Impact of periampullary diverticulum and relevant cannulation techniques on the outcomes of endoscopic retrograde cholangiopancreatography: a retrospective study

Abstract

Background

Periampullary diverticulum (PAD) is an incidental finding during endoscopic retrograde cholangiopancreatography (ERCP), occurring more frequently in elderly patients. The influence of PAD on the ERCP procedure has been a subject of debate. The aim of this study was to investigate the impact of PAD on ERCP outcomes.

Methods

Medical records of patients with naïve papilla who underwent ERCP between 2022–2024 were retrospectively reviewed. Patients were classified into PAD and non-PAD groups. Patients with PAD were subclassified into three groups: type I, II, and II, with the location of papilla inside, at the margins, and outside the PAD. Cannulation success, ERCP findings, and adverse events were compared between the groups.

Results

A total of 179 and 884 patients were included in the PAD and non-PAD groups, respectively. After 1:1 propensity score matching (151 patients in each group), there was no significant difference between the PAD and non-PAD groups regarding the rate of successful biliary cannulation (96.7% vs. 98.0%, p = 0.361), difficult cannulation (49.0% vs. 40.4%, p = 0.132), successful stone extraction (85.8% vs. 93.0%, p = 0.64), and post-ERCP pancreatitis (PEP) (13.9% vs. 14.5%, p = 0.869). Additionally, there was no significant difference in the rate of PEP when the same cannulation techniques were compared between the two groups (p > 0.05). Among the three subtypes of PAD, no significant difference was observed in cannulation success and adverse event rates (p > 0.05).

Conclusions

Presence of a PAD is not associated with increased risk of cannulation difficulty, procedural failure, or adverse events. Different cannulation techniques, if applied carefully and in accordance with the endoscopist's experience, could all be successful in patients with PAD.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is a widely utilized endoscopic technique for the diagnosis and treatment of various pancreatobiliary disorders [1]. A successful procedure requires deep cannulation through the duodenal papilla to either the common bile duct (CBD) or pancreatic duct (PD), depending on the purpose of the procedure [2]. During the ERCP procedure, several anatomic entities may be encountered, including periampullary diverticulum (PAD), which is often incidentally found in approximately one-third of patients undergoing ERCP [3, 4]. PAD is an outpouching measuring 2–3 cm that develops near the ampulla of the duodenum [5, 6]. The prevalence of PAD is directly associated with aging, with a reported overall prevalence of 65% in the elderly population [7]. The primary etiologies of PAD are increased intraduodenal pressure and the progression of intestinal smooth muscle weakening, leading to disorders of duodenal motility [8].

It is debatable whether the presence of PAD will affect ERCP outcomes. While some studies have shown no association between PAD and ERCP outcomes [4, 9, 10], others suggest that PAD may complicate the procedure by increasing cannulation time, difficulty, or post-ERCP adverse events [11–14]. However, it has also been concluded that ERCP can be successfully and technically performed in patients with PAD by experienced endoscopists, with no significant difference in adverse events, including post-ERCP pancreatitis (PEP), perforation, bleeding, and cholangitis, between the PAD and non-PAD groups [15]. Furthermore, some studies have compared ERCP outcomes among different PAD types, yielding varying results for each type [12].

Due to the relatively high prevalence of PAD, particularly in the elderly population, and the ongoing controversy regarding ERCP outcomes in patients with PAD, this study aims to investigate whether PAD influences ERCP outcomes and, more specifically, how each PAD type individually influences these outcomes, given the limited data available. Moreover, it is essential to identify specific cannulation techniques that can maximize the rate of successful cannulation in these patients while minimizing post-ERCP adverse events.

Patients and methods

Study design

This study retrospectively analyzed a prospective ERCP registry (IR.SBMU.RIGLD.REC.1398.043) of consecutive patients who underwent ERCP between April 2022 and July 2024 at the ERCP unit of Taleghani Hospital, a tertiary referral center for pancreatobiliary disorders located in Tehran, Iran. During this period, all patients underwent ERCP with obvious indications for biliary access, based on physical examination and paraclinical tests. All patients with naïve major duodenal papillae (MDP) were included in this study. The exclusion criteria were as follows: (1) age < 18 years, (2) pregnancy or breastfeeding, (3) surgically altered upper gastrointestinal anatomy, (4) severe coagulopathy, (5) chronic pancreatitis, (6) suspected dysfunction of the sphincter of Oddi, (7) presence of an ampullary tumor, (8) planned PD cannulation, and (9) at least two unintentional PD cannulations/opacifications. This study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences (SBMU) under the ethical code IR.SBMU.RETECH.REC.1403.410.

ERCP procedures

All included procedures were performed by three experienced endoscopists who performed at least 500 therapeutic ERCPs annually. Trainees were not involved in the procedure. A 100 mg dose of indomethacin or diclofenac suppository was administered to all patients 30 min prior to the procedure. Before each procedure, opioid agents and benzodiazepines were administered as premedications. The dosage was adjusted according to each patient's age and tolerance level. A side-viewing therapeutic duodenoscope (JF-240 or JF-260 V; Olympus, Tokyo, Japan) was used. Additionally, each patient was hydrated with normal saline solution following a standard protocol (1.5 ml/kg/hr during the procedure, followed by 8 h post-procedure). No prophylactic or therapeutic PD stent was used in this study.

Patient follow-up

The patients were closely monitored for clinical symptoms suggestive of immediate adverse events, including bleeding, abdominal pain, local tenderness, respiratory distress, loss of consciousness, and emphysema. Clinical symptoms and vital signs were monitored in the recovery room for at least 6 h during the reversal stages of anesthesia and 24 h of hospitalization. Amylase, lipase, and hemoglobin levels were routinely assessed in all patients. In the absence of any significant signs and symptoms, the patients thoroughly informed of potential warning signs and subsequently discharged. If PEP, perforation, cholangitis, bleeding, or other significant complaints were present, the patient was hospitalized for a longer period of time.

Definitions and classifications

PAD was defined as an outpouching of extraluminal mucosa in the duodenum that arose within a 2–3 cm radius of the ampulla of Vater. PAD was subdivided into three types based on their location relative to the papilla: type I, II, and III, with the papilla located inside, at the margins, and outside the PAD, respectively (Fig. 1).

Fig. 1.

PAD subtypes based on their location relative to the papilla. a type I (papilla located inside the PAD), b type II (papilla located at the margin of PAD), and c type III (papilla located outside the PAD)

Difficult biliary cannulation was defined in accordance with the European Society of Gastrointestinal Endoscopy criteria as (I) more than five contacts with the papilla, (II) more than five minutes of cannulation attempts, or (III) at least two inadvertent PD cannulations or opacifications [16]. A normal CBD diameter was defined as a CBD with a diameter of less than 7 mm. In contrast, a CBD diameter of up to 10 mm was considered normal in patients with a history of cholecystectomy. Additionally, an increase of 1 mm per decade in CBD diameter was considered normal in patients over 60 years of age.

PEP was defined as acute pancreatitis causing new-onset or worsening abdominal pain, as well as an elevation of pancreatic enzymes to at least three times the upper limit of normal, resulting in an extended post-ERCP hospital stay. Based on the Atlanta criteria, PEP was categorized into mild, moderate, and severe [17]. Major bleeding was characterized by the occurrence of hematochezia, melena, or hematemesis accompanied by a reduction in hemoglobin levels of at least 2 g/dl or the requirement for a blood transfusion. Perforation was defined as the occurrence of contrast leakage or retroperitoneal air, due to the formation of an unintended pathway following sphincterotomy or fistulotomy.

Statistical analysis

All analyses were conducted using STATA® version 17.0 (StataCorp, College Station, Lakeway, TX, USA) and Python 3.12.7 (Python Software Foundation). Continuous variables were compared using the Kruskal–Wallis test or the one-way ANOVA. The Fisher's exact test or the Pearson's chi-square test was used to compare the categorical variables. Binary logistic regression was used to determine univariate and multivariate odds ratios (ORs) and their corresponding confidence intervals (CIs) for outcomes. Statistical significance was set at a p value < 0.05.

To reduce confounding, we employed propensity score matching (PSM) to estimate the effect of biliary stenting on the outcomes of ERCP. The PSM process was restricted to patients with choledocholithiasis as the indication, involved matching patients with PAD with those without PAD, based on their propensity scores. To analyze the outcomes of all cases for PSM, we selected age, sex, body mass index (BMI), comorbidities, and cannulation technique as covariates. A logistic regression model was used to estimate propensity scores, and a nearest neighbor matching algorithm with 1:1 ratio was applied within a caliper of 0.2 standard deviations of the propensity scores.

Results

Of the 1205 patients, 1063 patients ultimately met the eligibility criteria and were included in the study. These patients were divided into two cohorts: I) Cohort I, which consisted of a PAD group (n = 179) and a non-PAD group (n = 884), and II) Cohort II, in which patients with PAD were subsequently classified into three subgroups: type I (n = 95), type II (n = 51), and type III (n = 30). Figure 2 illustrates the process in detail.

Fig. 2.

Algorithm showing study protocol and patients who met the eligibility criteria. Abbreviations: PAD: periampullary diverticulum, PD: pancreatic duct, SOD: sphincter of oddi dysfunction, UGI: upper gastrointestinal

Cohort I (PAD versus non-PAD)

Patients were divided into two groups based on the presence or absence of PAD: the PAD group (n = 179) and the non-PAD group (n = 884). Figure 3 illustrates the correlation coefficients and Table 1 presents the baseline characteristics and ERCP outcomes of the investigated variables in this cohort. The mean age of the PAD group was 70.9 ± 14.0 years, whereas the mean age of the non-PAD group was 56.2 ± 17.2 years (p < 0.001). No statistically significant differences were found between the PAD and non-PAD groups in terms of female sex (55.9% vs. 51.7%, p = 0.308), BMI (25.4 vs. 25.2 kg/m², p = 0.756), diabetes mellitus (14.5% vs. 13.4%, p = 0.675), and opium addiction (12.8% vs. 12.4%, p = 0.840). In contrast, hypertension (32.4% vs. 20.4%, p < 0.0001) and coronary artery disease (16.8% vs. 8.4%, p = 0.001) were significantly more common in the PAD group. However, multivariate analysis adjusted for age revealed that hypertension (OR = 1.06; 95% CI: 0.72–1.57) and coronary artery disease (OR = 1.37; 95% CI: 0.84–2.26) were not independent risk factors for PAD, and their higher prevalence in PAD patients is attributed to the higher age in this group (OR = 1.06; 95% CI: 1.04–1.07). Regarding the indications for ERCP, choledocholithiasis was more common in the PAD group than in the non-PAD group (96.2% vs. 78.7%, p < 0.001).

Fig. 3.

Correlation matrix showing the correlation coefficients between the most important variables. Abbreviations: BMI: body mass index, CAD: coronary artery disease, CBD: common bile duct, DM: diabetes mellitus, HTN: hypertension, PAD: periampullary diverticulum, PEP: post-ERCP pancreatitis, PD: pancreatic duct, TPBS: trans-pancreatic biliary sphincterotomy

Table 1.

Baseline characteristics and outcomes of ERCP in patients with and without PAD

Variable	Before matching			After matching
	PAD group (n = 179)	Non-PAD group (n = 884)	p-value	PAD group (n = 151)	Non-PAD group (n = 151)	p-value
Baseline characteristics
Age (years)	70.9 ± 14.0	56.2 ± 17.2	< 0.001	69.1 ± 12.4	70.2 ± 13.0	0.465
Female sex	100 (55.9%)	457 (51.7%)	0.308	82 (54.3%)	78/73 (48.3%)	0.300
BMI (kg/m2)	25.4 ± 4.8	25.2 ± 4.5	0.756	25.3 ± 4.5	26.0 ± 5.0	0.226
Hypertension	58 (32.4%)	180 (20.4%)	< 0.001	47 (31.1%)	47 (31.1%)	1.000
Coronary artery disease	30 (16.8%)	74 (8.4%)	0.001	26 (17.2%)	27 (17.9%)	0.880
Diabetes mellitus	26 (14.5%)	118 (13.4%)	0.675	21 (13.9%)	20 (13.2%)	0.867
Opium addiction	23 (12.8%)	110 (12.4%)	0.840	21 (13.9%)	29 (19.2%)	0.216
Indications
CBD stone CBD stricture Bile leak Pancreatic tumor Parasitic infestation CBD dilation	172 (96.2%) 4 (2.2%) 2(1.1%) 0 0 1 (0.5%)	696 (78.7%) 128 (14.5%) 18 (2%) 28 (3.2%) 5 (0.6%) 9 (1%)	< 0.001	151 (100%) 0 0 0 0 0	151 (100%) 0 0 0 0 0	1.000
ERCP outcomes
Successful cannulation	174 (97.2%)	868 (98.2%)	0.389	146 (96.7%)	148 (98.0%)	0.361
Cannulation technique
STP NKF TPBS PP DGT	109 (60.9%) 24 (13.4%) 27 (15.1%) 15 (8.4%) 4 (2.2%)	347 (39.2%) 443 (50.1%) 60 (6.8%) 21 (2.4%) 13 (1.5%)	< 0.001	96 (63.5%) 23 (15.2%) 20 (13.3%) 9 (6.0%) 3 (2.0%)	93 (61.6%) 26 (17.2%) 20 (13.3%) 10 (6.6%) 2 (1.3%)	0.975
Cannulation time
< 5 min 5–10 min  > 10 min	87 (48.6%) 31 (17.3%) 61 (34.1%)	502 (56.8%) 160 (18.1%) 222 (25.1%)	0.041	77 (51.0%) 28 (18.5%) 46 (30.5%)	90 (59.6%) 29 (19.2%) 32 (21.2%)	0.170
Number of cannulation attempts	3.8 ± 1.7	3.4 ± 1.6	0.005	3.8 ± 1.7	3.5 ± 1.6	0.103
CBD diameter
Normal Abnormal	22 (12.3%) 157 (87.7%)	96 (10.9%) 788 (89.1%)	0.578	18 (11.9%) 133 (88.1%)	20 (13.3%) 131 (86.7%)	0.729
Difficult cannulation	92 (51.4%)	382 (43.2%)	0.045	74 (49.0%)	61 (40.4%)	0.132
Inadvertent PD cannulation	37 (20.7%)	178 (20.1%)	0.871	30 (19.9%)	26 (17.2%)	0.554
Balloon dilatation of SO	167 (93.3%)	746 (84.4%)	0.002	141 (93.4%)	135 (89.4%)	0.218
Successful stone extractiona	139 (89.7%)	653 (84.8%)	0.115	103 (85.8%)	120 (93.0%)	0.064
Stone number	2.5 ± 2.2	2.7 ± 2.5	0.568	2.3 ± 1.5	2.4 ± 1.7	0.724
Stone size	11.5 ± 5.2	9.3 ± 5.0	< 0.001	11.4 ± 5.1	10.1 ± 4.3	0.062
Biliary stent	44 (24.6%)	249 (28.2%)	0.327	37 (24.5%)	23 (15.2%)	0.043
Post-ERCP adverse events
PEP (overall)b Mild Moderate Severe	23 (12.9%) 15 (8.4%) 8 (4.5) 0	117 (13.2%) 80 (8.9%) 34 (3.9%) 3 (0.4%)	0.889	21 (13.9%) 14 (9.3%) 7 (4.6%) 0	22 (14.5%) 15 (9.9%) 7 (4.6%) 0	0.869
Bleeding	1 (0.6%)	8 (0.9%)	1.000	0	1 (0.7%)	1.000
Perforation	0	6 (0.7%)	0.597	0	1 (0.7%)	1.000

The quantitative data are presented as the means ± standard deviations; the qualitative data are presented as numbers (percentages)

Abbreviations: BMI body mass index, CBD common bile duct, DGT double guidewire technique, PAD periampullary diverticulum, PD pancreatic duct, NKF needle-knife fistulotomy, PEP post-ERCP pancreatitis, PP precut papillotomy, SO sphincter of oddi, STP standard transpapillary, TPBS trans-pancreatic biliary sphincterotomy

^aOf those with confirmed CBD stone during ERCP

^bBased on the revised Atlanta criteria; mild: no organ failure, moderate: transient organ failure (resolves within 48 h), severe: persistent organ failure (> 48 h)

The cannulation success rates were 97.2% in the PAD group and 98.2% in the non-PAD group, with no statistically significant difference (p = 0.389). In contrast, the number of cannulation attempts was significantly higher in the PAD group than in the non-PAD group (3.8 vs. 3.4, p = 0.041). The standard transpapillary technique was the most common cannulation technique in the PAD group (60.9%), whereas needle-knife fistulotomy was the most common technique in the non-PAD group (50.1%). Although difficult cannulation was more common in the PAD group (51.4% vs. 43.2%, p = 0.045), there was no significant difference in the rates of inadvertent PD cannulation (20.7% vs. 20.1%, p = 0.871), successful stone extraction (89.7% vs. 84.4%, p = 0.115), and biliary stent placement (24.6% vs. 28.2%, p = 0.33) between the two groups.

Regarding post-ERCP adverse events, there were no significant differences between the PAD and non-PAD groups in PEP (12.9% vs. 13.2%, p = 0.889), bleeding (0.6% vs. 0.9%, p = 1.000), and perforation (0% vs. 0.7%, p = 0.597). Table 2 presents the rate of PEP based on cannulation technique in both the PAD and non-PAD groups, showing no significant difference in PEP rates across cannulation techniques (p > 0.05).

Table 2.

PEP incidence based on the cannulation technique in patients with and without PAD

Cannulation technique	Difficult cannulation	PAD group (n = 179)	Non-PAD group (n = 884)	p-value
STP	No	8/76 (10.5%)	26/260 (10%)	0.893
	Yes	6/33 (18.2%)	14/87 (16.1%)	0.783
NKF	No	0/7 (0%)	21/235 (8.9%)	1.000
	Yes	3/17 (17.6%)	40/208 (19.2%)	1.000
TPBS	No	0/1 (0%)	1/4 (25%)	1.000
	Yes	4/26 (15.4%)	9/56 (16.1%)	1.000
PP	No	1/2 (50%)	0/1 (0%)	1.000
	Yes	0/13 (0%)	3/20 (15%)	0.261
DGT	No	0/1 (0%)	0/2 (0%)	1.000
	Yes	1/3 (33.3%)	3/11 (27.3%)	1.000

Abbreviations: DGT double guidewire technique, PAD periampullary diverticulum, NKF needle-knife fistulotomy, PP precut papillotomy, STP standard transpapillary, TPBS trans-pancreatic biliary sphincterotomy

To reduce confounding, a subgroup of the PAD group with choledocholithiasis was matched 1:1 to the non-PAD group using PSM. The final cohort consisted of 302 patients who were matched in terms of demographics, comorbidities, and cannulation technique (151 patients in each group). After PSM, previously significant differences in age, hypertension, coronary artery disease, and cannulation technique between the groups were no longer observed (p > 0.05). Baseline characteristics, ERCP findings, interventions, and adverse events in this matched cohort are presented in detail in Table 1. Similar to the unmatched cohort, there was no statistically significant difference between the PAD and non-PAD groups regarding the rates of cannulation success (96.7% vs. 98.0%, p = 0.361), inadvertent PD cannulation (19.9% vs. 17.2%, p = 0.554), successful stone extraction (85.8% vs. 93.0%, p = 0.064), and PEP (13.9% vs. 14.5%, p = 0.869). However, in contrast to the unmatched cohort, there was no statistically significant difference between the groups regarding the number of cannulation attempts (3.8 vs. 3.5, p = 0.103) and the difficult cannulation rate (49.0% vs. 40.4%, p = 0.554).

Cohort II (PAD subtypes)

The PAD group was divided into three subtypes: type I (n = 95), type II (n = 51), and type III (n = 30). Table 3 presents the baseline characteristics and ERCP outcomes based on the PAD subtype. There were no statistically significant differences in demographics, comorbidities, or indications among the types I, II, and III (p > 0.05). Although difficult cannulation was significantly more common in type III (70.4%, p = 0.035), the cannulation success rate was similar across all subtypes (p = 0.708). Furthermore, there were no significant differences among the three subtypes regarding inadvertent PD cannulation, cannulation time, the number of cannulation attempts, successful stone extraction, and biliary stent placement (p > 0.05). Additionally, no significant differences were observed among the subtypes regarding post-ERCP adverse events, including PEP (p = 0.955), bleeding, and perforation (p = 1.000).

Table 3.

Baseline characteristics and outcomes of ERCP based on the PAD type

Variable	Type I (n = 95)	Type II (n = 51)	Type III (n = 30)	p-value
Baseline characteristics
Age (years)	70.3 ± 14.7	70.9 ± 13.8	73.9 ± 11.8	0.388
Female sex	48 (50.5%)	33 (64.7%)	17 (56.7%)	0.257
BMI (kg/m2)	25.1 ± 4.9	26.1 ± 5.1	24.7 ± 3.9	0.761
Hypertension	27 (28.4%)	20 (39.2%)	10 (33.3%)	0.411
Coronary artery disease	16 (16.8%)	10 (19.6%)	4 (13.3%)	0.766
Diabetes mellitus	15 (15.8%)	5 (9.8%)	6 (20%)	0.421
Opium addiction	11 (12.5%)	6 (15.8%)	6 (20.7%)	0.551
Indications
CBD stone CBD stricture Bile leak CBD dilation	91 (95.8%) 3 (3.2%) 1 (1.0%) 0	48 (94.3%) 1 (1.9%) 1 (1.9%) 1 (1.9%)	30 (100%) 0 0 0	0.785
ERCP outcomes
Successful cannulation	93 (97.9%)	49 (96.1%)	29 (96.7%)	0.708
Cannulation time
< 5 min 5–10 min  > 10 min	53 (55.8%) 13 (13.7%) 29 (30.5%)	22 (43.1%) 9 (17.7%) 20 (39.2%)	9 (30%) 9 (30%) 12 (40%)	0.093
Number of cannulation attempts	3.6 ± 1.7	3.9 ± 1.8	4.3 ± 1.6	0.093
CBD diameter
Normal Abnormal	12 (12.6%) 83 (87.4%)	5 (9.8%) 46 (90.2%)	5 (16.7%) 25 (83.3%)	0.665
Difficult cannulation	42 (44.2%)	29 (56.9%)	21 (70%)	0.035
Inadvertent PD cannulation	19 (20%)	14 (27.5%)	4 (13.3%)	0.336
Balloon dilatation of SO	90 (94.7%)	48 (94.1%)	29 (96.7%)	1.000
Successful stone extractiona	73 (88%)	39 (88.6%)	25 (96.1%)	0.555
Stone number	2.6 ± 2.4	2.5 ± 1.7	2.7 ± 2.8	0.882
Stone size	11.3 ± 5.6	12.0 ± 5.1	11.3 ± 4.2	0.786
Biliary stent	24 (25.3%)	14 (27.5%)	6 (20%)	0.794
Post-ERCP adverse events
PEP (overall)b Mild Moderate	13 (13.7%) 9 (9.5%) 4 (4.2%)	6 (11.8%) 4 (7.9%) 2 (3.9%)	4 (13.4%) 2 (6.7%) 2 (6.7%)	0.955
Bleeding	1 (1%)	0	0	1.000
Perforation	0	0	0	1.000

The quantitative data are presented as the means ± standard deviations; the qualitative data are presented as numbers (percentages)

Abbreviations: BMI body mass index, CBD common bile duct, PAD periampullary diverticulum, PD pancreatic duct, PEP post-ERCP pancreatitis, SO sphincter of oddi

^aOf those with confirmed CBD stone during ERCP

^bBased on the revised Atlanta criteria; mild: no organ failure, moderate: transient organ failure (resolves within 48 h), severe: persistent organ failure (> 48 h)

As illustrated in Fig. 4, the most commonly used cannulation technique in all PAD subtypes was the standard transpapillary technique, and there were no significant statistical differences in the utilization of the different cannulation techniques and associated PEP among PAD types I, II, and III.

Fig. 4.

Bar chart showing the frequency percent of each cannulation technique based on the PAD subtype. Abbreviations: DGT: double guidewire technique, NKF: needle-knife fistulotomy, PEP: post-ERCP pancreatitis, PP: precut papillotomy, STP: standard transpapillary, TPBS: trans-pancreatic biliary sphincterotomy

Discussion

PAD is a relatively prevalent anatomical abnormality, with an incidence that ranges widely from 5–23% [18]. PAD is usually asymptomatic, although rare manifestations such as hemorrhage are reported [19]. It is often discovered incidentally during ERCP and computed tomography scans, although barium contrast and magnetic resonance imaging can also be useful in its detection [6, 20]. Given that PAD is often asymptomatic, its importance lies in its potential impact on the performance of ERCP, particularly when it is discovered during the procedure. There has been an ongoing debate regarding whether PAD can influence the outcome of ERCP and which cannulation technique is most effective in such cases, a topic debated for over a decade. In our study population, the incidence of PAD was 16.8%. PAD was most commonly observed in the elderly, with the majority of patients with PAD being aged ≥ 70 years. The mean age of the non-PAD group was significantly lower than that of the PAD group. No association was found between PAD and patient sex, although some previous studies have reported a female predominance [13, 21]. In the current study, no statistically significant difference was found in the overall success rate between the PAD and non-PAD groups, which supports a meta-analysis conducted in 2018 that included 16 studies and concluded that ERCP is increasingly successful and technically feasible in the presence of PAD when performed by an expert [15]. Although the number of cannulation attempts and the difficult cannulation rate were significantly higher in the PAD group, these differences were no longer observed after matching. Nonetheless, these results contradict a study by Panteris et al. that suggested easier cannulation in the presence of a diverticulum [22]. Regarding post-ERCP adverse events, the results of the current study showed no association between the presence of PAD and an increased risk of the most common adverse events that occur after ERCP, including pancreatitis, perforation, and bleeding.

In the late 1900 s and early 2000 s, in the absence of various cannulation techniques, studies largely concluded that the presence of PAD led to decreased successful cannulation, as well as a significantly higher risk of post-ERCP adverse events following retained CBD stones [8, 11]. In more recent years, although most studies still suggested a negative effect of PAD on cannulation success and ERCP adverse events [13, 23, 24], Corral et al. concluded in 2018 that PAD was not associated with hindrance of ERCP success [10]. However, this study did not specify the cannulation technique used to achieve this result. Needle-knife fistulotomy is becoming increasingly popular due to a lower rate of PEP compared with conventional techniques [25, 26]. However, it is not extensively explored in patients with PAD. Karaahmet et al. recommended needle-knife fistulotomy as a feasible technique for use in patients with PAD, despite finding that PAD was associated with increased cannulation adverse events, regardless of the cannulation technique employed [13]. In the current study, the needle-knife fistulotomy rate was significantly higher in the non-PAD group compared to the PAD group. This is mostly because of our experience with needle-knife fistulotomy as a safe and successful biliary cannulation technique [27]. Nonetheless, this technique was utilized less in the PAD group. Although the results revealed no statistically significant difference in outcomes between this technique and other cannulation techniques, this should be interpreted with caution due to the small sample size in the PAD subgroups. Importantly, in cases of Type I PAD, a significantly dilated CBD is often necessary to safely perform needle-knife fistulotomy, as limited space and poor orientation may increase the risk of perforating the PAD. Caution is advised when applying this technique in such settings, particularly for less experienced endoscopists. Further large-scale research is needed to shed light on this field.

In recent years, several studies have suggested that although PAD increases the number of cannulation attempts and prolongs cannulation time, it does not alter the overall success rate [14, 28]. This advancement may be attributed to the emergence of novel cannulation techniques and equipment, as well as improvements in ERCP specialists'capabilities due to the large number of procedures they perform and their deepening understanding of PAD over time. However, this does not apply to all recent studies, and the results of numerous studies still imply that PAD is a hindrance in the process of cannulating the CBD [13, 23]. A meta-analysis by Mu et al. in 2020, which included 26 studies (8 prospective and 18 retrospective studies), concluded that PAD increased the overall cannulation failure rate only in studies published before 2000, but not in those published afterward [29].

Another recent advancement was the emergence of new classifications for different types of PAD. Previously, PAD was mostly classified into two subtypes: intradiverticular papilla and juxtapapillary diverticulum [8]. Later, PAD was most commonly classified into three subtypes: type I (papilla inside the diverticulum), type II (papilla at the margin of the diverticulum), and type III (papilla near the diverticulum) [28]. This alteration in classification helped improve understanding of how to approach each PAD type more efficiently. The presence of a diverticulum inside the papilla (type I) was noted to be associated with more difficult cannulation [28]. This classification was also utilized in the current study for comparing different PAD types, where difficult cannulation was significantly more common in type III PAD, which may be due to the compressive pressure of PAD on CBD. Moreover, there were increasing trends of cannulation time and number of cannulation attempts from the type I PAD to the type III PAD. Although these trends were not statistically significant, but due to small sample size and limited statistical power, these clinically relevant results should be interpreted with caution. Shi et al. later divided type II into two subtypes (type IIa and type IIb), which was based on the location of the diverticulum on the inner or outer margin of the papilla, respectively, and mentioned that this classification was more efficient in evaluating the outcomes of ERCP in PAD patients compared to the traditional classification. Based on the mentioned study, while type IIa was the most challenging subtype to cannulate, type IIb was much easier [30]. Lastly, the Li-Tanaka classification was introduced, which divided PAD into four types (type I, II, III, IV), and further subdivided types II and IV into two subtypes each. This classification was proposed to provide good clinical significance with regards to comparing different types of PAD [12]. Since the Li-Tanaka classification yields a more detailed categorization, enabling better understanding of how each variation influences ERCP outcomes by considering anatomical variations, clinicians can subsequently predict the likelihood of successful cannulation of the specific PAD type present. Moreover, the standardized terminology used in the Li-Tanaka classification can facilitate clearer communication in healthcare settings, especially if multiple specialists are involved. Therefore, it was suggested that this classification be further used in prospective studies [12]. Table 4 summarizes the most notable published studies regarding the impact of PAD on ERCP outcomes and how different PAD classifications could predict the complexity of the procedure.

Table 4.

An overview of the published studies regarding PAD impact on the ERCP outcomes

Authors	Publication year	Study design	Number of patients	Classification of PAD subtypes	Cannulation techniques	Purpose of the study	Outcomes
Shi et al. [30]	2023	Retrospective	Non-PAD: 177, PAD: 209 (Type I: 27, Type IIa: 35, Type IIb: 36, Type III: 111)	Type I (papilla completely inside the diverticulum), Type IIa and type IIb (papilla in the inner and outer margin of the diverticulum respectively), Type III (papilla outside the diverticulum)	NR	-Evaluation of adequacy of the traditional classification of PAD into 3 subtypes -Evaluation of how PAD may affect ERCP outcomes	-Classification of PAD in 4 subtypes is more efficient than the traditional classification - Type I and IIb was easier to cannulate than the non-PAD group -Type IIa was the most challenging subtype for cannulation -PAD did not increase the risk of PEP
Xia et al. [28]	2022	Retrospective	Non-PAD: 4885, PAD: 705 (Type 1:59, Type 2: 101, Type 3: 545)	Type I: papilla inside the diverticulum, Type II: papilla in the margin of the diverticulum, Type III: papilla near the diverticulum	Guidewire-assisted technique, NKF, TPBS, precut biliary sphincterotomy	-Investigation of the techniques and factors related to safe and successful ERCP in patients with PAD	-Although there was a higher difficult cannulation rate in PAD patients, PAD did not negatively affect clinical or technical success rates in ERCP -No significant difference between PAD and non-PAD group regarding adverse events -Type I PAD and pancreatic indications for ERCP were associated with higher rates of difficult cannulation -Using small endoscopic sphincterotomy in combination with balloon dilatation was associated with clinical success, independently
Yue et al. [12]	2020	Retrospective	Non-PAD: 2597, PAD: 967 (Type I: 65, Type IIa: 241, Type IIb:414, Type III: 105, Type IVa: 119, Type IVb: 23)	Type I: papilla inside the diverticulum and not adjacent to the margin Type II: papilla in the margin of the diverticulum (type IIa, inside of the margin; type IIb, outside of the margin, < 1 cm) Type III: papilla outside of the margin, ≥ 1 cm Type IV: papilla in the margin of the diverticulum and ≥ 2 diverticula present (type IVa: outside the margins of at least one diverticulum, < 1 cm; type IVb: outside the margins of all of the diverticula, ≥ 1 cm)	NR	Verifying the clinical values of Li-Tanaka classification, a newly proposed classification for PAD and its comparison with two previously proposed PAD classifications	Based on the Li-Tanaka classification; -Cannulation was more difficult in type I PAD compared to the non-PAD group -Type II PAD had higher successful cannulation rate compared to the non-PAD group -There was no significant difference between type III or IV PAD and the non-PAD group -A good clinical significance was seen using Li-Tanaka classification for ERCP cannulation
Tabak et al. [14]	2020	Prospective	Non-PAD: 510, PAD: 126 (Type 1:15, Type 2: 18, Type 3: 93)	Type I: papilla inside the diverticulum, Type II: papilla in the margin of the diverticulum, Type III: papilla near the diverticulum	Guidewire-assisted, TPBS, Needle-knife precut	Investigation of the impact of PAD on biliary cannulation and on the outcomes of ERCP	-Although presence of PAD was associated with increased difficulty and longer cannulation time, it did nit affect the overall success rate of ERCP -Presence of PAD was not associated with increased post-ERCP adverse events
Hu et al. [23]	2020	Retrospective	Non-PAD: 111, PAD: 72	Type A: papilla located outside or on the margin of the diverticulum Type B: papilla located inside the diverticulum	Double guidewire	Investigation of the impact of PAD on ERCP outcomes for the treatment of common bile duct stones	-PAD significantly affected ERCP outcomes regarding removal of CBD stones -PAD decreased complete stone removal rate and increased the need for mechanical lithotripsy compared to the control group
Karaahmet et al. [13]	2018	Retrospective	Non-PAD: 663, PAD: 164	NR	NKF, guidewire-assisted, sphincterotomy	Investigation of the relationship between PAD and post-ERCP adverse events and outcomes, focusing on needle-knife fistulotomy technique	-Independent of the cannulation technique, PAD was strongly associated with increased cannulation difficulty -Post-ERCP adverse events (PEP, perforation, bleeding) was higher in PAD group -NKF was recommended as a feasible technique for successful cannulation in certain patients with PAD
Corral et al. [10]	2018	Retrospective	Non-PAD: 3267, PAD: 1089	NR	NR	Evaluation of the impact of PAD on performing ERCP	-PAD did not hinder ERCP success rate and performance
Loffeld et al. [33]	2016	Retrospective	Non-PAD: 1881, PAD: 211	NR	NR	Investigation of outcomes of ERCP in the context of duodenal diverticulum	-PAD complicated ERCP procedure and lead to higher rates of inconclusive results -Adverse events such as biliary pancreatitis appeared to be seen less frequently in the presence of PAD
Alizadeh et al. [24]	2013	Prospective	Non-PAD: 736, PAD: 44	NR	Standard transpapillary, NKF, needle-knife precutting	Evaluation of the impact of PAD on performing ERCP	-Failure rates and difficulty of biliary cannulation was significantly increased in the presence of PAD
Panteris et al. [22]	2008	Prospective	Non-PAD: 484, PAD: 117	Type I: papilla at the rim or within 2 cm from the edge of the diverticulum, Type II: papilla inside or at the middle of the bottom edge of the diverticulum or between 2 adjacent diverticula	NR	Investigation of success rate, cannulation difficulty, and adverse events between PAD and non-PAD group	- Presence of PAD could be indicator of an easier cannulation attempt, provided that the papilla was found with confidence -PAD did not increase the risk for post-ERCP adverse events
Rajnakova et al. [11]	2003	Retrospective	Non-PAD: 554, PAD: 72	NR	NR	Comparison of PAD and non-PAD group regarding ERCP outcomes	-Common bile duct cannulation was more difficult in the presence of PAD -PAD was associated with increased risk for retained stones which may lead to higher risk of post-ERCP adverse events
Lobo et al. [8]	1998	Prospective	Non-PAD: 1102, PAD: 100 (IDP: 42, JPD: 58)	IDP: papilla contained within a diverticulum, JPD: a diverticulum in the 2 cm radius of (not containing) the papilla	NR	Evaluation of effects of PAD on ERCP outcome and success rate, Determination of the consequences of failed ERCP in patients with PAD	-PAD contributed to failed ERCP, particularly in the elderly patients -Failure rates were higher in IDP than JPD -Following a failed ERCP procedure, surgery was effective and safe

Abbreviations: CBD common bile duct, ERCP endoscopic retrograde chonagiopancreatography, IDP intradiverticular papilla, JPD juxtapapillary diverticulum, NKF needle-knife fistulotomy, NR not reported, PAD periampullary diverticulum, PEP post-ERCP pancreatitis, TPBS trans-pancreatic biliary sphincterotomy

Post-ERCP adverse events, namely pancreatitis, bleeding, and perforation, can occur during or after the procedure [31, 32]. There are conflicting data regarding whether the presence of PAD contributes to an increased risk of post-ERCP adverse events. Jayaraj et al., following an analysis of 12 studies that evaluated PEP in a meta-analysis, concluded that patients with PAD were not at increased risk for PEP [15]. On the other hand, in another meta-analysis including 19 studies, the analysis showed an association between PAD and higher rates of early pancreatitis, bleeding, and perforation [29]. The difference between the results of the two mentioned studies may be attributed to the differing number of studies included in each. While Mu et al. indicated that they included all published data comparing the cannulation failure rate and adverse events in the presence of PAD, Jayaraj et al. mentioned that their careful exclusion of redundant studies was a strength of their study. Some studies have indicated that patients with PAD are more prone to adverse events [11, 13]. However, Loeffeld et al. stated that in the presence of a diverticulum, adverse events, especially biliary pancreatitis, were less frequently seen [33]. In this study, PAD was not associated with an increased risk of post-ERCP adverse events, and the assessed rates of PEP, bleeding, and perforation did not differ between the PAD and non-PAD groups, consistent with several previous studies [22, 23, 28, 30, 34]. Furthermore, the evaluation of PAD subtypes indicated no statistically significant difference in the rate of adverse events among PAD types I, II, and III. The study also investigated the influence of each cannulation technique on PEP, finding no significant differences in the risk of PEP associated with any of the mentioned techniques (standard transpapillary, needle-knife fistulotomy, trans-pancreatic biliary sphincterotomy, precut papillotomy, and double guidewire technique) in either the PAD or non-PAD groups.

This study has several limitations. First, and most importantly, its retrospective design may introduce selection bias and limit the generalizability of the findings. Second, all procedures were performed by three experienced endoscopists, which may not reflect the outcomes achievable by less experienced operators. Third, the small number of patients in some groups, especially PAD subtypes, may have obscured the true effect of PAD on the occurrence of relatively rare post-ERCP adverse events Moreover, the presence of multiple risk factors made it challenging to attribute adverse events specifically to PAD. Finally, information about delayed (after discharge) adverse events in patients undergoing ERCP was not included in this study, which highlights the need for prospective studies with an extended follow-up period. Thus, prospective studies with larger, multicenter cohorts and extended follow-up are warranted to validate these findings.

Conclusions

This study found no significant associations between presence of a PAD with increased risk of cannulation difficulty, procedural failure, or adverse events. Different cannulation techniques, if applied carefully and in accordance with the endoscopist's experience, could all be successful in patients with PAD.

Abbreviations

BMI

Body mass index

CAD

Coronary artery disease

CBD

Common bile duct

CI

Confidence interval

DM

Diabetes mellitus

ERCP

Endoscopic retrograde cholangiopancreatography

HTN

Hypertension

MDP

Major duodenal papilla

OR

Odds ratio

PAD

Periampullary diverticulum

PD

Pancreatic duct

PEP

Post-ERCP pancreatitis

SBMU

Shahid Beheshti university of medical sciences

SO

Sphincter of oddi

SOD

Sphincter of oddi dysfunction

TPBS

Trans-pancreatic biliary sphincterotomy

UGI

Upper gastrointestinal

Authors’ contributions

Author contributions: EA: Study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content. AS: study concept and design, performing ERCPs, drafting the manuscript, critical revision of the manuscript for important intellectual content. AR: acquisition of data, analysis and interpretation of data, and drafting of the manuscript. RR: data acquisition and manuscript drafting MA: Study concept and design, critical revision of the manuscript for important intellectual content. MRZ: Study concept and design, critical revision of the manuscript for important intellectual content.

Funding

None.

Data availability

The original contributions presented in this study are included in this article, further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of SBMU under the ethical code IR.SBMU.RETECH.REC.1403.410. The need for informed consent was waived by the institutional review board of SBMU because the study involved retrospective analysis of anonymized data.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.