A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome.

Objectives—Liver disease in Alagille syndrome 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 under the age of 5 years that could predict the ultimate outcome of liver disease in Alagille syndrome. Methods—A retrospective review of laboratory data from 33 Alagille syndrome subjects was performed. Patients greater than 10 years of age were stratified into mild (22) and severe (11) hepatic outcome groups. Non-parametric analysis was performed on longitudinal data from birth-5years 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 (p= 0.0001), conjugated bilirubin (p =0.0066), and cholesterol (p =0.0022). Further analysis revealed cutoff values that differentiated between severe and mild outcomes; total bilirubin 6.5mg/dL(111micromol/L), conjugated bilirubin 4.5mg/dL(77micromol/L) and cholesterol 520mg/dL(13.5mmol/L). Genetic analysis of JAGGED1 mutations did not reveal genotype-phenotype correlation. Conclusions—Total bilirubin above 6.5mg/dL, conjugated bilirubin above 4.5mg/dL and cholesterol above 520mg/dL under the age of 5 years 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.