[en] BACKGROUND: 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.
METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-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.
RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children 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% 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 novel therapies.
Disciplines :
Pediatrics
Author, co-author :
Vandriel, Shannon M ; The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, Canada
Li, Li-Ting; Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
She, Huiyu ; Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
Wang, Jian-She; Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
Gilbert, Melissa A; 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, Irena; The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
Czubkowski, Piotr; The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
Gliwicz-Miedzińska, Dorota; The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
Gonzales, Emmanuel M ; 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, Emmanuel; 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, Jérôme; 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
Spinner, Nancy B; 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
Loomes, Kathleen M
Piccoli, David A
D'Antiga, Lorenzo ; Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy
Nicastro, Emanuele; Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy
Sokal, Étienne ; Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium
Demaret, Tanguy ; Université de Liège - ULiège > Faculté de Médecine > Mast. spéc. gén. clin. ; Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium
Ebel, Noelle H; Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, United States
Feinstein, Jeffrey A; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California, United States
Fawaz, Rima; Yale University School of Medicine, Department of Pediatrics, New Haven, United States
Nastasio, Silvia ; Boston Children's Hospital and Harvard Medical School, Division of Gastroenterology, Hepatology, & Nutrition, Boston, United States
Lacaille, Florence; Department of Pediatric Gastroenterology, and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France
Debray, Dominique; 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, Henrik; 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, Björn; Astrid Lindgren Children's Hospital, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Paediatric Digestive Diseases, Stockholm, Sweden
Siew, Susan; The Children's Hospital at Westmead, Department of Gastroenterology, Sydney, Australia
Stormon, Michael; The Children's Hospital at Westmead, Department of Gastroenterology, Sydney, Australia
Karpen, Saul J; Children's Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, United States
Romero, Rene; Children's Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, United States
Kim, Kyung Mo; Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea, Republic of
Baek, Woo Yim; Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea, Republic of
Hardikar, Winita; Royal Children's Hospital, Department of Gastroenterology and Clinical Nutrition, Melbourne, Australia
Shankar, Sahana; Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India
Roberts, Amin J; Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand
Evans, Helen M; Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand
Jensen, M Kyle; University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Salt Lake City, United States
Kavan, Marianne; University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Salt Lake City, United States
Sundaram, Shikha S; 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, Alexander; 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
Sanchez, Maria Camila; Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina
Cavalieri, Maria Lorena; Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina
Verkade, Henkjan J; University Medical Center Groningen, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen, Netherlands
Lee, Way Seah; Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
Squires, James E ; University of Pittsburgh School of Medicine, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Pittsburgh, United States
Hajinicolaou, Christina; Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa
Lertudomphonwanit, Chatmanee; Ramathibodi Hospital Mahidol University, Division of Gastroenterology, Department of Pediatrics, Bangkok, Thailand
Fischer, Ryan T ; Children's Mercy Kansas City, Department of Gastroenterology, Section of Hepatology, Kansas City, United States
Larson-Nath, Catherine; University of Minnesota, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Minneapolis, United States
Mozer-Glassberg, Yael; Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
Arikan, Cigdem; Koc University School of Medicine, Department of Pediatric Gastroenterology and Organ Transplant, Istanbul, Turkey
Lin, Henry C; Oregon Health and Science University, Division of Pediatric Gastroenterology, Department of Pediatrics, Portland, United States
Alam, Seema ; Institute of Liver and Biliary Sciences, Department of Pediatric Hepatology, New Delhi, India
Kelly, Deirdre; Liver Unit, Birmingham Women's & Children's Hospital NHS Trust and University of Birmingham, Birmingham, United Kingdom
Carvalho, Elisa; Pediatric Gastroenterology Department, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brazil
Ferreira, Cristina Targa; 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, Giuseppe; Department Neurofarba, University of Florence and Meyer Children's University Hospital, Paediatric and Liver Unit, Florence, Italy
Quiros-Tejeira, Ruben E; Children's Hospital & Medical Center and University of Nebraska Medical Center, Department of Pediatrics, Omaha, United States
Bulut, Pinar; Phoenix Children's Hospital, Division of Pediatric Gastroenterology and Hepatology, Phoenix, United States
Calvo, Pier Luigi; Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy
Önal, Zerrin; Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey
Valentino, Pamela L ; Yale University School of Medicine, Department of Pediatrics, New Haven, United States
Desai, Dev M; Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, United States
Eshun, John; Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital and The University of Tennessee Health Science Center, Memphis, United States
Rogalidou, Maria; Division of Gastroenterology & Hepatology,"Agia Sofia" Children's Hospital, First Department of Pediatrics, University of Athens, Athens, Greece
Dezsőfi, Antal; First Department of Paediatrics, Semmelweis University, Budapest, Hungary
Wiecek, Sabina; Medical University of Silesia in Katowice, Department of Pediatrics, Katowice, Poland
Nebbia, Gabriella; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy
Borges Pinto, Raquel; Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil
Wolters, Victorien M; Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands
Tamara, María Legarda; Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain
Zizzo, Andréanne N ; Children's Hospital, London Health Sciences Centre, Division of Paediatric Gastroenterology and Hepatology, Western University, London, Ontario, Canada
Garcia, Jennifer; Division of Pediatric Gastroenterology, Hepatology and Nutrition/ Miami Transplant Institute, University of Miami, Miami, United States
Schwarz, Kathleen; University of California San Diego, Rady Children's Hospital San Diego, Division of Pediatric Gastroenterology, San Diego, United States
Beretta, Marisa; Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa
Sandahl, Thomas Damgaard; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
Jimenez-Rivera, Carolina; Children's Hospital of Eastern Ontario, Division of Gastroenterology, Hepatology and Nutrition, Ottawa, Canada
Kerkar, Nanda; University of Rochester Medical Center, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rochester, New York, United States
Brecelj, Jernej; University Medical Center Ljubljana, Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, Ljubljana, Slovenia
Mujawar, Quais; University of Manitoba, Section of Pediatric Gastroenterology, Department of Pediatrics, Winnipeg, Canada
Rock, Nathalie; Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
Busoms, Cristina Molera; Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Karnsakul, Wikrom; Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, United States
Lurz, Eberhard; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
Santos-Silva, Ermelinda; CentroHospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal
Blondet, Niviann; Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, United States
Bujanda, Luis; 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, Uzma; Harvard Medical School, Massachusetts General Hospital for Children, Boston, United States
Thompson, Richard J; Institute of Liver Studies, King's College London, London, United Kingdom
Hansen, Bettina E; Toronto General Hospital University Health Network, Toronto, Canada ; Institute of Health Policy, Management and Evaluation, Toronto, Canada
Kamath, Binita M; The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, Canada
Alagille D, Odièvre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975;86:63–71.
Alagille D, Estrada A, Hadchouel M, Gautier M, Odièvre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987;110:195–200.
Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29:822–9.
Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G, McEldrew D, et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40:2197–220.
Kamath BM, Ye W, Goodrich NP, Loomes KM, Romero R, Heubi JE, et al. Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol Commun. 2020;4:387–98.
Shneider BL, Spino C, Kamath BM, Magee JC, Bass LM, Setchell KD, et al. Placebo-controlled randomized trial of an intestinal bile salt transport inhibitor for pruritus in Alagille syndrome. Hepatol Commun. 2018;2:1184–98.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81.
Aghazadeh-Attari J, Mobaraki K, Ahmadzadeh J, Mansorian B, Mohebbi I. Quality of observational studies in prestigious journals of occupational medicine and health based on Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: a cross-sectional study. BMC Res Notes. 2018;11:266.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.
Bass LM, Shneider BL, Henn L, Goodrich NP, Magee JC, Childhood Liver Disease Research Network. Clinically evident portal hypertension: an operational research definition for future investigations in the pediatric population. J Pediatr Gastroenterol Nutr. 2019;68:763–7.
Shneider BL, Abel B, Haber B, Karpen SJ, Magee JC, Romero R, et al. Portal hypertension in children and young adults with biliary atresia. J Pediatr Gastroenterol Nutr. 2012;55:567–73.
Mouzaki M, Bass LM, Sokol RJ, Piccoli DA, Quammie C, Loomes KM, et al. Early life predictive markers of liver disease outcome in an international, multicentre cohort of children with Alagille syndrome. Liver Int. 2016;36:755–60.
Gonzales E, Hardikar W, Stormon M, Baker A, Hierro L, Gliwicz D, et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021;398:1581–92.
Karpen SJ, Kamath BM, Alexander JJ, Ichetovkin I, Rosenthal P, Sokol RJ, et al. Use of a comprehensive 66-gene cholestasis sequencing panel in 2171 cholestatic infants, children, and young adults. J Pediatr Gastroenterol Nutr. 2021;72:654–60.
Arnon R, Annunziato R, Schiano T, Miloh T, Baisley M, Sogawa H, et al. Orthotopic liver transplantation for adults with Alagille syndrome. Clin Transplant. 2012;26:E94–100.
Kamath BM, Yin W, Miller H, Anand R, Rand EB, Alonso E, et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 2012;18:940–8.
Luong R, Feinstein JA, Ma M, Ebel NH, Wise-Faberowski L, Zhang Y, et al. Outcomes in patients with Alagille syndrome and complex pulmonary artery disease. J Pediatr. 2021;229:86–94.e4.
Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. 1995;127:220–4.
Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall TR, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. 1999;29:431–7.
