Research ArticleBiliary Atresia

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

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Science Translational Medicine  22 Nov 2017:
Vol. 9, Issue 417, eaan8462
DOI: 10.1126/scitranslmed.aan8462

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Bile duct injury marker to the rescue

Biliary atresia is a poorly understood pediatric disease, which is associated with progressive bile duct obstruction and liver injury in young infants. Early diagnosis of this condition is crucial for restoring bile flow and protecting the liver from irreversible damage, but the disease can be difficult to distinguish from more common causes of cholestasis. By performing proteomics on large sets of patient samples, Lertudomphonwanit et al. identified the serum concentration of a protein called matrix metalloproteinase-7 as a promising diagnostic marker of this disease, especially when used together with γ-glutamyltranspeptidase, a less specific marker of cholestasis. The authors also investigated the mechanistic role of matrix metalloproteinase-7 in bile ducts, supporting the biological relevance of this marker.

Abstract

Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with γ-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.

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