Introduction 

Gallstones/choledocholithiasis and alcohol use/abuse are the most common causes of acute pancreatitis (AP).¹ When the cause of acute pancreatitis remains unidentified despite a thorough history, physical examination, laboratory tests, review of medications, and imaging studies, it is classified as idiopathic acute pancreatitis (IAP). IAP can present in two patterns: isolated, where no recurrence occurs after an initial episode, and idiopathic acute recurrent pancreatitis (IARP). IARP is characterized by two or more episodes of IAP.² The incidence of IAP varies widely, ranging from 10%-30%; primarily due to missed diagnoses of underlying conditions that may become apparent during subsequent investigations.^2,3 With the growing understanding of etiologies and advancements in diagnostic technologies, IAP should account for no more than 20% of AP cases in any given population.⁴ The initial evaluation of IAP includes screening for alcohol use disorder, ultrasound imaging to assess for gallstones or sludge, measurement of triglyceride levels, serum immunoglobulin G4 levels, contrast enhanced computed tomography and a review of medications and recent medical procedures or interventions to identify potential iatrogenic causes.⁵ A negative initial evaluation warrants consideration for further testing such as genetic testing and advanced pancreaticobiliary imaging, including magnetic resonance cholangiopancreatography (MRCP),  endoscopic ultrasound (EUS), and endoscopic retrograde cholangiopancreatography (ERCP).^5,6

Role of EUS in Diagnosis and Management of Idiopathic Pancreatitis 

2.1. EUS Technology

EUS combines a flexible endoscope with a high-frequency miniature ultrasound probe at its distal end, enabling direct visualization of mucosal lesions, the gastrointestinal tract, and extramural structures. Unlike other cross-sectional imaging techniques, EUS offers a closer proximity to tissue, minimizing interference from subcutaneous tissue, bones, and gas.⁷ With advancements in technology, EUS produces high-resolution, real-time images, allowing for the assessment of minute lesions and pancreaticobiliary structures.⁸ This makes EUS one of the most important diagnostic tools for the evaluation of IAP.⁹

2.2. Timing of EUS

Guidelines recommend repeating a right upper quadrant (RUQ) ultrasound after discharge to improve the diagnostic yield in patients with presumed IAP due to microlithiasis or sludge.⁹ EUS is the next step in evaluating the etiology of IAP; however, the optimal timing for performing EUS after an episode of acute pancreatitis is uncertain and different operators may have varying opinions on this issue. Performing EUS too soon after an episode of acute pancreatitis may result in missed subtle lesions or undiagnosed CP, as residual inflammation (which reduces tissue resolution and increases artifacts) in the pancreas could obscure these findings. Additionally, ongoing inflammation may affect the safety of the procedure.^6,9 Various studies have examined different intervals for performing EUS, but most experts suggest a short delay of 2 to 6 weeks to ensure complete resolution of inflammation.^9,10 A recent single-center retrospective study evaluated the EUS appearance of pancreatic tissue at 4 and 6 weeks in patients with IAP. The study found that 84% of patients had normal-appearing pancreatic tissue at 6 weeks, compared to 73% at 4 weeks.¹¹Additionally, a higher CT severity index score at the time of diagnosis was associated with an increased likelihood of detecting inflamed pancreatic tissue during the EUS examination at 4 to 6 weeks.¹¹ Cortes et al. developed a scoring system (DORM65) using five variables, which includes delayed EUS (at least 82 days) as one of the factors, to predict positive EUS findings after an episode of IAP. A score of 3 or more was associated with a positive predictive value of 86%, with sensitivity and specificity of 35% and 92%, respectively.¹² The scoring system is not in widespread use, but can be considered.

2.3. Sensitivity and Diagnostic Accuracy of EUS

The diagnostic yield of EUS in identifying one or more potential etiologies of IAP varies widely, ranging from 32% to 88%.¹³ This variation can be attributed to several factors, including the efficacy of EUS in detecting specific etiologies (e.g., gallstones, neoplastic, or anatomical), operator expertise, and the timing of the procedure in relation to the episode of pancreatitis in question.^11,14–16 Additionally, the diagnostic yield may be influenced by whether other diagnostic evaluations were performed prior to EUS, which might have already identified the underlying cause.¹³ 

2.3.1. Microlithiasis and Choledocholithiasis

Microlithiasis (stones <3 mm) or larger stones could explain up to 75% presumed IAP in patients with an intact gallbladder.¹⁷ (Figures 1 and 2) Patients with a first episode of AP and/or those with an intact gallbladder have a higher likelihood of biliary microlithiasis or sludge being detected on EUS compared to patients with IARP and/or prior cholecystectomy.¹⁸ Studies have shown a significant reduction in the risk and severity of recurrent acute pancreatitis in patients who underwent cholecystectomy and removal of CBD stones, if present.^5,19 

A meta-analysis of 22 studies involving 1,490 patients with IAP reported that EUS identified the etiology in 59% of cases, with biliary causes accounting for 30%. However, none of the included studies conducted the complete standard diagnostic workup as per IAP/APA guidelines prior to EUS study. This is important as repeat transabdominal ultrasound after the discharge can increase the diagnostic yield, especially when the underlying etiology is biliary lithiasis/sludge.^9,20 

In a prospective study of  35 patients with biliary colic, both initial and repeat abdominal ultrasound examinations were normal or inconclusive. Subsequent EUS detected gallbladder sludge or small stones in 33 patients and common bile duct (CBD) sludge or microlithiasis in 21 patients.²¹ 

Compared to imaging modalities such as MRCP, EUS demonstrates a higher diagnostic yield in identifying presumed IAP due to biliary etiology, including cholelithiasis, choledocholithiasis, microlithiasis, and biliary sludge. Wan et al. reported a diagnostic yield of 34% for EUS, compared to just 9% for MRCP, in detecting biliary etiologies of IAP. ^14,15

2.3.2. Chronic Pancreatitis 

Chronic pancreatitis (CP) is the second most common cause of IAP in patients with an intact gallbladder and the most common cause in those without a gallbladder.^16,20 EUS is one of the most accurate techniques for diagnosing CP, owing to its ability to position the transducer close to the pancreatic parenchyma.²² Previously unknown or unanticipated CP is identified as the underlying cause of IAP in approximately 7% to 12% of patients undergoing EUS evaluation.²³ EUS is either superior to or comparable with other diagnostic imaging modalities, such as MRCP and CT.^10,24 Early CP often involves changes in ductal side branches, sparing the main pancreatic duct (PD). Combining EUS and MRCP significantly improves sensitivity and specificity for the diagnosis of CP.²⁵ 

2.3.3. Neoplasia

Pancreatic neoplasms can cause AP by transiently or permanently obstructing the pancreatic or common bile duct (or both) and/or by inducing local inflammation in the pancreatic parenchyma. A retrospective study utilizing clinical and insurance claim data reported that 11% of patients experienced one or more episodes of AP within the three years preceding a diagnosis of pancreatic ductal carcinoma. On EUS, pancreatic neoplasms are identified as the underlying cause in 2% to 6% of presumed IAP cases.^4,16 Bartell et al. reported that EUS-guided fine-needle aspiration (EUS-FNA) identified pancreatic cancer in 5.3% of cases (out of 530 patients) with presumed IAP or idiopathic CP, despite negative initial CT and/or MRCP findings for a pancreatic mass lesion.²⁶ 

2.3.4. Pancreatic Anatomical Abnormalities 

Among congenital pancreatic anomalies, pancreatic divisum is the most common.²⁷ It should be noted that many patients are told that pancreatic divisum is an illness, but it is not. Bernard et al. reported a 7.5% incidence of pancreatic divisum in a study of 1,825 ERCPs. Pancreatic divisum was significantly more frequent in patients presenting with acute idiopathic pancreatitis than in controls or the general population.²⁸  ERCP is considered the gold standard for diagnosing pancreatic divisum; however, its use is generally limited to cases where therapeutic intervention is also needed. EUS, particularly with a linear array echoendoscope, is increasingly used for diagnosis due to its higher sensitivity and lower adverse event rate compared to ERCP.²⁹ Kushnir et al. reported an 84% diagnostic sensitivity of EUS for pancreatic divisum among patients evaluated for idiopathic acute pancreatitis (58%), unexplained pancreatic-type abdominal pain (35%), and CP (7%).³⁰ A meta-analysis by Umans et al. identified pancreatic divisum as the underlying etiology of IAP in 87 out of 1,490 patients.²⁰ Less common pancreatic anomalies, such as annular pancreas, pancreaticobiliary maljunction a.k.a. anomalous pancreaticobiliary junction, and high confluence of the pancreaticobiliary ducts, have been reported as etiologies of IAP in only a few studies.^31,32 Annular pancreas is best diagnosed using cross-sectional abdominal imaging, whereas pancreaticobiliary maljunction and high confluence of the pancreaticobiliary ducts are typically identified via ERCP.³¹ Studies evaluating the sensitivity of EUS in diagnosing these anomalies are lacking.

2.4. Therapeutic Role of EUS

EUS has a limited direct therapeutic role in idiopathic pancreatitis. It facilitates ERCP in difficult cannulation through techniques like EUS-Rendezvous when ERCP alone is unsuccessful.³³ It is useful in performing celiac plexus blocks to manage chronic pain in patients with IARP progressed to CP.¹⁰ While not routinely used, interventions such as EUS-guided sphincterotomy for CBD stones and alcohol ablation of pancreatic cysts have been reported. With advancements in EUS-guided therapies, it may become possible to perform therapeutic interventions while simultaneously investigating the etiology of IAP in select cases.^10,34

Role of ERCP in Diagnosis and Management of Idiopathic Pancreatitis 

ERCP has played both a diagnostic and therapeutic role in the management of IARP. Earlier studies demonstrated that ERCP-based evaluations, such as bile analysis for microcrystals, minor papilla cannulation, and sphincter of Oddi manometry, identified the underlying etiology in up to 79% of cases.³⁵ However, with the advent of high-resolution imaging techniques like EUS and MRCP, the diagnostic role of ERCP has declined, and it is now primarily used for therapeutic interventions.¹⁵

3.1 Sphincter of Oddi Dysfunction

In older studies, reflecting a different era of thinking, Sphincter of Oddi dysfunction (SOD) has been reported in 15% to 73% of patients undergoing ERCP with sphincter of Oddi manometry (SOM) for the evaluation of IARP in previous studies.³⁶ SOM was the gold standard for diagnosing SOD; however, it is invasive, carries high risks of serious adverse events and its accuracy is operator-dependent with limited inter-reader reliability. Non-invasive tests, such as secretin-stimulated MRCP (ss-MRCP), quantitative hepatic scintigraphy, and fatty meal sonography, are less sensitive compared to SOM.^36,37 In current clinical practice, the diagnosis of SOD and the practice of SOM have essentially been abandoned due to high risks, limited data showing clinical efficacy, and questions about the validity of the concept of SOD as a whole.^38,39

3.2 Microlithiasis 

Due to the high diagnostic sensitivity of EUS for detecting microlithiasis, ERCP is no longer recommended for evaluating IAP suspected to be caused by microlithiasis.⁹ If transabdominal imaging and EUS fail to identify microlithiasis, bile microscopy during an ERCP may be considered but is rarely performed in practice.³⁵ The definitive treatment for microlithiasis causing recurrent AP is laparoscopic cholecystectomy to prevent recurrent pancreatitis and gallbladder related symptoms. In elderly patients or those with severe comorbidities that increase surgical risk, sphincterotomy alone can be an effective alternative. However, the role of sphincterotomy alone in preventing recurrent pancreatitis due to microlithiasis remains controversial among patients who are good surgical candidates.^40,41

3.3 Pancreatic Divisum and Annular Pancreas

ERCP is the gold standard for diagnosing pancreatic divisum; although this anatomic variant can be detected on EUS and MRI/MRCP as well.^9,42 (Figure 3) Endoscopic therapy (ERCP) is the first-line treatment for patients deemed to have true symptomatic pancreatic divisum. Previous retrospective studies have reported a 70-80% efficacy rate for endoscopic therapy in IARP patients with pancreatic divisum.³⁵ It is well established that the risk of recurrent pancreatitis is higher among pancreatic divisum patients with associated genetic mutations (the “two hit” hypothesis). Endoscopic therapy should be considered for IARP patients without any identifiable etiology other than pancreatic divisum, especially if the PD in the body and tail is dilated (suggesting obstruction at level of the duct of Santorini and/or the minor papilla).^6,9

Endoscopic techniques include minor papilla endoscopic sphincterotomy (mPES), balloon dilation, and trans-minor papilla dorsal duct stenting. mPES is well established for symptomatic pancreatic divisum and techniques to perform this maneuver include Wire-Guided Pull-Type Sphincterotomy, Needle-Knife Over Pancreatic Stent, Wire-Assisted Access Sphincterotomy, and Free-Hand Pre-Cut Needle-Knife Sphincterotomy.⁴² While mPES is effective, it is associated with a high risk of post-ERCP pancreatitis, which can be mitigated by prophylactic stenting and the use of rectal indomethacin.⁴³ Endoscopic therapy has comparable efficacy to surgical treatments, such as minor papilla sphincterotomy or sphincteroplasty, with the advantage of lower adverse event rates and mortality.⁴⁴

Annular pancreas is a rare condition and is associated with pancreatic divisum in 30-45% of cases. It commonly presents as duodenal obstruction (often in childhood) and IARP.^35,45 Gromski et al. reported a technical success rate of 91% for ERCP on the initial attempt, increasing to 100% with a second procedure when necessary.⁴⁵ Pancreaticobiliary symptoms, including recurrent pancreatitis, are frequently seen in adults and, when indicated, are effectively managed with pancreatic sphincterotomy, with or without stenting.⁴⁶

Other congenital anomalies, such as choledochocele (Type II choledochal cysts) and pancreaticobiliary maljunction, infrequently present as IARP. They are often identified on MRCP, and symptomatic cases are managed with biliary sphincterotomy.^35,47 

3.4. Pancreatic Duct Strictures and Stones

Strictures in the main PD are found in 5-10% of IARP cases.³⁵ Management depends on whether the stricture is benign or malignant. Benign etiologies include chronic pancreatitis, sequelae of acute pancreatitis, pseudocyst, trauma, or surgical complications.⁴⁸ EUS-FNA/FNB is often used for diagnostic evaluation, especially when a malignant etiology is suspected. Symptomatic benign PD strictures, such as those causing recurrent acute pancreatitis, are treated with PD sphincterotomy, stricture dilation, and stenting using plastic or metal stents.⁴⁸

PD stones are recognized as a cause of recurrent pancreatitis, which can progress to chronic pancreatitis. Floating PD stones <5 mm can be extracted using standard ERCP with pancreatic sphincterotomy, followed by balloon or basket retrieval. Larger stones may be more difficult to remove and may fail standard retrieval techniques.⁹ PD stones are typically harder to fracture than biliary stones, lowering success rates for ERCP-directed lithotripsy. Pancreatoscopy-directed lithotripsy, however, has shown greater success and is increasingly used for managing PD stones. Extracorporeal shockwave lithotripsy (ESWL) is not available at most centers but can help fragment stones prior to ERCP to increase clearance rates.^9,49 

3.5 Role of Empiric Sphincterotomy

Empiric sphincterotomy (ES) is defined as biliary or pancreatic sphincterotomy based on clinical suspicion without definitive evidence of obstructive etiology, aimed at preventing IARP or recurrent biliary pain from presumed choledocholithiasis/microlithiasis. (Figure 4) The role of ES in preventing recurrent pancreatitis in patients with standard pancreatic ductal anatomy remains controversial.⁹ It has not been shown to reduce the frequency of recurrent acute pancreatitis episodes or alter the natural history of IARP.⁵⁰ ES is a reasonable alternative for patients at high risk for cholecystectomy, particularly when there is concern about future stone passage. ES should be considered after a discussion of its benefits and potential procedure-related risks. If performed, ERCP with biliary sphincterotomy alone may be preferable to dual sphincterotomy.

Conclusion

Increasing accessibility and continuous advancements in EUS technology have significantly improved the identification of the etiology of acute pancreatitis in cases initially considered idiopathic. The sensitivity and diagnostic accuracy of EUS often surpass traditional cross sectional imaging modalities like CT and MRI/MRCP. While primarily therapeutic, ERCP remains the gold standard for diagnosing and managing pancreaticobiliary anatomic abnormalities. Current diagnostic algorithms for IARP incorporate early EUS to effectively identify common etiologies such as microlithiasis and neoplasia. Future studies should focus on exploring the role of EUS in diagnosing pancreaticobiliary anatomical abnormalities. Optimizing the timing of EUS and ensuring careful patient selection for ERCP are crucial for enhancing diagnostic yield and minimizing complications among IARP patients. 

References

Download Tables, Images & References