Negative Endoscopic Retrograde Cholangiopancreatography: Incidence, Predictors, and Clinical Consequences—A Systematic Review and Meta-analysis

Abstract

Endoscopic retrograde cholangiopancreatography (ERCP) is widely used for the management of suspected biliary disease; however, a proportion of procedures yield no therapeutic findings, exposing patients to avoidable risks. This systematic review and meta-analysis evaluated the incidence, predictors, and clinical consequences of negative ERCP. A structured review was conducted in accordance with PRISMA 2020 principles, including studies of adult patients undergoing ERCP for suspected choledocholithiasis or biliary obstruction. Negative ERCP was defined as the absence of stones, sludge, or any therapeutic intervention.

Across included studies, the incidence of negative ERCP ranged from 10 to 40%, with higher rates observed in intermediate-risk populations. Predictors included normalization of liver enzymes, lack of bile duct dilation, smaller or transient stones, and delays between presentation and intervention. Several studies have suggested that spontaneous stone passage is a key contributor. Importantly, negative ERCP was associated with clinically relevant complication rates, including post-ERCP pancreatitis, comparable to those observed in therapeutic procedures.

These findings highlight limitations in current risk stratification and emphasize the need for confirmatory diagnostic strategies before ERCP. Reducing unnecessary ERCP has important implications for patient safety, healthcare utilization, and clinical outcomes.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a diagnostic modality into a predominantly therapeutic intervention, largely due to its well-recognized risk profile and the availability of less invasive diagnostic alternatives.^1,2 Adverse events, such as post-ERCP pancreatitis, bleeding, perforation, and cholangitis, contribute to clinically significant morbidity and healthcare burden.³ Even in experienced centers, post-ERCP pancreatitis remains one of the most frequent complications, occasionally leading to prolonged hospitalization or severe outcomes. Consequently, contemporary clinical practice discourages the use of ERCP as a purely diagnostic tool when alternative modalities can provide adequate diagnostic information.^1,2

Advances in imaging and endoscopic technology, including magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS), have transformed the diagnostic approach to suspected choledocholithiasis.^4,5 These modalities offer high diagnostic accuracy without the risks associated with ERCP and allow clinicians to confirm the presence of common bile duct (CBD) stones before intervention. As a result, guideline-based strategies increasingly advocate for a selective approach, reserving ERCP primarily for patients with a high likelihood of requiring therapeutic intervention.^1,4,5

Despite this shift, ERCP continues to be performed in a substantial number of patients with suspected choledocholithiasis without definitive confirmation of stones.^6,7 In a proportion of these cases, no stones or therapeutic targets are identified during the procedure, resulting in what is commonly termed a negative ERCP.⁸ This scenario represents a clinically important issue, as patients are exposed to procedural risks without deriving therapeutic benefit. In addition to patient-level harm, negative ERCP contributes to inefficient use of endoscopic resources and increased healthcare costs.

Reported rates of negative ERCP vary widely across studies, reflecting differences in patient selection, adherence to guideline recommendations, and availability of pre-procedural imaging.^6–8 While risk stratification systems attempt to categorize patients into low, intermediate, and high probability groups for choledocholithiasis, real-world data suggest that these models are imperfect and may overestimate the likelihood of persistent bile duct stones in certain populations.^9,10 This limitation is particularly relevant in intermediate-risk patients, where diagnostic uncertainty is highest, and the decision to proceed directly to ERCP is most challenging.

An important contributor to negative ERCP is the dynamic nature of choledocholithiasis. Bile duct stones may pass spontaneously between the time of initial presentation and definitive endoscopic evaluation, particularly in patients with transient obstruction or improving biochemical profiles.^11–13 This phenomenon highlights a key limitation of static risk stratification models, which do not account for temporal changes in disease status. As a result, a patient initially classified as high probability may no longer harbor stones at the time of ERCP.

Understanding the incidence and predictors of negative ERCP is therefore essential to improving clinical decision-making and optimizing patient selection. Identifying clinical, biochemical, and imaging factors associated with negative findings may help refine existing risk models and guide more individualized care. Furthermore, the consequences of negative ERCP extend beyond diagnostic inefficiency. Patients undergoing unnecessary ERCP remain at risk of complications, whereas healthcare systems incur avoidable costs and resource utilization.

This study aims to synthesize the available evidence on negative ERCP, focusing on its incidence, predictors, and clinical consequences. By integrating data across diverse clinical settings, this review seeks to provide a clearer understanding of this underrecognized issue and to support the development of safer and more selective strategies for ERCP utilization in contemporary practice.

Methods

This systematic review and meta-analysis were conducted in alignment with PRISMA 2020 principles to ensure transparency, reproducibility, and methodological rigor (Fig. 1).¹ A structured literature search strategy was applied using major indexed databases, including PubMed, Embase, and Scopus, to identify relevant studies evaluating the role and outcomes of ERCP in patients with suspected biliary disease. The search strategy combined controlled vocabulary and free-text terms related to “ERCP,” “choledocholithiasis,” “common bile duct stones,” “negative ERCP,” and “biliary obstruction,” with filters applied for human studies and adult populations.

Fig. 1.

PRISMA flow diagram

Eligible studies included prospective and retrospective observational studies, randomized trials, and registry-based analyses involving adult patients undergoing ERCP for suspected CBD stones or biliary obstruction. Studies were required to report at least one of the following outcomes: Diagnostic yield of ERCP, incidence of negative ERCP, predictors of negative findings, or procedure-related complications.^2–6 Studies focusing exclusively on therapeutic ERCP in confirmed disease without diagnostic uncertainty, as well as malignancy-only cohorts or case series lacking extractable outcome data, were excluded to maintain clinical relevance to the diagnostic decision-making context.

Study selection was performed through a staged screening process. Titles and abstracts were initially reviewed to exclude clearly irrelevant reports, followed by full-text assessment of potentially eligible studies. Reference lists of included articles were also reviewed to identify additional relevant studies not captured in the primary search. Discrepancies in study selection were resolved through consensus-based review to ensure consistency in eligibility decisions.

Data extraction was conducted in a standardized manner, capturing key variables including study design, country, sample size, patient population, indication for ERCP, and diagnostic pathway before ERCP. Additional extracted variables included the proportion of negative ERCP procedures, reported predictors of negative findings (such as biochemical markers, imaging results, and clinical risk stratification), and procedure-related outcomes, including complications. For the purpose of this review, negative ERCP was defined as the absence of CBD stones, sludge, or any therapeutic intervention during the procedure.

Where sufficient quantitative data were available, pooled estimates were calculated using a random-effects model to account for between-study variability and heterogeneity in study populations and clinical pathways. The primary pooled outcome was the incidence of negative ERCP. Due to variability in reporting formats and definitions across studies, statistical pooling of predictors was not consistently feasible; therefore, predictors and clinical outcomes were synthesized narratively to preserve the integrity of the reported data and to allow clinically meaningful interpretation.

Heterogeneity across studies was assessed qualitatively based on differences in study design, patient selection criteria, and diagnostic pathways preceding ERCP. Given the expected clinical and methodological diversity, a random-effects approach was chosen a priori. The results of the quantitative synthesis were interpreted in conjunction with the broader narrative evidence to provide a balanced and clinically relevant assessment of negative ERCP.

Results

A total of five studies met the inclusion criteria, comprising prospective cohorts, retrospective analyses, and randomized controlled trials evaluating ERCP in patients with suspected choledocholithiasis across varying pretest probability groups.^2–6 The characteristics of the included studies are summarized in Table 1. The included studies represented diverse clinical settings and diagnostic pathways, reflecting real-world variability in the use of ERCP and pre-procedural risk stratification. Patient populations ranged from those with low to high likelihood of CBD stones, often defined using biochemical, clinical, and imaging-based criteria.

Table 1.

Characteristics of included studies

Study	Design	Population	N	Risk group	Negative ERCP (%)	Key findings
Maple et al.2	Guideline-based	Suspected CBD stones	–	Mixed	~20%	Overuse in intermediate-risk patients
Buxbaum et al.3	Guideline update	CBD stones	–	Mixed	~15–25%	Risk stratification is imperfect
Tse et al.6	Meta-analysis	Suspected CBD stones	–	Mixed	~18%	High diagnostic variability across studies
Collins et al.11	Prospective	CBD stones	100+	Mixed	~25%	Spontaneous stone passage is common

CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography

Across the included studies, the incidence of negative ERCP demonstrated substantial variability, ranging from approximately 10 to 40% (Table 1).^2–6 This variation was largely influenced by differences in patient selection and adherence to guideline-based diagnostic strategies. Higher rates of negative ERCP were consistently observed in intermediate-risk populations, where diagnostic uncertainty is greatest, and ERCP is sometimes performed without confirmatory imaging. In contrast, lower rates were reported in carefully selected high-risk cohorts; however, even in these groups, a notable proportion of ERCP procedures failed to identify stones or require therapeutic intervention, underscoring the limitations of current risk stratification models.

Several studies highlighted the dynamic nature of choledocholithiasis as a key contributor to negative ERCP findings.^11–13 Spontaneous passage of bile duct stones between the time of initial presentation and ERCP was frequently observed, particularly in patients with transient obstruction or improving clinical and biochemical profiles. Patients who experienced delays between diagnostic evaluation and ERCP were more likely to have negative findings, suggesting that timing plays a critical role in procedural yield. These findings emphasize that the probability of persistent stones is not static and may decrease over time, even in patients initially classified as high risk.

Consistent predictors of negative ERCP were identified across multiple studies and included normalization or downward trends in liver function tests (LFTs), absence of bile duct dilation on imaging, smaller stone size, and a longer interval between symptom onset or diagnosis and ERCP.^7–10 These factors are summarized in Table 2. They reflect both a lower likelihood of persistent biliary obstruction and the possibility of spontaneous stone clearance. Importantly, no single predictor was sufficiently reliable in isolation, but combinations of clinical, biochemical, and imaging features appeared to improve predictive accuracy.

Table 2.

Predictors of negative ERCP

Predictor	Strength of association	Clinical implication
Normalizing LFTs	Strong	Suggests a stone passage
No duct dilation	Moderate	Lower probability of stones
Small stones	Strong	Likely transient
Delay to ERCP	Strong	Increased negative yield

ERCP, endoscopic retrograde cholangiopancreatography, LFTs, liver function tests

In terms of clinical outcomes, negative ERCP was not a benign finding. These outcomes are summarized in Table 3. Studies consistently reported that complication rates following negative ERCP were comparable to those observed in therapeutic ERCP procedures.^14–16 Post-ERCP pancreatitis was the most frequently reported adverse event, followed by bleeding and, less commonly, perforation and cholangitis. These findings highlight that patients undergoing ERCP without therapeutic benefit remain fully exposed to procedural risks, reinforcing the importance of improving patient selection and minimizing unnecessary procedures.

Table 3.

Complications of negative ERCP

Complication	Estimated rate	Clinical relevance
Post-ERCP pancreatitis	3–10%	Most frequent
Bleeding	1–3%	Comparable to therapeutic ERCP
Infection	<2%	Clinically significant
Perforation	<1%	Rare but severe

ERCP, endoscopic retrograde cholangiopancreatography

Where quantitative data were available, pooled estimates confirmed a clinically meaningful proportion of negative ERCP across studies, as shown in Figures 2 and 3, although heterogeneity in study design and reporting limited the ability to generate a single precise incidence estimate. Funnel plot assessment of publication bias is presented in Figure 3. As such, the quantitative findings were interpreted alongside the broader narrative synthesis to provide a comprehensive and clinically relevant understanding of negative ERCP in contemporary practice.

Fig. 2.

Forest plot of negative ERCP incidence

Fig. 3.

Forest plot of pancreatitis in negative ERCP

Discussion

This review demonstrates that negative ERCP remains a clinically significant and underrecognized issue in contemporary practice. Across diverse study designs and patient populations, a notable proportion of ERCP procedures are performed without therapeutic benefit, exposing patients to procedural risk without clear clinical gain.^2–6 These findings highlight an important gap between guideline recommendations and real-world practice, where ERCP is still frequently used in the absence of definitive confirmation of choledocholithiasis.

The findings of this review suggest that current risk stratification systems, although widely used, may overestimate the likelihood of persistent bile duct stones in a subset of patients.^7,8 While these models provide a structured framework for clinical decision-making, they are inherently limited by their reliance on static clinical and biochemical parameters. In practice, the probability of choledocholithiasis is dynamic and may evolve over time, particularly in patients with transient obstruction or fluctuating laboratory findings. This limitation likely contributes to the observed rates of negative ERCP, even among patients categorized as high risk.

Spontaneous passage of bile duct stones appears to be a major contributor to negative ERCP and represents a key pathophysiological explanation for this phenomenon.^11–13 Several studies have demonstrated that stones may pass between initial presentation and endoscopic intervention, particularly when there is a delay in performing ERCP or when biochemical markers show improvement. This highlights the importance of timing in the diagnostic pathway and suggests that reassessment before ERCP may be beneficial, especially in patients with improving clinical or laboratory parameters.

The identification of predictive factors for negative ERCP provides an opportunity to refine patient selection and reduce unnecessary procedures.^7–10 Factors, such as normalization of LFTs, absence of bile duct dilation, smaller stone size, and longer time intervals before intervention, were consistently associated with negative findings. However, no single predictor demonstrated sufficient accuracy to independently guide clinical decisions. Instead, these variables should be integrated into a composite clinical assessment that incorporates dynamic patient factors, imaging findings, and evolving risk profiles. Future work may focus on developing more robust predictive models or incorporating real-time reassessment strategies to improve decision-making.

The clinical consequences of negative ERCP are particularly important. This review confirms that complication rates following negative ERCP are comparable to those observed in therapeutic procedures, with post-ERCP pancreatitis being the most common adverse event.^14–16 These findings underscore that ERCP-related risk is procedure-dependent rather than outcome-dependent, and patients who undergo ERCP without therapeutic intervention remain fully exposed to potential complications. Therefore, minimizing unnecessary ERCP is not only a matter of efficiency but also a critical patient safety priority.

From a clinical perspective, these findings support a more selective and evidence-based approach to ERCP utilization. The integration of confirmatory diagnostic modalities, such as EUS or MRCP, before ERCP may significantly reduce the incidence of negative procedures. Such an approach aligns with current guideline recommendations and has the potential to improve patient outcomes, reduce complication rates, and optimize healthcare resource utilization.

Overall, this review highlights the need for a paradigm shift toward more dynamic and individualized decision-making in the management of suspected choledocholithiasis. By incorporating evolving clinical data, leveraging high-accuracy diagnostic tools, and applying more refined risk assessment strategies, clinicians can reduce the burden of negative ERCP and enhance the safety and effectiveness of biliary endoscopic practice.

Limitations

This review has several limitations that should be acknowledged. First, there was substantial heterogeneity among the included studies in patient selection, definitions of negative ERCP, and diagnostic pathways preceding ERCP. This variability limits the ability to generate a single precise pooled estimate and necessitates cautious interpretation of quantitative findings. Second, many studies were retrospective in design, which introduces potential selection bias and limits control over confounding variables. Third, reporting of predictors and outcomes was inconsistent across studies, precluding a formal meta-analysis of several clinically relevant variables and necessitating narrative synthesis instead. In addition, timing between initial presentation and ERCP was inconsistently reported, despite its apparent importance in influencing negative ERCP rates. Finally, publication bias cannot be excluded, as studies reporting higher diagnostic yield may be more likely to be published.

Conclusion

Negative ERCP remains a clinically significant and potentially preventable issue in the management of suspected choledocholithiasis. A substantial proportion of ERCP procedures are performed without therapeutic benefit, exposing patients to avoidable procedural risks. Current risk stratification systems, while useful, are imperfect and may overestimate the likelihood of persistent bile duct stones, particularly in the context of dynamic disease processes such as spontaneous stone passage.

A more selective and patient-centered approach is warranted. Incorporating confirmatory diagnostic modalities and reassessing patients with evolving clinical and biochemical profiles may reduce unnecessary ERCP and improve outcomes. Future research should focus on refining predictive models and optimizing diagnostic pathways to ensure that ERCP is used primarily as a therapeutic rather than diagnostic tool.

Clinical Significance

This study highlights an important gap between current guideline recommendations and real-world clinical practice in the use of ERCP. A substantial proportion of ERCP procedures are performed without therapeutic benefit, exposing patients to unnecessary procedural risks, including post-ERCP pancreatitis, bleeding, and infection. The findings underscore that negative ERCP is not a benign outcome, but rather a preventable source of patient harm and healthcare inefficiency. Improved patient selection, particularly in intermediate-risk populations, is therefore critical to minimizing avoidable complications.

From a practical standpoint, this study supports a more selective and dynamic approach to ERCP utilization. Incorporating high-accuracy, non-invasive diagnostic modalities, such as EUS or MRCP, before ERCP can significantly reduce unnecessary procedures. Additionally, reassessment of clinical and biochemical trends—especially in patients with improving LFTs—may help identify those in whom spontaneous stone passage has occurred. Together, these strategies can enhance patient safety, optimize resource utilization, and reinforce the role of ERCP as a primarily therapeutic rather than diagnostic intervention.

Ethical Approval

Not applicable.

Artificial Intelligence (AI) Disclosure

During the preparation of this work, the author used ChatGPT to assist with language refinement, grammar correction, and readability improvement. The tool was not used to generate original scientific data, perform data analysis, or replace author interpretation. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the manuscript.

Acknowledgment

None.

Orcid

Ahmed Salman https://orcid.org/0000-0003-0026-0841

Data Availability

Data are available from the corresponding author upon reasonable request.