Comparison of preoperative serum MMP-7 to liver two-dimensional shear wave elastography and its integration into a novel nomogram for predicting the native liver survival of infants with biliary atresia

Introduction

Biliary atresia (BA) is a rare and severe cholangiopathy in infants, characterized by progressive fibro-inflammatory damage to the intrahepatic and extrahepatic bile ducts. It manifests as persistent neonatal cholestasis, progressive liver fibrosis, and cirrhosis (1). Its pathogenesis remains unclear, and most untreated patients succumb to liver failure before the age of 1 year (2). Despite advancements in surgical techniques and perioperative care, 60–75% of patients with BA still require liver transplantation by the age of 18 years, making BA the most common indication for pediatric liver transplantation (1,3).

Early diagnosis of BA is crucial for achieving complete jaundice clearance following the Kasai portoenterostomy (KPE) (4). Ultrasound is recommended as the initial diagnostic tool for BA, with an area under the curve (AUC) exceeding 0.90 and relatively high specificity (5,6). However, ultrasound’s accuracy heavily depends on the operator’s expertise. Matrix metalloproteinase-7 (MMP-7), a key member of the matrix metalloproteinase family, is released by hepatocytes and bile duct epithelial cells during bile duct injury (7). Numerous studies have demonstrated that serum MMP-7 is a significant biomarker for the early diagnosis of BA, with an AUC ranging from 0.90 to 0.99 (8-13). A recent network meta-analysis confirmed serum MMP-7 as the optimal diagnostic method for BA, demonstrating superior accuracy compared to other serum biomarkers or imaging techniques (14).

Successful jaundice clearance is associated with prolonged native liver survival (NLS), while failed KPE often necessitates early liver transplantation (15,16). Several risk factors, including later age at surgery and higher liver stiffness measured by transient elastography or two-dimensional shear wave elastography (2D-SWE), are associated with a higher likelihood of liver transplantation and worse NLS (17-19). Postoperative serum MMP-7 was also identified as a significant predictor of 2-year NLS (10). However, to our knowledge, the value of preoperative serum MMP-7 levels in predicting outcomes post-KPE has not yet been reported. Despite the identification of risk factors, accurately predicting outcomes remains a challenge for clinicians. Early and precise predictions are critical for designing individualized treatment strategies.

In this prospective cohort study, we investigated both the diagnostic and prognostic values of several laboratory biomarkers, including serum MMP-7, serum γ-glutamyltransferase (GGT), the aspartate aminotransferase-to-platelet ratio index (APRI), and liver stiffness measured by 2D-SWE for distinguishing BA from other cholestatic diseases and predicting NLS post-KPE. We further developed an optimized nomogram and risk score to enhance the prediction of NLS post-KPE. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-872/rc).

Methods

Study design and patients

This prospective cohort study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of West China Hospital, Sichuan University (approval No. 2021-1317). Informed consent was obtained from all included participants’ legal guardians. From July 2020 to September 2024, a total of 180 consecutive infants with conjugated hyperbilirubinemia [serum direct bilirubin >17 µmol/L and direct-to-total-bilirubin ratio >20% (20)] were evaluated with serum MMP-7. Additionally, serum liver function and other laboratory tests, including total bilirubin, direct bilirubin, indirect bilirubin, GGT, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bile acid (TBA), platelet (PLT), and international normalized ratio (INR) were collected. APRI was calculated as follows (21): APRI=ASTULNPLT(109/L)×100. A serum AST level of 40 U/L was used as the upper limit of normal (ULN). The liver stiffness was measured via 2D-SWE conducted within 1 week before KPE. The reference diagnosis was intraoperative cholangiography, liver biopsy, or the resolution of jaundice. Twenty-six patients were excluded for the following reasons: loss to follow-up (n=11) or an unclear final diagnosis (n=15). Ultimately, 154 infants were included in the study, 83 of whom were diagnosed with BA. Among all patients, 80 underwent open KPE, and 65 patients had a follow-up for NLS time longer than 2 years (Figure 1).

Figure 1 Flowchart of the study design. 2D-SWE, two-dimensional liver shear wave elastography; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyltransferase; INR, international normalized ratio; MMP-7, matrix metalloproteinase-7; NLS, native liver survival; PLT, platelet.

MMP-7 sample acquisition and measurement

In this study, 2–4 mL of peripheral blood was drawn from participants by nurses in the Department of Pediatric Surgery of West China Hospital, Sichuan University, via coagulation-promoting tubes. The samples were centrifuged at 4 ℃ (4,000 rpm for 5 minutes), and the supernatant was collected into Eppendorf tubes and stored at 4 ℃. Within 2 hours, the samples were packed in a thermally insulated box with dry ice and transported to Shanghai for testing within 72 hours. According to the experimental protocol, serum MMP-7 levels were measured with an enzyme-linked immunosorbent assay (ELISA) kit (cat. no. DMP700; R&D Systems, Minneapolis, MN, USA). Serum samples were diluted 20-fold, and each sample was tested in triplicate, with the average value included in the final analysis. All testing was conducted by WuXi Diagnostics (Shanghai, China), with technicians blinded to the patients’ clinical information.

Liver stiffness measurement

A linear array AixPlorer scanner (Supersonic Imagine, Aix-en-Provence, France) was employed for the study. Measurements were obtained from segments V or VI of the liver. Liver 2D-SWE was conducted by either H.Y. or J.L., both of whom have over 3 years of experience in elastography. A rectangular region of interest (ROI) was positioned over an isoechoic region of the liver parenchyma, with care being taken to avoid any vessels, nodules, or other structures. The analysis box was positioned 5- to 10-mm beneath the hepatic capsule. A successful measurement was defined as most of the ROI box being filled with a homogeneous color maintained for at least one respiratory cycle. Each measurement was repeated at least three times, with an interquartile range ≤30% of the median required to ensure measurement reliability (22,23). The median value of the ROI was recorded (Figure S1).

Follow-up of patients

For all included inpatients, data on intraoperative cholangiography, details of KPE, and liver biopsy results were collected. For outpatients, follow-up serum marker levels were recorded. Patients were categorized into the non-BA group if their serum bilirubin levels normalized during follow-up or if they were diagnosed with other conditions, such as Alagille syndrome, by a pediatrician.

Patients with BA who underwent KPE were routinely followed up monthly at our hospital for the first 3 months after KPE. Subsequent follow-up was conducted every 3 months until 2 years after KPE. Follow-up evaluations included serum liver function tests, routine blood tests, ultrasound examinations, and liver stiffness measurements. The primary endpoint for NLS was liver transplantation or patient death; otherwise, patients were noted as having NLS until the last follow-up.

Statistical analysis

X-tile software version 3.6.1 (Yale University School of Medicine, New Haven, CT, USA), SPSS version 25.0 (IBM Corp., Armonk, NY, USA), and R version 4.4.2 (The R Foundation for Statistical Computing) were used for statistical analysis. The Kolmogorov-Smirnov test was used to test the normality of variables. Continuous variables were compared with the Student’s t-test, and categorical variables were compared with the χ² test. Receiver operating characteristic (ROC) curves were constructed to compare the diagnostic performance of different variables in distinguishing BA from non-BA. The comparison of different AUCs was performed with the DeLong test. The corresponding sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of each variable were calculated.

The X-tile program automatically determined the optimal cutoff point based on the highest χ² value and lowest P value. Kaplan-Meier survival curves for NLS were generated with the Kaplan-Meier method and assessed with the log-rank test. Univariate Cox regression analyses were performed to estimate hazard ratios (HRs) for factors associated with NLS. A multivariate Cox regression analysis was conducted using backward likelihood ratio selection to identify significant factors. A nomogram was constructed based on the selected NLS factors. The concordance index (C-index) and a calibration curve were used to evaluate the performance of the nomogram. A P value <0.05 was considered statistically significant.

Results

Patient characteristics

After the final diagnosis was confirmed by intraoperative cholangiography or follow-up, 154 infants were included in the study, comprising 83 with BA and 71 with non-BA. The median age of the participants was 66 days, and 86 (56%) were male. No significant differences in age or sex ratio were observed between the BA and non-BA groups. The serum MMP-7 level in the BA group (80.5±47.6 ng/mL) was approximately six times higher than that in the non-BA group (13.2±9.3 ng/mL) (P<0.001; Table 1). Similarly, the serum GGT level in the BA group was approximately three times higher than that in the non-BA group (P<0.001; Table 1). The liver stiffness, as measured by 2D-SWE, was also significantly greater in the BA group than in the non-BA group (median 14.3 vs. 7.1 kPa; P<0.001; Table 1). Additionally, serum levels of total bilirubin, direct bilirubin, and TBA were significantly higher in the BA group than in the non-BA group (all P<0.05; Table 1). No significant differences were observed in other serum biomarkers between the BA and non-BA groups.

Among the follow-up group, the median KPE day of the BA group was 70 days. Moreover, 26 (40%) patients reached clearance of jaundice within 6 months after KPE, 38 (58%) patients underwent liver transplantation, with a median time of 140 days after KPE; and 7 (11%) patients died during follow-up. The median NLS time was 182 days (Table 1).

Diagnostic performance of serum MMP-7, GGT, and liver 2D-SWE in determining BA

The AUC for liver 2D-SWE in diagnosing BA was 0.87 [95% confidence interval (CI): 0.81–0.94]. At a cutoff value of 10.5 kPa, liver 2D-SWE demonstrated a sensitivity of 82% and a specificity of 84% (Table 2). The AUC for serum GGT in diagnosing BA was 0.87 (95% CI: 0.80–0.93). At a cutoff value of 228.5 U/L, serum GGT showed a sensitivity of 78% and a specificity of 82% (Table 2). Among all the variables examined, MMP-7 had the highest AUC at 0.95 (95% CI: 0.91–0.99), achieving a sensitivity of 93%, a specificity of 88%, and an accuracy of 91% at a cutoff value of 17.4 ng/mL (Table 2, Figure 2, and Table S1). However, combining serum MMP-7 with liver 2D-SWE or GGT did not yield a significantly higher AUC as compared to serum MMP-7 alone (Table S1).

Figure 2 The receiver operator characteristic curves of liver 2D-SWE and serum MMP-7 and GGT in the diagnosis of biliary atresia. The AUC for liver 2D-SWE, serum MMP-7, and serum GGT in the diagnosis of biliary atresia was 0.87 (95% CI: 0.81–0.94), 0.95 (95% CI: 0.91–0.99), and 0.87 (95% CI: 0.80–0.93), respectively. 2D-SWE, two-dimensional shear wave elastography; AUC, area under the curve; CI, confidence interval; GGT, γ-glutamyltransferase; MMP-7, matrix metalloproteinase-7.

Survival analyses and Cox regression analyses of HRs for factors associated with NLS post-KPE

After the optimal cutoff values were determined with X-tile, the univariate Cox regression analyses revealed that the significant variables influencing NLS were surgery age; serum MMP-7, GGT, and TBA levels; liver stiffness (2D-SWE); and APRI (all P<0.05; Table 3). Among these, liver 2D-SWE had the highest HR at 4.56 (95% CI: 1.07–19.42; Table 3). Kaplan-Meier survival analyses further demonstrated that patients with an age at surgery over 80 days, serum MMP-7 levels exceeding 70 ng/mL, serum TBA levels over 128 µmol/L, serum GGT levels below 449 U/L, APRI values greater than 1.5, and liver 2D-SWE measurements above 11.4 kPa had a shorter NLS time (all P<0.05; Figure 3).

Figure 3 Kaplan-Meier survival curves of NLS according to (A) surgery age, (B) serum MMP-7, (C) liver 2D-SWE, (D) serum GGT, (E) APRI, and (F) serum TBA. 2D-SWE, two-dimensional shear wave elastography; APRI, aspartate-aminotransferase-to-platelet ratio index; NLS, native liver survival; MMP-7, matrix metalloproteinase-7; TBA, total bile acid.

Additionally, multivariate Cox regression analysis identified serum MMP-7 level (HR 3.31, 95% CI: 1.40–7.86; P=0.007), serum GGT level (HR 3.81, 95% CI: 1.67–8.69; P=0.001), age at surgery (HR 2.21, 95% CI: 1.02–4.76; P=0.043), and liver 2D-SWE (HR 11.47, 95% CI: 2.61–50.32; P=0.001) as independent risk factors for NLS (Table 4).

The established nomogram for predicting NLS post-KPE

We used the multivariate risk factors to develop a nomogram for predicting NLS. Given the significant correlation between serum MMP-7 level and liver 2D-SWE (r=0.625; P<0.001), these two factors could not be incorporated into the same nomogram. Therefore, we constructed two separate nomograms for predicting NLS in patients with BA.

Nomogram A consisted of serum MMP-7, serum GGT, and age at surgery, as shown in Figure 4A. The total score, obtained as the sum of the points assigned to each of these three variables, reflected the probability of achieving 6-, 12-, or 24-month NLS (Figure 4A). The calibration curve demonstrated strong concordance between the predicted and actual 12-month NLS probabilities (Figure 4B). Nomogram A achieved a C-index of 0.76 (95% CI: 0.67–0.85), significantly outperforming any individual risk factor (all P<0.05; Table 5 and Table S2). MMP-7 had incremental value beyond age at surgery or serum GGT (Table S3).

Figure 4 The nomograms and calibration curves for NLS prediction. (A) Development of Nomogram A for predicting the probability of 6-, 12-, and 24-month NLS with the following three predictors: serum MMP-7, serum GGT, and age at surgery. (B) The calibration curve of 12-month NLS of Nomogram A. (C) Development of Nomogram B for predicting the probability of 6-, 12-, and 24-month NLS with the following three predictors: liver 2D-SWE, serum GGT, and age at surgery. (D) The calibration curve of 12-month NLS of Nomogram B. 2D-SWE, two-dimensional shear wave elastography; GGT, γ-glutamyltransferase; MMP-7, matrix metalloproteinase-7; NLS, native liver survival.

Similarly, we constructed Nomogram B, consisting of liver 2D-SWE, serum GGT, and age at surgery, as illustrated in Figure 4C. The total score was used to estimate the probability of achieving 6-, 12-, or 24-month NLS (Figure 4C), and the calibration curve demonstrated good agreement between the predicted and actual 12-month NLS probabilities (Figure 4D). However, Nomogram B yielded a C-index of 0.69 (95% CI: 0.59–0.79), which was significantly lower than that of Nomogram A (P<0.001; Table 5 and Table S2).

Additionally, we developed a risk score for each patient based on the three risk factors in Nomogram A using the following formula: risk score = 1.068 × serum MMP-7 level + 1.456 × serum GGT level + 0.789 × age at surgery. In this formula, if the serum MMP-7 level exceeded 70 ng/mL, the serum GGT level was below 449 U/L, or the age at surgery was over 80 days, the value was set to 1; otherwise, it was set to 0. Patients with a risk score greater than 2 were classified as high risk, while those with a risk score below 2 were classified as low risk. Survival analysis revealed that the NLS time in the high-risk group was significantly lower than that in the low-risk group (P<0.001; Figure 5).

Figure 5 Kaplan-Meier survival curves of NLS in high-risk group and low-risk group according to the risk score. NLS, native liver survival.

Discussion

In this study, we demonstrated that serum MMP-7 level can not only distinguish infants with BA from other cholestatic infants with a high diagnostic performance (AUC 0.95; higher than that of liver 2D-SWE) but also effectively predict the NLS post-KPE. For the first time, we developed a risk nomogram for the prediction of NLS, incorporating three predictors: serum MMP-7 level, serum GGT level, and age at surgery without liver 2D-SWE. This nomogram achieved a high C-index and effectively stratified patients into high-risk and low-risk groups for NLS.

Serum MMP-7 has been widely recognized as an optimal biomarker for BA diagnosis, with multiple studies reporting high diagnostic AUCs exceeding 0.9 (9,10,24). However, the cutoff values for diagnosing BA vary largely (9,24), and two primary factors contribute to this inconsistency. First, the differences in laboratory technologies or assay methods result in varying MMP-7 measurements. Pandurangi et al. (12) reported that different assay technologies applied to the same patients’ samples produced divergent cutoff values for serum MMP-7. Second, variations in patient composition, such as differing disease distributions in control groups and varying ages of patients with BA, also influence cutoff values. Nonetheless, cutoff values within each study remained internally consistent, yielding comparably high AUCs. A multicenter, large-scale clinical trial and the standardization of MMP-7 measurement method may help resolve this issue.

Serum MMP-7 plays a crucial role in the pathogenesis of BA. MMP-7, primarily expressed by cholangiocytes, is released upon epithelial injury and contributes to the experimental disease phenotype (8). Thus, serum MMP-7 levels may serve as a reliable predictor of BA prognosis post-KPE. Wu et al. (24) reported that elevated postoperative serum MMP-7 levels 6 months after KPE were associated with an increased likelihood of liver transplantation. Similarly, Chi et al. (10) demonstrated that serum MMP-7 levels at 6 weeks and 3 months post-KPE could predict NLS at 2 years post-KPE, with AUCs of 0.796 and 0.861, respectively. However, no previous studies have shown that preoperative serum MMP-7 levels can predict BA prognosis post-KPE. Our study revealed that preoperative serum MMP-7 levels not only facilitate BA diagnosis but also effectively predict NLS post-KPE, which is both practical and critical for guiding personalized clinical decision-making.

Liver 2D-SWE is significantly correlated with histopathological stages of liver fibrosis (25) and has been established as an independent prognostic biomarker for BA following KPE (26-28). Wang et al. found that liver 2D-SWE serves as an independent predictor of NLS, reporting a high HR (HR 4.0) and contributing to a nomogram for NLS prediction with a C-index of 0.74 (18). Our findings similarly indicate that liver 2D-SWE is a significant risk factor for NLS, exhibiting a high HR. However, for the first time, we demonstrated that serum MMP-7 is not inferior to liver 2D-SWE in NLS prediction and can be included in a novel nomogram that does not require liver 2D-SWE. This nomogram enhances convenience for clinical practice and facilitates more effective treatment decision-making.

Because patients with BA experience persistent neonatal cholestasis and progressive liver fibrosis, delayed KPE may result in poor outcomes. Serinet et al. (16) found that patients with BA undergoing KPE before 46 days of age had longer NLS and better outcomes compared to those undergoing KPE after 46 days. Similarly, Wang et al. (18) reported that KPE performed after 81 days of age was associated with shorter NLS. Additionally, in a multicenter study in Japan, younger age at KPE was significantly associated with improved prognosis (15).

Serum GGT is a key marker of neonatal cholestasis, playing a significant role in BA diagnosis (8). Low-GGT cholestasis represents a distinct clinical entity that has traditionally been attributed to defects in bile acid synthesis or transport, often resulting in a more severe form of liver injury (29). GGT catalyzes the transfer of the glutamyl moiety from glutathione, supporting the restoration of intracellular glutathione levels. Low GGT levels may indicate an impaired adaptive response to oxidative stress, leading to increased hepatocyte injury (29). BA with low GGT appears to represent a distinct entity associated with poor prognosis. Our previous study demonstrated that lower preoperative GGT levels are associated with unresolved jaundice post-KPE (30). Similarly, other research has reported that patients with BA and lower preoperative GGT levels exhibit poorer liver function and worse NLS (29,31), which is in line with our results.

Our study involved several limitations that should be addressed. First, the sample size was relatively small, with only 154 infants (83 with BA and 71 without BA) in the diagnostic cohort and 65 patients with BA in the prognostic cohort. The clearance rate and NLS at 2 years were relatively low, which may lack of generalizability. We plan to increase the sample size and include patients from multiple centers in future studies. Second, due to limited laboratory data in the prognostic cohort, we were unable to calculate the pediatric end-stage liver disease score. Third, as this study was conducted at a single medical center, validation in other centers or through multicenter studies is necessary and planned for the future.

Conclusions

Preoperative serum MMP-7 levels are valuable for both diagnosing BA and predicting post-KPE prognosis. The novel nomogram and risk score, incorporating preoperative serum MMP-7, serum GGT, and age at surgery, effectively predict NLS following KPE, offering critical and practical guidance for optimizing BA treatment strategies. Future studies with larger sample sizes and multicenter validations are required to confirm its utility.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-872/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-872/dss

Funding: This work was supported by the National Natural Science Foundation of China (No. 82402298) and the Natural Science Foundation of Sichuan Province (No. 2022NSFSC0838).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-872/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board of West China Hospital, Sichuan University (No. 2021-1317) and informed consent was obtained from all participants’ legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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