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. 2025 Aug 22;111(12):9726–9741. doi: 10.1097/JS9.0000000000003227

Risk factors for cholangitis after Kasai procedure in biliary atresia patients: a systematic review and meta-analysis

Xiaoyang Liu 1, Yixuan Wang 1, Jichang Han 1, Yue Qi 1, Xintao Zhang 1, Chuncan Ma 1, Dong Sun 1, Qiongqian Xu 1, Xixi He 1, Xue Ren 1, Dongming Wang 1, Aiwu Li 1,*
PMCID: PMC12695348  PMID: 40844888

Abstract

Background:

Cholangitis is a clinically significant complication following Kasai portoenterostomy in patients with biliary atresia (BA). This meta-analysis aimed to review the available literature on the risk factors for post-Kasai cholangitis.

Methods:

The PubMed, Web of Science, Embase, Cochrane Library, Google Scholar, and Chinese databases (CNKI, Wanfang, VIP, and SinoMed) were searched to identify relevant studies published until April 2025. Three researchers independently evaluated the literature quality and extracted data individually. Statistical synthesis was performed using RevMan 5.4 (The Cochrane Collaboration), with supplementary analyses including sensitivity testing and bias assessment conducted in Stata version 18.0 (StataCorp).

Results:

Fifty-seven studies with 3007 cholangitis from 7024 BA patients met the inclusion criteria. Operative age >60 days [I2 = 15%, relative risk (RR) = 0.85, 95% confidence interval (CI): 0.74–0.99, P = 0.03], high risk of malnutrition (I2 = 49%, RR = 3.11, 95% CI: 1.76–5.48, P < 0.0001), low vitamin D receptor (VDR) expression (I2 = 0%, RR = 2.73, 95% CI: 1.44–5.17, P = 0.002), bile lake (I2 = 15%, RR = 2.30, 95% CI: 1.63–3.23, P < 0.00001), and persistent jaundice (I2 = 88%, RR = 1.32, 95% CI: 1.01–1.71, P = 0.04) were significant risk factors of post-Kasai cholangitis. Anti-reflux valve (I2 = 47%, RR = 0.81, 95% CI: 0.72–0.91, P = 0.0002), steroids (I2 = 0%, RR = 1.24, 95% CI: 1.06–1.45, P = 0.006), high-dose steroid (I2 = 1%, RR = 0.60, 95% CI: 0.48–0.75, P < 0.00001), and probiotics (I2 = 0%, RR = 2.97, 95% CI: 1.29–6.85, P = 0.01) were significant protective factors of post-Kasai cholangitis.

Conclusion:

The present meta-analysis identified four risk factors and four protective factors for post-Kasai cholangitis, emphasizing the necessity of rigorous monitoring throughout the therapeutic process.

Keywords: biliary atresia, cholangitis, meta-analysis, risk factors, systematic review

Introduction

Biliary atresia (BA) is a congenital cholestatic disorder characterized by inflammatory-mediated obstruction of the hepatic biliary ducts, involving both intrahepatic and extrahepatic systems with variable segmental distribution. Progressive hepatic fibrosis in untreated BA evolves through sequential stages of cirrhosis to terminal hepatic insufficiency, establishing it as the predominant etiology necessitating liver transplantation therapy in pediatric populations[1,2]. Epidemiological data indicate marked geographical variations in BA incidence, with rates ranging from 1:5000–10 000 live births in Asian populations to 1:15 000–20 000 in Western cohorts[3]. The pathogenesis of BA remains unclear, with both developmental abnormalities and environmental factors implicated[4,5].

HIGHLIGHTS

  • This pioneering study constitutes the most comprehensive systematic review and meta-analysis to date examining determinants influencing cholangitis development following Kasai procedure in BA patients.

  • Operative age >60 days, high risk of malnutrition, low VDR expression, and bile lake are identified as risk factors of post-Kasai cholangitis factors.

  • Anti-reflux valve, steroids, high-dose steroid, and probiotics are identified as protective factors of post-Kasai cholangitis factors.

Kasai portoenterostomy (HPE), the primary surgical intervention for BA, is a palliative operation designed to restore bile flow and relieve biliary obstruction[2]. Cholangitis emerges as the predominant complication during the postoperative phase of HPE, representing the principal morbidity determinant in BA surgical intervention. The diagnostic presentation in post-Kasai cholangitis comprises pyrexia, acholic stools, abdominal discomfort (with or without jaundice), and confirmed bacteremia after excluding alternative infectious etiologies[6]. The incidence of post-Kasai cholangitis is estimated to range from 40% to 93%, with peak onset clustered within the first postoperative year[7].

Post-Kasai cholangitis impairs biliary drainage, inducing cholestasis that exacerbates hepatic injury progression and promotes fibrotic tissue deposition[8]. Cholangitis episodes and suboptimal therapeutic interventions significantly impair quality of life and reduce native liver survival rates in pediatric patients. Identification of modifiable risk factors following HPE is critical for developing targeted preventive strategies and improving long-term outcomes[9,10].

In recent years, advances in pediatric surgery have prompted numerous observational and experimental studies investigating risk factors for post-Kasai cholangitis. However, these studies have reported inconsistent findings due to variations in the risk factors examined[11]. To address this limitation, we performed a comprehensive meta-analytic review of published studies to establish evidence-based predictors of post-Kasai cholangitis, thereby creating a scientific foundation for developing clinical interventions to mitigate its occurrence. Our meta-analysis is compliant with the TITAN Guidelines 2025-governing declaration and use of AI (TITAN Guideline Checklist 2025, Supplemental Digital Content 1, available at: http://links.lww.com/JS9/E906)[12].

Materials and methods

This systematic review with meta-analysis adhered to established methodological frameworks, including the Cochrane Handbook for Systematic Reviews of Interventions, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA, Supplemental Digital Content 2, available at: http://links.lww.com/JS9/E907, Supplemental Digital Content 3, available at: http://links.lww.com/JS9/E908) guidelines[13,14], and A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2, Supplemental Digital Content 4, available at: http://links.lww.com/JS9/E909)[15] quality assessment criteria, ensuring methodological rigor throughout the research process.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) study designs comprised clinical observational studies and randomized controlled trials (RCTs); (2) all cases were definitively diagnosed as BA through intraoperative cholangiography or surgical exploration; (3) studies reporting at least one risk factor for post-Kasai cholangitis in BA patients; and (4) the study reported original data.

The exclusion criteria were as follows: (1) letters, comments, case reports, reviews, and experimental animal studies; (2) the same dataset from different studies; and (3) non-core Chinese journals.

Literature search

A structured database search encompassing five international (PubMed, Web of Science, Embase, Cochrane Library, and Google Scholar) and four Chinese biomedical repositories (CNKI, Wanfang, VIP, and SinoMed) was conducted to identify eligible publications through April 2025. The detailed search strategy is presented in Supplemental Digital Content 5, available at: http://links.lww.com/JS9/E910.

Study selection

Three authors independently screened all records through a three-stage process (title/abstract review, full-text assessment, and data extraction), resolving discrepancies through fourth-researcher consultation (a highly experienced Chief Physician in Pediatric Surgery). All researchers involved underwent a training session using a subset of articles to calibrate their application of the inclusion/exclusion criteria and ensure consistent understanding. This training focused on the specific nuances of our research question and the detailed criteria outlined in the protocol.

Data extraction

Three researchers independently conducted data extraction, with any inconsistencies resolved through consensus-based review or consultation with an additional independent reviewer. The dataset encompassed authorship, publication year, journal, geographic origin, study design, risk factors, exposed cases, and total cases.

Risk factors

Our meta-analysis of risk factors for post-Kasai cholangitis includes preoperative factors, intraoperative factors, and postoperative factors.

Preoperative factors

Operative age, designated as the chronological age of BA patients at HPE, was evaluated as a potential factor in this study. The <60-day and <90-day thresholds were selected for analysis, as these age cutoffs align with the stratification criteria adopted in the majority of referenced literature. The preoperative nutritional status was assessed using the STRONGkids questionnaire[16]. 0 points indicate low risk of malnutrition, 1–3 points indicate moderate risk of malnutrition, and 4–5 points indicate high risk of malnutrition. Cytomegalovirus (CMV) infection was defined as the BA patients who were diagnosed with CMV positive after HPE. The vitamin D receptor (VDR) expression refers to the expression of VDR in intrahepatic bile duct epithelial cells of BA patients after HPE, and in the present study, patients were classified into the low VDR expression group and the normal/high VDR expression group by using immunohistochemical staining.

Intraoperative factors

Patients were stratified into laparotomy and laparoscope groups or laparotomy and robotic-laparoscope groups according to the surgical approach employed. Patients were categorized into anti-reflux valve and non-anti-reflux valve groups based on whether the procedure was performed during surgery. The length of the Roux-en-Y limb was defined as the length of the jejunal biliary limb employed for biliary reconstruction during HPE. According to findings from most of the retrieved studies, patients were categorized into <40 cm and ≥40 cm groups.

Postoperative factors

Bile lake was defined as intrahepatic cystic lesions develop after HPE in BA patients. Persistent jaundice and jaundice clearance were stratified according to postoperative bilirubin resolution rates. Based on the literature search findings, postoperative administration of antibiotics, steroids, immunoglobulin, and probiotics were evaluated as potential risk factors and subsequently incorporated into the meta-analysis.

Quality assessment

Cohort study quality metrics were quantified through Newcastle–Ottawa Scale (NOS)[17], which evaluates three domains: selection, comparability, and outcome through eight items. The maximum scores for these domains are 4, 2, and 3 points respectively, with total scores ranging from 0 to 9. Studies were categorized as low (A: 7–9 points), moderate (B: 4–6 points), or high (C: 1–3 points) risk of bias[14]. The present meta-analysis applied ≥6 validated inclusion metrics as selection thresholds. RCTs underwent methodological appraisal via the Cochrane risk-of-bias tool in RevMan 5.4, with inter-rater variances adjudicated through consensus-based deliberation.

Statistical analyses

Statistical analyses were conducted in RevMan 5.4 with relative risk (RR) as the primary effect measure, with P < 0.05 indicating statistical significance. Heterogeneity across studies was quantified through I2 statistics complemented by Q-test evaluations. Pooled analyses were initiated when at least two independent studies reported equivalent risk factors for post-Kasai cholangitis in BA cases. Fixed-effects modeling was implemented for homogeneous datasets (I2 < 50%), while random-effects approaches were adopted for heterogeneous conditions (I2 ≥ 50%). Pooled risk factor data from eligible studies underwent analysis via dichotomous variables, RR with 95% confidence intervals (CIs), computed using the Mantel–Haenszel method under fixed or random-effects models. Effect estimates were visually represented through forest plots. Statistical analyses encompassing sensitivity evaluation and publication bias assessment were conducted using Stata 18.0. Publication bias assessment incorporated funnel plot visualization supported by Begg’s rank correlation and Egger’s regression tests.

Result

Literature screening process

Preliminary database queries retrieved 2952 unique records across major repositories (PubMed: 182; Web of Science: 1044; Embase: 290; Cochrane Library: 27; and Google Scholar: 993; CNKI/VIP/Wanfang/SinoMed: 416). Following deduplication and title/abstract screening, 197 full-text articles underwent eligibility assessment, ultimately yielding 57 studies meeting inclusion criteria for systematic synthesis. The final analytical cohort comprised 3 RCTs and 54 observational cohort studies. Figure 1 presents the PRISMA-compliant selection flowchart, with detailed study characteristics cataloged in Table 1[18–73].

Figure 1.

Figure 1.

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Flow diagram of literature search and selection of included studies for meta-analysis.

Table 1.

Characteristics of the included studies in meta-analysis

Study Year Country Design Journal Case Total cases Risk factors
Wang et al[17] 2007 China Cohort study Chinese Journal of Pediatric Surgery 55 123 Age, jaundice
Wang et al[18] 2023 China Cohort study Journal of Clinical Pediatric Surgery 71 109 Gender, age, CMV infection, steroid, jaundice
Li et al[19] 2017 China Cohort study Pediatric Surgery International 28 106 Nutritional status
Chen et al[20] 2016 China Cohort study Chinese Journal of Pediatrics 28 66 Nutritional status
Shen et al[21] 2008 China Cohort study World Journal of Pediatrics 7 27 CMV infection
Zhao et al[22] 2023 China Cohort study Journal of Clinical Pediatric Surgery 17 91 CMV infection
Cheng et al[23] 2022 China Cohort study Chinese Journal of Applied Clinical Pediatrics 14 38 VDR expression
Liu et al[24] 2023 China Cohort study International Journal of Pediatrics 22 48 VDR expression
Yan et al[25] 2015 China Cohort study Chinese Journal of Pediatric Surgery 11 16 Bile lake
Ginstrom, Daniel A et al[26] 2019 Finland Cohort study Journal of Pediatric Gastroenterology and Nutrition 26 61 Bile lake
Ren et al[27] 2023 China Cohort study Journal of Clinical Pediatric Surgery 22 30 Surgical approach
Seung Hwan Baek et al[28] 2020 Korea Cohort study Journal of Pediatric Gastroenterology and Nutrition 126 160 Gender, steroid
Kin Wai E Chan et al[29] 2014 China Cohort study Pediatric Surgery International 18 43 Surgical approach
J H Chuang et al[30] 2000 China Cohort study Pediatric Surgery International 15 30 Anti-reflux valve
Ho Yu Chung et al[31] 2008 China Cohort study Pediatric Surgery International 10 30 Steroid
Dong et al[32] 2013 China Cohort study Gastroenterology Research and Practice 142 380 Steroid
Mauricio A Escobar et al[33] 2006 America Cohort study Journal of Pediatric Surgery 25 43 Steroid
Guan et al[34] 2021 China Cohort study Translational Pediatrics 52 77 Jaundice
Huang et al[35] 2018 China Cohort study Journal of Laparoendoscopic & Advanced Surgical Techniques 16 23 Surgical approach
Ji et al[36] 2020 China Cohort study Surgical Endoscopy 145 238 Surgical approach
Tien-Hau Lien et al[37] 2015 China RCT Journal of Pediatric Gastroenterology and Nutrition 10 20 Probiotics
Naruhiko Murase et al[38] 2019 Japan Cohort study Journal of Hepato-Biliary-Pancreatic Sciences 22 127 Surgical approach
Yuki Ogasawara et al[39] 2003 Japan Cohort study Journal of Pediatric Surgery 11 21 Anti-reflux valve
Ewa Orłowska et al[40] 2021 Poland RCT Clinics and Research in Hepatology and Gastroenterology 11 30 Probiotics
Andrea Pietrobattista et al[41] 2020 Italy Cohort study Journal of Pediatric Gastroenterology and Nutrition 13 43 Antibiotic, steroid
Mark D Stringer et al[42] 2007 United kingdom Cohort study Journal of Pediatric Surgery 26 60 Steroid
Thomas M Tarro et al[43] 2020 America Cohort study Open Forum Infectious Diseases 7 91 Antibiotic
Paisarn Vejchapipat et al[44] 2007 Thailand Cohort study Journal of Pediatric Surgery 24 53 Steroid
Momoko Wada et al[45] 2014 Japan Cohort study Pediatric Surgery International 9 23 Surgical approach
Wang et al[46] 2006 China Cohort study Chinese Journal of Pediatric Surgery 21 52 Steroid
Shen et al[47] 2011 China Cohort study Chinese Journal of Pediatric Surgery 93 281 Steroid
E T Wu et al[48] 2001 China Cohort study Pediatric Surgery International 78 107 Antibiotic
Yan et al[49] 2024 China Cohort study American Journal of Translational Research 125 173 Gender, age, jaundice
Zhang et al[50] 2023 China Cohort study Medicine 28 168 Roux-en-Y limb
Zheng et al[51] 2012 China RCT Chinese Journal of Pediatric Surgery 35 60 Probiotics
Zheng et al[52] 2024 China Cohort study Journal of Pediatric Surgery 23 31 Surgical approach
Dong et al[53] 2013 China Cohort study Journal of Clinical Pediatric Surgery 34 112 Age, jaundice
Hou et al[54] 2008 China Cohort study Chinese Journal of Applied Clinical Pediatrics 18 68 Surgical approach
Xiao et al[55] 2017 China Cohort study Journal of Clinical Pediatric Surgery 48 166 Roux-en-Y limb
Li et al[56] 2015 China Cohort study Chinese Journal of Pediatric Surgery 58 99 Jaundice
Lin et al[57] 2012 China Cohort study Master degree thesis of Guizhou Medical University 85 149 Age, jaundice
Pan et al[58] 2011 China Cohort study Master degree thesis of Zhengzhou University 15 34 Steroid
Willemien de Vries et al[59] 2012 The Netherlands Cohort study The Journal of Pediatrics 118 204 Antibiotic
Wang et al[60] 2021 China Cohort study Master degree thesis of Guangxi Medical University 40 115 Surgical approach
Wang et al[61] 2018 China Cohort study Chinese Journal of Pediatric Surgery 51 60 Anti-reflux valve
Wei et al[62] 2020 China Cohort study Journal of Hepatobiliary Surgery 29 82 Steroid
Zhang et al[63] 2019 China Cohort study Master degree thesis of China Medical University 75 80 Age, jaundice, CMV infection
Zhao et al[64] 2021 China Cohort study Chinese Journal of Pediatric Surgery 33 125 Bile lake
Claude Ecoffey et al[65] 1988 France Cohort study The Journal of Pediatrics 46 101 Antibiotic
K P Lally et al[66] 1989 America Cohort study Pediatrics 9 50 Antibiotic, Roux-en-Y limb
Rebecka L. Meyers et al[67] 2003 America Cohort study Journal of Pediatric Surgery 10 28 Steroid
Oliver B. Lao et al[68] 2010 America Cohort study The American Journal of Surgery 49 208 Steroid
Masaki Nio et al[69] 2017 Japan Cohort study Pediatric Surgery International 838 2019 Anti-reflux valve, Roux-en-Y limb
Saeki, M et al[70] 1991 Japan Cohort study Journal of Pediatric Surgery 18 55 Anti-reflux valve
Kobayashi, H et al[71] 2005 Japan Cohort study Journal of Pediatric Surgery 10 63 Steroid
Yumi Inoue et al[72] 2008 Japan Cohort study Journal of Pediatric Surgery 10 65 Bile lake
Ramachandran, P[73] 2019 India Cohort study Journal of Indian Association of Pediatric Surgeons 27 62 Age, jaundice
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CMV, cytomegalovirus; VDR, vitamin D receptor.

Quality assessment of the studies

Methodological rigor was systematically evaluated using the NOS. Among the analyzed studies, 44 studies demonstrated high-quality evidence (16 attaining 8-star ratings and 27 achieving 7-star scores), while 10 studies met criteria for moderate quality (uniformly scoring 6 stars), as detailed in Table 2.

Table 2.

Quality evaluation of the cohort studies included in meta-analysis

Study ID Selection Comparability Outcome Quality assessment score
Representativeness of the exposed cohort Selection of the non-exposed cohort Ascertainment of exposure Demonstration that outcome of interest was not present at start of study Comparability of cohorts on the basis of the design or analysis Assessment of outcome Was follow-up long enough for outcomes to occur Adequacy of follow up of cohorts
Wang[17] ★ ★ ★ ★ ★ ★ ★ 7
Lei Wang[18] ★ ★ ★ ★ ★★ ★ ★ ★ 9
Dandan Li[19] ★ ★ ★ ★ ★ ★ 6
Xiaoai Chen[20] ★ ★ ★ ★ ★★ ★ ★ ★ 9
Chun Shen[21] ★ ★ ★ ★ ★ ★ ★ 7
Yilin Zhao[22] ★ ★ ★ ★★ ★ ★ 7
Jiwen Cheng[23] ★ ★ ★ ★ ★ ★ 6
Na Liu[24] ★ ★ ★ ★ ★★ ★ ★ 8
Peihong Yan[25] ★ ★ ★ ★ ★★ ★ ★ 8
Ginstrom, Daniel A[26] ★ ★ ★ ★ ★ ★ 6
Yuqi Ren[27] ★ ★ ★ ★ ★★ ★ ★ ★ 9
Seung Hwan Baek[28] ★ ★ ★ ★ ★ ★ ★ 7
Kin Wai E Chan[29] ★ ★ ★ ★ ★ ★ ★ 7
J H Chuang[30] ★ ★ ★ ★ ★★ ★ ★ 8
Ho Yu Chung[31] ★ ★ ★ ★ ★ ★ 6
Rui Dong[32] ★ ★ ★ ★ ★ ★ ★ 7
Mauricio A Escobar[33] ★ ★ ★ ★ ★ ★ ★ 7
Xisi Guan[34] ★ ★ ★ ★ ★ ★ ★ 7
Sheng-Yang Huang[35] ★ ★ ★ ★ ★ ★ 6
Yi Ji[36] ★ ★ ★ ★ ★★ ★ ★ 8
Naruhiko Murase[38] ★ ★ ★ ★ ★★ ★ ★ 8
Yuki Ogasawara[39] ★ ★ ★ ★ ★★ ★ ★ 9
Andrea Pietrobattista[41] ★ ★ ★ ★ ★ ★ 6
Mark D Stringer[42] ★ ★ ★ ★ ★ ★ ★ 7
Thomas M Tarro[43] ★ ★ ★ ★ ★ ★ ★ 7
Paisarn Vejchapipat[44] ★ ★ ★ ★ ★ ★ ★ 7
Momoko Wada[45] ★ ★ ★ ★ ★ ★ ★ 7
Wei Wang[46] ★ ★ ★ ★ ★ ★ ★ 7
Wenjun Shen[47] ★ ★ ★ ★ ★ ★ ★ 7
E T Wu[48] ★ ★ ★ ★ ★ ★ ★ 7
Longying Yan[49] ★ ★ ★ ★ ★★ ★ ★ 8
Yuhong Zhang[50] ★ ★ ★ ★ ★ ★ ★ 7
Zebing Zheng[52] ★ ★ ★ ★ ★ ★ ★ 7
Chunqiang Dong[53] ★ ★ ★ ★ ★ ★ ★ 7
Wenying Hou[54] ★ ★ ★ ★ ★★ ★ ★ 8
HuiXiao[55] ★ ★ ★ ★★ ★ 6
Yanyang Li[56] ★ ★ ★ ★ ★ ★ ★ 7
HaiWei Lin[57] ★ ★ ★ ★ ★ ★ ★ ★ 8
Juntao Pan[58] ★ ★ ★ ★ ★ ★ 6
Willemien de Vries[59] ★ ★ ★ ★★ ★ ★ ★ 8
Yixi Wang[60] ★ ★ ★ ★★ ★ ★ 7
Yi Wang[61] ★ ★ ★ ★ ★ ★ ★ 7
Yuan Wei[62] ★ ★ ★ ★ ★ ★ ★ 7
Jingru Zhang[63] ★ ★ ★ ★★ ★ ★ ★ 8
Shengqiao Zhao[64] ★ ★ ★ ★ ★ ★ ★ ★ 8
Claude Ecoffey[65] ★ ★ ★ ★ ★ ★ ★ 7
K P Lally[66] ★ ★ ★ ★ ★ ★ 6
Rebecka L. Meyers[67] ★ ★ ★ ★ ★ ★ ★ 7
Oliver B. Lao[68] ★ ★ ★ ★ ★ ★ ★ 7
Masaki Nio[69] ★ ★ ★ ★★ ★ ★ ★ 8
Saeki, M[70] ★ ★ ★ ★ ★ ★ ★ 7
Kobayashi, H[71] ★ ★ ★ ★★ ★ ★ 7
Yumi Inoue[72] ★ ★ ★ ★ ★ ★ 6
Ramachandran, P[73] ★ ★ ★ ★ ★★ ★ ★ 8
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Three investigators independently conducted critical appraisals of RCTs guided by the Cochrane Handbook for Systematic Reviews of Interventions. The assessment framework encompassed seven methodological domains: randomization protocols, allocation concealment mechanisms, blinding methodologies (participants and outcome assessors), data completeness, selective reporting risks, and potential confounding biases. Methodological components were stratified into three bias risk categories: low, high, or indeterminate, as shown in Figure 2 and Figure 3.

Figure 2.

Figure 2.

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Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Figure 3.

Figure 3.

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Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

Synthesis of the results

Preoperative factors

Gender

Five cohort studies examined gender-specific susceptibility to post-Kasai cholangitis (Fig. 4). Meta-analysis demonstrated no significant gender-based differential risk (I2 = 0%, RR = 0.99, 95% CI: 0.90–1.10, P = 0.89).

Figure 4.

Figure 4.

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Forest plot of gender for post-Kasai cholangitis.

Operative age

Pooled data from four studies identified operative age >60 days as clinically significant (I2 = 15%, RR = 0.85, 95% CI: 0.74–0.99, P = 0.03) (Fig. 5), whereas operative age >90 days showed no association (I2 = 0%, RR = 1.01, 95% CI: 0.77–1.33, P = 0.93) (Fig. 6).

Figure 5.

Figure 5.

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Forest plot of operative age >60 days for post-Kasai cholangitis.

Figure 6.

Figure 6.

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Forest plot of operative age >90 days for post-Kasai cholangitis.

Preoperative nutritional status

Comparative analysis of two studies revealed severe preoperative malnutrition tripled cholangitis risk versus moderate deficiency (I2 = 49%, RR = 3.11, 95% CI: 1.76–5.48, P < 0.0001) (Fig. 7).

Figure 7.

Figure 7.

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Forest plot of high nutritional risk for post-Kasai cholangitis.

CMV infection

CMV positive showed no pathological correlation across four studies (I2 = 23%, RR = 0.91, 95% CI: 0.74–1.11, P = 0.35) (Fig. 8).

Figure 8.

Figure 8.

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Forest plot of CMV positive for post-Kasai cholangitis. CMV, cytomegalovirus.

VDR expression

Significantly low VDR expression emerged as a risk factor from the pooled data in two studies (I2 = 0%, RR = 2.73, 95% CI: 1.44–5.17, P = 0.002) (Fig. 9).

Figure 9.

Figure 9.

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Forest plot of significantly low VDR expression for post-Kasai cholangitis. VDR, vitamin D receptor.

Intraoperative factors

Surgical methods

Eight studies analyzed the relationship of the surgical methods and post-Kasai cholangitis. Conventional laparotomy versus laparoscopic techniques (7 studies) showed equivalent outcomes (I2 = 0%, RR = 0.97, 95% CI: 0.78–1.20, P = 0.77) (Fig. 10). Robotic-assisted laparoscope (2 studies) similarly demonstrated non-significant differences (I2 = 0%, RR = 0.83, 95% CI: 0.55–1.25, P = 0.37) (Fig. 11).

Figure 10.

Figure 10.

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Forest plot of laparoscope for post-Kasai cholangitis.

Figure 11.

Figure 11.

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Forest plot of robotic- laparoscope for post-Kasai cholangitis.

Anti-reflux valve

Pooled analysis of five studies demonstrated a significant protective effect of anti-reflux valve implantation during Kasai procedures against cholangitis development (I2 = 47%, RR = 0.81, 95% CI: 0.72–0.91, P = 0.0002) (Fig. 12).

Figure 12.

Figure 12.

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Forest plot of anti-reflux valve for post-Kasai cholangitis.

The length of the Roux-en-Y limb

Roux-en-Y limb lengths <40 cm exhibited no risk modification in four studies (I2 = 53%, RR = 1.13, 95% CI: 0.78–1.64, P = 0.53) (Fig. 13).

Figure 13.

Figure 13.

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Forest plot of Roux-en-Y limb lengths <40 cm for post-Kasai cholangitis.

Postoperative factors

Bile lake

Hepatic bile lake formation predicted post-Kasai cholangitis in four studies (I2 = 15%, RR = 2.30, 95% CI: 1.63–3.23, P < 0.00001) (Fig. 14).

Figure 14.

Figure 14.

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Forest plot of bile lake for post-Kasai cholangitis.

Postoperative rate of jaundice subsiding

Nine studies were enrolled to investigate the impacts of postoperative rate of jaundice subsiding on post-Kasai cholangitis. Persistent jaundice correlated with post-Kasai cholangitis (I2 = 88%, RR = 1.17, 95% CI: 0.90–1.53, P = 0.24) (Fig. 15).

Figure 15.

Figure 15.

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Forest plot of persistent jaundice for post-Kasai cholangitis.

Antibiotic

Systematic evaluation of six studies indicated that postoperative antibiotic prophylaxis did not significantly affect cholangitis risk after Kasai procedures (I2 = 83%, RR = 0.84; 95% CI: 0.66–1.68, P = 0.84) (Fig. 16).

Figure 16.

Figure 16.

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Forest plot of antibiotic for post-Kasai cholangitis.

Steroids

The analysis of the data from 12 studies revealed that the absence of postoperative steroids increased the incidence of post-Kasai cholangitis (I2 = 52%, RR = 1.40, 95% CI: 1.13–1.74, P = 0.002) (Fig. 17). The sensitivity analysis identified the study by Shen et al[48] as the main source of heterogeneity, with I² decreasing to 0% upon its exclusion (I2 = 0%, RR = 1.24, 95% CI: 1.06–1.45, P = 0.006) (Fig. 18).

Figure 17.

Figure 17.

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Forest plot of steroids for post-Kasai cholangitis.

Figure 18.

Figure 18.

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Forest plot of steroids for post-Kasai cholangitis after removing the main source of the heterogeneity.

High-dose steroid regimens demonstrated superior protection versus low-dose protocols (three studies: I2 = 1%, RR = 0.60, 95% CI: 0.48–0.75, P < 0.00001) (Fig. 19).

Figure 19.

Figure 19.

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Forest plot of high-dose steroid for post-Kasai cholangitis.

Probiotics

Meta-analysis of three RCTs demonstrated that probiotic did not yield significant protective effects against post-Kasai cholangitis (I2 = 64%, RR = 1.84, 95% CI: 0.76–4.45, P = 0.17) (Fig. 20). Zheng et al[52] found that the sensitivity analysis was the main source of the heterogeneity, and the I2 was reduced to 0% after the study was removed (I2 = 0%, RR = 2.97, 95% CI: 1.29–6.85, P = 0.01) (Fig. 21).

Figure 20.

Figure 20.

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Forest plot of probiotics for post-Kasai cholangitis.

Figure 21.

Figure 21.

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Forest plot of probiotics for post-Kasai cholangitis after removing the main source of the heterogeneity.

Sensitivity analysis and publication bias

A leave-one-out sensitivity analysis was conducted to assess the impact of individual trials on both summary effect estimates and between-study heterogeneity. Funnel plot inspection revealed no evident asymmetry. Quantitative assessment through Begg’s test and Egger’s test (P > 0.05) confirmed the absence of significant publication bias. The results are presented in Supplemental Digital Content 6, available at: http://links.lww.com/JS9/E911.

Discussion

Cholangitis represents a prevalent and clinically significant postoperative complication following the HPE, posing a substantial risk for progressive hepatic dysfunction and end-stage liver disease[74]. This meta-analysis systematically analyzed risk factors for post-Kasai cholangitis, identifying 16 potential risk factors with 8 demonstrating significant clinical associations (Table 3).

Table 3.

Risk factors for post-Kasai cholangitis

Factors studied I2 (%) P for heterogeneity Model RR 95% CI P
Gender 0 0.96 Fixed 0.99 0.90–1.10 0.89
Operative age >60 d 15 0.32 Fixed 0.85 0.74–0.99 0.03
Operative age >90 d 0 0.52 Fixed 1.01 0.77–1.33 0.93
High risk of malnutrition 49 0.16 Fixed 3.11 1.76–5.48 <0.0001
CMV positive 23 0.27 Fixed 0.91 0.74–1.11 0.35
Low VDR expression 0 0.97 Fixed 2.73 1.44–5.17 0.002
Laparoscope 0 0.62 Fixed 0.97 0.78–1.20 0.77
Robotic-laparoscope 0 0.57 Fixed 0.83 0.55–1.25 0.37
Anti-reflux valve 47 0.11 Fixed 0.81 0.72–0.91 0.0002
The length of the Roux-en Y limb 53 0.09 Random 1.13 0.78–1.64 0.53
Bile lake 15 0.32 Fixed 2.30 1.63–3.23 <0.00001
Persistent jaundice 88 <0.00001 Random 1.17 0.90–1.53 0.24
Antibiotic 83 <0.0001 Random 0.84 0.66–1.68 0.84
Steroids 0 0.59 Fixed 1.24 1.06–1.45 0.006
High-dose steroid 52 0.36 Fixed 0.6 0.48–0.75 <0.00001
Probiotics 0 0.53 Fixed 2.97 1.29–6.85 0.01
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There is conflicting and controversial evidence regarding whether age influences post-Kasai cholangitis. Yan et al[50], Dong et al[54], and Lin et al[58] found that the occurrence of cholangitis was not related to the age of surgery. Wang et al[19] identified advanced age at HPE as a significant risk factor for subsequent cholangitis development. The result from the present meta-analysis showed that the operative age more than 60 days were associated with increased odds of post-Kasai cholangitis. This result may be attributed to reduced hepatic impairment, increased patency of microscopic bile ducts, and better postoperative biliary drainage in patients undergoing earlier surgical intervention[8,75].

Current findings demonstrate universal manifestation of compromised nutritional status in BA populations[76,77]. The present meta-analysis revealed a significant correlation between preoperative nutritional status and cholangitis occurrence in pediatric patients with BA. Patients with high risk of malnutrition demonstrated a significantly higher propensity for post-Kasai cholangitis development. This phenomenon may stem from pathological alterations including impaired immune function, diminished secretion of intestinal immunoproteins, and compromised intestinal mucosal integrity, which collectively compromise antimicrobial defenses, thereby predisposing patients with high risk of malnutrition to infectious complications[78,79].

Low VDR expression was also considered a risk factor associated with post-Kasai cholangitis. The reason may be that the VDR deficiency impairs intrahepatic bile duct epithelial cells’ immunocompetence and disrupts intercellular junctional complexes.

The application of anti-reflux valve in HPE has been documented since 1990[80], yet their efficacy in preventing postoperative cholangitis remains inconsistent. Our meta-analysis showed the anti-reflux valve was a significant protective factor of post-Kasai cholangitis. Contemporary HPE employs diverse anti-reflux valve designs, all sharing a unified operative principle: narrowing biliary limb caliber to reduce retrograde migration of enteric contents and bacteria into the portoenterostomy site and intrahepatic ducts, thereby preventing bacterial colonization[81].

Bile lake formation following HPE is widely considered strongly associated with cholangitis[82–84]. Our meta-analysis data demonstrated that bile lake presence constitutes a significant risk factor for cholangitis. Cholestasis reduces bile flow into the intestine, exacerbating stasis and inducing inflammatory cell infiltration leading to cholangitis.

Controversy persists regarding postoperative steroid use in BA, focusing on steroid administration versus withholding, and high-dose versus low-dose comparisons. Contrary to similar meta-analyses[85,86], our study incorporating more literature identified postoperative steroids as a significant protective factor of post-Kasai cholangitis. In addition, high-dose steroid therapy demonstrates a lower incidence of postoperative cholangitis compared to low-dose regimens[68]. Steroids, as the most widely used immunosuppressants, exert multifaceted effects: enhancing bile flow via improved canalicular membrane electrolyte transport, suppressing inflammatory and immune pathways, and mitigating hepatic fibrosis.

Our meta-analysis of three RCTs demonstrated that probiotic administration postoperatively serves as a protective factor against post-Kasai cholangitis. Clinical investigations by Isolauri et al[87] establish that standardized probiotics may rebalance intestinal microecology, attenuating pathogenic colonization and offering therapeutic potential in managing gastrointestinal infections and immune-related enteropathies[88].

Strengths and limitations

This study presents the inaugural meta-analysis investigating risk factors for post-Kasai cholangitis. Employing the largest cohort to date, we systematically evaluated long-standing controversies and uncovered novel risk modifiers through stringent methodology. Notably, we established steroid dosage-dependent efficacy and demonstrated superior protection with high-intensity regimens compared to traditional approaches, thus resolving an important point of contention within the conflicting literature. Our study further confirms probiotic interventions as a clinically meaningful strategy for gut-liver axis modulation. Beyond resolving existing debates, we identify VDR expression in biliary epithelium as a previously unrecognized biomarker linked to immune dysregulation, opening new avenues for risk stratification. Surgical practice is also refined through two key insights: quantifiable benefit of implanting anti-reflux valves and a defined risk threshold for delayed intervention beyond 60 days of life that optimizes patient prioritization.

Clinically, these findings crystallize into actionable protocols: enforcing HPE before 60 days of age, adopting high-potency steroid protocols supplemented by postoperative probiotics, and standardizing anti-reflux valve implementation. Vigilant monitoring for bile lake formation and persistent jaundice emerges as essential for early cholangitis detection, while preoperative nutritional optimization proves imperative.

This meta-analysis has limitations requiring consideration. First, the predominance of retrospective studies necessitates rigorously designed prospective investigations to validate risk factor associations. in post-Kasai cholangitis. Second, for certain factors, such as nutritional status, VDR expression and probiotic had a limited number of included studies, resulting in small sample sizes for these analyses. In addition, although post-Kasai cholangitis demonstrates consistent clinical manifestations across various studies, the definition of cholangitis was not consistent across all studies, which resulted in between-study variance. Third, the majority of existing studies are retrospective cohort designs, with confounding factors potentially introducing selection bias, necessitating more high-quality RCTs and highlighting the urgent need for comprehensive investigations. Finally, our study identified a significant geographical concentration, with 36 of the 57 included studies originating from China. This predominance of evidence derived from a single geographic region constitutes a methodological limitation, raising concerns regarding potential external validity bias and the generalizability of the findings to broader populations.

Conclusion

The current meta-analysis indicated that operative age >60 days, high risk of malnutrition, low VDR expression and bile lake were significant risk factors of post-Kasai cholangitis. Anti-reflux valve, steroids, high-dose steroid, and probiotics were significant protective factors of post-Kasai cholangitis. Future researches should prioritize developing targeted interventions addressing these risk factors to mitigate post-Kasai cholangitis incidence. Our findings provide guidance for clinical management and future research directions.

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.lww.com/international-journal-of-surgery.

Published online 22 August 2025

Contributor Information

Xiaoyang Liu, Email: 1150402426@qq.com.

Yixuan Wang, Email: yixuanwang225@163.com.

Jichang Han, Email: hanjichang@mail.sdu.edu.cn.

Xintao Zhang, Email: SDUzxt@163.com.

Dong Sun, Email: f13521651736@163.com.

Xue Ren, Email: 17865197268@163.com.

Dongming Wang, Email: wangdongming431x@163.com.

Ethical approval

This meta-analysis did not require ethical approval.

Consent

Not applicable.

Sources of funding

This research was funded by the National Natural Science Foundation of China (Nos. 82271743, 82071682).

Author contributions

X.L.: conceptualization, data curation, formal analysis, investigation, methodology, project administration, validation, writing – original draft, and visualization. Y.W.: data curation, formal analysis, methodology, and visualization. J.H.: data curation, formal analysis, methodology, and visualization. Y.Q.: methodology, and writing – review and editing. X.Z.: formal analysis and writing – review and editing. C.M.: formal analysis and investigation. D.S.: formal analysis, investigation, and methodology. Q.X.: formal analysis and investigation. X.H.: formal analysis and methodology. X.R.: investigation and methodology. D.W.: conceptualization, formal analysis, methodology, project administration, resources, supervision, and writing – review and editing. A.L.: conceptualization, formal analysis, funding acquisition, methodology, project administration, resources, supervision, and writing – review and editing. All authors read and approved the final manuscript.

Conflicts of interest disclosure

The authors declare no competing interests.

Guarantor

Aiwu Li.

Research registration unique identifying number (UIN)

1. Name of the registry: Prospero. Unique Identifying number or registration ID: CRD420251046362. Hyperlink to your specific registration (must be publicly accessible and will be checked): https://www.crd.york.ac.uk/PROSPERO/view/CRD420251046362.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

This is a meta-analysis article, data availability is not applicable, please contact the corresponding author if some data needed.

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Associated Data

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Data Availability Statement

This is a meta-analysis article, data availability is not applicable, please contact the corresponding author if some data needed.

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