title: Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome.
abstract: Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10-20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome.
  
  
  
  Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected.
  
  
  
  Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups (P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome (P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792.
  
  
  
  The long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin between the ages of 12-24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Marialena
authors.initials: M
authors.lastname: Mouzaki
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Bass
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sokol
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Piccoli
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Quammie
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Loomes
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Heubi
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Hertel
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Beatrix Children's Hospital, University Medical Center, Groningen, Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Scheenstra
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Nemours/AI. duPont Hospital for Children, Wilmington, DW, USA.
authors.forename: Katryn
authors.initials: K
authors.lastname: Furuya
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Nemours/AI. duPont Hospital for Children, Wilmington, DW, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Kutsch
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Robbins
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Venkat
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, UCSF Benioff Children's Hospital, San Francisco, CA, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenthal
authors.affiliation: Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.affiliation: Paediatric Liver Centre, King's College Hospital, London, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Baker
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Binita M
authors.initials: BM
authors.lastname: Kamath
mesh_terms: D016738:Alagille Syndrome / Q000473:pathology* / Q000503:physiopathology*; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002675:Child, Preschool; D002779:Cholestasis / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood; D005060:Europe; D005260:Female; D006801:Humans; D007223:Infant; D007391:International Cooperation; D008103:Liver Cirrhosis / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D009656:North America; D012372:ROC Curve; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D002784:Cholesterol; D001663:Bilirubin
keywords: Alagille syndrome; cholestasis; outcome; paediatric