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Published on: April 28, 2020
A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome
Binita M Kamath1, Pedro S Munoz, Natalie Bab
1Division of Gastroenterology, Children's Hospital of Philadelphia, USA. binita.kamath@sickkids.ca
Insights
In Alagille syndrome (AGS), high total bilirubin, conjugated bilirubin, and cholesterol levels in children under five can predict severe liver disease. These markers help guide timely and aggressive treatment strategies for AGS patients.
Area of Science:
- Pediatric Hepatology
- Genetic Liver Diseases
- Biochemical Markers
Background:
- Alagille syndrome (AGS) presents with highly variable liver disease, making prediction of progression challenging.
- Current methods lack the ability to reliably predict the clinical course of liver disease in young AGS patients.
- Accurate prediction is crucial for timely therapeutic intervention in pediatric AGS cases.
Purpose of the Study:
- To identify early laboratory markers in children younger than 5 years with AGS.
- To establish predictive criteria for the ultimate severity of liver disease in AGS.
- To aid clinicians in timing therapeutic strategies for AGS.
Main Methods:
- Retrospective review of laboratory data from 33 AGS subjects.
- Stratification of patients (>10 years) into mild (22) and severe (11) hepatic outcome groups.
- Nonparametric analysis of longitudinal data (birth to 5 years) and JAGGED1 mutational analysis.
Main Results:
- Total bilirubin (TB), conjugated bilirubin (CB), and cholesterol levels were significantly different between severe and mild outcome groups.
- Established cutoff values: TB >6.5 mg/dL, CB >4.5 mg/dL, cholesterol >520 mg/dL.
- JAGGED1 mutation analysis did not correlate with AGS genotype-phenotype.
Conclusions:
- Elevated TB, CB, and cholesterol in children <5 years predict severe liver disease in AGS.
- These biochemical markers provide crucial cutoff values for predicting liver disease outcomes.
- Findings can guide management decisions, indicating when more aggressive therapy may be warranted.
Objectives:
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.
