Accumulating data indicate that the prevalence of PD is no greater in IP compared to the general population. Initially, investigators using ERCP reported a greater prevalence of PD in IP compared to the general population [4–6]. These data later were contradicted by other ERCP studies [7–9]. Multiple factors might account for these differences; the early studies [4–6] might have been biased by referral pattern, patient selection, and inclusion of subjects with poorly characterized pancreatic disease (see “Terminology for Pancreatitis”).

DiMagno and DiMagno [1•] recently reported a comprehensive analysis of primary sources from 23 autopsy studies, 41 ERCP studies, and 13 MRCP studies to determine the prevalence of PD in IP compared to the general population and in idiopathic “acute pancreatitis” compared to CP. Patients were categorized as having no pancreatitis, IP, and acute pancreatitis and CP when sufficient detail supported this designation. In the autopsy and MRCP studies, the prevalence of PD in the general population was about 8% (Fig. 1A). In the ERCP studies, however, the prevalence of PD was about 4% in the general population and about 8% in patients with IP (Fig 1A). These data support the conclusion that in ERCP studies, the prevalence of PD in the general population is because of under recognition and/or referral bias, and that there is no association between PD and IP.

Controversy about this conclusion exists. For example, analysis of six of the 41 ERCP studies and two of the seven S-MRCP studies that classified IP patients as acute pancreatitis or CP shows a prevalence of PD that was significantly greater in acute pancreatitis compared to CP in ERCP but not in S-MRCP studies (12.0 vs 6.8) [1•]. The validity of this finding is questionable, however, because the increased PD prevalence in acute pancreatitis was directly attributable to two publications from the same investigators [5, 10]. There was no increased prevalence of PD in acute pancreatitis compared to autopsy in most studies, and the authors of the largest ERCP study of 304 patients with PD reported a similar prevalence of PD in acute pancreatitis and CP groups (7.5% vs 6.4%) [8]. To explain the contrasting observations among studies, it is noteworthy that a dorsal duct pancreatogram was performed 50% less frequently in studies reporting an increased prevalence of PD in acute pancreatitis compared to the study by Delhaye et al. [8], indicating that a diligent search for PD (by examining both ductal systems) was not always performed in patients without a pancreatitis history. Hence, we interpret these data as indicating that PD is no more prevalent in idiopathic acute pancreatitis compared to CP.

Barthet et al. [14] reported that the clinical course and morphological features of 40 patients with calcifying CP associated with heavy alcohol use were not modified by PD. Twenty had PD and 20 had a normally fused pancreas. The only significant difference in clinical characteristics was that pancreatic calcifications were less common in the PD group (8 vs 14; P = 0.05). Cambridge classification was similar among groups, but the PD group had minor differences of uncertain significance, including less frequent irregularity of the main pancreatic duct and more frequent dilation of side branches. Further evidence that PD was an incidental finding is that isolated dorsal segment disease occurred in only 45% of patients with PD. The lower than expected frequency of isolated dorsal duct involvement was corroborated by Spicak et al. [15•] (see below) and by the pooled analysis of DiMagno and DiMagno [1•].

Spicak et al. [15•] recently reinvestigated whether PD associated with an altered natural history of CP by evaluating 87 patients with CP, 30 with PD and 57 without PD. Similar to the study by Barthet et al. [14], most patients in both groups had heavy alcohol use and there were no significant differences among gender, age at onset of disease, clinical presentation, course of the disease, and frequency of complications. Additional data that do not support PD predisposing to pancreatitis by obstructing the dorsal duct are that most patients had disease involving the ventral segment whether PD was present or not (75% vs 72%), and that isolated dorsal segment disease was less frequent than expected and occurred nearly equally in the alcoholic versus nonalcoholic groups (25% vs 28%). These clinical and anatomic data indicate that PD does not modify the natural course of chronic nonalcoholic or alcoholic pancreatitis and that PD does not play a dominant role in the pathogenesis of CP, if it plays a role at all.

Although prevalence data (Fig. 1B), natural history studies, and the results of endoscopic treatment studies (see section on therapy) do not support a meaningful association between PD and CP, it is important to recognize if a subset of IRAP patients with or without PD present as, or evolve into, CP. In 10% to 20% of persons with a first attack of acute pancreatitis, no cause is identified after completing a routine clinical evaluation, biochemical tests, transabdominal ultrasound, and/or CT [16]. Of these with a first attack of IP, more intensive evaluation with endoscopic ultrasound (EUS) may identify a cause in about 80% [17]. Fewer than 15% of patients with a first attack of acute pancreatitis develop RAP [18], and far fewer develop IRAP (no identifiable cause of RAP). Few studies combine complete diagnostic testing with prospective follow-up, but available data indicate that most patients labeled as having IRAP eventually will have an identifiable cause of RAP, including idiopathic CP, genetic mutations (see “Association of IP with Genetic Mutations and PD”), biliary disease (gallbladder microlithiasis, choledocholithiasis, biliary sludge), or unusual lesions such as ampullary lesions or pancreatic cancer.

CFTR mutations may confer increased susceptibility to IP by at least two mechanisms: pancreatic ductal plugging and obstruction by viscous, proteinaceous ductal secretions [35] and by sensitizing the pancreas to an exuberant inflammatory response to injury [36, 37]. SPINK1 mutations may predispose to IP by disrupting the capacity of pancreatic acinar cells to limit trypsin activity when premature activation occurs intracellularly. It is tantalizing to consider that other patients with IP have a less common gene mutation (eg, chymotrypsinogen C gene [38] or calcium-sensing receptor gene [39, 40]), a yet to be discovered gene mutation, or a nongenetic alteration in protein function, a premise based on findings that patients may have a variant CF phenotype without CFTR gene mutations [41, 42], including those with CP from known causes [43].

Patients with IP, with or without PD, have a similar prevalence of CFTR and/or SPINK1 gene mutations. Investigators from the University of Indiana [31], who used a limited screening test, reported that in a Caucasian population, the frequency of CFTR mutations was higher in patients with PD and IP compared to PD without IP (22% vs 0%). The true prevalence of CFTR mutations in IP and PD is likely higher because the frequency of CFTR mutations in IP is greater when investigators use an exhaustive genetic screening test [24, 25, 30]. Furthermore, even when genetic testing identifies no CFTR mutations, CFTR functional impairments are common in patients with IP and PD. Gelrud et al. [44] studied 12 patients with IP and PD and found that nasal potential difference, an indicator of CFTR ion channel function, was intermediate between those observed for healthy controls and classic CF patients. In addition, Gelrud’s study implies that IP with PD is uncommon (only 12 patients found at three institutions) and that in this uncontrolled study, patients who have CFTR ion channel dysfunction generally do not respond to endoscopic therapy; only two of 12 patients who underwent endoscopic or surgical interventions had resolution of symptoms, even though all had multiple ERCPs (range 2–5), 10 had either pancreatic stent and/or sphincterotomy, and eight had cholecystectomy.

Recently, investigators from New Delhi, India, found the frequency of SPINK1 mutations was increased but similar in three pancreatitis groups: 41.6% of IP with PD (5 of 12), 43.3% of CP (13 of 30), and 35.7% of RAP without PD (5 of 14) compared to 2% of healthy controls (1 of 50) [45]. No patients had CFTR mutations but frequencies of CFTR polymorphisms were increased and similar in the two pancreatitis groups: 25% of IP and PD (3 of 12) and 33.3% of CP (10 of 30) compared to 0% of healthy controls (0 of 50). The authors claim that relative obstruction at the minor papilla owing to PD plays a definite role in the pathogenesis of pancreatitis because endoscopic therapy in eight of 12 patients with PD had a 50% reduction per year in the frequency of attacks of pancreatitis, including three of five with SPINK1 mutations. This response contrasts with the negative endoscopic outcomes reported by Gelrud et al. [44], but may be explained by the short duration of follow-up, lack of treatment controls, and possibly the involvement of different gene mutations.

In a recent, retrospective study, Chacko et al. [52•] reported that the minor papilla endotherapy (MPE) response rate or clinical improvement was 76% for IRAP but much lower for CP (42%) and chronic abdominal pain (33%). The authors defined improvement as a ≥ 50% reduction in any endpoint for IRAP, CP or chronic abdominal pain. Specific endpoints for IRAP included annual episodes of acute pancreatitis, emergency department visits or hospitalizations. Endpoints for CP and chronic abdominal pain were pain scores, use of narcotic analgesics, annual emergency department visits or hospitalizations. The authors concluded that MPE is a reasonable first step in the absence of chronic pain. An important limitation acknowledged by the authors is that short-term follow-up may be inadequate to assess response in some patients with IRAP, who have long, pain-free intervals. A further challenge in assessing the response rate in patients with IRAP is that some develop chronic pain. Multiple additional factors limit the generalizability of this study: the investigators included patients with incomplete PD and previous endotherapy, some patients classified as having IRAP had evidence of CP, follow-up was short, endpoints were heterogeneous, and there was no intention-to-treat analysis. An editorial [53] concluded that patients with IRAP represent the subset of patients most likely to have clinical benefit from MPE, but that further studies are needed to evaluate the long-term benefit from MPE, preferably designed as randomized, controlled studies in which details of disease presentation and pre-procedural natural history are documented.

Liao et al. [11•] reported in a systematic review that response to endotherapy and surgery in patients with PD depends on whether patients have IRAP, CP, or chronic abdominal pain. The greatest response rates, defined broadly as the percentage of patients with complete, partial, or overall pain relief at follow-up, occurred in IRAP (79.2%–83.2%) but significantly less in CP (69.0%–66.7%) and chronic abdominal pain (54.4%–51.6%). This analysis of uncontrolled studies supports the findings of multiple previous studies that either the endoscopic or surgical papillary therapy is “effective.” Unfortunately, as described above, these studies lack proper controls and randomization, outcome measures remain too broadly defined, and follow-up is limited. These limitations apply mostly to IRAP patients, who are purported to benefit greatest from minor papillary therapy.