Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study
Issued Date
2023-02-01
Resource Type
ISSN
02709139
eISSN
15273350
Scopus ID
2-s2.0-85138168945
Pubmed ID
36036223
Journal Title
Hepatology
Volume
77
Issue
2
Start Page
512
End Page
529
Rights Holder(s)
SCOPUS
Bibliographic Citation
Hepatology Vol.77 No.2 (2023) , 512-529
Suggested Citation
Vandriel S.M., Li L.T., She H., Wang J.S., Gilbert M.A., Jankowska I., Czubkowski P., Gliwicz-Miedzińska D., Gonzales E.M., Jacquemin E., Bouligand J., Spinner N.B., Loomes K.M., Piccoli D.A., D'Antiga L., Nicastro E., Sokal A., Demaret T., Ebel N.H., Feinstein J.A., Fawaz R., Nastasio S., Lacaille F., Debray D., Arnell H., Fischler B., Siew S., Stormon M., Karpen S.J., Romero R., Kim K.M., Baek W.Y., Hardikar W., Shankar S., Roberts A.J., Evans H.M., Jensen M.K., Kavan M., Sundaram S.S., Chaidez A., Karthikeyan P., Sanchez M.C., Cavalieri M.L., Verkade H.J., Lee W.S., Squires J.E., Hajinicolaou C., Lertudomphonwanit C., Fischer R.T., Larson-Nath C., Mozer-Glassberg Y., Arikan C., Lin H.C., Bernabeu J.Q., Alam S., Kelly D.A., Carvalho E., Ferreira C.T., Indolfi G., Quiros-Tejeira R.E., Bulut P., Calvo P.L., Anal Z., Valentino P.L., Desai D.M., Eshun J., Rogalidou M., Dezsőfi A., Wiecek S., Nebbia G., Pinto R.B., Wolters V.M., Tamara M.L., Zizzo A.N., Garcia J., Schwarz K., Beretta M., Sandahl T.D., Jimenez-Rivera C., Kerkar N., Brecelj J., Mujawar Q., Rock N., Busoms C.M., Karnsakul W., Lurz E., Santos-Silva E., Blondet N., Bujanda L., Shah U., Thompson R.J., Hansen B.E., Kamath B.M. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology Vol.77 No.2 (2023) , 512-529. 529. doi:10.1002/hep.32761 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/88867
Title
Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study
Author(s)
Vandriel S.M.
Li L.T.
She H.
Wang J.S.
Gilbert M.A.
Jankowska I.
Czubkowski P.
Gliwicz-Miedzińska D.
Gonzales E.M.
Jacquemin E.
Bouligand J.
Spinner N.B.
Loomes K.M.
Piccoli D.A.
D'Antiga L.
Nicastro E.
Sokal A.
Demaret T.
Ebel N.H.
Feinstein J.A.
Fawaz R.
Nastasio S.
Lacaille F.
Debray D.
Arnell H.
Fischler B.
Siew S.
Stormon M.
Karpen S.J.
Romero R.
Kim K.M.
Baek W.Y.
Hardikar W.
Shankar S.
Roberts A.J.
Evans H.M.
Jensen M.K.
Kavan M.
Sundaram S.S.
Chaidez A.
Karthikeyan P.
Sanchez M.C.
Cavalieri M.L.
Verkade H.J.
Lee W.S.
Squires J.E.
Hajinicolaou C.
Lertudomphonwanit C.
Fischer R.T.
Larson-Nath C.
Mozer-Glassberg Y.
Arikan C.
Lin H.C.
Bernabeu J.Q.
Alam S.
Kelly D.A.
Carvalho E.
Ferreira C.T.
Indolfi G.
Quiros-Tejeira R.E.
Bulut P.
Calvo P.L.
Anal Z.
Valentino P.L.
Desai D.M.
Eshun J.
Rogalidou M.
Dezsőfi A.
Wiecek S.
Nebbia G.
Pinto R.B.
Wolters V.M.
Tamara M.L.
Zizzo A.N.
Garcia J.
Schwarz K.
Beretta M.
Sandahl T.D.
Jimenez-Rivera C.
Kerkar N.
Brecelj J.
Mujawar Q.
Rock N.
Busoms C.M.
Karnsakul W.
Lurz E.
Santos-Silva E.
Blondet N.
Bujanda L.
Shah U.
Thompson R.J.
Hansen B.E.
Kamath B.M.
Li L.T.
She H.
Wang J.S.
Gilbert M.A.
Jankowska I.
Czubkowski P.
Gliwicz-Miedzińska D.
Gonzales E.M.
Jacquemin E.
Bouligand J.
Spinner N.B.
Loomes K.M.
Piccoli D.A.
D'Antiga L.
Nicastro E.
Sokal A.
Demaret T.
Ebel N.H.
Feinstein J.A.
Fawaz R.
Nastasio S.
Lacaille F.
Debray D.
Arnell H.
Fischler B.
Siew S.
Stormon M.
Karpen S.J.
Romero R.
Kim K.M.
Baek W.Y.
Hardikar W.
Shankar S.
Roberts A.J.
Evans H.M.
Jensen M.K.
Kavan M.
Sundaram S.S.
Chaidez A.
Karthikeyan P.
Sanchez M.C.
Cavalieri M.L.
Verkade H.J.
Lee W.S.
Squires J.E.
Hajinicolaou C.
Lertudomphonwanit C.
Fischer R.T.
Larson-Nath C.
Mozer-Glassberg Y.
Arikan C.
Lin H.C.
Bernabeu J.Q.
Alam S.
Kelly D.A.
Carvalho E.
Ferreira C.T.
Indolfi G.
Quiros-Tejeira R.E.
Bulut P.
Calvo P.L.
Anal Z.
Valentino P.L.
Desai D.M.
Eshun J.
Rogalidou M.
Dezsőfi A.
Wiecek S.
Nebbia G.
Pinto R.B.
Wolters V.M.
Tamara M.L.
Zizzo A.N.
Garcia J.
Schwarz K.
Beretta M.
Sandahl T.D.
Jimenez-Rivera C.
Kerkar N.
Brecelj J.
Mujawar Q.
Rock N.
Busoms C.M.
Karnsakul W.
Lurz E.
Santos-Silva E.
Blondet N.
Bujanda L.
Shah U.
Thompson R.J.
Hansen B.E.
Kamath B.M.
Author's Affiliation
Mazumdar Shaw Medical Center
Ramathibodi Hospital
Institute of Health Policy, Management and Evaluation
Seattle Children's Hospital
Papa Giovanni XXIII Hospital
Université Paris Cité
Miami Transplant Institute
Children’s Hospital of Fudan University
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
Hospital Sant Joan de Déu Barcelona
Institute of Liver and Biliary Sciences
Physiopathologénèse et Traitement des Maladies du Foie
Universidade Federal de Ciencias da Saúde de Porto Alegre
Instytut "Pomnik - Centrum Zdrowia Dziecka"
University of the Witwatersrand Faculty of Health Sciences
Azienda Ospedaliero-Universitaria Meyer
Stanford University School of Medicine
University Medical Center Utrecht
University of California, San Diego
Hospital for Sick Children University of Toronto
Massachusetts General Hospital
University of Minnesota Twin Cities
Osakidetza, Cruces University Hospital
Universiti Malaya
Chris Hani Baragwanath Hospital
National and Kapodistrian University of Athens
University of Colorado School of Medicine
Slaski Uniwersytet Medyczny w Katowicach
The Children's Hospital at Westmead
Royal Children's Hospital, Melbourne
The University of Utah
Universidade de Brasília
Semmelweis Egyetem
University of Rochester Medical Center
Aarhus Universitetshospital
Toronto General Hospital
Univerzitetni Klinični Center Ljubljana
University of Birmingham
Karolinska Universitetssjukhuset
Children's Hospital of Eastern Ontario, Ottawa
Yale School of Medicine
Children's Medical Center Dallas
Doernbecher Children's Hospital
University of Nebraska Medical Center
Schneider Childrens Medical Center Israel
Hopital de Bicetre
Cliniques Universitaires Saint-Luc
Leeds Teaching Hospitals NHS Trust
Hospital Universitari Vall d'Hebron
İstanbul Tıp Fakültesi
Karolinska Institutet
King's College London
Western University
Hôpitaux Universitaires de Genève
University of Manitoba
Instituto Universitario del Hospital Italiano de Buenos Aires
Phoenix Children's Hospital
Osakidetza, Donostia University Hospital
Ospedale Maggiore Policlinico Milano
Koç Üniversitesi
University of Ulsan College of Medicine
Universitair Medisch Centrum Groningen
University of Pennsylvania Perelman School of Medicine
Harvard Medical School
Emory University School of Medicine
University of Tennessee Health Science Center
University of Pittsburgh School of Medicine
Johns Hopkins School of Medicine
Klinikum der Universität München
Children's Mercy Kansas City
Centro Hospitalar Universitário do Porto
Hospital da Criança Conceição
Starship Child Health
Ramathibodi Hospital
Institute of Health Policy, Management and Evaluation
Seattle Children's Hospital
Papa Giovanni XXIII Hospital
Université Paris Cité
Miami Transplant Institute
Children’s Hospital of Fudan University
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
Hospital Sant Joan de Déu Barcelona
Institute of Liver and Biliary Sciences
Physiopathologénèse et Traitement des Maladies du Foie
Universidade Federal de Ciencias da Saúde de Porto Alegre
Instytut "Pomnik - Centrum Zdrowia Dziecka"
University of the Witwatersrand Faculty of Health Sciences
Azienda Ospedaliero-Universitaria Meyer
Stanford University School of Medicine
University Medical Center Utrecht
University of California, San Diego
Hospital for Sick Children University of Toronto
Massachusetts General Hospital
University of Minnesota Twin Cities
Osakidetza, Cruces University Hospital
Universiti Malaya
Chris Hani Baragwanath Hospital
National and Kapodistrian University of Athens
University of Colorado School of Medicine
Slaski Uniwersytet Medyczny w Katowicach
The Children's Hospital at Westmead
Royal Children's Hospital, Melbourne
The University of Utah
Universidade de Brasília
Semmelweis Egyetem
University of Rochester Medical Center
Aarhus Universitetshospital
Toronto General Hospital
Univerzitetni Klinični Center Ljubljana
University of Birmingham
Karolinska Universitetssjukhuset
Children's Hospital of Eastern Ontario, Ottawa
Yale School of Medicine
Children's Medical Center Dallas
Doernbecher Children's Hospital
University of Nebraska Medical Center
Schneider Childrens Medical Center Israel
Hopital de Bicetre
Cliniques Universitaires Saint-Luc
Leeds Teaching Hospitals NHS Trust
Hospital Universitari Vall d'Hebron
İstanbul Tıp Fakültesi
Karolinska Institutet
King's College London
Western University
Hôpitaux Universitaires de Genève
University of Manitoba
Instituto Universitario del Hospital Italiano de Buenos Aires
Phoenix Children's Hospital
Osakidetza, Donostia University Hospital
Ospedale Maggiore Policlinico Milano
Koç Üniversitesi
University of Ulsan College of Medicine
Universitair Medisch Centrum Groningen
University of Pennsylvania Perelman School of Medicine
Harvard Medical School
Emory University School of Medicine
University of Tennessee Health Science Center
University of Pittsburgh School of Medicine
Johns Hopkins School of Medicine
Klinikum der Universität München
Children's Mercy Kansas City
Centro Hospitalar Universitário do Porto
Hospital da Criança Conceição
Starship Child Health
Other Contributor(s)
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.
