Comparison of the accuracy of serum MMP-7 and GGT in the diagnosis of biliary atresia: a systematic review and meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Haojun ¹ , Ainiwaer Keranmu ¹ ,  LI Wanfu ¹ , LIANG Peng ¹ , WANG Yaqi ¹ , ZHANG Tao ¹ , ZHAO Wenlong ² , LIU Chenmeng ³

1. Department of Pediatric General Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P. R. China;
2. Department of Pediatric Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P. R. China;
3. Department of Pediatric Cardiothoracic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P. R. China;

Corresponding?author：

LI Wanfu, Email: liwanfu71@163.com

Keywords：

Biliary atresia; Non-invasive diagnosis; Matrix metallopeptidase 7; Gamma-glutamyl transpeptidase; Biomarkers; Systematic review

DOI：

10.7507/1672-2531.202502027

Video：

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Objective Early diagnosis of biliary atresia (BA) is crucial for improving patient prognosis. This study aims to evaluate the accuracy of serum matrix metalloproteinase-7 (MMP-7) and gamma-glutamyl transferase (GGT) in diagnosing BA. Methods We conducted a comprehensive search of English-language databases (PubMed, Elsevier, Web of Science) and Chinese-language databases (CNKI, WanFang Data, VIP) for studies published from the inception of these databases up to December 30, 2024. Eligible studies included diagnostic data based on serum MMP-7 and GGT levels from children with BA and non-BA cholestasis. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. Meta-analysis was then performed by using RevMan 5.4, Meta-disc 1.4 and Stata 17.0 software. Results A total of 24 publications encompassing 33 studies were included, covering a combined cohort of 6 879 children with cholestasis. The results of the binary diagnostic model analysis revealed that the pooled sensitivity and specificity of serum matrix metalloproteinase-7 (MMP-7) were 93% (95%CI 92% to 94%) and 87% (95%CI 85% to 88%), respectively. The positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) for MMP-7 were 8.63 (95%CI 5.88 to 12.66), 0.09 (95%CI 0.06 to 0.13), and 115.31 (95%CI 69.08 to 192.48), respectively. The area under the receiver operating characteristic curve (AUC) for MMP-7 was 0.9659. In comparison, gamma-glutamyl transferase (GGT) demonstrated a pooled sensitivity of 76% (95%CI 73% to 78%) and specificity of 80% (95%CI 78% to 82%). The corresponding PLR, NLR, and DOR for GGT were 3.50 (95%CI 2.77 to 4.43), 0.30 (95%CI 0.25 to 0.36), and 12.69 (95%CI 9.18 to 17.55), respectively. The AUC for GGT was calculated to be 0.849 4. Conclusion Serum MMP-7 demonstrates higher diagnostic accuracy compared to GGT, which may significantly enhance the diagnostic efficiency for biliary atresia. However, due to its heterogeneity, further multicenter, large-sample, prospective studies that adhere strictly to experimental protocols are necessary to validate its diagnostic accuracy.

Citation： WANG Haojun, Ainiwaer Keranmu, LI Wanfu, LIANG Peng, WANG Yaqi, ZHANG Tao, ZHAO Wenlong, LIU Chenmeng. Comparison of the accuracy of serum MMP-7 and GGT in the diagnosis of biliary atresia: a systematic review and meta-analysis. Chinese Journal of Evidence-Based Medicine, 2025, 25(12): 1416-1421. doi: 10.7507/1672-2531.202502027 Copy

1.	Sanchez-Valle A, Kassira N, Varela VC, et al. Biliary atresia: epidemiology, genetics, clinical update, and public health perspective. Adv Pediatr, 2017, 64(1): 285-305.
2.	Kerola A, Lohi J, Heikkil? P, et al. Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia. Surgery, 2019, 165(5): 905-911.
3.	Lai M, Afdhal NH. Liver fibrosis determination. Gastroenterol Clin North Am, 2019, 48(2): 281-289.
4.	Chan WK, Chung PHY, Wong KKY. The value of hepatic scintigraphy in the diagnosis of biliary atresia. Front Pediatr, 2022, 10: 874809.
5.	Huang CC, Chuang JH, Chou MH, et al. Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis. Mod Pathol, 2005, 18(7): 941-950.
6.	Lertudomphonwanit C, Mourya R, Fei L, et al. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med, 2017, 9(417): eaan8462.
7.	諶亞星, 鄧蕾, 李燕翔, 等. 血清基質金屬蛋白酶-7在膽道閉鎖患兒診斷中的臨床價值評價. 中華小兒外科雜志, 2021, 42(9): 781-787.
8.	Yang L, Zhou Y, Xu PP, et al. Diagnostic accuracy of serum matrix metalloproteinase-7 for biliary atresia. Hepatology, 2018, 68(6): 2069-2077.
9.	Chi S, Xu P, Yu P, et al. Dynamic analysis of serum MMP-7 and its relationship with disease progression in biliary atresia: a multicenter prospective study. Hepatol Int, 2022, 16(4): 954-963.
10.	Wu JF, Jeng YM, Chen HL, et al. Quantification of serum matrix metalloproteinase 7 levels may assist in the diagnosis and predict the outcome for patients with biliary atresia. J Pediatr, 2019, 208: 30-37. e1.
11.	Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci, 2001, 38(4): 263-355.
12.	Liu CS, Chin TW, Wei CF. Value of gamma-glutamyl transpeptidase for early diagnosis of biliary atresia. CMJ, 1998, 61(12): 716-720.
13.	Rendón-Macías ME, Villasís-Keever MA, Casta?eda-Muci?o G, et al. Improvement in accuracy of gamma-glutamyl transferase for differential diagnosis of biliary atresia by correlation with age. Turk J Pediatr, 2008, 50(3): 253-259.
14.	Lee J, Mulder F, Leeflang M, et al. QUAPAS: an adaptation of the QUADAS-2 tool to assess prognostic accuracy studies. Ann Intern Med, 2022, 175(7): 1010-1018.
15.	Kuritz SJ, Landis JR, Koch GG. A general overview of Mantel-Haenszel methods: applications and recent developments. Annu Rev Public Health, 1988, 9: 123-160.
16.	George BJ, Aban IB. An application of meta-analysis based on DerSimonian and Laird method. J Nucl Cardiol, 2016, 23(4): 690-692.
17.	Li Z, Tong X, Ma Y, et al. Prevalence of depression in patients with sarcopenia and correlation between the two diseases: systematic review and meta-analysis. J Cachexia Sarcopenia Muscle, 2022, 13(1): 128-144.
18.	No authors listed. Spearman’s rank correlation coefficient. BMJ, 2018, 362: k4131.
19.	Nyaga VN, Arbyn M. Metadta: a Stata command for meta-analysis and meta-regression of diagnostic test accuracy data - a tutorial. Arch Public Health, 2022, 80(1): 95.
20.	Verbakel JY, Steyerberg EW, Uno H, et al. ROC curves for clinical prediction models part 1. ROC plots showed no added value above the AUC when evaluating the performance of clinical prediction models. J Clin Epidemiol, 2020, 126: 207-216.
21.	Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ, 2011, 343: d4002.
22.	P?tsch N, Vatteroni G, Clauser P, et al. Contrast-enhanced mammography versus contrast-enhanced breast MRI: a systematic review and meta-analysis. Radiology, 2022, 305(1): 94-103.
23.	Jiang J, Liu S, Du M, et al. Measurement of MMP-7 in micro-volume peripheral blood: development of dried blood spot approach. Front Pediatr, 2023, 11: 1293329.
24.	Jiang J, Dong R, Du M, et al. Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study. J Transl Med, 2024, 22(1): 636.
25.	Pandurangi S, Mourya R, Nalluri S, et al. Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort. Hepatology, 2024, 80(1): 152-162.
26.	Wang G, Zhang N, Zhang X, et al. Ultrasound characteristics combined with gamma-glutamyl transpeptidase for diagnosis of biliary atresia in infants less than 30 days. Pediatr Surg Int, 2021, 37(9): 1175-1182.
27.	殷潤開, 趙瑞芹, 付海燕, 等. 肝功能相關指標診斷嬰兒膽道閉鎖的價值. 實用醫學雜志, 2021, 37(12): 1607-1612.
28.	Jiang J, Wang J, Shen Z, et al. Serum MMP-7 in the diagnosis of biliary atresia. Pediatrics, 2019, 144(5): e20190902.
29.	Rohani P, Mirrahimi SB, Bashirirad H, et al. Serum matrix metalloproteinase-7 levels in infants with cholestasis and biliary atresia. BMC Pediatr, 2022, 22(1): 351.
30.	Sakaguchi H, Konishi KI, Yasuda R, et al. Serum matrix metalloproteinase-7 in biliary atresia: a Japanese multicenter study. Hepatol Res, 2022, 52(5): 479-487.
31.	Singh TR, Goel P, Bajpai M, et al. Serum matrix metalloproteinase 7 as a diagnostic and prognostic biomarker for extrahepatic biliary atresia. J Indian Assoc Pediatr Surg, 2022, 27(2): 227-235.
32.	Karbasian F, Mashhadiagha A, Anbardar MH, et al. Questioning diagnostic value of serum matrix metalloproteinase 7 for biliary atresia. J Clin Exp Hepatol, 2023, 13(2): 265-272.
33.	Lee CS, Ni YH, Chen HL, et al. A pilot study of biliary atresia newborn screening using dried blood spot matrix metalloproteinase-7. J Pediatr Gastroenterol Nutr, 2023, 76(4): 418-423.
34.	Aldeiri B, Si T, Huang Z, et al. Matrix metalloproteinase-7 and osteopontin serum levels as biomarkers for biliary atresia. J Pediatr Gastroenterol Nutr, 2023, 77(1): 97-102.
35.	Xu XD, Musha J, Wang XT, et al. The value of serum MMP-7 and SOX9 levels in the diagnosis and prognosis of biliary atresia. J Pediatr Surg Open, 2024, 6: 100135.
36.	付海燕, 趙瑞芹, 白革蘭, 等. 血清γ-谷氨酰轉肽酶聯合直接膽紅素診斷嬰兒膽道閉鎖的價值. 中國當代兒科雜志, 2019, 21(12): 1198-1202.
37.	Dillman JR, DiPaola FW, Smith SJ, et al. Prospective assessment of ultrasound shear wave elastography for discriminating biliary atresia from other causes of neonatal cholestasis. J Pediatr, 2019, 212: 60-65.
38.	段星星, 楊柳, 文歡, 等. 聲觸診彈性成像聯合谷氨酰轉肽酶檢測在膽道閉鎖診斷中的應用研究. 臨床小兒外科雜志, 2022, 21(1): 46-50.
39.	Liu Y, Peng C, Wang K, et al. The utility of shear wave elastography and serum biomarkers for diagnosing biliary atresia and predicting clinical outcomes. Eur J Pediatr, 2022, 181(1): 73-82.
40.	Bossuyt PM, Reitsma JB, Bruns DE, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med, 2003, 138(1): W1-W12.

1. Sanchez-Valle A, Kassira N, Varela VC, et al. Biliary atresia: epidemiology, genetics, clinical update, and public health perspective. Adv Pediatr, 2017, 64(1): 285-305.
2. Kerola A, Lohi J, Heikkil? P, et al. Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia. Surgery, 2019, 165(5): 905-911.
3. Lai M, Afdhal NH. Liver fibrosis determination. Gastroenterol Clin North Am, 2019, 48(2): 281-289.
4. Chan WK, Chung PHY, Wong KKY. The value of hepatic scintigraphy in the diagnosis of biliary atresia. Front Pediatr, 2022, 10: 874809.
5. Huang CC, Chuang JH, Chou MH, et al. Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis. Mod Pathol, 2005, 18(7): 941-950.
6. Lertudomphonwanit C, Mourya R, Fei L, et al. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med, 2017, 9(417): eaan8462.
7. 諶亞星, 鄧蕾, 李燕翔, 等. 血清基質金屬蛋白酶-7在膽道閉鎖患兒診斷中的臨床價值評價. 中華小兒外科雜志, 2021, 42(9): 781-787.
8. Yang L, Zhou Y, Xu PP, et al. Diagnostic accuracy of serum matrix metalloproteinase-7 for biliary atresia. Hepatology, 2018, 68(6): 2069-2077.
9. Chi S, Xu P, Yu P, et al. Dynamic analysis of serum MMP-7 and its relationship with disease progression in biliary atresia: a multicenter prospective study. Hepatol Int, 2022, 16(4): 954-963.
10. Wu JF, Jeng YM, Chen HL, et al. Quantification of serum matrix metalloproteinase 7 levels may assist in the diagnosis and predict the outcome for patients with biliary atresia. J Pediatr, 2019, 208: 30-37. e1.
11. Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci, 2001, 38(4): 263-355.
12. Liu CS, Chin TW, Wei CF. Value of gamma-glutamyl transpeptidase for early diagnosis of biliary atresia. CMJ, 1998, 61(12): 716-720.
13. Rendón-Macías ME, Villasís-Keever MA, Casta?eda-Muci?o G, et al. Improvement in accuracy of gamma-glutamyl transferase for differential diagnosis of biliary atresia by correlation with age. Turk J Pediatr, 2008, 50(3): 253-259.
14. Lee J, Mulder F, Leeflang M, et al. QUAPAS: an adaptation of the QUADAS-2 tool to assess prognostic accuracy studies. Ann Intern Med, 2022, 175(7): 1010-1018.
15. Kuritz SJ, Landis JR, Koch GG. A general overview of Mantel-Haenszel methods: applications and recent developments. Annu Rev Public Health, 1988, 9: 123-160.
16. George BJ, Aban IB. An application of meta-analysis based on DerSimonian and Laird method. J Nucl Cardiol, 2016, 23(4): 690-692.
17. Li Z, Tong X, Ma Y, et al. Prevalence of depression in patients with sarcopenia and correlation between the two diseases: systematic review and meta-analysis. J Cachexia Sarcopenia Muscle, 2022, 13(1): 128-144.
18. No authors listed. Spearman’s rank correlation coefficient. BMJ, 2018, 362: k4131.
19. Nyaga VN, Arbyn M. Metadta: a Stata command for meta-analysis and meta-regression of diagnostic test accuracy data - a tutorial. Arch Public Health, 2022, 80(1): 95.
20. Verbakel JY, Steyerberg EW, Uno H, et al. ROC curves for clinical prediction models part 1. ROC plots showed no added value above the AUC when evaluating the performance of clinical prediction models. J Clin Epidemiol, 2020, 126: 207-216.
21. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ, 2011, 343: d4002.
22. P?tsch N, Vatteroni G, Clauser P, et al. Contrast-enhanced mammography versus contrast-enhanced breast MRI: a systematic review and meta-analysis. Radiology, 2022, 305(1): 94-103.
23. Jiang J, Liu S, Du M, et al. Measurement of MMP-7 in micro-volume peripheral blood: development of dried blood spot approach. Front Pediatr, 2023, 11: 1293329.
24. Jiang J, Dong R, Du M, et al. Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study. J Transl Med, 2024, 22(1): 636.
25. Pandurangi S, Mourya R, Nalluri S, et al. Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort. Hepatology, 2024, 80(1): 152-162.
26. Wang G, Zhang N, Zhang X, et al. Ultrasound characteristics combined with gamma-glutamyl transpeptidase for diagnosis of biliary atresia in infants less than 30 days. Pediatr Surg Int, 2021, 37(9): 1175-1182.
27. 殷潤開, 趙瑞芹, 付海燕, 等. 肝功能相關指標診斷嬰兒膽道閉鎖的價值. 實用醫學雜志, 2021, 37(12): 1607-1612.
28. Jiang J, Wang J, Shen Z, et al. Serum MMP-7 in the diagnosis of biliary atresia. Pediatrics, 2019, 144(5): e20190902.
29. Rohani P, Mirrahimi SB, Bashirirad H, et al. Serum matrix metalloproteinase-7 levels in infants with cholestasis and biliary atresia. BMC Pediatr, 2022, 22(1): 351.
30. Sakaguchi H, Konishi KI, Yasuda R, et al. Serum matrix metalloproteinase-7 in biliary atresia: a Japanese multicenter study. Hepatol Res, 2022, 52(5): 479-487.
31. Singh TR, Goel P, Bajpai M, et al. Serum matrix metalloproteinase 7 as a diagnostic and prognostic biomarker for extrahepatic biliary atresia. J Indian Assoc Pediatr Surg, 2022, 27(2): 227-235.
32. Karbasian F, Mashhadiagha A, Anbardar MH, et al. Questioning diagnostic value of serum matrix metalloproteinase 7 for biliary atresia. J Clin Exp Hepatol, 2023, 13(2): 265-272.
33. Lee CS, Ni YH, Chen HL, et al. A pilot study of biliary atresia newborn screening using dried blood spot matrix metalloproteinase-7. J Pediatr Gastroenterol Nutr, 2023, 76(4): 418-423.
34. Aldeiri B, Si T, Huang Z, et al. Matrix metalloproteinase-7 and osteopontin serum levels as biomarkers for biliary atresia. J Pediatr Gastroenterol Nutr, 2023, 77(1): 97-102.
35. Xu XD, Musha J, Wang XT, et al. The value of serum MMP-7 and SOX9 levels in the diagnosis and prognosis of biliary atresia. J Pediatr Surg Open, 2024, 6: 100135.
36. 付海燕, 趙瑞芹, 白革蘭, 等. 血清γ-谷氨酰轉肽酶聯合直接膽紅素診斷嬰兒膽道閉鎖的價值. 中國當代兒科雜志, 2019, 21(12): 1198-1202.
37. Dillman JR, DiPaola FW, Smith SJ, et al. Prospective assessment of ultrasound shear wave elastography for discriminating biliary atresia from other causes of neonatal cholestasis. J Pediatr, 2019, 212: 60-65.
38. 段星星, 楊柳, 文歡, 等. 聲觸診彈性成像聯合谷氨酰轉肽酶檢測在膽道閉鎖診斷中的應用研究. 臨床小兒外科雜志, 2022, 21(1): 46-50.
39. Liu Y, Peng C, Wang K, et al. The utility of shear wave elastography and serum biomarkers for diagnosing biliary atresia and predicting clinical outcomes. Eur J Pediatr, 2022, 181(1): 73-82.
40. Bossuyt PM, Reitsma JB, Bruns DE, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med, 2003, 138(1): W1-W12.

Chinese Journal of Evidence-Based Medicine

Comparison of the accuracy of serum MMP-7 and GGT in the diagnosis of biliary atresia: a systematic review and meta-analysis

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