A number of serum biomarkers were investigated for their ability to predict liver stiffness in pediatric cholestatic liver diseases including alpha-1 antitrypsin deficiency (AATD), Alagille syndrome (ALGS), and biliary atresia (BA).

According to a study published in Hepatology, connective tissue growth factor (CTGF) was negatively correlated with liver stiffness measurements (R =-.38; P =.01) in patients with AATD. The correlation remained after adjustments for covariates (P =.004). Adding CTGF to a prediction model that already included aspartate aminotransferase (AST) to platelet ratio index (APRI), total bilirubin, and spleen size improved R2 from .524 to .577.

None of the biomarkers investigated had significant correlations with liver stiffness measurement values in ALGS patients. However, some were correlated with each other in these patients, however, including lysyl oxidase (LOX) with Mac-2-binding protein (Mac-2BP), interleukin-9 (IL-9) with endoglin, and matrix metalloproteinase-7 (MMP-7) with tissue inhibitor matrix metalloproteinase 1 (TIMP-1). TIMP-1 and IL-8 were also correlated with AST, APRI, bilirubin, and pediatric end-stage liver disease.

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In patients with BA, liver stiffness measurements were found to be positively correlated with IL-8 (P <.001), MMP-7 (P <.001), and endoglin (P =.02). Adding IL-8 and MMP-7 to a prediction model of liver stiffness measurements independently increased R2 values significantly.

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“As [liver stiffness measurements] via transient elastography is not yet clinically available or a standard of care in most pediatric hospitals, these commercially available biomarkers may offer additional non-invasive tools to guide decision making,” the authors said.

“Future investigations of imaging and serum biomarkers in pediatric cholestasis should use disease-specific thresholds and would benefit from evaluation of change in biomarker levels over time as predictors of clinical outcomes,” the authors suggested.

The study included a total of 330 participants enrolled in the FibroScan in Pediatric Cholestatic Liver Disease (FORCE; NCT02922751) study. The cohort was made up of 187 patients with BA, 78 with AATD, and 65 with ALGS. Liver stiffness was measured using vibration-controlled transient elastography. Biomarkers were analyzed through a targeted ELISA-based panel of 9 biomarkers—LOX, TIMP1, CTGF, IL-8, endoglin, periostin, Mac2-BP, MMP-3, and MMP-7.


Leung DH, Devaraj S, Goodrich NP, et al. Serum biomarkers correlated with liver stiffness assessed in a multi-center study of pediatric cholestatic liver disease. Hepatology. Published online September 7, 2022. doi:10.1002/hep.32777