MRCP has a very high sensitivity (95 %) and specificity (97 %) for detecting pancreatobiliary abnormalities [43]. The concomitant administration of supraphysiologic secretin promotes juice secretion and bicarbonate production from centroacinar and pancreatic ductal cells, thereby improving visualization of the main pancreatic duct and side branches [44]. In studies comparing the diagnostic yield of S-MRCP with ERCP for detecting pancreatobiliary abnormalities in patients with iRAP, no significant differences were found (66 % for S-MRCP, 64 % for ERCP) [44]. Also, S-MRCP has 100 % specificity (although low sensitivity of 57 %) for detecting obstructing lesions in the pancreatobiliary tree [45] and is associated with minimal risk of pancreatitis as opposed to ERCP [42, 45]. MRCP with magnetic resonance imaging may additionally identify occult pancreatic tumors, pancreas divisum , biliary sludge, or IPMN as a potential cause of pancreatitis, and some of these abnormalities would obviate the need for ERCP and prompt alternative interventions such as surgery. The incremental benefit of S-MRCP over MRCP was recently confirmed in a study of 252 patients with acute or acute recurrent pancreatitis who all underwent MRCP, S-MRCP, and ERCP within 30 days of each other with images reviewed by blinded experts [46]. Sensitivity of MRCP increased from 47 to 66 % (p 0.0001), while specificity decreased insignificantly from 90 to 85 % following secretin administration. Complete visualization of the pancreatic duct was possible in more patients using secretin (55 % versus 26 %, p 0.0001). S-MRCP facilitates the diagnosis of mild chronic pancreatitis and pancreas divisum by highlighting ductal anatomy [47–49] and may also be useful for diagnosing SOD, although additional studies are needed [44, 50, 51].

Compared to ERCP, EUS is a less invasive endoscopic modality that provides excellent imaging of the pancreatic parenchyma, pancreatic duct, and extrahepatic biliary tree, with no risk of AP in the absence of pancreatic fine needle aspiration or biopsy. EUS may identify a definitive etiology in 68–88 % of patients with idiopathic AP [20, 52–56], and is particularly useful for the detection of occult stones in the gallbladder or common bile duct [52]. Additionally, in patients with idiopathic AP who had previously undergone a cholecystectomy, EUS identified chronic pancreatitis (39 %) and pancreas divisum (10 %) in these patients [56]. EUS has high sensitivity for detecting pancreatic cancers not visualized on CT [18, 45] as well as early chronic pancreatitis [57]. Therefore, similar to S-MRCP, EUS may identify an etiology for AP that obviates the need for ERCP or SOM.

Even in the absence of a family history of pancreatitis or pancreatic cancer, several genetic abnormalities should be considered in adult individuals with iRAP or chronic pancreatitis. These include PRSS1 (cationic trypsinogen encoding gene), SPINK1 (serine peptidase inhibitor Kazal type 1), CTRC (chymotrypsin C gene), and CFTR (cystic fibrosis transmembrane conductance regulator protein) mutations [58]. There is emerging evidence highlighting the importance of newly discovered mutations in CLDN2 (claudin) and PRSS1-PRSS2 genes [59]. Patients with genetic abnormalities are more likely to present with AP at a younger age (although not necessarily during childhood), have pancreas divisum , and progress to chronic pancreatitis [49]. The long-term risk of pancreatic cancer requires further study, although mutations in PRSS1 probably confer a lifetime risk of 40 % [58].

In an adult population with iRAP, the timing and need for genetic testing are unclear. Since many patients with genetic abnormalities do not have a family history, this should not be considered a sine qua non. The treating physician must also consider the implications on patient anxiety and future insurability, should a mutation be confirmed. Furthermore, complete gene sequencing is now available, and may identify mutations of unknown significance, further confusing the picture [48]. We typically perform genetic testing in the following patients: age 40 and iRAP after structural abnormalities and autoimmune disease have been excluded, a family history of AP, a recurrent episode of AP after ERCP and cholecystectomy, and also on a case-by-case basis.

With improvements in cross-sectional imaging and EUS, the diagnostic yield of ERCP among patients with iRAP has likely decreased; however, this requires further investigation specifically among iRAP patients who have undergone thorough evaluation with MRCP, EUS, and laboratories that include autoimmune serologies and genetics before ERCP. ERCP may identify the underlying etiology for iRAP in 38–79 % of cases; however, this is based on older studies before the routine use of MRCP and EUS. The diagnostic yield varies widely depending on whether the gallbladder is intact [15, 20, 34, 60–64]. The likelihood of occult choledocholithiasis or microlithiasis (biliary crystals) is highest in patients with an intact gallbladder (50 %) compared to nearly none in patients post-cholecystectomy [20, 64], and structural abnormalities such as obstructing tumors and pancreas divisum are more likely in older (age 60) individuals [15]. The most common abnormalities discovered during ERCP for iRAP include SOD found in 15–65 % of patients and pancreas divisum in 1–23 % of patients (Fig. 14.4) [20, 34, 60, 62–64]. We recommend proceeding to ERCP with SOM in patients with iRAP only after they have undergone further laboratory testing for autoimmune disease and advanced imaging such as EUS, MRI/MRCP, or both [20, 65– 67].

Studies evaluating the efficacy of biliary, pancreatic, or dual sphincterotomies for the treatment of iRAP are limited by small sample sizes and short-term follow-up . Since microlithiasis or occult choledocholithiasis is often implicated as the underlying etiology especially in patients with an intact gallbladder, empiric biliary sphincterotomy has been advocated in certain cases (Fig. 14.5). This is extrapolated from studies demonstrating the efficacy of empiric cholecystectomy for iRAP. These older studies were performed in an era of inferior cross-sectional imaging and without EUS—when false negative rates for detecting cholelithiasis were higher. The efficacy of empiric cholecystectomy is substantially reduced when the patient has normal or near-normal liver chemistries and no evidence of gallstones on transabdominal US [27]. The likelihood of recurrent pancreatitis after cholecystectomy was significantly higher (61 %) when neither was present compared to patients with both these abnormalities (9 %). While a comparable study of biliary sphincterotomy is lacking, a small number of patients with iRAP and normal SOM who were randomized to biliary sphincterotomy (n = 11) or sham (n = 9) showed similar rates of recurrent pancreatitis during follow-up (50 % for both groups) [42]. Other studies suggest a benefit of biliary sphincterotomy when microlithiasis is suspected [15]. We recommend empiric biliary sphincterotomy when there is a reasonable suspicion for microlithiasis. This would include transient fluctuation in liver chemistries in association with episodes of AP , or a history of gallstone pancreatitis that preceded cholecystectomy. This recommendation is indirectly supported by epidemiological data showing a reduction in repeat hospitalizations when ERCP is performed during the initial admission for gallstone pancreatitis [44]. Empiric biliary sphincterotomy should not be performed in patients with normal liver tests.