Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort

Abstract

Background & Aims: High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort. Approach & Results: MMP-7 was measured in serum samples of 399 cholestatic infants in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p=0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved-fluorescence energy transfer (TR-FRET) assays. Discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an area under receiver operating curve (AUROC) of 0.90 (confidence interval [CI] 0.87-0.94). At cutoff 52.8 ng/mL, it produced sensitivity=94.03%, specificity=77.78%, positive predictive value=64.46%, and negative predictive value=96.82% for BA. AUROC for gamma-glutamyl transferase (GGT)=0.81 (CI 0.77-0.86), stool color=0.68 (CI 0.63-0.73), and pathology=0.84 (CI 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+GGT AUROC to 0.91 (CI 0.88-0.95). Serum concentrations produced by TR-FRET differed from single-plex, with optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs. Conclusions: Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in evaluation of cholestatic infants may simplify diagnostic algorithms and shorten time to hepatoportoenterostomy.

Serum matrix metalloproteinase-7 (MMP-7): As good as it gets?

“…Our own study, from Kings College Hospital, London, UK was retrospective, used biobank samples with 32 infants with BA and 27 cholestatic controls, and was much less discriminatory than the Asian series with an AUROC of 0.83 (sensitivity: 84%, specificity: 78%) 7 . The current study (BA, n=201), again using ChiLDRen stored biobank serum, now back in North America, is somewhat in between at 0.90 (CI: 0.87–0.94) 8 …”

“…[7] The current study (BA, n = 201), again using ChiLDRen stored biobank serum, now back in North America, is somewhat in between at 0.90 (CI: 0.87-0.94). [8] There have been some disconcerting methodological observations in that the cutoff levels varied considerably between studies. This appeared during the wave of enthusiastic Asian studies and was felt to be due to the actual choice of assay.…”