Management of Idiopathic Acute Pancreatitis and Recurrent Acute Pancreatitis

This article reviews the definitions of idiopathic acute pancreatitis (IAP) and idiopathic acute recurrent pancreatitis (IRAP), etiologies to consider in initial presumed IAP and IRAP, and the role of further diagnostic modalities in determining etiology. These modalities can be noninvasive, such as magnetic resonance cholangiopancreatography (MRCP), or invasive, such as endoscopic ultrasound (EUS) and, to a lesser extent, endoscopic retrograde cholangiopancreatography (ERCP), which now has more of a therapeutic role in the treatment of selected patients with IAP and IRAP.

Gallstone disease and alcohol dependence cause most cases of acute pancreatitis (AP), with gallstone disease estimated to cause between 40% to 70% of cases and alcohol estimated to cause 25% to 35%.^1-3 Other less common causes of AP include hypertriglyceridemia, hypercalcemia, adverse drug effects, pancreatic and ampullary neoplasia, complications of ERCP, and abdominal trauma. A comprehensive list of known causes is provided in the Table.

Table. Etiologies of Acute Pancreatitis
Alcohol
Ethyl alcohol Methyl alcohol
AIP
Type 1 Type 2 Type 3 (ICI-related pancreatic injury)
Biliary calculus disease
Macrolithiasis (bile duct stones) Microlithiasis (bile duct stones <3 mm, biliary sludge)
Biliary cystic disease
Choledochal cyst (including choledochocele) Duplication cyst
Congenital anomaly/anatomic causes
Annular pancreas Anomalous pancreaticobiliary junction Pancreas divisum Pancreatic duct stricture (trauma, necrosis) Sphincter of Oddi dysfunction
Duodenal obstruction
Afferent limb obstruction (Billroth II) Atresia Crohn’s disease Duodenal diverticulum Duodenal duplication cyst
Drug-induced pancreatitis
Genetic
Alpha 1-antitrypsin deficiency Cystic fibrosis Hereditary pancreatitis
Iatrogenic
ERCP Abdominal surgery
Idiopathic
Infections
Bacterial Parasitic/helminthic Viral
Metabolic
Hypercalcemia Hyperlipidemia Hypertriglyceridemia Inborn errors of metabolism
Neoplasm (benign and malignant)
Duodenal Ampullary Pancreatic Biliary Metastases from regional/distant organ malignancies
Papillary stenosis
Renal disease
Chronic Dialysis-related
Toxins
Organophosphate insecticides Scorpion venom
Trauma and postoperative state
Vascular
Vasculitis Systemic lupus erythematosus Emboli to pancreatic blood vessels Hypotension/ischemia
AIP, autoimmune pancreatitis; ERCP, endoscopic retrograde cholangiopancreatography; ICI, immune checkpoint inhibitor.

A significant proportion of patients with AP have no clearly identified etiology despite a thorough initial workup with laboratory tests and cross-sectional imaging. These patients, who are labeled as having presumed idiopathic acute pancreatitis (IAP), account for 10% to 30% of AP cases.^4,5 A proportion of patients with IAP eventually have a confirmed etiology after a second-tier workup, which may include cross-sectional imaging with MRCP if not done during the initial evaluation, EUS, autoimmune pancreatitis evaluation, and genetic testing. Those who still do not have a clear cause elucidated at this point may then be considered to have true IAP. The proportion of patients considered to have true IAP is estimated to be closer to 10%.⁶ Potential factors associated with true IAP have not been conclusively elucidated, but some proposed theories include unidentified genetic polymorphisms, exposure to smoking and other environmental toxins, and effects of coexisting diseases often associated with AP, including obesity and diabetes.⁷

Recurrent acute pancreatitis (RAP) is defined as the occurrence of 2 or more episodes of AP with complete resolution of symptoms between episodes and without concurrent clinical or imaging evidence supportive of chronic pancreatitis (CP). When a clear etiology is not elucidated for RAP, it is referred to as idiopathic recurrent acute pancreatitis (IRAP) and can be further described as presumed or true IRAP based on the definitions above. These subcategories are distinct from smoldering pancreatitis, in which patients recovering from AP experience unremitting abdominal pain, persistently elevated pancreatic enzyme levels, with inflammatory changes in and around the pancreas seen on imaging studies, in the absence of systemic or local complications.⁸

Recurrence after an index episode is estimated to occur in approximately 16% to 43% of cases.⁹ The risk for a second or additional episodes of AP in the absence of alcohol or tobacco use is estimated to be 10% to 30%, which increases to 24% to 30% in patients with ongoing alcohol use and 40% to 50% in patients with both alcohol and tobacco use.¹⁰

In a meta-analysis by Sankaran et al, the pooled CP prevalence was 10% after 1 AP event, with a rise to 36% in patients with RAP.¹¹ There are also data to suggest that RAP is associated with the development of exocrine and/or endocrine insufficiency.^12,13 A comprehensive workup to establish an etiology is, therefore, of great importance. Determination of the etiology may alleviate patient distress over diagnostic uncertainty, aid selection of the appropriate treatment and measures to prevent recurrence, and allow estimates of the risk for complications, including progression to CP, exocrine and endocrine insufficiency, and pancreas cancer. IRAP also may lead to high healthcare resource utilization, with a financial burden and psychological distress for the patient.

It should be emphasized, however, that the extent of evaluation should be tailored to the patient’s presentation and clearly identifiable risk factors for AP. For example, a patient who presents with 1 or more episodes of AP in the setting of persistently uncontrolled hypertriglyceridemia or ongoing alcohol use disorder may not warrant additional etiologic evaluation. Our algorithm at Indiana University for evaluation of presumed IAP and IRAP is shown in Figure 1.

Figure 1. Algorithm for workup of a patient with (presumed) idiopathic AP.

AP, acute pancreatitis; AIP, autoimmune pancreatitis; BES, biliary endoscopic sphincterotomy; ERCP, endoscopic retrograde cholangiopancreatography; IgG4, Immunoglobulin G4; S-MRCP, secretin-ehhanced magnetic resonance cholangiopancreatography; LFTs, liver function tests; PEth, phosphatidylethanol; RUQ, right upper quadrant; SOD, sphincter of Oddi dysfunction.

Pathophysiology of AP

The majority of available data on AP pathogenesis comes from animal models. While a detailed review of proposed AP pathophysiology is outside the scope of this review, a brief summary based on work by Rinderknecht, Keck, and Bhatia, is provided.^14-16 First, a triggering event, usually extrapancreatic in origin, occurs. This leads to activation of trypsinogen to trypsin in the pancreatic acinar cells. This, in turn, activates a cascade of enzymes, complement, and kinin systems. These active enzymes damage acinar cells, interstitium, and vascular endothelium. This damage to cells and tissue leads to the release of even more activated enzymes from the damaged cells and blood vessels, further amplifying and perpetuating the cycle of autodigestion. Microcirculatory injury also occurs and leads to an increase in vascular permeability and, thus, gland edema. It has been theorized that any event that causes ductal obstruction and consequent duct hypertension may result in inhibition of enzyme secretion.¹⁷ This results in colocalization of inactive pancreatic enzymes and lysosomal hydrolases with subsequent acinar cell injury.¹⁸ In cases in which there is evidence of ductal obstruction, endoscopic intervention may help relieve the obstruction, possibly preventing further episodes of pancreatitis.

Diagnostic Accuracy of MRCP and EUS

An initial workup for AP should include a comprehensive history, a thorough physical examination, laboratory testing (including liver function tests [LFTs], and measurement of calcium and triglycerides), and abdominal imaging.

Patients often underreport alcohol use, so it may be prudent to obtain objective evidence aligning with the history and additional available clues (eg, elevated mean corpuscular volume and/or aspartate aminotransferase level greater than alanine aminotransferase level). Since patients may have temporarily stopped drinking a few days before hospital presentation due to evolving abdominal pain, a blood alcohol level may not be an accurate representation of typical intake. The level of phosphatidylethanol (PEth), which can be detected in blood, hair, and urine, can be measured. The PEth blood test can detect alcohol up to 28 days after consumption.¹⁹

Commonly, patients undergo CT imaging in the emergency room at presentation, before hospital admission. However, CT may not provide specific details to aid in elucidating the etiology of the episode. A transabdominal ultrasound (TUS) may be more sensitive for identification of cholelithiasis, which might favor a biliary etiology in the appropriate setting.^20,21 However, TUS may have a reduced sensitivity for detection of cholelithiasis due to ileus and bowel distension,²² and additional imaging (or repeat examination once AP has resolved) may be required. When there is intermediate probability for a biliary etiology for AP, an MRI/MRCP is done during the index admission to confirm or refute this supposition and to triage patients either to ERCP for stone extraction or conservative management.

If the above initial in-hospital workup is negative, MRI/MRCP, secretin-enhanced MRCP (S-MRCP), and EUS are the usual second-level imaging modalities deployed in the outpatient setting to continue the workup for possible etiologies. These may help to exclude occult biliary disease while providing an assessment of structural pancreatic anomalies and the presence of CP. In older adults, it is also essential to rule out periampullary or pancreatic neoplasia (further discussed below). EUS and MRCP have assumed a central role in the evaluation of patients with presumed IAP because of their high diagnostic accuracy and low morbidity.²³ S-MRCP improves the diagnostic yield of MRCP for identifying underlying structural anomalies when present.^24,25 When these second-level evaluation modalities were used in a multicenter study by Hallensleben et al, an etiology was detected in twice the number of IRAP patients as patients who had only had 1 IAP episode (58% vs 27%; P<0.001).²⁶

There is no recommended timing for an MRCP or S-MRCP when there is a low probability for biliary disease during the index admission (normal LFTs, non-dilated CBD, etc). The practice at our center is to wait 4 weeks after the AP episode, which allows for resolution of pancreatic inflammation and may improve visualization. This timing also applies to EUS, as experts agree that inflammatory changes may reduce the detection of small or subtle lesions and interfere with CP assessment.^27-28

Selection of imaging modality is dependent on patient age, clinical scenario, and the suspected risk factors or etiologies that are higher on the differential diagnosis of IAP. The presence of contraindications to a particular modality (eg, non–MRI-compatible cardiac pacemaker or high risk for sedation precluding EUS) may also affect this decision. A recent meta-analysis by Wan et al found that overall, EUS was superior to MRCP (64% vs 34%) for determining an eventual etiology in patients with presumed IAP.²⁹ However, S-MRCP was superior to MRCP (without secretin) and EUS in the identification of pancreas divisum (PD).

In a study by Choudari et al presented only in abstract form, 21% of patients aged 40 to 60 years and 25% of patients older than 60 years had a neoplastic process as the cause of their AP, in contrast to only 3% of those younger than 40 years.³⁰ On the basis of this and other studies reporting similar findings,³¹ the American Gastroenterological Association (AGA) recommends proceeding with EUS in the evaluation of IAP in patients aged 40 and older.¹ This is our current approach as well because EUS after a first episode of IAP helps us assess for occult tumors or other structural causes of AP. With recent improvements in TUS technology, the sensitivity for detection of gallbladder stones exceeds 95%.³² However, if the TUS is negative for cholelithiasis and clinical suspicion warrants (eg, AP accompanied by elevated LFTs or preceding episodes of biliary colic), we consider EUS for this indication alone in patients of any age (see section on Occult Biliary Disease). MRCP may be considered as an alternative imaging modality in patients with contraindications to anesthesia or endoscopy, or a reluctance to undergo sedation, although it is not as sensitive as EUS for the diagnosis of occult biliary disease²⁹ and small pancreatic lesions.³³

ERCP now is used primarily as a therapeutic option, not as a diagnostic tool alone. It is best used in presumed IAP when a clear etiology has been newly identified by EUS or MRCP. Historically, ERCP was deemed to have additional diagnostic utility either for performance of sphincter of Oddi manometry (SOM) and/or aspiration of bile for crystals. These diagnostic uses are no longer routinely pursued, as discussed below.

Etiologies to Consider in IAP and IRAP

Occult Biliary Disease

Occult biliary disease has been implicated as a common cause of IAP, with the mechanism being transient obstruction at the ampulla of Vater. Microlithiasis (stones <3 mm in diameter) and biliary sludge—a suspension of crystals (cholesterol monohydrate, calcium bilirubinate, or calcium carbonate), mucin, glycoproteins, cellular debris, and proteinaceous material within bile—can be found within the gallbladder or bile ducts and may be missed by standard imaging. Prospective studies have found that approximately one-fifth to three-fourths of patients with presumed IAP have sludge or stones in the gallbladder, ^34,35 with diagnosis based on microscopic examination of bile for crystals and usually confirmed on evaluation of the resected gallbladder or follow-up gallbladder ultrasound showing gallstones and/or sludge.

In the past, at the time of ERCP, it was recommended that bile be collected from the duodenum or bile duct after gallbladder stimulation with cholecystokinin or by direct cannulation of the gallbladder.^36,37 Today, however, ERCP rarely is performed specifically for bile crystal analysis, given the risk for post-ERCP pancreatitis and the high sensitivity of EUS in detecting biliary sludge and microlithiasis (Figures 2 and 3A). Furthermore, TUS technology also has advanced significantly, with improved detection rates.

Figure 2. Sludge seen on EUS.

EUS, endoscopic ultrasound.

Figure 3A-B. A) Bile duct stone on EUS and B) bile duct stone on MRCP.

EUS, endoscopic ultrasound; MRCP, magnetic resonance cholangiopancreatography.

In a large meta-analysis, EUS was found to have a significant benefit in detecting occult biliary disease compared with MRCP (Figure 3B) in IAP.²⁹ Ardengh et al found gallbladder microlithiasis in 27 of 36 patients with IAP using EUS (75%).³⁸ When compared with the final surgical resection specimen, the sensitivity and specificity for EUS identification of gallbladder microlithiasis were 92.6% and 56%, respectively. The overall EUS accuracy in this study was 83.2%.

Intraductal ultrasonography is another modality that may be useful in detecting microlithiasis and sludge within the bile ducts, although this technique is not readily available in North America. Kim et al analyzed 31 patients with IRAP and negative findings on ERCP.³⁹ Intraductal ultrasound revealed microlithiasis in 5 patients (16.1%) and sludge in 3 patients (9.7%).

While confirmation of a biliary etiology may have management implications (eg, proceeding with cholecystectomy), the finding of gallbladder pathology does not definitively confirm a biliary etiology of IAP. As previously noted, a patient with alcohol use disorder or marked hypertriglyceridemia who presents with AP may have a readily identifiable etiology for the episode, regardless of whether gallbladder stones or microlithiasis are identified.

A 2019 systematic review of 28 studies with 1,850 patients found only a 2% AP recurrence rate over a mean follow-up period of 20.5 months in patients with biliary disease who underwent cholecystectomy.⁴⁰ Another meta-analysis of 1,679 patients by Umans et al found a 59% lower odds of recurrence of IAP (defined as episodes of AP where the etiology remained elusive despite an extensive workup including EUS or MRCP) in patients who had a cholecystectomy compared with patients managed conservatively.⁴¹ This suggests that an initially missed diagnosis of biliary pathology in the setting of AP can erroneously be labeled as IAP and that current diagnostics are insufficient to exclude a biliary cause.

When deciding if the finding of gallbladder sludge is truly the etiology of AP, it is important to keep in mind that gallbladder sludge may occur in patients who have been fasting during an AP episode. This may be the result, therefore, and not the cause of AP. Regardless, identification of microlithiasis, biliary sludge, or gallstones should prompt referral for cholecystectomy in otherwise unexplained AP, as this demonstrably reduces the odds of recurrent AP. If cholecystectomy is pursued, we recommend intraoperative cholangiography (IOC) if preoperative ERCP and biliary endoscopic sphincterotomy (BES) have not been done recently. Laparoscopic cholecystectomy’s overall favorable risk profile may influence physicians to advocate for empiric cholecystectomy, especially with repeated AP attacks. It is important, however, to have an informed discussion with the patient before a cholecystectomy about the possibility of no improvement in RAP if there are unidentified competing etiologies.

The benefit of an ERCP with empiric BES for presumed gallbladder sludge, microlithiasis or stones (ie, not clearly identified on imaging) in patients fit for surgery is controversial. There are data to suggest that patients undergoing ERCP for evaluation of AP have higher odds of developing post-ERCP pancreatitis.⁴² Our recommendation, therefore, is to not pursue ERCP in asymptomatic surgical candidates with a low likelihood or intermediate probability for choledocholithiasis without clearly demonstrated biliary pathology on EUS or MRCP.⁴³ However, in patients in whom bile duct sludge or choledocholithiasis is demonstrated clearly, an ERCP with BES is recommended.

For patients with a biliary etiology who are ineligible for cholecystectomy (eg, poor surgical candidates), BES provides a therapeutic benefit to prevent recurrence. In theory, recurrent biliary pancreatitis should not occur following an adequate BES because the biliary and pancreatic orifices are separated and an impacted stone at the orifice will not lead to pancreatic duct obstruction and pancreatitis.⁴⁴ Cholecystitis, cholangitis, and biliary colic, however, may still occur.

If ERCP and BES do not take place, performing cholecystectomy during the index admission diminishes the likelihood of recurrent biliary events.⁴⁵

Sphincter of Oddi Dysfunction

There is still some controversy about whether a true causative effect between sphincter of Oddi dysfunction (SOD) and AP exists, given the paucity of definitive evidence to that effect. While there is evidence to suggest that there is increased sphincter tone in 30% to 65% of patients with IAP,⁴⁶ it is unclear whether this sphincter hypertension leads to RAP episodes or if inflammation from the RAP episodes is what leads to sphincter hypertension.

Previously, some physicians believed that pancreatic SOD might be responsible for many cases of RAP in which a thorough etiologic evaluation was negative. Historically, endoscopic sphincterotomy via ERCP was done to reduce the basal pressure of the sphincter of Oddi. Biliary endoscopic sphincterotomy was the initial approach taken, based on limited data.⁴⁷ Subsequently, Guelrud et al demonstrated a reduced frequency of RAP episodes in a small cohort after pancreatic endoscopic sphincterotomy.⁴⁸ This finding was supported by similar results in three other small cohort studies,^36,49,50 so practice subsequently shifted to a combined pancreaticobiliary or dual endoscopic sphincterotomy.

Due to the lack of high-level evidence of benefit from this new approach, Cote et al conducted a randomized clinical trial to evaluate ERCP with SOM and sphincterotomy in patients with IRAP with or without an increase in basal pancreatic sphincter pressure.⁴⁶ Patients were followed for a median of 78 months. In 69 patients with pancreatic SOD, the frequency of RAP during the follow-up evaluation was similar among those randomized to biliary or dual sphincterotomy (48.5% vs 47.2%; P=1.0).

This study generated further controversy among clinicians, with some concluding that ERCP and sphincterotomy should not be offered to or performed in patients with IRAP because half the patients studied continued to present with RAP post-therapy. However, proponents of ERCP noted that half the patients studied did not present with further RAP episodes, with nearly 7-year follow-up. Furthermore, a subsequent post hoc analysis of these data demonstrated a reduction in RAP episode density in those who presented with recurrent episodes during the long follow-up period.⁵¹

BES alone may be considered in patients with IRAP in whom SOD is strongly suspected. It is important, however, to have a thorough discussion with patients on risk versus benefit, as well as to set patients’ expectations before proceeding with endoscopic therapy for several reasons. First, while a post hoc analysis of longer-term data from the above study by Cote et al,⁴⁶ orally presented in abstract form,⁵¹ suggests that there may be long-term benefit in reducing the frequency of AP attacks, a more recent study by the same author shows there is still a relatively high recurrence rate of AP (regardless of the type of endoscopic sphincterotomy performed) in the short term.⁵² Furthermore, this patient population has also been demonstrated to be at higher risk for post-ERCP pancreatitis.⁴² More high-quality randomized trials are needed to definitively determine if there is still a role for pancreatic sphincter therapy in patients with a normal pancreatogram at ERCP, particularly given the high restenosis rates observed.⁵³

Pancreas Divisum

PD, the failure of the dorsal and ventral buds to fuse during organogenesis, is the most frequent congenital variation of pancreatic anatomy. It results in drainage of most of the pancreatic exocrine juice through the dorsal pancreatic duct and into the duodenum through the minor papilla.⁵⁴ Autopsy series suggest that PD is found in 5% to 10% of the general population.^55-58

It remains controversial, however, whether PD is a primary cause, a predisposing factor, or an innocent bystander in the development of RAP, especially as studies suggest that only 5% of subjects with PD present with symptomatic pancreas disease. Conversely, up to 19% of patients with presumed IRAP have been found to have PD.³¹

There is also a demonstrated increased prevalence of genetic abnormalities in patients with PD and RAP,^44,59-62 with cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations identified in approximately 47% of patients with PD and RAP.^44,61 This suggests a synergistic effect of structural anomalies and genetics to induce AP. For patients with PD who have symptomatic pancreas disease, a potential mechanism may be pancreatic duct hypertension due to obstruction of pancreatic exocrine juice flow through the minor papilla, which in turn precipitates RAP. However, this presumably does not apply in all patients because the majority of patients with RAP and PD are found to have a non-dilated dorsal pancreatic duct when evaluated by MRCP or ERCP.⁶³ CFTR mutations likely increase pancreatic juice viscosity and acidity via impaired ion transport, exacerbating the impaired outflow. There is an excessive intrapancreatic inflammatory response, reduction in apoptosis, and disruption of intracellular signaling and mitochondrial function. These exacerbate pancreatic injury during AP episodes.⁶⁴

MRCP and S-MRCP are usually the diagnostic modalities of choice for PD, given their noninvasiveness (Figure 4). Studies have demonstrated the high diagnostic accuracy of S-MRCP.^65-67 Mosler et al found that S-MRCP had an overall sensitivity and specificity of 73% and 97%, respectively, when compared with ERCP in 19 patients.⁶⁵ The sensitivity and specificity improved to 83% and 99% in the subgroup of patients without CP. A meta-analysis and systematic review of 11 studies evaluating the utility of MRCP, S-MRCP, and EUS found similar results, with specificities of 99% for both MRCP and S-MRCP but a higher sensitivity of S-MRCP (83% vs 59%).⁶⁶ Data also suggest that S-MRCP could help identify a subgroup of patients who might respond to endoscopic therapy, as evidenced by a recently published retrospective study from 3 tertiary centers in China evaluating 120 patients with PD who underwent endoscopic retrograde pancreatography.⁶⁷ The investigators found that linear array EUS had a sensitivity of 90.8%, a specificity of 99.8%, and an overall diagnostic accuracy of 99%, suggesting it is a reasonable alternative to S-MRCP. They also noted that the degree of duct dilation suggested an obstructive process and might correlate with or predict a response to minor papilla intervention, but this assumption has not been proven conclusively to date.

Figure 4. Pancreas divisum demonstrated on MRCP.

MRCP, magnetic resonance cholangiopancreatography.

From a management standpoint, there has been a lack of high-quality evidence regarding the efficacy of endoscopic therapy. Small cohort studies have evaluated the effect of various combinations of therapies, including minor papilla endoscopic sphincterotomy (MiES), minor papilla dilation, repeated dorsal duct stenting, or a combination of these.^68-71 While a review of these trials suggests a potential benefit from endoscopic therapy, with 68% to 90% of patients having no further episodes of AP after intervention, it needs to be emphasized that the mean follow-up interval was 30 months.⁴⁴ Clearly, this is insufficient in an episodic illness (ie, RAP), when attacks may be separated by several years.

A meta-analysis of 323 PD patients from 13 retrospective studies treated with MiES showed an overall success rate of 77%, defined as no further episodes of RAP, reduction of episodes of RAP, or improvement in quality of life.⁷² When the subgroup of studies in this meta-analysis with a clear clinical success definition (“no further AP in the follow-up”) were evaluated, the pooled proportion achieving clinical success was 69.8%. When studies with other definitions of clinical success (reduction of RAP episodes, improvement in quality of life) were evaluated, the clinical success rate was 81.2%.

In the only randomized controlled trial published to date evaluating dorsal pancreatic duct stent placement for RAP in patients with PD, Lans et al demonstrated a remarkable improvement in symptoms for 90% of treated patients versus 11% of controls, with a follow-up period of 12 months.⁶⁸

However, systematic reviews and meta-analyses suggest a lower response rate for endotherapy in PD in the range of 62% to 70%.^69,73-76 In these studies, patients with RAP showed the most improvement in symptoms (75%-80%), followed by patients with CP (42%-69%). Patients with CP-like abdominal pain showed the least improvement (33%-54%). There were notable adverse events, including a post-ERCP pancreatitis incidence of 10% to 20% and a 19% incidence of minor papilla stenosis requiring re-intervention.^74-76 The mean follow-up period for these studies was 32 months, with most having a 36-month follow-up window.^54,69,73-76

This is problematic because patients often can remain asymptomatic for several years between pain episodes or pancreatitis flares but could potentially require reintervention at a much later time.⁷⁷ Also, dorsal duct stent placement requires repeated procedures for stent change, each with an associated risk for post-ERCP pancreatitis, as well as the ductal and parenchymal changes that may occur after pancreatic duct stent placement and may be irreversible.^78,79

Advocates of endoscopic therapy, therefore, have favored performance of MiES as a better option to enlarge the minor papilla orifice.^44,80 The short-term follow-up of these studies was the impetus for the SHARP trial, a randomized sham controlled trial evaluating the efficacy of MiES in patients with PD and RAP.⁸¹ This study was recently completed, with a reported median follow-up period of 33.5 months. Reported pre-publication results suggest that minor papilla endotherapy does not lead to a significant reduction in recurrent episodes of AP when compared with sham.⁸² This may lead to a practice change in the near future, with most patients no longer being offered endoscopic therapy.

Choledochal Cysts

Congenital pancreaticobiliary malformations, often incidentally found on MRI/MRCP, can lead to RAP. Choledochal cysts are cystic dilations of the intrahepatic or extrahepatic biliary tree and may be single or multiple. Todani type III choledochal cysts, or choledochoceles, are cystic lesions that arise from the intramural bile duct or intra-ampullary common channel (Figure 5A, 5B).⁸³ In type A choledochoceles, as originally defined by Sarris and Tsang,⁸⁴ the intramural bile duct communicates with a cystically dilated segment, which then drains into the duodenal lumen via the separate papillary orifice.^85,86 In type B choledochoceles, the bile duct drains normally into the duodenum, with the choledochocele arising as a diverticulum from the intra-ampullary common channel.^44,87

Figure 5A-B. A) Endoscopic view of choledochocele during ERCP and B) cholangiogram showing choledochocele.

ERCP, endoscopic retrograde cholangiopancreatography.

During ERCP, the papilla associated with the type A choledochocele may be recognized by its bulging intramural portion of the bile duct, but it is soft when probed with a catheter tip.⁸⁸ Alternatively, the papilla may appear less prominent but progressively enlarges with contrast injection that fills the cyst. Type B choledochoceles often appear endoscopically as a pendulous duodenal mass, with the ampullary orifice immediately proximal to this mass.⁸⁷

Choledochoceles commonly present with pancreatitis (38%-70%),^44,89 but they are an uncommon overall cause of IAP due to their low prevalence.⁸⁹ The most widely accepted mechanism of AP in patients with choledochoceles is obstruction of outflow with subsequent ductal hypertension, or bile reflux into the pancreatic duct.⁹⁰

MRCP can detect choledochoceles with reasonable accuracy. In a study of 72 patients using ERCP as the gold standard, the sensitivity and specificity of MRCP in diagnosing type III choledochal cysts was 73% and 100%, respectively.⁹¹

EUS is also a viable diagnostic modality, but its utility in the diagnosis of choledochoceles is limited to case reports.^92,93

While surgical therapy (either excision or sphincteroplasty) has been the historical approach to choledochoceles, endoscopic therapy with ERCP is considered to be a safe and effective alternative in most patients.⁸⁷ Endoscopic management involves either unroofing the cyst, BES, snare resection, or a combination of the above, depending on cyst type and endoscopist preference. A review of published case reports suggests a resolution of AP episodes in 13 of 14 cases (93%) after endoscopic intervention.^85,94-97 Anomalous pancreaticobiliary junction is rare, occurring in 0.2% of European populations, but is more prevalent in Asian populations and often is associated with choledochal cysts (40%-70%).^44,98 Patients with anomalous pancreaticobiliary junction may experience AP through bile reflux into the pancreatic duct, and BES can be beneficial in preventing further AP episodes.

Although choledochal cysts are associated with increased risk for biliary tract malignancy, malignancy complicating a choledochocele rarely is seen and has been limited to case reports.⁴⁴ Malignancy can develop after endoscopic therapy, but surveillance protocols have not been defined.

Other Anatomic Causes

A number of non-neoplastic structural lesions of the pancreas have been associated with AP. These can be evaluated with ERCP, EUS, and/or MRCP and are listed in the Table.

Five to seven percent of patients with benign or malignant pancreatobiliary and ampullary tumors present with IAP.⁹⁹ These lesions can be solid or cystic and should be considered in the differential diagnosis of patients 40 years or older presenting with IAP. The presumed pathophysiology for these conditions, whether benign or malignant, is obstruction of the pancreatic duct.

Mucinous Tumors

Mucinous tumors of the pancreas, both intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), may present as RAP.^31,100-102 Unlike IPMNs, MCNs rarely communicate with the pancreatic duct, and, thus, the presenting symptoms of MCNs are often due to compression of adjacent structures or organs. Rarely, MCNs can precipitate AP by extrinsic compression of the pancreatic duct. On the other hand, both side-branch and main-duct IPMNs may lead to AP through mucin production and, thus, duct obstruction. Both mucinous lesions are premalignant, with varying malignant potential, typically based on high-risk imaging findings such as mural nodules or associated solid components, diffuse or focal dilation of the main pancreatic duct greater than 5 mm, size of 3 cm or more, or continued increase in cyst size of 3 mm or more per year.^103,104

Mucinous cysts typically are surveilled with MRI/MRCP, EUS, or both in an alternating fashion, based on the presence or absence of high-risk features and, if available, cyst fluid analysis. ERCP has no role in the diagnosis of MCNs but on occasion may be helpful in IPMN diagnosis and management planning. Rarely, an IPMN may be identified only by subtle intraductal cast-like filling defects (eg, mucin) seen with good ERCP technique, a finding that MRCP could have missed, particularly if S-MRCP had not been performed. Indeed, it is not uncommon to find patients with an IPMN presenting with RAP for many years before the diagnosis has been made.¹⁰⁵ Similarly, it may be difficult to determine whether a patient who presents after several RAP episodes and is found to have a small pancreatic cyst and a prominent but non-dilated pancreatic duct has an IPMN or CP.

EUS-guided cyst or pancreatic duct aspiration has been associated with postoperative pancreatitis, with one study finding an up to 8% incidence of post EUS-FNA pancreatitis in patients with branch-duct IPMNs compared with 1.3% with other cyst types.¹⁰⁶ ERCP may be considered as an alternative in such cases, particularly for main-duct IPMNs, perhaps with pancreatoscopy for more detailed analysis. This may be dependent on local expertise.

When an IPMN results in RAP, this is considered a worrisome feature that warrants further evaluation with consideration of cyst fluid sampling, as well as multidisciplinary discussion regarding the need for possible surgical resection, per the 2018 American College of Gastroenterology guidelines.¹⁰³

Solid Tumors

Solid tumors (benign and malignant) are identified as the etiology in 5% to 7% of AP cases initially believed to be idiopathic⁹⁹ and should be suspected in older patients as well as those with preexisting constitutional symptoms or new-onset diabetes accompanying AP. A cohort study using a representative database from the United States found that 5.9% of patients with an eventual diagnosis of pancreatic cancer in their cohort had a sentinel event of AP within 90 days of diagnosis.¹⁰⁷

Ampullary tumors, either benign (Figure 6A) or malignant (Figure 6B), also may present with AP. A wide variety of benign tumors can arise at the major papilla, including adenoma, lipoma, fibroma, lymphangioma, leiomyoma, and hamartoma, with adenomas being the most common.¹⁰⁸ Patients with hereditary conditions such as familial adenomatous polyposis may have duodenal adenomas involving the major papilla, which can lead to presentation at a young age with AP.

Figure 6A-B. Images of A) ampullary adenoma and B) ampullary cancer.

Endoscopic therapy is the treatment of choice for most ampullary adenomas (snare papillectomy, thermal ablation, or a combination of the two).^109-111 Primary malignant tumors of the major papilla include carcinoma, lymphoma, and neuroendocrine tumors.¹¹⁰ Although most patients with malignant tumors of the papilla present with obstructive jaundice, occasionally patients develop AP as the first sign of their disease.

Lastly, metastases to the pancreas from other organs can occur, with renal cell carcinoma, lung cancer, breast cancer, and melanoma most frequently seen, although AP due to pancreatic duct obstruction is an uncommon complication. Uroepithelial malignancies, sarcomas, and lymphoma also may metastasize to the pancreas^112-114 and potentially cause AP due to duct obstruction.

While CT and MRI/MRCP have clear utility in this scenario, EUS outperforms cross-sectional imaging from a diagnostic standpoint, as it has a higher sensitivity for smaller (1-3 cm) lesions³³ and has the added advantage of same-session tissue acquisition for a definitive diagnosis. EUS, however, does not provide additional staging information above that provided by a good-quality, contrast-enhanced, thin-cut CT scan.¹¹⁵ As noted earlier, given the increased prevalence of neoplasia in older adults with IAP and the importance of an early diagnosis, the AGA recommends EUS for evaluation in patients 40 years and older, even in the absence of red flags.¹ The primary role of ERCP in these patients is therapeutic because biliary stent placement in malignant biliary obstruction can be offered to unresectable patients or surgical candidates receiving neoadjuvant chemotherapy.¹¹⁶ With ampullary lesions, targeted biopsies are best obtained with side-viewing endoscopy.

Genetic Mutations

The prevalence of genetic mutations in IRAP is thought to be approximately 30% to 60%.^117,118 The true incidence of genetic mutations, however, is almost certainly underestimated because routine genetic evaluation after an episode of IAP has yet not been adopted into widespread clinical practice. Mutations of the cationic trypsinogen gene (serine protease 1 gene; PRSS1) are associated with hereditary or familial pancreatitis,¹¹⁹ onset of AP in childhood, and frequent progression to CP.^120,121 Serine protease inhibitor Kazal type 1 (SPINK1) mutations have been detected in 16% to 23% of patients with apparent IAP, compared with only about 2% of healthy controls,¹²² supporting an association. CFTR gene mutations are associated with the most common inherited disease of the exocrine pancreas. Although CFTR gene mutations occur in 5% of White European and North American populations, IAP may occur in up to 20% of CFTR heterozygotes.¹²³ Chymotrypsin C (CTRC) variants have been shown to increase the risk for rapid progression to CP.¹²⁴ There are other genetic mutations that have been associated with IAP, but a full assessment of the role of genetic polymorphisms is outside of the scope of this review.

A 2015 study by Culetto et al prospectively investigated 309 IAP patients and identified genetic mutations in 10% of patients 35 years of age or younger, compared with 1.5% of patients older than age 35.¹²⁵ Another study found that mutations in 3 genes (CFTR, SPINK1 and PRSS1) were present in up to 32% of young patients (<30 years of age) with IAP.¹²⁶ In another retrospective single-center study evaluating 97 IRAP patients, all of whom underwent genetic testing,¹¹⁸ 56 patients (58%) had 1 or more pathogenic variants, with CFTR being the most common (48), followed by SPINK1 in 22, PRSS1 in 5, and CTRC in 2 patients. Among patients in that cohort who were younger than age 35 and had 1 unexplained episode of AP, 63% had at least 1 pathogenic variant identified. Multiple logistic regression analysis identified both IRAP (odds ratio [OR], 18.2; P=0.008) and IAP (OR, 2.46; P=0.017) in patients younger than age 35 were independently associated with pathogenic variants. Based on the above evidence, it is reasonable to recommend genetic testing for patients with IAP, particularly if they are less than age 35.

Genetic testing can be performed on blood or saliva. There are few available options for intervention in genetic-associated IAP, although CFTR gene modulator medications appear to have some utility in the management of CF heterozygote-related RAP.¹²⁷ Identification of pathogenic mutations may help establish a cause-and-effect relationship, allowing a more informed prognostic assessment of the risk for future RAP, subsequent progression to CP, and additional complications of the disease, including pancreatic adenocarcinoma. Genetic counseling is important for both patients and family members. While ERCP and pancreatic endotherapy may still be considered in patients with a genetic etiology, it should be anticipated that this therapy will be unlikely to result in long-lasting or durable benefit. Supportive measures, including medications for symptom control, should be continued, and timely surgical evaluation, including candidacy for total pancreatectomy with islet auto transplantation in selected candidates, may be considered to reduce or eliminate the future risk for RAP and malignant transformation.¹²⁸

Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is an uncommon cause of IAP and IRAP.¹²⁹ It is a chronic inflammatory disease of the pancreas (Figure 7). Historically, 2 main types of AIP have been described, with a third type associated with the use of immune checkpoint inhibitors recognized more recently. Various diagnostic criteria from different countries have been proposed to make the diagnosis of AIP.^130-131 An international consensus on diagnosis initially subdivided AIP into type 1 and type 2.^132,133

Figure 7. EUS images of a hyperechoic bile duct in a patient with AIP.

AIP, autoimmune pancreatitis.

Type 1 AIP often is characterized by diffuse enlargement of the pancreas on imaging, with segmental irregular narrowing of the main pancreatic duct, typically without upstream pancreatic duct dilation. MRI/MRCP has a sensitivity of 84% and a specificity of 97% (compared with a sensitivity of 59% and specificity of 99% for CT) in the diagnosis of AIP.¹³⁴ EUS has a higher sensitivity of 93% and a specificity of 99.3%, particularly in cases when an irregular, narrow main pancreatic duct in association with duct wall thickening is seen.¹³⁵ Type 1 AIP is associated with the presence of several other autoantibodies and elevated levels of serum immunoglobulin G-4 (IgG4) subtype on serology. Fibrotic changes with lymphoplasmacytic infiltration are seen histologically.¹²⁹ An international multicenter survey showed that obstructive jaundice was a more frequent presentation in type 1 versus type 2 (75% vs 47%; P<0.001), whereas abdominal pain (41% vs 68%; P<0.001) and AP (5% vs 34%; P<0.001) were more frequent in type 2.¹³⁶

Type 2 AIP usually presents without multiorgan involvement and typically occurs in younger patients. There is no gender predilection, and it is associated with inflammatory bowel disease in up to 30% of cases.¹³⁷ It does not have the classic elevation of serum IgG4, and, thus, a negative serologic test is not sufficient to exclude a diagnosis of AIP when there is significant clinical suspicion. The inflammatory infiltrate in type 2 AIP is typically periductal, with identification of granulocytic epithelial lesions rather than the IgG4-positive plasma cells seen in type 1 AIP.

Type 1 and type 2 AIP respond dramatically to steroids. Relapse after steroid therapy is frequent in type 1 AIP, often requiring repeat steroid therapy or the addition of steroid-sparing agents or other immunomodulators, such as rituximab. Relapse is uncommon in type 2 AIP. Laboratory screening with serum immunoglobulins with IgG subtypes and, if necessary, core biopsies of the pancreas obtained at EUS should be considered in selected IAP patients with clinical or radiological features suggestive of AIP.¹³⁸ Positive IgG4 immunostaining of major papilla biopsies via the use of a side-viewing duodenoscope are specific for AIP, with a reported range of 89% to 100%, but this finding has a lower sensitivity (52%-80%).^139,140 Such immunostaining is, therefore, a reasonable alternative when there is a strong suspicion for AIP but serum IgG4 levels are normal and pancreatic tissue samples cannot be obtained.

Conclusion

IAP and IRAP represent a challenging clinical problem. EUS and MRCP have assumed a central role in the evaluation of patients with these conditions, and an etiology can be found in a significant proportion of patients using second-line imaging modalities, laboratory testing (including genetic evaluation), and/or histologic evaluation of pancreas tissue. From an imaging standpoint, EUS has assumed a central role in the evaluation of IAP and IRAP, particularly with patients older than 40 years of age, with S-MRCP being an invaluable imaging modality. As a result, the role of ERCP as a diagnostic modality has greatly diminished, but it has retained a defined but important role as a therapeutic option in selected cases. Patients with IAP and IRAP are best evaluated in centers where specialized pancreatic expertise and advanced endoscopic methods are available. The algorithm we recommend in our unit is shown in Figure 1.

Research gaps remain in this challenging clinical scenario, and future high-quality multicenter studies evaluating optimal diagnostic modalities and interventions will help determine the optimal cost-effective approach for these patients.

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Management of Idiopathic Acute Pancreatitis And Recurrent Acute Pancreatitis

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