A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome.
OBJECTIVE
Liver disease in Alagille syndrome (AGS) is highly variable, ranging from biochemical abnormalities only to end-stage disease. It is not possible to predict whether a child with cholestasis will have improvement or progression of liver disease. This poses a challenge to the clinician in terms of timing therapies. The study aim was to identify laboratory markers present in children younger than 5 years that could predict the ultimate outcome of liver disease in AGS.


METHODS
A retrospective review of laboratory data from 33 subjects with AGS was performed. Patients older than 10 years of age were stratified into mild (22) and severe (11) hepatic outcome groups. Nonparametric analysis was performed on longitudinal data from birth to 5 years to determine association with hepatic outcome. JAGGED1 mutational analysis was performed on available samples.


RESULTS
The following variables were statistically different between severe and mild outcome groups: total bilirubin (TB, P = 0.0001), conjugated bilirubin (CB, P = 0.0066), and cholesterol (P = 0.0022). Further analysis revealed cutoff values that differentiated between severe and mild outcomes; TB 6.5 mg/dL (111 micromol/L), CB 4.5 mg/dL (77 micromol/L), and cholesterol 520 mg/dL (13.5 mmol/L). Genetic analysis of JAGGED1 mutations did not reveal genotype-phenotype correlation.


CONCLUSIONS
TB >6.5 mg/dL, CB >4.5 mg/dL, and cholesterol >520 mg/dL in children younger than 5 years of age are likely to be associated with severe liver disease in later life. These data represent cutoff values below which a child is likely to have a benign outcome and above which more aggressive therapy may be warranted, and can thus be used to guide management.
Kamath
Binita M
BM
Division of Gastroenterology, Children's Hospital of Philadelphia, USA. binita.kamath@sickkids.ca
Munoz
Pedro S
PS
Bab
Natalie
N
Baker
Alastair
A
Chen
Zhongxue
Z
Spinner
Nancy B
NB
Piccoli
David A
DA
D016738:Alagille Syndrome / Q000097:blood* / Q000235:genetics; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood*; D018450:Disease Progression; D005838:Genotype; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008107:Liver Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics; D008137:Longitudinal Studies; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D012016:Reference Values; D012189:Retrospective Studies; D000072099:Serrate-Jagged Proteins; D012720:Severity of Illness Index
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D002784:Cholesterol; D001663:Bilirubin