About this item:

86 Views | 17 Downloads

Author Notes:

Binita M. Kamath, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8M, Canada. Email: binita.kamath@sickkids.ca

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

We would like to thank the following agencies for their generous funding support: The Alagille Syndrome Alliance, Mirum Pharmaceuticals, Inc., and Albireo Pharma, Inc., who provided unrestricted educational grants to the Hospital for Sick Children (SickKids Foundation). The National Natural Science Foundation of China (81873543 and 81570468) provided funding to the Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China. The authors would also like to acknowledge Mikayla Sonnenberg, Aly Fawzy, Mila Valcic, and Corey Forster from the GALA DCC at the Hospital for Sick Children. Finally, the authors would like to thank all local research teams who helped with data collection.

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.

Subjects:

Research Funding:

This study received funding support from the following agencies: The Alagille Syndrome Alliance, Mirum Pharmaceuticals, Inc., and Albireo Pharma, Inc., who provided unrestricted educational grants to the Hospital for Sick Children (SickKids Foundation). The study sponsors were not involved in the conduct of the research study or preparation of the manuscript.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • TRANSPLANTATION
  • CHOLESTASIS
  • OUTCOMES
  • PAUCITY
  • ADULTS

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

Show all authors Show less authors

Tools:

Journal Title:

HEPATOLOGY

Volume:

Volume 77, Number 2

Publisher:

, Pages 512-529

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
Export to EndNote