vandriel; Li-Ting Li; Huiyu She; Jian-She Wang; Melissa A Gilbert; Irena Jankowska; Piotr Czubkowski; Dorota Gliwicz-Miedzińska; Emmanuel M Gonzales; Emmanuel Jacquemin; Jérôme Bouligand; Nancy B Spinner; Kathleen M Loomes; David A Piccoli; Lorenzo D'Antiga; Emanuele Nicastro; Étienne Sokal; Tanguy Demaret; Noelle H Ebel; Jeffrey A Feinstein; Rima Fawaz; Silvia Nastasio; Florence Lacaille; Dominique Debray; Henrik Arnell; Björn Fischler; Susan Siew; Michael Stormon; Saul J Karpen; Rene Romero; Kyung Mo Kim; Woo Yim Baek; Winita Hardikar; Sahana Shankar; Amin J Roberts; Helen M Evans; M Kyle Jensen; Marianne Kavan; Shikha S Sundaram; Alexander Chaidez; Palaniswamy Karthikeyan; Maria Camila Sanchez; Maria Lorena Cavalieri; Henkjan J Verkade; Way Seah Lee; James E Squires; Christina Hajinicolaou; Chatmanee Lertudomphonwanit; Ryan T Fischer; Catherine Larson-Nath; Yael Mozer-Glassberg; Cigdem Arikan; Henry C Lin; Jesus Quintero Bernabeu; Seema Alam; Deirdre A Kelly; Elisa Carvalho; Cristina Targa Ferreira; Giuseppe Indolfi; Ruben E Quiros-Tejeira; Pinar Bulut; Pier Luigi Calvo; Zerrin Önal; Pamela L Valentino; Dev M Desai; John Eshun; Maria Rogalidou; Antal Dezsőfi; Sabina Wiecek; Gabriella Nebbia; Raquel Borges Pinto; Victorien M Wolters; María Legarda Tamara; Andréanne N Zizzo; Jennifer Garcia; Kathleen Schwarz; Marisa Beretta; Thomas Damgaard Sandahl; Carolina Jimenez-Rivera; Nanda Kerkar; Jernej Brecelj; Quais Mujawar; Nathalie Rock; Cristina Molera Busoms; Wikrom Karnsakul; Eberhard Lurz; Ermelinda Santos-Silva; Niviann Blondet; Luis Bujanda; Uzma Shah; Richard J Thompson; Bettina E Hansen; Binita M Kamath; Global ALagille Alliance (GALA) Study Group

doi:10.1002/hep.32761

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

Hepatology. 2023 Feb 1;77(2):512-529. doi: 10.1002/hep.32761. Epub 2022 Oct 13.

Authors

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.

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.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Alagille Syndrome* / epidemiology
Child
Cholestasis*
Female
Humans
Hypertension, Portal* / etiology
Male
Retrospective Studies

Grants and funding

UL1 TR001863/TR/NCATS NIH HHS/United States