A nomogram model based on routine serum markers for predicting the occurrence of primary cholangitis after Kasai operation for biliary atresia

Introduction

Biliary atresia (BA) constitutes a critical surgical disorder that impacts the hepatobiliary system in children. This condition is chiefly marked by the fibrotic blockage of intrahepatic and extrahepatic bile ducts, culminating in a progressive cascade of inflammation, liver fibrosis, and, eventually, hepatic failure. The implementation of surgical procedures is essential for the effective management of BA, as the lack of prompt intervention may lead to dire consequences for the affected pediatric population (1-3).

The Kasai procedure continues to be the most favored and efficient treatment method for BA. In cases where the chance to perform Kasai surgery is overlooked, liver transplantation can be regarded as a viable alternative treatment strategy (4,5). It is important to highlight that cholangitis represents the most common complication associated with Kasai surgery, significantly impacting both the quality of life and the survival rates of the children who are affected (6). Statistical data indicates that the occurrence of cholangitis within a year following surgical procedures varies between 54.6% and 91.9% (7,8). Significantly, it is broadly recognized that cholangitis following Kasai surgery can impair the rate of jaundice resolution after the procedure, acting as a vital factor influencing the prognosis of the children affected (6,9). Nonetheless, a substantial gap persists in the availability of a reliable clinical model that can accurately forecast the development of cholangitis subsequent to Kasai surgery.

In this research, our aim is to develop a clinically relevant model capable of forecasting the onset of cholangitis subsequent to Kasai surgery. To improve its applicability, we seek to construct this predictive model using widely available serological indicators. We present this article in accordance with the TRIPOD reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-170/rc).

Methods

Patients

The criteria for selecting participants for both the training and validation cohorts in this research were defined as follows: pediatric patients diagnosed with BA via intraoperative cholangiography and liver biopsy conducted during surgical intervention, who later received Kasai surgery. For the training cohort, a total of 80 children who underwent Kasai surgery for BA at Tianjin Children’s Hospital from January 2017 to November 2023 were included. Each of these patients had undergone intraoperative cholangiography and liver biopsy to validate the BA diagnosis.

The criteria for exclusion in this investigation included the absence of complete preoperative or postoperative routine blood tests and liver function data, in addition to patients who were not available for follow-up. Upon the application of these criteria, a final cohort of 56 children was incorporated into the training dataset.

The diagnosis of cholangitis in patients was characterized by the occurrence of an unexplained fever (≥38 ℃) along with at least one additional clinical manifestation. These manifestations included recurrent jaundice or pale stools, a direct bilirubin (DBIL) level of 20 µmol/L or higher, a white blood cell count (WBC) of 10×10⁹/L or more, or a C-reactive protein (CRP) measurement of 10 mg/L or greater (9-11).

This study was approved by the ethics committee of Tianjin Children’s Hospital (No. 2022-SYYJCYJ-008) and informed consent was obtained from each participant’s guardians. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

In the present investigation, we gathered data from pediatric patients diagnosed with BA who received Kasai surgery at Xi’an Children’s Hospital during the period from January 2018 to November 2019. These pediatric subjects constituted the validation cohort for our predictive model. Initially, a total of 62 children were recruited for this validation group. Nevertheless, following the application of specific exclusion criteria—such as incomplete or absent preoperative and postoperative hematological and liver function data, along with instances of patients being lost to follow-up—the final validation cohort comprised 54 children.

All children have undergone anti-reflux valve surgery, and the length of the Roux-en-Y limb is 40–45 cm. All children follow the same postoperative antibiotic and corticosteroid treatment regimens. The antibiotic treatment regimen: children are given sulperazon intravenously for 2 weeks after the operation to fight infection, then switched to oral cefixime for 2 weeks, and then oral south China moxazole for another 2 weeks. The corticosteroid application regimen: intravenous infusion of methylprednisolone at a dose of 10 mg/kg/d is given for 5 days after the operation, then the dose is gradually reduced. After 7 days, it is changed to oral prednisolone at a dose of 1 mg/kg/d, and stopped after 4 weeks. Clinical and laboratory serological information was obtained from the medical records of each patient. This dataset comprised the age of the patients at the time of surgery, their gender, and the serological markers, which are detailed in Table 1.

Preoperative serological data were obtained from the most recent tests conducted within a 3-day window prior to surgical intervention, which ensured the data’s accuracy and relevance. Conversely, postoperative serological information was collected from tests carried out within one week following the surgery, thus reflecting early alterations in serological indicators. For the pediatric subjects included in the validation cohort, the interval to cholangitis was calculated with precision. Specifically, cholangitis time was defined as the period extending from the date of surgery to the initial occurrence of cholangitis. In instances where cholangitis did not develop by the conclusion of the follow-up duration, the time to cholangitis was established as the period between the surgical procedure and the end of the follow-up, measured accurately in days. This methodology provided a thorough evaluation of both the incidence of cholangitis and its timing in relation to the surgical event.

By employing the serological data obtained both before and after surgery, we calculated the postoperative-to-preoperative ratio (PPR) for each respective serological marker. This ratio acts as a quantitative indicator, signifying the alteration in serological levels observed between the preoperative and postoperative phases. Through the examination of these ratios, our objective is to enhance our comprehension of the serological responses elicited by surgical procedures in the patients being analyzed. The findings are presented in Table 2.

Establishment and evaluating performance of the nomogram

Within the training cohort, we utilized univariate logistic regression to investigate the association between several potential factors and the incidence of primary cholangitis. This preliminary analysis enabled us to discern variables that exhibited a noteworthy correlation with primary cholangitis, specifically those with P values below 0.1. Subsequently, these identified variables were selected as candidates for additional examination.

Subsequently, we developed a multivariate logistic regression model to evaluate the independent impact of each candidate variable on cholangitis. Variables that exhibited no significant contribution to the model, indicated by P values equal to or exceeding 0.05, were omitted from further analysis. The variables that demonstrated a robust and independent correlation with cholangitis were then utilized to create a more precise logistic regression model.

In order to enhance the clinical utility of our model, we constructed a nomogram utilizing the Xiantao Academic software. This nomogram assigns a weighted score to each variable based on its corresponding β-coefficient. By aggregating the scores associated with the specific values of the variables for an individual patient, we are able to efficiently and effectively estimate the patient’s risk of developing cholangitis.

In conclusion, we assessed the predictive efficacy of our nomogram through two principal metrics: the area under the curve (AUC) and the calibration curve. The AUC serves as an indicator of the nomogram’s overall accuracy in distinguishing between patients who are likely to develop cholangitis and those who are not. Conversely, the calibration curve evaluates the degree to which the predicted probabilities produced by the nomogram correspond with the actual observed outcomes. Collectively, these metrics enable us to evaluate the clinical applicability of our nomogram in forecasting the risk of cholangitis.

Statistical analysis

The statistical analysis was conducted utilizing SPSS version 27 (IBM Corp, New York, USA), R version 4.2.2 (R Development Core Team), and Xiantao Academic software. A P value of less than 0.05 was established as the threshold for statistical significance

Results

Patient characteristic

The dataset utilized for this investigation included a total of 56 participants, divided into two separate cohorts based on the incidence of postoperative primary cholangitis. The first cohort, referred to as Group 1, consisted of 41 pediatric patients who experienced cholangitis following surgical intervention, comprising 20 males and 21 females. The average age at the time of surgery for this group was recorded at 66.7±24.8 days. Conversely, Group 2 was made up of 15 children who did not exhibit cholangitis after the operation, with a gender distribution of 8 males and 7 females, and an average surgical age of 59.5±19.4 days. The demographic details of these groups are presented in Tables 3,4.

Descriptive statistics are expressed as numerical values (percentages), mean ± standard deviation (mean ± SD), or median [interquartile range (IQR)] for data that do not follow a normal distribution. To identify statistically significant differences among groups for categorical data, the χ² test or Fisher’s exact test was utilized. For continuous variables, methodologies such as analysis of variance (ANOVA), t-test, and Wilcoxon test were applied.

Univariate logistic regression analysis of variables significantly associated with cholangitis

In the dataset utilized for this investigation, a comprehensive total of 38 preoperative serological markers, 38 postoperative serological markers, along with their corresponding ratios were incorporated. However, the basophil ratio from postoperative to preoperative (BASO% PPR) and the basophil count from postoperative to preoperative ratio (BASO PPR) were omitted from the analysis due to the absence of data for certain patients, as the divisor yielded a value of zero. Consequently, 112 distinct indicators were analyzed through univariate logistic regression to ascertain variables that could be linked to the incidence of cholangitis following Kasai surgery. Variables exhibiting a P value below 0.1 during the univariate logistic regression (Table S1) were deemed to have a correlation with the outcome and were subsequently included in the multivariate logistic regression analysis. Five specific indicators were identified as being associated with the onset of cholangitis post-Kasai surgery: platelet post-operation (PLTPO), mean volume post-operation (MV PO), neutrophil ratio from postoperative to preoperative (NEU PPR), alkaline phosphatase ratio from postoperative to preoperative (ALP PPR), and mean volume pre-operation (MV PRO). Thus, the following indicators were retained for further multivariate logistic regression analysis: PLTPO [odds ratio (OR) =0.997; 95% confidence interval (CI): 0.992–1.001; P=0.09], MV PO (OR =0.568; 95% CI: 0.294–1.101; P=0.09), MV PRO (OR =0.594; 95% CI: 0.324–1.088; P=0.09), neutrophil ratio post-operative to pre-operative ratio (NEU% PPR) (OR =2.145; 95% CI: 0.916–5.020; P=0.08), and alkaline phosphatase post-operative to pre-operative ratio (ALP PPR) (OR =421.410; 95% CI: 4.453–39877.2457; P=0.009).

Establishment of the nomogram model

Employing the five indicators of PLT PO, MV PO, MV PRO, NEU% PPR, and ALP PPR, the outcomes derived from the multivariate logistic regression analysis are presented as follows: NEU% PPR exhibited an OR of 3.953 with a 95% CI ranging from 1.285 to 12.161 and a P value of 0.02. Conversely, MV PRO demonstrated an OR of 0.704, accompanied by a 95% CI of 0.418 to 1.185 and a P value of 0.19. Furthermore, PLT PO recorded an OR of 0.995, with a 95% CI between 0.989 and 1.001 and a P value of 0.11. Lastly, ALP PPR showed a significant OR of 4,014.727 with a 95% CI spanning from 5.583 to 2,887,192.1501 and a P value of 0.01, as illustrated in Table 5.

NEU% PPR and ALP PPR have been recognized as distinct prognostic factors for primary cholangitis subsequent to Kasai surgery, and these variables were utilized to develop a clinical nomogram model (refer to Figure 1). We use a specific patient case to demonstrate the application of Figure 1. For the 30th child in our cohort, the NEU% PPR is 2.558824, which is converted to a score of approximately 34 from the nomogram. The ALP PPR of the child is 0.510903, which is also converted to a score of approximately 34. The total score is 34+34=68. Through score conversion, the probability of developing cholangitis is 0.4 (40%). It is predicted that the probability of cholangitis after surgery for this child is low, and the child did not have an attack of cholangitis after the operation. The predicted result is consistent with the actual result of the child’s cholangitis attack.

Figure 1 The clinical nomogram model based on NEU% PPR and ALP PPR for cholangitis following Kasai surgery. The nomogram was used by summing the points identified on the points scale for each factor. The total points projected on the bottom scales match the probability cholangitis occurrence of patient. ALP PPR, alkaline phosphatase post-operative to pre-operative ratio; NEU% PPR, neutrophil ratio post-operative to pre-operative ratio.

Validation of the model in predicting cholangitis

Utilizing the two identified risk factors from the training dataset alongside the predicted probability of cholangitis occurrence obtained from the model equation, a receiver operating characteristic (ROC) curve (illustrated in Figure 2A) was constructed. The AUC values were computed as follows: the NEU% PPR yielded an AUC of 0.706, the ALP PPR resulted in an AUC of 0.748, while the overall prediction model demonstrated a superior AUC of 0.829. Notably, the prediction probability derived from the model formula surpassed those based on the individual risk factors. The cut-off value of NEU% PPR is 1.7176, the cut-off value of ALP PPR is 0.5011, and the cut-off value of the model is 0.76201.

Figure 2 The ROC curves and calibration curves of the model training set and validation set. The ROC curve of the nomogram and comparison with NEU% PPR and ALP PPR (A). The ROC curve of the validation set (B). The nomogram-predicted probability of cholangitis in the training data set (C). The nomogram-predicted probability of cholangitis in the validation data set (D). ALP PPR, alkaline phosphatase post-operative to pre-operative ratio; AUC, area under the curve; CI, confidence interval; FPR, false positive rate; NEU% PPR, neutrophil ratio post-operative to pre-operative ratio; ROC, receiver operating characteristic; TPR, true positive rate.

By utilizing the validation dataset, we estimated the likelihood of cholangitis occurrence as per the model’s formula and subsequently produced a ROC curve (refer to Figure 2B). The AUC value obtained for the validation dataset was 0.690.

The calibration curves for both the training and validation datasets are presented in Figure 2C,2D. The findings indicate that the probabilities predicted by the model for cholangitis closely matched the observed probabilities, thereby reflecting an alignment between the predictions and the actual incidence of cholangitis. Furthermore, the results suggest that the nomogram’s ability to discriminate cholangitis predictions is likely applicable to diverse populations and holds potential for integration into clinical practice.

Considering the occurrence of primary cholangitis at various intervals post-Kasai surgery, we employed the Kaplan-Meier (KM) method to assess two independent predictors (Figure 3A,3B). Patients were categorized into low and high NEU% PPR groups based on the median value (P=0.14, HR =0.63), and a similar classification was applied to the ALP PPR groups (P=0.006, HR =0.40). The frequency of cholangitis was notably lower in the low ALP PPR group in comparison to the high ALP PPR group, with this disparity becoming more pronounced over time.

Figure 3 The Kaplan-Meier analysis in NEU% PPR and ALP PPR. The Kaplan-Meier analysis in NEU% PPR (A). The Kaplan-Meier analysis in ALP PPR (B). ALP PPR, alkaline phosphatase post-operative to pre-operative ratio; CI, confidence interval; HR, hazard ratio; NEU% PPR, neutrophil ratio post-operative to pre-operative ratio.

Discussion

Cholangitis that arises after Kasai surgery is a crucial determinant of the prognosis for BA, frequently manifesting within the initial year following the operation (12,13). Preventive strategies aimed at mitigating cholangitis following Kasai surgery encompass the implementation of anti-reflux techniques during the surgical procedure, the administration of steroids in the postoperative period, and the provision of prophylactic antibiotics. Nevertheless, there remains an ongoing debate concerning the effectiveness of intraoperative anti-reflux interventions and the use of postoperative steroids in significantly decreasing the incidence of postoperative cholangitis (14-20). Prophylactic administration of oral antibiotics is essential in managing postoperative cholangitis (21-23). Nevertheless, prolonged administration of antibiotics has the potential to disturb the microbiota within the body, resulting in various complications. Should it be feasible to anticipate the onset of cholangitis following Kasai surgery proactively, administering prophylactic antibiotics to children identified as being at elevated risk for developing cholangitis could prove beneficial. Consequently, the development of a predictive model for cholangitis post-Kasai surgery is of paramount importance.

In this retrospective investigation, we gathered data from 56 pediatric patients who underwent Kasai surgery at Tianjin Children’s Hospital. We compiled a total of 114 serological markers and derived indicators, all sourced from standard blood tests and biochemical analyses routinely conducted during hospitalization. These indicators can be acquired in a cost-effective, efficient, rapid, and non-invasive manner in most healthcare facilities, thereby significantly reducing the barriers for general practitioners in utilizing our model. The comparison of preoperative and postoperative indicators provides insights into the patient’s prognosis following surgery and may serve as a predictive tool for the initial occurrence of postoperative cholangitis. Additionally, we employed an independent external dataset as a validation cohort, which reinforces the reliability of our validation process.

In this research, we have effectively established the inaugural clinical prediction model specifically designed for primary cholangitis in pediatric patients with BA who have received Kasai surgery. Importantly, this model has been crafted for ease of use and uncomplicated implementation, thereby promoting its applicability in clinical environments. The independent predictors identified within this model include NEU% PPR and ALP PPR. NEU%, recognized as one of the most frequently utilized serological markers in clinical practice, is extensively employed in evaluating prognostic outcomes across a range of diseases (24-28). The NEU% PPR assesses the degree of variation in neutrophil percentage following surgery compared to baseline pre-surgery levels, offering valuable insights into the fluctuations of granulocytes throughout the perioperative phase. This measure could potentially act as a predictor for the risk of postoperative inflammation to some extent.

The NEU% is recognized as one of the most prevalent biomarkers associated with inflammation (29). During bacterial infections, the NEU% exhibits a considerable rise, and it is recognized as the most sensitive and earliest indicator of inflammation. This parameter can be utilized to assess the effectiveness of treatment interventions (30). Yamaguchi has proposed that the earliest biomarker indicative of cholangitis is the NEU%, which demonstrates a certain predictive capability regarding the prognosis of this condition (31). The alteration in NEU% before and after surgical intervention serves as an indicator of its predictive capacity regarding prognosis, suggesting that NEU% may act as a viable prognostic marker for cholangitis following Kasai surgery.

ALP is an important variable assessed during liver function evaluations in clinical settings. The hepatic form of ALP is predominantly localized within the hepatic canaliculi (32). Increased levels of ALP are a typical indication of cholestasis, primarily resulting from dysfunctional bile secretion in the canaliculi (33). The research indicates that ALP levels are markedly elevated in pediatric patients diagnosed with BA (34), demonstrating its strong predictive capacity for the diagnosis of BA. Furthermore, when utilized in conjunction with serological markers like gamma-glutamyl transpeptidase (GGT), ALP considerably improves the diagnostic accuracy for the early detection of BA (35-37). Recent studies indicate that preoperative ALP levels may serve as a predictive marker for postoperative outcomes in pediatric patients undergoing Kasai surgery (38).

In the present investigation, we identified, for the first time, the prognostic significance of the ALP PPR in relation to cholangitis. Fluctuations in alkaline phosphatase concentrations serve as a proxy for the extent of biliary stasis, with a decline in these levels signifying mitigation in the severity of biliary stasis. Furthermore, the ALP PPR has been previously employed in clinical models to forecast outcomes in liver cancer, hepatic fibrosis, and liver failure (39-43). Current reports indicate that ALP serves as an important predictor in clinical models for the diagnosis of BA (36,37). To a certain degree, the ALP PPR functions as a proxy indicator for the modifications in bile duct patency that occur from the preoperative to postoperative phase. This suggests alterations in the flow dynamics within smaller bile ducts, which may allow for the prediction of postoperative cholangitis risk. Furthermore, it is identified as a significant independent risk factor not only during the construction of predictive models but also in the subsequent KM analysis. In this analysis, the incidence of cholangitis is notably lower in patients within the low ALP PPR cohort when compared to those in the high ALP PPR cohort. Over time, the disparity in cholangitis occurrence between these two cohorts becomes increasingly pronounced. Consequently, the ALP PPR may represent a clinically significant determinant related to the development of cholangitis following Kasai surgery.

Although our investigation offers valuable insights into the diagnostic implications of nomograms in BA, several recognized limitations warrant consideration. To begin with, the model was developed retrospectively, which may inadvertently lead to selection bias. Furthermore, the relatively small sample size of our study underscores the need for additional research encompassing a larger cohort. Notwithstanding these constraints, we are pioneers in examining the relationship between the occurrence of cholangitis following Kasai surgery and NEU% PPR along with ALP PPR. Furthermore, this research represents the inaugural effort to create a nomogram aimed at predicting cholangitis post-Kasai surgery, exhibiting commendable predictive efficacy. In the realm of precision medicine, this model has the potential to enhance clinical decision-making and optimize the management of patients diagnosed with BA.

Conclusions

Our nomogram model integrates two distinct variables: NEU% PPR and ALP PPR, which serve as reliable predictors for the initial onset of cholangitis following Kasai surgery. This could significantly enhance clinical decision-making processes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-170/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-170/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-170/prf

Funding: This study was supported by the Tianjin Science and Technology Program (No. 21ZXGWSY00070) and the Tianjin Applied Basic Research Project (No. 22JCZDJC00290).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-170/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. This study was approved by the ethics committee of Tianjin Children’s Hospital (No. 2022-SYYJCYJ-008) and informed consent was obtained from each participant’s guardians. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

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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