Serum MMP-7 in the Diagnosis of Biliary Atresia Jingying Jiang, MD, Junfeng Wang, MD, PhD, Zhen Shen, MD, Xuexin Lu, MD, Gong Chen, MD, Yanlei Huang, MD, Rui Dong, MD, PhD, Shan Zheng, MD, PhD BACKGROUND: The overlapping features of biliary atresia (BA) and other neonatal cholestasis with abstract alternative causes (non-BA) have posed challenges for diagnosis. Matrix metalloproteinase-7 (MMP-7) has been reported to be promising in diagnosing BA. We aimed to validate the diagnostic accuracy of MMP-7 for BA in a large population sample. METHODS: We enrolled 288 patients with neonatal obstructive jaundice from March 2017 to October 2018. Serum MMP-7 levels were measured by using an enzyme-linked immunosorbent assay. Receiver operating characteristic curves were constructed, and decision curve analysis was done. A Pearson correlation coefficient test was conducted to assess the correlation between MMP-7 levels and other characteristics. RESULTS: The median serum MMP-7 levels were 38.89 ng/mL (interquartile range: 22.96–56.46) for the BA group and 4.4 ng/mL (interquartile range: 2.73–6.56) for the non-BA group (P , .001). The area under the receiver operating characteristic curve value was 0.9829 for MMP-7, and the sensitivity, specificity, positive predictive value, and negative predictive value were 95.19%, 93.07%, 97.27%, and 91.43%, respectively, at a cutoff value of 10.37 ng/mL. When MMP-7 was combined with g glutamyl transferase, the diagnostic accuracy was slightly improved without significance when compared with MMP-7 alone and had an area under the curve of 0.9880 (P = .08). Decision curve analysis also showed potential for MMP-7 to be used for clinical applications. A significant correlation was found with fibrosis stage from liver biopsy (R = 0.47; P , .001). CONCLUSIONS: MMP-7 demonstrated good accuracy in diagnosing BA and holds promise for future clinical application. Furthermore, its correlation with liver fibrosis indicated its potential use as a therapeutic target or prognostic biomarker. Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth WHAT’S KNOWN ON THIS SUBJECT: Matrix Defects, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China metalloproteinase-7 was reported to have promising diagnostic accuracy for biliary atresia, but the related Drs Jiang and Wang conceptualized and designed the study, conducted the matrix studies are rare with a small sample size, and the metalloproteinase-7 measurement and the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Shen, Lu, Chen, and Huang collected the serum sample cutoff value has not yet been established. and data, designed the data collection instruments, and reviewed and revised the manuscript; Drs WHAT THIS STUDY ADDS: We validated matrix Dong and Zheng conceptualized and designed the study, coordinated and supervised data collection, metalloproteinase-7 efficacy in a larger population and and critically reviewed the manuscript for important intellectual content; and all authors approved found good performance in diagnosing biliary atresia. the final manuscript as submitted and agree to be accountable for all aspects of the work. Also, a significant correlation was found with fibrosis DOI: https://doi.org/10.1542/peds.2019-0902 stage, indicating its potential use as a therapeutic Accepted for publication Aug 19, 2019 target or prognostic biomarker. Address correspondence to Shan Zheng, MD, PhD, Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, 399 Wan Yuan Rd, Shanghai To cite: Jiang J, Wang J, Shen Z, et al. Serum MMP-7 in 201102, China. E-mail: [email protected] the Diagnosis of Biliary Atresia. Pediatrics. 2019;144(5): e20190902 Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 144, number 5, November 2019:e20190902 ARTICLE Biliary atresia (BA) is a serious liver improvement.17 Although radiologic the diagnosis of BA. We evaluated the disease affecting newborns, with investigations (such as ultrasound, diagnostic accuracy of using MMP-7 higher incidence seen in the Asia- MRI, and hepatobiliary scintigraphy) alone and GGT alone or in Pacific region (∼1.06 in 10 000 live were reported to be helpful in combination as well as assessing the births) than within the United States differentiating BA from other correlation of MMP-7 with patient – (4.47 in 100 000).1 3 It is obstructive cholestasis, they are time age, liver function testing, and liver – characterized by inflammation and consuming and costly.18 23 Therefore, biopsy. atresia of extra and intrahepatic bile an effective biomarker would be This study was reviewed and ducts, resulting in obstructive extremely valuable for the approved by the ethics committee of jaundice and subsequent liver preoperative diagnosis of BA. the Children’s Hospital of Fudan fibrosis. The Kasai portoenterostomy Matrix metalloproteinase-7 (MMP-7), University (Shanghai, China) with procedure has been the first-line a protease responsible for tissue a waiver of requirement for informed treatment of BA since 1959, although remodeling, was discovered to be consent because of the use of left the pathogenesis is largely – associated with liver fibrosis in blood samples from routine unknown.3 8 Several studies have patients with BA.24,25 Lately, the investigations along with patient proposed that early diagnosis and Bezerra group26 identified that MMP- anonymity. The study was performed treatment is key to the restoration of – 7 was superior to all other potential in compliance with the Declaration of bile flow and favorable prognosis.9 13 biomarkers and had a significantly Helsinki and other relevant However, many other non-BA higher concentration in patients with regulations. cholestatic diseases, such as BA when compared with non-BA idiopathic cholestasis, Alagille using a high-throughput proteomic syndrome, and progressive familial Study Subjects assay (SOMAscan). This revealed its intrahepatic cholestasis, are similar to This study was conducted at potential role in the pathogenesis of BA in symptoms and noninvasive Children’s Hospital of Fudan BA and thereby its use as a potential laboratory and radiologic test results, University, an urban, tertiary-care biomarker and therapeutic target.26 leading to difficulties in the accurate academic children’s hospital in Recently, Yang et al27 compared diagnosis of BA. Our previous Shanghai, China. Infants between 30 serum MMP-7 concentration among retrospective study showed that 14% and 150 days of age with obstructive patients with BA and without BA and of 602 patients with BA-like neonatal jaundice (defined as a DB serum level healthy control infants and confirmed jaundice were found to be non-BA by .17 mmol/L and .20% of total its diagnostic accuracy with a cutoff using invasive diagnostic procedures bilirubin [TB]) were recruited from value of 52.85 ng/mL. The area under such as intraoperative March 2017 to October 2018. Blood the curve (AUC) was 0.99 with cholangiography and liver biopsy.14 samples were obtained from routine a sensitivity, specificity, and PPV of Therefore, it is critical to develop laboratory tests at admission, and the 98.67%, 95%, and 98.28%, a noninvasive diagnostic method with sera were stored at 280°C respectively.27 However, most good reliability and validity to avoid immediately after extraction. recently, Wu et al28 found that unnecessary invasive procedures. Intraoperative cholangiography and a serum MMP-7 level of .1.43 ng/mL subsequent histologic examination of was predictive of BA in infants with g glutamyl transferase (GGT), is 1 of liver biopsies were used to confirm cholestasis with a sensitivity of the factors measured in biochemical the diagnosis of BA. The gallbladders 97.30% and a specificity of 83.20%. liver function tests and is widely used of some patients were seen to be The cutoff value was different in the 2 to differentiate BA from non-BA, with completely atrophic, and the injection studies, although the patients were all an accuracy of 76% to 88% at a cutoff of contrast was hard to achieve, so BA from a Chinese cohort. Therefore, we value of ∼300 IU/L.15,16 However, in the infant would be diagnosed at conducted a single-center validation GGT alone is not enough to accurately once. Otherwise, a cholangiography diagnostic test for serum MMP-7 diagnose BA. We have developed and would be performed to further levels in a larger patient population validated a novel nomogram evaluate the anatomy of the to further evaluate diagnostic diagnostic model based on 5 intrahepatic bile ducts before a final accuracy and the cutoff value. variables, including sex, weight, direct diagnosis was made. Patients without bilirubin (DB), ln(GGT), and BA were confirmed by intraoperative ln(alkaline phosphatase [ALP]), which METHODS cholangiography demonstrating achieved better sensitivity (85.7%), a patent biliary tree. Percutaneous specificity (80.3%), and positive Study Design needle liver biopsy was also used to predictive value (PPV) (0.969). There This is a single-center diagnostic test exclude BA. These were also is, however, still room for to validate the use of serum MMP-7 in confirmed by genetic tests Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 JIANG et al demonstrating specific gene biopsy were described by n (%). underwent diagnostic surgery. Fifty- mutations or the resolution of Continuous variables, including age,