Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China.
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
J Transl Med. 2024 Jul 8;22(1):636. doi: 10.1186/s12967-024-05442-x.
Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients.
This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA).
The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively.
The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.
准确快速地区分胆汁淤积患儿中的胆道闭锁（BA）至关重要。基质金属蛋白酶-7（MMP-7）有望成为 BA 的诊断标志物。本研究旨在探讨特定年龄的血清 MMP-7 对鉴别 BA 和其他胆汁淤积性儿科患者的准确性。
这是一项单中心诊断准确性和验证性研究，包括回顾性和前瞻性队列。使用 ELISA 试剂盒测量血清 MMP-7 浓度，在无肝胆疾病的 0 至 365 天龄健康婴儿队列（n=284）中研究其随年龄的变化轨迹。临床 BA 诊断基于术中胆管造影和随后的组织学检查。在回顾性队列（n=318，172 例 BA）中评估特定年龄的血清 MMP-7 截断值的诊断准确性，并在前瞻性队列（n=687，包括 395 例 BA）中进行验证。
MMP-7 浓度随年龄呈非线性下降，在健康新生儿中水平较高，且在新生儿胆汁淤积症中截断值更高。回顾性队列的 ROC 曲线下面积（AUROC）为 0.967（95%置信区间 [CI]：0.946-0.988），18ng/mL 的截断值可获得 93.0%（95%CI：88.1-96.3%）、93.8%（95%CI：88.6-97.1%）、94.7%（95%CI：90.1-97.5%）和 91.9%（95%CI：86.4-95.8%）的敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）。MMP-7 在更大的前瞻性队列中成功验证了其性能，导致诊断敏感性为 95.9%（379/395；95%CI：93.5-97.7%）、特异性为 87.3%（255/292；95%CI：83.0-90.9%）、PPV 为 91.1%（379/416；95%CI：87.9-93.7%）和 NPV 为 94.1%（255/271；95%CI：90.6-96.6%）。此外，0-30 天龄婴儿的截断值为 28.1ng/mL，可获得最佳的敏感性、特异性、PPV 和 NPV，分别为 86.4%（95%CI：75.0-94.0%）、95.5%（95%CI：77.2-99.9%）、98.1%（95%CI：89.7-100%）和 72.4%（95%CI：52.8-87.3%）。
血清 MMP-7 可准确可靠地区分 BA 和非 BA 胆汁淤积，有望成为 BA 诊断算法中的一种应用，并在未来关于 BA 发病机制的研究中具有重要作用。
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