Accurate prediction of biliary atresia with an integrated model using MMP-7 levels and bile acids

Abstract

Background: Biliary atresia (BA) is a rare fatal liver disease in children, and the aim of this study was to develop a method to diagnose BA early.

Methods: We determined serum levels of matrix metalloproteinase-7 (MMP-7), the results of 13 liver tests, and the levels of 20 bile acids, and integrated computational models were constructed to diagnose BA.

Results: Our findings demonstrated that MMP-7 expression levels, as well as the results of four liver tests and levels of ten bile acids, were significantly different between 86 BA and 59 non-BA patients (P < 0.05). The computational prediction model revealed that MMP-7 levels alone had a higher predictive accuracy [area under the receiver operating characteristic curve (AUC) = 0.966, 95% confidence interval (CI): 0.942, 0.989] than liver test results and bile acid levels. The AUC was 0.890 (95% CI 0.837, 0.943) for liver test results and 0.825 (95% CI 0.758, 0.892) for bile acid levels. Furthermore, bile levels had a higher contribution to enhancing the predictive accuracy of MMP-7 levels (AUC = 0.976, 95% CI 0.953, 1.000) than liver test results. The AUC was 0.983 (95% CI 0.962, 1.000) for MMP-7 levels combined with liver test results and bile acid levels. In addition, we found that MMP-7 levels were highly correlated with gamma-glutamyl transferase levels and the liver fibrosis score.

Conclusion: The innovative integrated models based on a large number of indicators provide a noninvasive and cost-effective approach for accurately diagnosing BA in children. Video Abstract (MP4 142103 KB).

Keywords: Bile aid; Biliary atresia; Diagnosis; Liver fibrosis; Liver test; MMP-7.

Fig. 1

Significantly different levels of MMP-7 and liver tests between the BA and non-BA patients. a–e Represent the levels comparison of MMP-7, GGT, TP, GLO, and A/G ratio between the BA and non-BA groups. The BA group comprised 86 patients, and the non-BA group comprised 59 patients. Chi-squared and Mann-Whitney U tests were used for between-group comparisons, and a P value of less than 0.05 was considered statistically significant. MMP-7 Matrix metalloproteinase-7, BA biliary atresia, GGT gamma-glutamyl transferase, TP total protein, GLO globulin, A/G ratio albumin to globulin (A/G) ratio

Fig. 2

Significantly different indicators of bile acid levels between BA and non-BA participants. a–j Represent the level comparisons of CA, UDCA, GCA, GCDCA, GUDCA, TCA, TUDCA, total CA, Total DCA, and total UDCA between the BA and non-BA groups. The BA group comprised 86 patients, and the non-BA group comprised 59 patients. Chi-squared and Mann-Whitney U tests were used for between-group comparisons, and a P value of less than 0.05 was considered statistically significant. BA biliary atresia, CA cholic acid, UDCA ursodeoxycholic acid, GCA glycocholic acid, GCDCA glycochenodeoxycholic acid, GUDCA glycoursodeoxycholic acid, TCA taurocholic acid, TUDCA tauroursodeoxycholic acid, Total CA CA + TCA + GCA, DCA deoxycholic acid, TDCA taurodeoxychoic acid, GDCA glycodeoxycholic acid, Total DCA DCA + TDCA + GDCA, TCDCA taurochenodeoxycholic acid, Total UDCA UDCA + TUDCA + GUDCA

Fig. 3

The prediction model was based on MMP-7 alone, liver test results (including GGT levels and the A/G ratio), bile acid levels [including TUDCA levels, the GUDCA to UDCA ratio, log₂(GUDCA to UDCA ratio + 1)], and GGT. ROC plot showing the efficiency of the models for distinguishing BA and non-BA. (BA: n = 86, non-BA: n = 59). MMP-7 Matrix metalloproteinase-7, BA biliary atresia, GGT gamma-glutamyl transferase, A/G albumin to globulin (A/G) ratio, ROC receiver operating characteristic, AUC area under the ROC curve, UDCA ursodeoxycholic acid, GUDCA glycoursodeoxycholic acid, TUDCA tauroursodeoxycholic acid

Fig. 4

The prediction model based on MMP-7 combined with liver tests and bile acids. ROC plot showing the efficiency of the models for distinguishing BA and non-BA. (BA: n = 86, non-BA: n = 59). MMP-7 matrix metalloproteinase-7, BA biliary atresia, ROC receiver operating characteristic, AUC area under the ROC curve

Fig. 5

Correlation analysis of serum MMP-7 expression level with GGT and A/G ratio. a is the Spearman’s rank correlation coefficient between MMP-7 and GGT. b shows the Spearman’s rank correlation coefficient between MMP-7 and the A/G ratio. MMP-7 Matrix metalloproteinase-7, GGT gamma-glutamyl transferase, A/G Albumin to globulin (A/G) ratio

Fig. 6

Correlation of liver fibrosis score with age, serum MMP-7, liver tests, and bile acids. a Spearman’s rank correlation coefficient among liver fibrosis score, age, MMP-7 expression level and liver tests. b was the Spearman’s rank correlation coefficient among liver fibrosis score and bile acids. A statistically significant difference was defined as a P value < 0.05, and we only showed the correlation coefficients of the significantly different comparisons. MMP-7 matrix metalloproteinase-7, A/G albumin to globulin (A/G) ratio, ADA adenosine deaminase, ALB albumin, ALP alkaline phosphatase, ALT alanine transaminase, AST aspartate aminotransferase, CHOL cholesterol, DB direct bilirubin, GGT gamma-glutamyl transferase, GLO globulin, IB indirect bilirubin, LDH lactate dehydrogenase, TB total bilirubin, TP total protein, PAB prealbumin, CHE cholinesterase, PLT platelet, APRI aspartate aminotransferase to platelet ratio index, CA cholic acid, CDCA chenodeoxycholic acid, UDCA ursodeoxycholic acid, HDCA hyodeoxycholic acid, LCA lithocholic acid, GCA glycocholic acid, GCDCA glycochenodeoxycholic acid, GDCA glycodeoxycholic acid, GUDCA glycoursodeoxycholic acid, GHDCA glycohyodeoxycholic acid, TCA taurocholic acid, TCDCA taurochenodeoxycholic acid, TDCA taurodeoxychoic acid, TUDCA tauroursodeoxycholic acid, THDCA taurohyodeoxycholic acid, TLCA taurolithocholic acid, DHCA dihydroxycholestanoic acid, THCA trihydroxycholestanoic acid, total CA CA + TCA + GCA, total CDCA CDCA + TCDCA + GCDCA, total DCA DCA + TDCA + GDCA, total UDCA UDCA + TUDCA + GUDCA, total BAs Total CA + total CDCA + total DCA + total UDCA