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.

胆道闭锁是一种复杂发病机制的进行性婴儿胆管病变。尽管早期诊断和手术是治疗反应的最佳预测指标，但当前的诊断方法不精确且耗时。在诊断胆道闭锁和其他胆汁淤积综合症（用作疾病控制）时，我们使用了大规模的定量血清蛋白质组学来鉴定疾病的生物标志物。在70名受试者的发现队列中，主要生物标志物是基质金属蛋白酶7（MMP-7），在两个验证队列中，它们保留了胆道闭锁的高区别特征。值得注意的是，当MMP-7与胆汁淤积的标志物γ-谷氨酰转肽酶（GGT）结合使用时，诊断性能达到95％。利用人体组织和胆道闭锁的实验模型，我们发现MMP-7主要由胆管细胞表达，在上皮损伤后释放，并促进实验性疾病表型。因此，我们建议血清MMP-7（单独或与GGT联合使用）是胆道闭锁的诊断生物标志物，可作为治疗靶标。