Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study
Por:
Vandriel SM, Li LT, She H, Wang JS, Gilbert MA, Jankowska I, Czubkowski P, Gliwicz-Miedzinska D, Gonzales EM, Jacquemin E, Bouligand J, Spinner NB, Loomes KM, Piccoli DA, D'Antiga L, Nicastro E, Sokal É, Demaret T, Ebel NH, Feinstein JA, Fawaz R, Nastasio S, Lacaille F, Debray D, Arnell H, Fischler B, Siew S, Stormon M, Karpen SJ, Romero R, Kim KM, Baek WY, Hardikar W, Shankar S, Roberts AJ, Evans HM, Jensen MK, Kavan M, Sundaram SS, Chaidez A, Karthikeyan P, Sanchez MC, Cavalieri ML, Verkade HJ, Lee WS, Squires JE, Hajinicolaou C, Lertudomphonwanit C, Fischer RT, Larson-Nath C, Mozer-Glassberg Y, Arikan C, Lin HC, Quintero Bernabeu J, Alam S, Kelly D, Carvalho E, Ferreira CT, Indolfi G, Quiros-Tejeira RE, Bulut P, Calvo PL, Önal Z, Valentino PL, Desai DM, Eshun J, Rogalidou M, Dezsofi A, Wiecek S, Nebbia G, Borges Pinto R, Wolters VM, Tamara ML, Zizzo AN, Garcia J, Schwarz K, Beretta M, Sandahl TD, Jimenez-Rivera C, Kerkar N, Brecelj J, Mujawar Q, Rock N, Molera C, Karnsakul W, Lurz E, Santos-Silva E, Blondet N, Bujanda L, Shah U, Thompson RJ, Hansen BE and Kamath BM
Publicada:
1 feb 2023
Ahead of Print:
1 oct 2022
Resumen:
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 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.
Filiaciones:
Vandriel SM:
The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, Canada
Li LT:
Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
She H:
Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
Wang JS:
Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
Gilbert MA:
The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania, United States
Jankowska I:
The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
Czubkowski P:
The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
Gliwicz-Miedzinska D:
The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
Gonzales EM:
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. Université Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hepatinov, University of Paris-Saclay, Orsay, France
Jacquemin E:
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. Université Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hepatinov, University of Paris-Saclay, Orsay, France
Bouligand J:
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, 7The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Philadelphia, Pennsylvania, United States
Spinner NB:
The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania, United States
D'Antiga L:
Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy
Nicastro E:
Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy
Sokal É:
Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium
Demaret T:
Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium
Ebel NH:
Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, United States
Feinstein JA:
Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California, United States
Fawaz R:
Yale University School of Medicine, Department of Pediatrics, New Haven, United States
Nastasio S:
Boston Children's Hospital and Harvard Medical School, Division of Gastroenterology, Hepatology, & Nutrition, Boston, United States
Lacaille F:
Department of Pediatric Gastroenterology, and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France
Debray D:
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
Arnell H:
Astrid Lindgren Children's Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
Fischler B:
Astrid Lindgren Children's Hospital, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Paediatric Digestive Diseases, Stockholm, Sweden
Siew S:
The Children's Hospital at Westmead, Department of Gastroenterology, Sydney, Australia
Stormon M:
The Children's Hospital at Westmead, Department of Gastroenterology, Sydney, Australia
Karpen SJ:
Children's Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, United States
Romero R:
Children's Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, United States
Kim KM:
Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea, Republic of
Baek WY:
Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea, Republic of
Hardikar W:
Royal Children's Hospital, Department of Gastroenterology and Clinical Nutrition, Melbourne, Australia
Shankar S:
Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India
Roberts AJ:
Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand
Evans HM:
Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand
Jensen MK:
University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Salt Lake City, United States
Kavan M:
University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Salt Lake City, United States
Sundaram SS:
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, United States
Chaidez A:
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, United States
Karthikeyan P:
Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, United Kingdom
Sanchez MC:
Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina
Cavalieri ML:
Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina
Verkade HJ:
University Medical Center Groningen, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen, Netherlands
Lee WS:
Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
Squires JE:
University of Pittsburgh School of Medicine, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Pittsburgh, United States
Hajinicolaou C:
Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa
Lertudomphonwanit C:
Ramathibodi Hospital Mahidol University, Division of Gastroenterology, Department of Pediatrics, Bangkok, Thailand
Fischer RT:
Children's Mercy Kansas City, Department of Gastroenterology, Section of Hepatology, Kansas City, United States
Larson-Nath C:
University of Minnesota, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Minneapolis, United States
Mozer-Glassberg Y:
Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
Arikan C:
Koc University School of Medicine, Department of Pediatric Gastroenterology and Organ Transplant, Istanbul, Turkey
Lin HC:
Oregon Health and Science University, Division of Pediatric Gastroenterology, Department of Pediatrics, Portland, United States
Quintero Bernabeu J:
Hospital Universitari Vall d'Hebron, Pediatric Hepatology and Liver Transplant Department, Barcelona, Spain
Alam S:
Institute of Liver and Biliary Sciences, Department of Pediatric Hepatology, New Delhi, India
Kelly D:
Liver Unit, Birmingham Women's & Children's Hospital NHS Trust and University of Birmingham, Birmingham, United Kingdom
Carvalho E:
Pediatric Gastroenterology Department, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brazil
Ferreira CT:
Pediatric Gastroenterology Service, Hospital da Criança Santo Antônio, Universidade Federal de Ciências da Saúde de Porto Alegre, Complexo Hospitalar Santa Casa, Porto Alegre, RS, Brazil
Indolfi G:
Department Neurofarba, University of Florence and Meyer Children's University Hospital, Paediatric and Liver Unit, Florence, Italy
Quiros-Tejeira RE:
Children's Hospital & Medical Center and University of Nebraska Medical Center, Department of Pediatrics, Omaha, United States
Bulut P:
Phoenix Children's Hospital, Division of Pediatric Gastroenterology and Hepatology, Phoenix, United States
Calvo PL:
Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy
Önal Z:
Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey
Valentino PL:
Yale University School of Medicine, Department of Pediatrics, New Haven, United States
Desai DM:
Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, United States
Eshun J:
Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital and The University of Tennessee Health Science Center, Memphis, United States
Rogalidou M:
Division of Gastroenterology & Hepatology,"Agia Sofia" Children's Hospital, First Department of Pediatrics, University of Athens, Athens, Greece
Dezsofi A:
First Department of Paediatrics, Semmelweis University, Budapest, Hungary
Wiecek S:
Medical University of Silesia in Katowice, Department of Pediatrics, Katowice, Poland
Nebbia G:
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy
Borges Pinto R:
Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil
Wolters VM:
Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands
Tamara ML:
Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain
Zizzo AN:
Children's Hospital, London Health Sciences Centre, Division of Paediatric Gastroenterology and Hepatology, Western University, London, Ontario, Canada
Garcia J:
Division of Pediatric Gastroenterology, Hepatology and Nutrition/ Miami Transplant Institute, University of Miami, Miami, United States
Schwarz K:
University of California San Diego, Rady Children's Hospital San Diego, Division of Pediatric Gastroenterology, San Diego, United States
Beretta M:
Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa
Sandahl TD:
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
Jimenez-Rivera C:
Children's Hospital of Eastern Ontario, Division of Gastroenterology, Hepatology and Nutrition, Ottawa, Canada
Kerkar N:
University of Rochester Medical Center, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rochester, New York, United States
Brecelj J:
University Medical Center Ljubljana, Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, Ljubljana, Slovenia
Mujawar Q:
University of Manitoba, Section of Pediatric Gastroenterology, Department of Pediatrics, Winnipeg, Canada
Rock N:
Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
Molera C:
Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Karnsakul W:
Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, United States
Lurz E:
Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
Santos-Silva E:
CentroHospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal
Blondet N:
Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, United States
Bujanda L:
Department of Hepatology and Gastroenterology, Bioodonostia 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
Shah U:
Harvard Medical School, Massachusetts General Hospital for Children, Boston, United States
Thompson RJ:
Institute of Liver Studies, King's College London, London, United Kingdom
Hansen BE:
Toronto General Hospital University Health Network, Toronto, Canada
Institute of Health Policy, Management and Evaluation, Toronto, Canada
Kamath BM:
The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, Canada
Green Submitted, gold
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