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

Sindhu Pandurangi; Reena Mourya; Shreya Nalluri; Lin Fei; Shun Dong; Sanjiv Harpavat; Stephen L Guthery; Jean P Molleston; Philip Rosenthal; Ronald J Sokol; Kasper S Wang; Vicky Ng; Estella M Alonso; Evelyn K Hsu; Saul J Karpen; Kathleen M Loomes; John C Magee; Benjamin L Shneider; Simon P Horslen; Jeffrey H Teckman; Jorge A Bezerra; and the Childhood Liver Disease Research Network

doi:10.1097/HEP.0000000000000827

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

Hepatology. 2024 Mar 6. doi: 10.1097/HEP.0000000000000827. Online ahead of print.

Authors

Sindhu Pandurangi¹, Reena Mourya¹, Shreya Nalluri², Lin Fei³, Shun Dong⁴, Sanjiv Harpavat⁵, Stephen L Guthery⁶, Jean P Molleston⁷, Philip Rosenthal⁸, Ronald J Sokol⁹, Kasper S Wang¹⁰, Vicky Ng¹¹, Estella M Alonso¹², Evelyn K Hsu¹³, Saul J Karpen¹⁴, Kathleen M Loomes¹⁵, John C Magee¹⁶, Benjamin L Shneider⁴, Simon P Horslen¹⁷, Jeffrey H Teckman¹⁸, Jorge A Bezerra¹; and the Childhood Liver Disease Research Network

Affiliations

¹ Children's Medical Center of Dallas and Division of Pediatric Gastroenterology, Hepatology and Nutrition of the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
² Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ University of Kansas School of Business, Lawrence, KS, USA.
⁵ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Houston, TX, USA.
⁶ Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Utah and Intermountain Primary Children's Hospital, Salt Lake City, UT, USA.
⁷ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of California, San Francisco, CA, USA.
⁹ Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, USA.
¹⁰ Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA (current address: The Hospital for Sick Children, Toronto, Ontario, CA).
¹¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, CA.
¹² Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
¹³ Division of Pediatric Gastroenterology and Hepatology, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA, USA.
¹⁴ Division of Pediatric Gastroenterology, Hepatology, and Nutrition Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹⁵ Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁶ Division of Transplant Surgery, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Division of Pediatric Gastroenterology, UPMC Children's Hospital, Pittsburgh, PA, USA.
¹⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatrics, Cardinal Glennon Children's Hospital, Saint Louis, MO, USA.

PMID: 38446707
DOI: 10.1097/HEP.0000000000000827

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.

Grants and funding

U01 DK103140/DK/NIDDK NIH HHS/United States