Abstract
Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and liver fibrosis. The early diagnosis of BA is still challenging. This study aimed to evaluate the diagnostic values of matrix metalloprotease-7 (MMP-7), interleukin-8 (IL-8), and gamma-glutamyl transferase (GGT) in BA. Infants diagnosed with BA and non-BA between 2013 and 2018 were retrospectively analyzed. Plasma levels of MMP-7, IL-8, and GGT were measured in these infants. The receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were used to assess the diagnostic values of MMP-7, IL-8, and GGT. The expression of MMP-7 and IL-8 in the livers was detected by immunofluorescence staining. A total of 229 infants were enrolled in this study: 156 BA infants and 73 non-BA infants including 16 ones with infantile hepatitis syndrome. The plasma levels of MMP-7, IL-8, and GGT in BA infants had a median of 11.8 ng/mL (interquartile range, IQR: 5.3–57.5), 1.5 ng/mL (IQR: 1.0–2.8), and 381.0 U/L (IQR: 197.0–749.0), respectively, which were higher than non-BA subjects [MMP-7, 4.4 ng/mL (IQR: 3.3–6.1); IL-8, 0.7 ng/mL (IQR: 0.5–1.0); GGT, 59.0 U/L (IQR: 26.0–124.0)]. The AUC values of MMP-7, IL-8, and GGT for the diagnosis of BA were 0.8035, 0.8083, and 0.9126, respectively. The AUC values of MMP-7 + IL-8, MMP-7 + GGT, IL-8 + GGT, and MMP-7 + IL-8 + GGT for the diagnosis of BA were 0.8248, 0.9382, 0.9168, and 0.9392, respectively. The AUC values of MMP-7, IL-8, and GGT for differentiating BA infants with cholic stool from non-BA infants with cholic stool were 0.8006, 0.8258, and 0.9141, respectively. The expression of MMP-7 and IL-8 was increased in the cholangiocytes in BA livers.
Conclusion: Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA and may be reliable biomarkers for BA.
What is Known: • Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and progressive liver fibrosis. • Although early diagnosis of BA is crucial for good outcomes, it remains a clinical challenge. | |
What is New: • Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA. • Plasma MMP-7, IL-8, and GGT have good accuracy for differentiating BA infants with cholic stool from non-BA infants with cholic stool. |
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Abbreviations
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- AUC:
-
Area under the curve
- BA:
-
Biliary atresia
- CK19:
-
Cytokeratin 19
- DBil:
-
Direct bilirubin
- ELISA:
-
Enzyme-linked immunosorbent assay
- GGT:
-
Gamma-glutamyl transferase
- HPE:
-
Hepatic portoenterostomy
- IHC:
-
Intrahepatic cholestasis
- IHS:
-
Infantile hepatitis syndrome
- IL-8:
-
Interleukin-8
- IQR:
-
Interquartile range
- MMP-7:
-
Matrix metalloprotease-7
- ROC:
-
Receiver operating characteristic
- TBA:
-
Total bile acid
- TBil:
-
Total bilirubin
References
Hartley JL, Davenport M, Kelly DA (2009) Biliary atresia. Lancet 374(9702):1704–1713. https://doi.org/10.1016/S0140-6736(09)60946-6
Asai A, Miethke A, Bezerra JA (2015) Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. Nat Rev Gastroenterol Hepatol 12(6):342–352. https://doi.org/10.1038/nrgastro.2015.74
Luo Y, Brigham D, Bednarek J, Torres R, Wang D, Ahmad S, Mack CL (2021) Unique cholangiocyte-targeted IgM autoantibodies correlate with poor outcome in biliary atresia. Hepatology 73(5):1855–1867. https://doi.org/10.1002/hep.31504
Ortiz-Perez A, Donnelly B, Temple H, Tiao G, Bansal R, Mohanty SK (2020) Innate immunity and pathogenesis of biliary atresia. Front Immunol 11:329. https://doi.org/10.3389/fimmu.2020.00329
Serinet MO, Wildhaber BE, Broue P, Lachaux A, Sarles J, Jacquemin E, Gauthier F, Chardot C (2009) Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening. Pediatrics 123(5):1280–1286. https://doi.org/10.1542/peds.2008-1949
Wang KS, Section on S, Committee on F, Newborn, Childhood Liver Disease Research N (2015) Newborn screening for biliary atresia. Pediatrics 136(6):e1663–e1669. https://doi.org/10.1542/peds.2015-3570
Lertudomphonwanit C, Mourya R, Fei L, Zhang Y, Gutta S, Yang L, Bove KE, Shivakumar P, Bezerra JA (2017) Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med 9(417):eaan8462. https://doi.org/10.1126/scitranslmed.aan8462
Jiang J, Wang J, Shen Z, Lu X, Chen G, Huang Y, Dong R, Zheng S (2019) Serum MMP-7 in the diagnosis of biliary atresia. Pediatrics 144(5):e20190902. https://doi.org/10.1542/peds.2019-0902
Hsieh CS, Chuang JH, Huang CC, Chou MH, Wu CL, Lee SY, Chen CL (2005) Evaluation of matrix metalloproteinases and their endogenous tissue inhibitors in biliary atresia-associated liver fibrosis. J Pediatr Surg 40(10):1568–1573. https://doi.org/10.1016/j.jpedsurg.2005.06.028
Kobayashi H, Li ZX, Yamataka A, Lane GJ, Miyano T (2002) Clinical evaluation of serum levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases as predictors of progressive fibrosis in postoperative biliary atresia patients. J Pediatr Surg 37(7):1030–1033
Kerola A, Lampela H, Lohi J, Heikkila P, Mutanen A, Hagstrom J, Tervahartiala T, Sorsa T, Haglund C, Jalanko H et al (2016) Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia. J Pathol Clin Res 2(3):187–198. https://doi.org/10.1002/cjp2.50
Yang L, Zhou Y, Xu PP, Mourya R, Lei HY, Cao GQ, Xiong XL, Xu H, Duan XF, Wang N et al (2018) diagnostic accuracy of serum matrix metalloproteinase-7 for biliary atresia. Hepatology 68(6):2069–2077. https://doi.org/10.1002/hep.30234
Godbole N, Nyholm I, Hukkinen M, Davidson JR, Tyraskis A, Eloranta K, Andersson N, Lohi J, Heikkila P, Kyronlahti A et al (2021) Prognostic and pathophysiologic significance of IL-8 (CXCL8) in biliary atresia. J Clin Med. https://doi.org/10.3390/jcm10122705
Dong R, Zheng S (2015) Interleukin-8: a critical chemokine in biliary atresia. J Gastroenterol Hepatol 30(6):970–976. https://doi.org/10.1111/jgh.12900
Shankar S, Bolia R, Foo HW, D’Arcy CE, Hardikar N, Wensing M, Hardikar W (2020) Normal gamma glutamyl transferase levels at presentation predict poor outcome in biliary atresia. J Pediatr Gastroenterol Nutr 70(3):350–355. https://doi.org/10.1097/MPG.0000000000002563
He L, Ip DKM, Tam G, Lui VCH, Tam PKH, Chung PHY (2021) Biomarkers for the diagnosis and post-Kasai portoenterostomy prognosis of biliary atresia: a systematic review and meta-analysis. Sci Rep 11(1):11692. https://doi.org/10.1038/s41598-021-91072-y
Haafiz AB (2010) Liver fibrosis in biliary atresia. Expert Rev Gastroenterol Hepatol 4(3):335–343
Vij MA-O, Rela M (2020) Biliary atresia: pathology, etiology and pathogenesis. Future Sci OA 6(5):FSO466. https://doi.org/10.2144/fsoa-2019-0153
Shen WJ, Chen G, Wang M, Zheng S (2019) Liver fibrosis in biliary atresia. World J Pediatr 15(2):117–123. https://doi.org/10.1007/s12519-018-0203-1
Arafa RS, Abdel Haie OM, El-Azab DS, Abdel-Rahman AM, Sira MM (2016) Significant hepatic expression of IL-2 and IL-8 in biliary atresia compared with other neonatal cholestatic disorders. Cytokine 79:59–65. https://doi.org/10.1016/j.cyto.2015.12.023
El-Faramawy AA, El-Shazly LB, Abbass AA, Ismail HA (2011) Serum IL-6 and IL-8 in infants with biliary atresia in comparison to intrahepatic cholestasis. Trop Gastroenterol 32(1):50–55
Nobili V, Marcellini M, Giovannelli L, Girolami E, Muratori F, Giannone G, Devito R, De Benedetti F (2004) Association of serum interleukin-8 levels with the degree of fibrosis in infants with chronic liver disease. J Pediatr Gastroenterol Nutr 39(5):540–544
Dong R, Chen G, Zheng S, Xia HH (2015) Hepatic expression of interleukin 8 in diagnosing biliary atresia. Hepatology 61(2):731–732. https://doi.org/10.1002/hep.27229
Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Rao M, Jegga AG, Bezerra JA (2014) Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease. Hepatology 60(1):211–223. https://doi.org/10.1002/hep.27045
Honsawek S, Chongsrisawat V, Vejchapipat P, Thawornsuk N, Tangkijvanich P, Poovorawan Y (2005) Serum interleukin-8 in children with biliary atresia: relationship with disease stage and biochemical parameters. Pediatr Surg Int 21(2):73–77. https://doi.org/10.1007/s00383-004-1329-x
Changho S, Ahmed AA (2010) Neutrophils in biliary atresia. A study on their morphologic distribution and expression of CAP37. Pathol Res Pract 206(5):314–317. https://doi.org/10.1016/j.prp.2010.02.001
Sira MM, Taha M, Sira AM (2014) Common misdiagnoses of biliary atresia. Eur J Gastroenterol Hepatol 26(11):1300–1305
Soares KC, Kim Y, Spolverato G, Maithel S, Bauer TW, Marques H, Sobral M, Knoblich M, Tran T, Aldrighetti L et al (2015) Presentation and clinical outcomes of choledochal cysts in children and adults: a multi-institutional analysis. JAMA Surg 150(6):577–584. https://doi.org/10.1001/jamasurg.2015.0226
Nomden M, Beljaars L, Verkade HJ, Hulscher JBF, Olinga P (2020) Current concepts of biliary atresia and matrix metalloproteinase-7: a review of literature. Front Med (Lausanne) 7:617261. https://doi.org/10.3389/fmed.2020.617261
Acknowledgements
The authors are grateful to Beilin Gu for helping in managing the samples and grateful to the funding support (the National Natural Science Foundation of China, 81974058).
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This study was supported by the National Natural Science Foundation of China (81974058).
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Bo Wu, Ying Zhou, Wei Cai, and Yongtao Xiao designed the study, analyzed the data, and drafted the manuscript. Bo Wu, Ying Zhou, and Xinbei Tian performed the experiments. Wei Cai and Yongtao Xiao revised the manuscript. All authors have read and approved to submit the manuscript.
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Wu, B., Zhou, Y., Tian, X. et al. Diagnostic values of plasma matrix metalloproteinase-7, interleukin-8, and gamma-glutamyl transferase in biliary atresia. Eur J Pediatr 181, 3945–3953 (2022). https://doi.org/10.1007/s00431-022-04612-7
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DOI: https://doi.org/10.1007/s00431-022-04612-7