Common bile duct (CBD) stones represent a significant public health burden, with a reported prevalence of 8–18% in patients with symptomatic gallbladder stones.¹ CBD stones can lead to pain, jaundice, and sepsis, hence the recommendation for removing CBD stones even in asymptomatic patients.²

CBD stones may be complicated by cholangitis and acute pancreatitis, which can be fatal in severe cases. In particular, gallstones impacted at the duodenal papilla can completely block the papillary orifice, causing simultaneous biliary and pancreatic duct obstructions. Thus, the urgent removal of impacted papillary stones (IPS) is necessary, with endoscopic retrograde cholangiopancreatography (ERCP) being the standard method for CBD stone extraction. The clinical features of IPS have been evaluated in several studies.^3-5 On the other hand, these were all single-arm studies, including only IPS cases, lacking a comparison between IPS and CBD stones without impaction. This study compared the clinical features of IPS and CBD stones without impaction.

The ERCP database of Kangwon National University Hospital and Gyeongsang National University Changwon Hospital, in which the patient data were collected continuously and maintained prospectively, was analyzed retrospectively from January 2017 to December 2023. The inclusion criteria included the following: (1) age ≥18 years; (2) naïve papilla of Vater, indicating no prior ERCP; (3) confirmed presence of a CBD stone during ERCP. The exclusion criteria were as follows: (1) surgically altered anatomy (i.e., gastrectomy, pancreaticoduodenectomy, or any operation involving the pancreatobiliary tract except cholecystectomy); (2) malignant neoplasm of the pancreatobiliary tract; (3) pregnancy.

Patients diagnosed with IPS were identified from the endoscopic images and grouped into the IPS category. The endoscopic findings of IPS were defined as the direct visualization of the stone or an enlarged papilla with the disappearance of transverse folds and exposure of the stone during an incision of the papilla. These patients were compared with those presenting with overt CBD stones but not IPS (NIPS group); the NIPS group was selected randomly at threefold the number of patients in the IPS group (Fig. 1). An overt CBD stone was defined as a CBD stone identified during ERCP.

Figure 1. Flow of subject inclusion. ERCP, endoscopic retrograde cholangiopancreatography; EST, endoscopic sphincterotomy.

The clinical manifestations were reviewed: abdominal pain, fever, symptom onset, shock, and comorbidities like hypertension and diabetes. Fever was defined as a body temperature ≥38°C and shock as systolic blood pressure ≤90 mmHg, requiring fluid resuscitation or inotropic support. Cholangitis and acute pancreatitis (AP) were defined according to the Tokyo guidelines (TG18)⁶ and the revised Atlanta classification,⁷ respectively.

The assessments included the blood chemistry, blood culture results, and CT imaging for the visibility of the CBD stone and the maximal diameter of the CBD analyzed on a coronal plane. The presence of a bile duct penetrating the duodenal wall sign (BPDS)⁸ was also evaluated on CT scans. An evaluation of the type of stone, presence of periampullary diverticulum, and pus was conducted through endoscopic imaging. In addition, using a needle knife or mechanical lithotriptor during the procedure was assessed. The largest CBD stone was identified by measuring the diameter on CT, magnetic resonance imaging, endoscopy, and fluoroscopy (Fig. 2).

Figure 2. An 88-year-old female underwent ERCP for acute cholangitis. (A) An impacted gallstone was observed at the duodenal papilla. (B) Bile duct penetrating duodenal wall sign was visualized on coronal CT. The arrow indicates the impacted stone. (C) Needle knife fistulotomy was performed, resulting in the drainage of pus from the bile duct. (D) The impacted stone was removed. ERCP, endoscopic retrograde cholangiopancreatography.

Post-ERCP complications, including pancreatitis, bleeding, perforation, and cholangitis, were documented. The assessments also included admissions to the intensive care unit (ICU) and whether a cholecystectomy had been performed before discharge.

The categorical variables are presented as the frequency and percentages, while the continuous variables are expressed as mean±standard deviation. All statistical analyses were performed using SPSS software, version 26 (IBM, Armonk, NY, USA). The institutional review board approved the study protocol (KNUH-2024-02-005). The Chi-square test or Fisher's exact test was used to compare the categorical variables, and a Student's t-test was used for the continuous variables. Variables that showed significant differences between the two groups (p<0.05) were examined further using univariate regression analysis, and those with p<0.10 underwent multivariate analysis. The odds ratios (ORs) and confidence intervals (CIs) for IPS were determined by logistic regression analyses (enter method). A p-value of less than 0.05 was considered significant.

1. Patient characteristics

Forty-five and 135 patients were enrolled in the IPS and NIPS groups, respectively. The mean age of the IPS group was 63.9±15.6 years, with 27 out of 45 (60.0%) being male. The mean onset of symptoms was 3.1±6.2 days prior. Abdominal pain was reported by 40 patients (88.9%), and fever was detected in 15 patients (33.3%). A history of hypertension was present in 24 patients (53.3%), while 12 (26.7%) and five (11.1%) had histories of diabetes and cholecystectomy, respectively. Among the patients whose gallbladder remains intact without surgery, 67.5% had gallstones. Cholangitis was reported in 73.3% of cases, with half classified as mild. Shock was observed in six patients (13.3%).

The mean age of the IPS group was significantly lower than that of the NIPS group (63.9 vs. 70.6 years, p=0.020). Abdominal pain was more prevalent in the IPS group (88.9%) than in the NIPS group (74.8%, p=0.047). AP occurred more frequently in the IPS group (35.6%) than in the NIPS group (10.4%, p<0.001). The other clinical characteristics were similar in the IPS and NIPS groups. Table 1 lists the baseline characteristics.

Table 1 . Clinical Characteristics of the Patients

Characteristic	No impaction (n=135)	Impaction (n=45)	p-value
Mean age (years)	70.6±17.0	63.9±15.6	0.020
Gender: Male	75 (55.6)	27 (60.0)	0.602
Symptom onset (days ago)	3.0±4.1	3.1 ± 6.2	0.912
Abdominal pain	101 (74.8)	40 (88.9)	0.047
Fever	59 (43.7)	15 (33.3)	0.221
Shock	17 (12.6)	6 (13.3)	0.897
Hypertension	67 (49.6)	24 (53.3)	0.667
Diabetes	31 (23.0)	12 (26.7)	0.614
Previous cholecystectomy	25 (18.5)	5 (11.1)	0.248
Gallbladder stone	76 (69.1)	27 (67.5)	0.853
Cholangitis	105 (77.8)	33 (73.3)	0.542
Mild	57 (54.3)	17 (51.5)
Moderate	30 (28.6)	11 (33.3)	0.866
Severe	18 (17.1)	5 (15.2)
Acute pancreatitis	14 (10.4)	16 (35.6)	<0.001

Categorical variables are presented as frequencies and percentages, while continuous variables are conveyed as means±standard deviation.

2. Laboratory findings

The mean serum amylase level was significantly higher in the IPS group (638.2 IU/L) than in the NIPS group (196.0 IU/L, p=0.009). The other laboratory tests showed no significant differences between the groups. The rate of positive blood cultures was 18.4% (7/38) in the IPS group, compared to 28.3% in the NIPS group (32/113, p=0.228, Table 2).

Table 2 . Laboratory Findings of the Patients

Laboratory test	No impaction (n=135)	Impaction (n=45)	p-value
WBC (/mm3)	10715.3±5298.3	11471.0±5502.7	0.413
Platelets (/mm3)	203.8±78.4	220.8±87.1	0.221
CRP (mg/dL)	7.0±7.4	5.0±6.4	0.105
Total bilirubin (mg/dL)	3.1±3.1	3.8±2.4	0.169
AST (IU/L)	210.9±312.2	283.1±237.1	0.157
ALT (IU/L)	216.9±236.1	287.1±253.3	0.092
ALP (IU/L)	221.3±153.3	248.0±156.9	0.316
Albumin (g/dL)	3.8±0.5	4.0±0.6	0.129
Creatinine (mg/dL)	0.9±0.5	0.9±0.3	0.487
Amylase (IU/L)	196.01±517.9	638.2±1011.8	0.009
Procalcitonin (ng/mL)	9.1±29.4	5.2±12.5	0.570
Blood culture positivity	28.3%	18.4%	0.228

Continuous variables are conveyed as means±standard deviation.

WBC, white blood cell; SD, standard deviation; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.

3. Image and endoscopic findings

CBD stones were observed less frequently in the IPS group than in the NIPS group on CT images (60.0% vs. 78.5%, p=0.014). By contrast, BPDS occurred more commonly in the IPS group (53.3%) than in the NIPS group (6.7%, p<0.001). The sensitivity and specificity of BPDS were 53.3% and 93.3%, respectively.

The mean size of IPS was 6.3±3.7 mm on the endoscopic images. During ERCP, periampullary diverticulum was observed less frequently in the IPS group than in the NIPS group (24.4% vs. 52.6%, p=0.001). Pus (28.9% vs. 3.2%, p<0.001) and black stones (44.4% vs. 23.0%, p=0.011) were detected more commonly in the IPS group than in the NIPS group. The mean largest stone size was smaller in the IPS group than in the NIPS group (7.6 mm vs. 10.5 mm, p=0.002). Although the successful biliary cannulation rate tended to be higher in the IPS group than in the NIPS group, the difference was not significant (100% vs. 94.1%, p=0.204). A needle knife was used more frequently in the IPS group than in the NIPS group (60.0% vs. 20.0%, p<0.001). Mechanical lithotripsy was only performed in the NIPS group (Table 3).

Table 3 . Image and Endoscopic Findings of the Patients

Findings	No impaction (n=135)	Impaction (n=45)	p-value
CT scan findings
Visible stones	106 (78.5)	27 (60.0)	0.014
CBD diameter (mm)	11.0±4.2	10.8±4.9	0.770
BPDS	9 (6.7)	24 (53.3)	<0.001
Endoscopic findings
Periampullary diverticulum	71 (52.6)	11 (24.4)	0.001
Pus	3 (2.2)	13 (28.9)	<0.001
Successful biliary cannulation	127 (94.1)	45 (100)	0.204
Needle knife	27 (20.0)	27 (60.0)	<0.001
Mechanical lithotripsy	6 (4.7)	0 (0)	0.342
Type of stone
Cholesterol	11 (8.1)	5 (11.1)	0.011
Brown	93 (68.9)	20 (44.4)
Black	31 (23.0)	20 (44.4)
Largest stone size (mm)	10.5±5.5	7.6±4.9	0.002

Categorical variables are shown as frequencies and percentages, and continuous variables as means±standard deviation.

BPDS, bile duct penetrating duodenal wall sign.

4. Factors associated with IPS

Multivariate analysis was conducted to identify the factors associated with IPS. The serum amylase level and stone type were excluded from the analysis because of multicollinearity with AP and stone visibility on CT, respectively. The analysis showed that AP (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.17–12.17, p=0.026), BPDS (OR 12.09, 95% CI: 3.92 –37.33, p<0.001), and the presence of pus (OR 27.05, 95% CI: 4.92–148.85, p<0.001) were independently associated with IPS. By contrast, the presence of a periampullary diverticulum (OR 0.28, 95% CI: 0.10–0.82, p=0.021) and stones ≥10 mm (OR 0.31, 95% CI: 0.10–0.96, p=0.043) were negatively associated with IPS. The patients’ age, abdominal pain, and visibility on CT were similar in both groups (Table 4).

Table 4 . Factors associated with Impacted Stone on Multivariate Logistic Regression Analysis

Variables	OR (95% CI)	p-value
Age ≥70 years	0.38 (0.13–1.09)	0.072
Abdominal pain	1.94 (0.43–8.84)	0.390
Combined AP	3.78 (1.17–12.17)	0.026
Visibility on CT	0.89 (0.32–2.45)	0.820
BPDS	12.09 (3.92–37.33)	<0.001
Periampullary diverticulum	0.28 (0.10–0.82)	0.021
Pus	27.05 (4.92–148.85)	<0.001
Size of stone ≥10 mm	0.31 (0.10–0.96)	0.043

OR, odds ratio; CI, confidence interval; AP, acute pancreatitis; BPDS, bile duct penetrating duodenal wall sign.

5. Outcome of patients

The complete stone removal rate tended to be higher in the IPS group (97.8%) than in the NIPS group (88.2%), even though the difference was not statistically significant (p=0.073). The post-ERCP complication rates were comparable between the IPS and NIPS groups (11.1% vs. 6.7%, p=0.344). Post-ERCP pancreatitis was the most common complication. The ICU admission rates showed no significant differences between the IPS and NIPS groups (2.2% vs. 5.2%, p=0.681). The IPS group underwent more cholecystectomies than the NIPS group before discharge (35.6% vs. 20.0%, p=0.034, Table 5).

Table 5 . Outcomes of the Patients

Outcomes	No impaction (n=135)	Impaction (n=45)	p-value
Complete stone extraction	112 (88.2)	44 (97.8)	0.073
Post-ERCP complication	9 (6.7)	5 (11.1)	0.344
Pancreatitis	8 (5.9)	3 (6.7)	>0.99
Bleeding	1 (0.7)	2 (4.4)	0.155
Perforation	1 (0.7)	0 (0)	>0.99
Cholangitis	0 (0)	0 (0)	-
ICU admission	7 (5.2)	1 (2.2)	0.681
Cholecystectomy	27 (20.0)	16 (35.6)	0.034

Variables are presented as frequencies and percentages.

ICU, intensive care unit.

In this study, IPS was associated with pancreatitis, BPDS, and acute suppurative cholangitis, whereas periampullary diverticulum and the stone size were inversely correlated with IPS. Selective biliary cannulation was successful in all patients, and the stone was removed completely in more than 97% of patients. The post-ERCP complications were similar in both groups, indicating that IPS removal is no more hazardous than the removal of other CBD stones.

IPS is located near the duodenum or exposed to the duodenal lumen, allowing for relatively easy removal using a needle knife without selective biliary cannulation during ERCP. After removing IPS, selective biliary cannulation can be performed easily as the biliary orifice is easy to locate, and the distal CBD is usually dilated. In addition, the needle knife can be used safely to remove IPS. Despite the risk of duodenal perforation when performing a precut or fistulotomy with a needle knife,⁹ the risk of perforation with IPS may be lower than with typical CBD stone removal.³ Consequently, even operators with less experience can perform the procedure relatively easily and safely. This study was conducted expecting IPS to exhibit different clinical characteristics from other CBD stones.

Males were slightly more prevalent (60.0%) than females (40.0%) in the IPS group, whereas the gender distribution was more balanced in the NIPS group. According to a Korean nationwide study, the male-to-female ratio for CBD stones is 1:1.2¹⁰. The mean age was significantly lower in the IPS group than in the NIPS group, which may be linked to the prevalence of periampullary diverticulum. The prevalence of periampullary diverticulum increases with age¹¹ and shows an inverse correlation with IPS.

Multivariate analysis showed that the presence of pus was most strongly associated with IPS, followed by BPDS and AP. On the other hand, periampullary diverticulum and stones ≥ 10 mm revealed a negative association with IPS. In the IPS group, pus was present in approximately one-third of the patients but was observed more frequently than in the NIPS group (28.9% vs. 3.2%, p<0.001). IPS remains stationary, blocking the bile duct orifice and completely obstructing bile flow, potentially leading to severe inflammation and acute suppurative cholangitis (presence of pus in the bile ducts). Despite acute suppurative cholangitis being more common in the IPS group than in the NIPS group, there were no significant differences between the two groups regarding fever, blood culture positivity, the presence or severity of cholangitis, and ICU admission rate. Earlier studies showed that IPS patients do not exhibit severe systemic inflammation as expected. Joo et al. reported that the typical clinical features of acute cholangitis (Charcot's triad) were observed in only 21.7% of cases.³ Takano et al. reported a severe cholangitis rate of only 27%, according to the Tokyo guideline.⁴ This suggests that local inflammation caused by IPS might not immediately lead to severe systemic inflammation. The cause remains uncertain, but it may be due partly to patients presenting early to the hospital with severe abdominal pain, precluding the full development of cholangitis symptoms.³

Shintani et al. reported that BPDS is a useful CT imaging finding for identifying IPS. The sensitivity and specificity of BPDS were 84.6% and 85.2%, respectively.⁸ In the present study, BPDS occurred more frequently in the IPS group than in the NIPS group, with sensitivity and specificity figures at 53.3% and 93.3%, respectively. Hence, BPDS is an effective indicator of the presence of IPS.

AP was present in one-third of the IPS patients and was significantly more prevalent than in the NIPS group. Joo et al. reported that 37.0% of patients with IPS were also affected by AP.³ IPS is associated with an increased frequency of AP because it is more likely to block the pancreatic duct opening than other CBD stones.

Periampullary diverticulum occurred less frequently in the IPS group than in the NIPS group (24.4% vs. 52.6%, p=0.001). An earlier study on the IPS cohort reported a 26.1% prevalence of periampullary diverticulum, aligning with the present findings.³ Periampullary diverticulum may result in partial loss of the sphincter of Oddi muscle function.¹² Therefore, in patients with periampullary diverticulum, CBD stones are more likely to pass into the duodenal lumen without impaction upon reaching the ampulla of Vater.

The mean largest stone size was smaller in the IPS group than in the NIPS group (7.6 mm vs. 10.5 mm, p=0.002). An excessively large CBD stone would not reach the ampulla of Vater because it cannot pass through the narrow distal CBD. On the other hand, relatively small stones can navigate the distal bile duct and reach the ampulla. Although smaller stones may pass through the ampulla without impaction, overly large stones cannot even reach the ampulla. In the present study, the mean size of IPS on the endoscopic image was 6.3 mm.

The rates of successful biliary cannulation (100% vs. 94.1%, p=0.204) and complete stone removal (97.8% vs. 88.2%, p=0.073) were higher in the IPS group than in the NIPS group, but these differences were not statistically significant. No significant difference in post-ERCP complications was observed between the groups, suggesting that IPS removal is no more hazardous than the removal of other CBD stones. Cholecystectomy was performed more frequently in the IPS group than in the NIPS group. The mean age was lower in the IPS group, potentially leading to more surgery.

This study had several limitations. Stones were classified primarily based on their color, as observed in endoscopic images. On the other hand, external appearances, such as the color or shape and the cross-sectional shape and composition, are crucial for accurately classifying gallstones.^13,14 Thus, the gallstone classification in this study was of low accuracy and unsuitable for multivariate analysis. In addition, this was a retrospective study with a small number of patients from only two institutions, limiting the generalizability of these findings. Further research will be needed to validate these results.

In conclusion, IPS has distinct clinical characteristics compared to other CBD stones. It is associated with AP, BPDS, and acute suppurative cholangitis, while periampullary diverticulum and stone size are negatively associated with IPS. IPS can be removed relatively easily and safely during ERCP.

The study was supported by 2021 Research Grant from Kangwon National University.

None.