Synopsis  

ERCP plays an expanding role in both the diagnosis and therapy of acute and relapsing pancreatitis of various etiologies. Although initially used in the diagnosis and treatment of biliary disorders causing pancreatitis, endoscopic interventions are now increasingly directed towards the pancreatic sphincter and ducts as well. In certain settings such as acute gallstone pancreatitis, the value of ERCP has been proven in randomized controlled trials. There are also data to support the role of ERCP in treatment of acute relapsing pancreatitis due to various disorders such as pancreas divisum and to a lesser degree sphincter of Oddi dysfunction. Other applications include use of ERCP to treat smoldering pancreatitis and pancreatic ductal disruptions in the setting of acute and chronic pancreatitis, and most recently in the setting of evolving pancreatic necrosis. Many causes of otherwise unexplained acute recurrent pancreatitis can be found after an extensive evaluation and treated by advanced ERCP techniques. The role of ERCP in acute and especially recurrent pancreatitis should be primarily therapeutic with diagnosis first established whenever possible by other techniques including endoscopic ultrasound and MRCP. ERCP for diagnosis and treatment of severe or acute relapsing pancreatitis is optimally performed in a multidisciplinary context involving primary or critical care, advanced hepatobiliary–pancreatic surgery, and interventional radiology when appropriate.

 Introduction   

ERCP appeared in the early 1970s and soon evolved as a diagnostic and therapeutic technique for biliary tract disorders. Biliary therapy including sphincterotomy was then applied to biliary causes of acute pancreatitis such as gallstone pancreatitis. Over the last decade, the application of pancreatic diagnostic and therapeutic techniques has expanded to incorporate a wider range of pancreatic techniques including pancreatic sphincterotomy, stenting, stricture dilation, and stone extraction via the major and minor papillae. These techniques have allowed the endoscopist to approach therapy of a wider range of causes of acute pancreatitis.

We will review established and investigational applications of ERCP for diagnosis and treatment of acute and recurrent acute pancreatitis.

 Interdisciplinary management; complex ERCP   

ERCP for diagnosis and treatment of non-biliary acute or relapsing pancreatitis is optimally performed in a multidisciplinary context involving primary or critical care, advanced hepatobiliary–pancreatic surgery, and interventional radiology when appropriate (Fig. 1). The majority of endoscopists performing ERCP are capable of performing biliary therapy including sphincterotomy and stone extraction, affording them the ability to diagnose and treat biliary pancreatitis. However, performance of pancreatic endotherapy is considerably more technically challenging, requires more complex equipment and accessories, and generally carries higher risk, and is thus best performed primarily at tertiary centers with extensive expertise in these techniques (Fig. 2). The role of ERCP in acute pancreatitis should be primarily therapeutic with diagnosis established whenever possible by other techniques including endoscopic ultrasound and MRCP. It is also important to perform ERCP on the appropriate patients using optimal timing and techniques.

 Acute gallstone pancreatitis   

Gallstone disease accounts for approximately half of the cases of acute pancreatitis in the Western world [52,117,143]. Biliary pancreatitis may result in severe, necrotizing, life-threatening, or fatal pancreatitis as it often occurs in a previously healthy gland. As many as 25% of patients with biliary pancreatitis may develop severe pancreatitis and mortality may be as high as 10%. The role of ERCP in acute biliary pancreatitis has long been recognized and there is now substantial evidence from randomized controlled trials that early ERCP with biliary sphincterotomy and stone extraction (Fig. 3) can improve outcome of properly selected patients with acute biliary pancreatitis.

Clinical diagnosis of acute gallstone pancreatitis   

Biliary pancreatitis is usually suspected in the setting of acute abdominal pain with hyperamylasemia or hyperlipasemia, in the absence of another etiology such as alcohol, and in the presence of gallstones as documented by ultrasound, computed tomography, or other imaging techniques [5,43]. There is usually elevation of liver chemistries although the pattern is not consistent, and may include elevated serum bilirubin, transaminase, or alkaline phosphatase. Jaundice and a dilated bile duct are further supporting evidence of biliary etiology in the context of biliary stone disease. The sensitivity and specificity of predictors of acute biliary pancreatitis are also variable but acute biliary pancreatitis is more likely in patients with markedly elevated serum amylase or elevated serum transaminase.

Predicting severity of acute pancreatitis   

Assessment of severity of acute pancreatitis is a complex topic beyond the scope of this chapter [6]. Various indices including Ranson's criteria, Apache II score, presence of organ failure, and CT severity index [4,14], all have important prognostic value. Elevated serum hematocrit indicating hemoconcentration has recently been proposed as another predictor of poor outcome [2].

Acute treatment   

In patients suspected to have severe pancreatitis, resuscitation is critical and intensive care unit management is advised. There is little role for early cholecystectomy in severe cases [71]. The relevant issue for the endoscopist is whether to perform ERCP in patients with acute suspected biliary pancreatitis.

The role of early ERCP   

There are substantial data regarding efficacy of ERCP in this setting, including four randomized controlled trials comparing early ERCP with biliary sphincterotomy to no intervention.

British study   

A British group was the first study to prospectively evaluate the role of ERCP in acute biliary pancreatitis [97]. In that study, 121 patients with acute pancreatitis and ultrasound evidence of gallstone disease were randomized to either conventional medical management or urgent ERCP within 72 h. Patients were stratified by severity of illness; one-half of the patients randomized to ERCP had severe pancreatitis. CBD stones were found in 63% of patients with severe pancreatitis, but only 25% of those with mild pancreatitis. Sphincterotomy was performed in those patients found to have bile duct stones. In the group randomized to intervention with ERCP and sphincterotomy, there was a significant reduction in complications in those with severe disease, 24% with 4% mortality vs. 61% with 18% mortality. However, there was no difference in outcomes of patients with mild pancreatitis.

Hong Kong study   

In a subsequent study from Hong Kong [40], 195 patients with acute pancreatitis were randomized to receive ERCP with sphincterotomy vs. conservative management within 24 hours of admission. Stones were found in 65% of the patients. The major difference in outcome of the group undergoing ERCP was a reduction in biliary sepsis (0% after ERCP vs. 14% in the conservative group). There was a tendency towards fewer complications in the ERCP group vs. conservative management group, especially in those with severe pancreatitis, and a slight trend towards reduction in mortality. Applicability of this study has been questioned as bile duct stones in Asians are more often primary bile duct stones rather than cholesterol stones originating from the gallbladder, and thus reflecting different pathophysiology than in Western patients.

Polish study   

A randomized controlled trial from Poland has been presented only in abstract form [99]. 280 patients with acute biliary pancreatitis all underwent ERCP within 24 h of admission. All patients with bile duct stones were treated with biliary sphincterotomy while the remaining patients without common bile duct stones were randomized to sphincterotomy or conventional treatment. There were significant reductions in complications in sphincterotomy-treated patients vs. the conservatively treated patients (17% vs. 36%) and a significant reduction in mortality (2% vs. 13%). The benefits of intervention appeared to apply to patients with all severities of pancreatitis, including those with mild disease. Problems with this study include the fact that it has not been published in a peer-reviewed journal, a lack of true randomization, and the fact that some of the patients with empty ducts may have had more severe irreversible damage, or may have had pancreatitis due to other etiologies than stone disease.

German study   

The most contentious study is the German multicenter study published in the New England Journal of Medicine[41], in which 238 patients with suspected biliary pancreatitis were randomized to early ERCP within 72 h of presentation or conservative management. Patients with jaundice were excluded. 58 of 121 patients randomized to the ERCP arm were found to have bile duct stones. In the control arm, 13 of 112 were crossed over to ERCP for apparent bile duct stones. In this study, there was no improvement in outcome from early sphincterotomy. Paradoxically, there appeared to be more severe complications including respiratory failure in the early ERCP group, and a numerically increased mortality. Major criticisms of this study have included the fact that patients most likely to benefit from ERCP, i.e. those with jaundice, were excluded from the study. Furthermore, many contributing centers enrolled fewer than two patients per year, raising questions about technical proficiency at ERCP.

Meta-analysis of studies of early ERCP, and current consensus   

A meta-analysis of these randomized controlled trials has suggested that early intervention with ERCP in acute biliary pancreatitis results in a lower complication rate and a numerically lower mortality group rate [24] (Fig. 4) Meta-analysis found that complications occurred in 25% of treated patients vs. 38.2% of controls, p < 0.001, with a mortality of 5.2% in treated patients vs. 9.1% in control patients (p = NS). The number needed to treat (NNT) for avoidance of complications and death was 7.6 and 25.6, respectively. Therefore, it is probably safe to say that early ERCP with sphincterotomy in patients with gallstone pancreatitis and persistent bile duct stones is effective in reducing complications, particularly in patients with severe pancreatitis.

ERCP is rarely indicated before cholecystectomy in patients with gallstone pancreatitis   

Unless there is reasonably clear evidence of a persistent bile duct stone such as a rising serum bilirubin or an imaging study clearly showing an intraductal stone, routine use of ERCP is unnecessary and adds avoidable risk in patients with mild to moderate biliary pancreatitis in whom cholecystectomy is planned. For the majority of patients with suspected biliary pancreatitis, bile duct stones have passed by the time cholangiography is performed. ERCP can be deferred and any remaining ductal stones can be identified at intraoperative cholangiography during laparoscopic cholecystectomy. These stones can then be removed by postoperative or even intraoperative ERCP, or in those few centers with the appropriate expertise, by laparoscopic common bile duct exploration. If ERCP is unsuccessful, the patient can be referred to a tertiary endoscopy center where biliary access is virtually always possible.

Acute pancreatitis postcholecystectomy   

ERCP is appropriate in postcholecystectomy patients with suspected biliary pancreatitis, but in many of these patients the etiology is of a non-biliary stone etiology such as sphincter of Oddi dysfunction, a setting in which conventional diagnostic and therapeutic ERCP techniques can be highly risky [44,45], and protective measure such as placement of a pancreatic stent may be advisable [126,146].

Treatment by biliary sphincterotomy alone?   

Empirical biliary sphincterotomy for suspected biliary pancreatitis may be appropriate in certain settings without cholecystectomy, especially in elderly patients who are not good candidates for surgery due to severe medical comorbidity [38,94,133,158,167]. Under these circumstances, biliary sphincterotomy is sometimes performed in the absence of demonstration of a definite bile duct stone or as a semidefinitive treatment in lieu of cholecystectomy. Several studies have suggested effectiveness of endoscopic biliary sphincterotomy in preventing future episodes of acute biliary pancreatitis [58]. These uncontrolled case series mostly suggest a reduction in the frequency of pancreatitis attacks, although recurrent bile duct stones and cholecystitis may be problematic [62]. Caution must be applied to patients who might have other etiologies. Empirical biliary sphincterotomy in patients with recurrent pancreatitis and mildly abnormal enzymes may in fact be due to sphincter of Oddi dysfunction, especially in women, younger to middle-aged patients, and those who are postcholecystectomy or do not have clearly documented gallstone disease. Empirical biliary sphincterotomy and even diagnostic ERCP in this setting may be quite hazardous [44,45] and less likely to be of benefit.

 Pancreatic duct disruptions   

Acute disruptions of the main pancreatic duct or side branches may occur during acute pancreatitis of various etiologies such as gallstones or alcohol, or may be the primary mechanism of pancreatitis in cases such as trauma. These disruptions may result in localized fluid collections, pseudocysts, ascites, or pancreatico-pleural or cutaneous fistulas.

Stenting for duct disruption   

ERCP with transpapillary pancreatic duct stenting has been described as an effective technique to close pancreatic duct disruptions in a variety of settings in acute and chronic pancreatitis [74,77,155] (Figs 5 and 6). Unlike for biliary strictures, it may often be necessary to bridge the main pancreatic duct beyond the point of disruption with a stent in order to obtain closure of a pancreatic duct leak, especially if there is a small-caliber, diseased, or strictured pancreatic duct.

Kozarek and colleagues from Seattle have reported use of transpapillary pancreatic duct stenting in evolving acute necrosis or complicated pancreatitis [73]. They have pursued a theory that main pancreatic ductal disruption is integral to the pathophysiology of acute pancreatic necrosis, and suggested that transpapillary pancreatic stenting might be beneficial in the course of this difficult group of patients by relieving downstream obstruction and thus reducing complications. In patients with pancreatic necrosis in various stages of evolution at the time of transfer to their institution, this group reported a management strategy including ERCP, with findings of main pancreatic duct disruptions in two-thirds of patients that were treated with transpapillary pancreatic stent plus/minus biliary sphincterotomy. In general, organized necrosis or fluid collections were drained separately by surgical, percutaneous, or endoscopic routes. They reported a very low mortality in this case series of over 100 patients. Although an intriguing concept, this approach deserves further study in a randomized controlled trial. Special concerns with performance of ERCP in the setting of acute necrosis include the risk of introducing infection into otherwise sterile pancreatic necrosis and/or fluid collections.

 Smoldering pancreatitis   

Rapid resolution of persistent smoldering pancreatitis without associated pancreatic duct disruption has been reported to occur with placement of a transpapillary stent. We and others have also found this quite effective in patients with a prolonged course of smoldering pancreatitis that persists for 2 to 3 weeks or more, with pain and hyperamylasemia despite fasting and total parenteral nutrition, and often without significant pancreatic injury evident by CT scan. Regardless of the etiology of pancreatitis, placement of a transpapillary stent can often interrupt and hasten resolution of the process [66,67]. There are limited data supporting this approach, with no randomized controlled trials.

 Acute recurrent pancreatitis   

Acute recurrent pancreatitis is most commonly the result of alcohol or gallstone disease. Other etiologies include medications such as azathioprine, tetracycline, or estrogens [148,156,157]. Metabolic causes such as severe hypertriglyceridemia [152] or hypercalcemia may be revealed by laboratory investigation.

'Idiopathic' pancreatitis   

Some 10–30% of patients with acute recurrent pancreatitis may have no etiology apparent by history, laboratory, and non-invasive imaging studies such as computed tomography or ultrasound. Such patients are often labeled as having 'idiopathic' pancreatitis. 'Unexplained acute pancreatitis' and 'unexplained acute recurrent pancreatitis' are more appropriate terms, reserving the label 'idiopathic' for pancreatitis whose etiology remains unidentified after a truly exhaustive and advanced evaluation. Advanced diagnostic investigation may reveal etiologies such as microlithiasis, sphincter of Oddi dysfunction, congenital anomalies such as pancreas divisum, annular pancreas, intraductal papillary mucinous neoplasia, occult malignancy, idiopathic chronic pancreatitis with ductal pathology such as stones or strictures, or anatomical causes such as choledochocele. Only the remainder with normal pancreaticobiliary anatomy and no other etiology are appropriately labeled as 'idiopathic'.

Microlithiasis and occult gallstones   

Microlithiasis, biliary sludge, and occult gallstones are part of a spectrum of biliary disorders that may cause acute recurrent pancreatitis. The perceived prevalence of these disorders as a cause for recurrent pancreatitis, and the appropriate strategy for diagnosis and therapy are the matter of some debate [59,84,140]. Patients with microlithiasis as a cause of pancreatitis usually have an intact gallbladder, and may or may not have associated abnormalities in liver chemistries. The best known study linking biliary sludge to recurrent pancreatitis included many patients with fairly suggestive evidence of a biliary cause such as visible sludge at ultrasonography, or abnormal liver chemistries, and thus included patients whose pancreatitis would not be considered as 'unexplained' or 'idiopathic' in most centers [84].

Detecting microlithiasis   

Imaging techniques such as transcutaneous ultrasound may reveal layering sludge in the gallbladder or be entirely normal. Alternative diagnostic strategies include endoscopic ultrasound, which may be more sensitive for subtle gallbladder stone disease than transcutaneous ultrasound [32,34,92,144], and analysis of bile for crystals.

Bile crystals   

Bile analysis may be performed directly on the bile duct aspirates via retrograde cannulation at ERCP [49], ideally after gallbladder contraction is induced with cholecystokinin, or on duodenal bile collected by tube or endoscopy after gallbladder contraction is induced [98]. Bile is analyzed by a polarizing microscope for the presence of crystals. Problems with bile analysis include (1) interobserver variation in technique and interpretation of analysis; (2) sensitivity and specificity of microscopic analysis for detecting biliary stone disease [95]; and (3) uncertain correlation between findings of bile abnormalities and response to therapeutic intervention such as cholecystectomy or biliary sphincterotomy [115]. In general, crystal analysis has been found to be of limited value with a very low prevalence after cholecystectomy [69,106]. Treatment of microlithiasis as a cause for acute pancreatitis can include cholecystectomy, endoscopic biliary sphincterotomy, or ursodeoxycholic acid [84,110].

Empiric cholecystectomy?   

In the patient with unexplained acute pancreatitis and intact gallbladder, it may be more prudent to consider empiric laparoscopic cholecystectomy rather than subjecting the patient to a potentially risky ERCP just to perform bile analysis of unclear predictive value. In patients who are postcholecystectomy, the low probability of a positive finding and high risk of performing ERCP just to make this diagnosis make the practice of bile analysis questionable. Other less invasive diagnostic modalities such as EUS or MRCP may be indicated prior to considering cholecystectomy as diagnosis of occult tumors may otherwise be delayed.

Sphincter of Oddi dysfunction (SOD)   

Sphincter of Oddi dysfunction is thought by many to be an important cause of acute recurrent pancreatitis, accounting for up to one-third of otherwise unexplained cases [86,89]. Approaches to suspected sphincter of Oddi dysfunction vary widely and are the subject of much controversy. This disorder is most often suspected as a cause of recurrent pancreatitis in women who are postcholecystectomy, often with relatively mild pancreatitis and intermittent or continuous abdominal pain between overt attacks of pancreatitis.

Diagnosis of SOD   

The diagnosis is generally based on findings of an abnormal sphincter of Oddi manometry with a basal pressure of greater than 40 mmHg [48,63,80]. A number of studies have demonstrated the discordance of manometric findings between the biliary and pancreatic sphincters, and thus stress the importance of assessing both sphincters [39,47,128,135] (Fig. 7).

Endoscopic therapy for SOD   

Although the traditional approach has been to perform biliary sphincterotomy or other biliary therapy to treat recurrent pancreatitis or other symptoms of sphincter of Oddi dysfunction [23,50,96,109,153,154,166], recent data suggest that combined pancreatic as well as biliary sphincterotomy, whether performed simultaneously (Fig. 8) or sequentially (Fig. 9), is optimal to treat patients who have concomitant pancreatic sphincter hypertension [57]. The desired result is a 'septotomy' in which a 'double-barrel' appearance of the biliary and pancreatic sphincters is achieved (Fig. 10). In one study, biliary sphincterotomy alone resulted in improvement in only 25% of patients; in contrast, either sequential biliary and pancreatic sphincterotomy (78% response) or simultaneous dual sphincterotomy (82% response) resulted in significantly better outcomes [57].

Sphincterotomy without sphincter manometry?   

Some centers avoid sphincter of Oddi manometry or pancreatic endotherapy in these patients, advocating empiric biliary sphincterotomy [140,149] or alternative diagnostic tests such as quantitative scintigraphy [68], fatty-meal sonography, or secretin-stimulated assessment of pancreatic duct dilation [33] instead.

Is sphincter manometry dangerous?   

This is based in part on the assumption that sphincter of Oddi manometry is the principal danger, and that merely avoiding this investigation will reduce risk [29]. The risk of any type of ERCP in these types of patients (women with recurrent abdominal pain and normal serum bilirubin) cannot be overemphasized; recent prospective multicenter multivariate studies [44,45] have shown clearly that diagnostic ERCP or empiric biliary sphincterotomy carries substantial risk of pancreatitis (approximately 20% or higher), including the majority of severe and necrotizing cases. Newer techniques of aspirated sphincter manometry have been shown to add little or no independent risk to ERCP (127). Importantly, placement of a transpapillary pancreatic stent significantly reduces risk of pancreatitis in patients with sphincter of Oddi dysfunction (from 27% to 7% in one randomized controlled trial) [145], and virtually eliminates the risk of severe post-ERCP pancreatitis (Fig. 11). Recent data suggest that in patients with suspected sphincter of Oddi dysfunction, pancreaticobiliary manometry followed by combined pancreaticobiliary therapy that includes a pancreatic stent is actually safer than simple biliary sphincterotomy [125]. Prophylactic pancreatic stenting is now done routinely in many centers after pancreatic investigation in these types of patients [122,126]. Placement of pancreatic stents can range from technically easy (Fig. 12) to very challenging (Fig. 13) depending on pancreatic ductal anatomy and expertise. Pancreatic stents have potential to cause damage, especially to normal ducts [75,132,138] (Fig. 14) and should be removed within 10–14 days from normal ducts.

The trend is now to use smaller stents (3 or 4 French) compared with traditional larger (5–7 French) stents, because they are thought to cause less ductal injury and lower post-ERCP pancreatitis rates. Many centers now use longer 3FG stents (8-12cm long), without any internal flaps; most of these pass spontaneously in 1-3 weeks, and a simple abdominal radiograph is taken to confirm. This confers the same protection against pancreatitis, and removes the need for a second procedure in most cases. Short (2cm) straight stents may still be necessary for the 15% of patients with very tortuous small-caliber ducts, in whom passage of a guidewire to the tail may be difficult or impossible.

Without any type of pancreatic stent, however, available data suggest that the risk of empiric biliary sphincterotomy for suspected sphincter of Oddi dysfunction (about 25% pancreatitis) is about equal to its efficacy (approximately 25%).

SOD in patients with intact gallbladders   

Whether sphincter of Oddi dysfunction should be suspected in patients with intact gallbladder is contentious. We generally recommend empiric cholecystectomy in most cases prior to investigation for sphincter of Oddi dysfunction as a cause for recurrent pancreatitis.

Pancreas divisum   

Pancreas divisum is the most common congenital anomaly of the pancreas and may be present in up to 5% of the general population [61] (Figs 15 and 16). The diagnosis of pancreas divisum can be made by ERCP, MRCP [8,18], or endoscopic ultrasound [10] demonstrating a small or absent ventral pancreatic duct draining into the major papilla that does not communicate with the dorsal duct draining entirely through the minor papilla. In patients with symptomatic pancreas divisum, the dorsal duct may be normal, dilated, or may contain evidence of chronic pancreatitis including dorsal duct pancreatic stones (Fig. 17a–c). Partial or vestigial communication between dorsal and ventral pancreatic ducts is called 'incomplete pancreas divisum' and behaves functionally similar to complete pancreas divisum [65]. Findings of apparent pancreas divisum at MRCP or ERCP can be mimicked by small tumors or strictures at the junction of the ducts of Wirsung and Santorini in patients with otherwise normal pancreatic ductal anatomy (see section on neoplastic disorders).

Does pancreas divisum cause pancreatitis?   

There has been some controversy about whether pancreas divisum is an innocent bystander or a cause of acute recurrent pancreatitis. The preponderance of evidence suggests that the dorsal duct outflow obstruction at the minor papilla can be the etiology of acute and chronic pancreatitis [5,9,163]. Evidence includes: an increased prevalence of pancreas divisum in patients with pancreatitis, the findings at autopsy of chronic pancreatitis isolated to the dorsal pancreas in patients with pancreas divisum, and data suggesting improved outcomes in patients undergoing minor papilla drainage procedures, either endoscopic or surgical [15,16,70,87,107]. Evidence for efficacy of endoscopic therapy includes a number of case series [27,28,37,88,90,139] and one randomized controlled trial [82] indicating improvement in frequency and severity of attacks after minor papillotomy and/or stenting.

Endoscopic treatment for pancreas divisum   

Endoscopic therapy for symptomatic pancreas divisum consists of minor papilla sphincterotomy plus/minus dorsal duct pancreatic stenting or stone extraction [78](Figs 18–20). Evidence suggests that results of minor papilla therapy for pancreas divisum are best in patients with acute recurrent pancreatitis, with improvement seen in about 80% of patients (Fig. 21). In the sole randomized controlled trial of dorsal duct therapy for pancreas divisum, improvement was seen in 90% of treated patients vs. 11% of controls with reduction in hospitalizations for acute pancreatitis over 12-month follow-up. Pain response is less evident in patients with chronic pancreatitis, with response rates of 40–50%. Whether or not there is any role for dorsal duct endotherapy in patients with pancreas divisum and pain only without evidence of pancreatic disease is controversial, but most series suggest responses of 20–30%, rates which may be no better than placebo. In one study, secretin-stimulated dilation of the dorsal pancreatic duct by endoscopic ultrasound predicted favorable outcome to minor papilla therapy, a concept that deserves further scrutiny and corroboration [21].

Minor papilla therapy for pancreas divisum usually includes minor papilla sphincterotomy, which can be either performed after placement of a pancreatic stent using a needle knife (Fig. 18), or using a conventional traction sphincterotome (Figs 19–20). Many endoscopists including this author now favor use of a wire-guided traction sphincterotome in most cases, as it assists with gauging the optimal extent and depth of the minor papilla sphincter incision. Eversion of the sphincter with a partially bowed papillotome may allow assessment of the length of the remaining sphincter segment.

Stenting for pancreas divisum   

A few centers advocate long-term pancreatic duct stenting; however, in the presence of a normal dorsal pancreatic duct there is substantial risk of inducing pancreatic duct strictures or irregularities (up to 70% in one series). Most authorities recommend minor papillotomy with only short-term stenting, less than 2 weeks in most cases. Exceptions are presence of a pancreatic duct stricture or a pancreatic duct stone in association with pancreas divisum (Fig. 17c), in which case longer-term stenting and/or adjunctive methods such as extracorporeal shock-wave lithotripsy may be necessary.

Problems with endoscopic therapy   

Major problems with dorsal duct therapy for pancreas divisum include technical difficulty, complications including post-ERCP pancreatitis, and restenosis of the minor papillotomy.

Chronic pancreatitis (idiopathic, alcohol, familial, other)   

A relatively common finding in patients with acute recurrent pancreatitis is unsuspected chronic pancreatitis (Figs 21–25). Such patients may or may not have a history of alcohol abuse or family history of pancreatitis [102] and may have a normal or non-specific CT scan, but further investigation including endoscopic ultrasound may reveal moderate to severe chronic pancreatitis with normal-caliber or minimally dilated main pancreatic ducts, often with small intraductal stones and/or strictures [19,22,42,116,142,170]. The role of genetic abnormalities such as CFTR mutations and cationic trypsinogen gene mutations has been explored in the pathogenesis of idiopathic chronic and hereditary pancreatitis [24–26,53,123,168,169], but is of uncertain practical value in the management of patients with unexplained pancreatitis at present.

Endoscopic therapy for chronic pancreatitis   

Pancreatic ductal abnormalities are often amenable to endoscopic therapy in the form of pancreatic sphincterotomy, pancreatic stone extraction with or without extracorporeal shock-wave lithotripsy, and/or stricture dilation with stenting [12,30,36,76,79,104,136,137]. Figures 21–25 show examples of endoscopic therapy in patients with acute relapsing pancreatitis due to chronic pancreatitis with intraductal stones or strictures of etiologies ranging from idiopathic (Fig. 22) to familial (Figs 23–24) to former alcohol abuse (Fig. 25).

Pancreatitis due to neoplastic obstruction   

One of the most important and easily missed etiologies of unexplained acute pancreatitis is occult neoplastic disease. Ampullary tumors and larger solid and cystic pancreatic tumors are usually diagnosable by conventional techniques including ERCP [3,105,118,120,121,131,134,160,171]. However, CT scan, MRI, and diagnostic ERCP all are of limited value in identification of small (less than 2 cm) solid tumors of the pancreas, such as pancreatic ductal adenocarcinoma, islet cell, or other neuroendocrine tumors, and for diagnosis of early or side-branch variants of intraductal or papillary mucinous tumors of the pancreas [1,85]. Endosonography can be essential to diagnose these tumors [101,111–113,171] (Fig. 26). In our center's series of 102 patients with unexplained acute pancreatitis, none of whom had a mass on CT scan, 15 were diagnosed definitively to have occult neoplasms by linear-array endoscopic ultrasound with fine-needle aspiration; 9 could not be diagnosed by any other technique including CT or ERCP [119](Figs 27–28). The majority (8 of 10) were found to be resectable at time of surgery.

Endoscopic management of neoplastic obstruction   

There is a role for ERCP in the palliation of acute pancreatitis in certain patients with obstructing pancreatic neoplasms. In patients with recurrent pancreatitis due to obstructing ampullary adenomas, or poor surgical candidates with ampullary carcinomas, endoscopic snare ampullectomy, often in combination with ablative thermal therapy such as argon plasma or bipolar coagulation, is a reasonable method to achieve palliation or cure of the underlying lesion [11,64,81,103,108]. The technique of ampullectomy increasingly includes pancreatic sphincterotomy and placement of a pancreatic stent to reduce risk of both immediate and relapsing pancreatitis, which can otherwise be substantial [64]. There may be also a role for pancreatic sphincterotomy to palliate acute recurrent pancreatitis by preventing mucin impaction in patients with mucin-secreting tumors (IPMT) who are not surgical candidates.

Stenting for smoldering pancreatitis due to malignancy   

Some patients with pancreatic ductal adenocarcinoma or other solid tumors obstructing the pancreatic duct may present with acute or smoldering pancreatitis. ERCP in such cases often demonstrates a focal stricture with upstream dilation. In such patients, placement of a transpapillary stent through the pancreatic stricture may often interrupt or resolve the pancreatitis, either as a preoperative maneuver or as definitive palliation [150](Fig. 29). In selected patients with unresectable pancreatic neoplasms and smoldering or acute pancreatitis, we have placed self-expanding metallic stents through pancreatic strictures for more long-term palliation (Fig. 30).

Choledochocele   

Cystic dilation of the intramural segment of the distal pancreaticobiliary segment is called a choledochocele (type III choledochal cyst). These may range in size from a few millimeters to several centimeters and may herniate in the duodenum. These may be associated with both pancreatic and biliary obstruction and may cause acute recurrent pancreatitis [51,54,60,93,100,147,161]. Although biliary sphincterotomy is classically thought to be definitive treatment for these, a substantial number of these patients eventually require pancreatic as well as biliary sphincterotomy for long-term palliation.

Other rare causes of pancreatitis   

Other miscellaneous conditions such as annular pancreas [35,56,91], anomalous pancreaticobiliary junction [72], or pancreatic intraductal parasites have been reported to cause acute or recurrent pancreatitis. These may be diagnosed by EUS, MRCP, or ERCP and may sometimes be amenable to endoscopic intervention.

 Overall approach to unexplained acute pancreatitis   

The approach to unexplained acute or recurrent pancreatitis varies widely among centers and is the subject of substantial controversy [151]. Recommended approaches for endoscopy vary from treatment based on analysis of bile for crystals, to empiric cholecystectomy, to ERCP with empiric biliary sphincterotomy [140], to ERCP with performance of sphincter of Oddi manometry focused on the biliary sphincter segment, to sphincter of Oddi manometry focused on the pancreatic sphincter segment. The use of alternative imaging techniques such as MRCP [7,8,17,130,141,159] and endoscopic ultrasound in evaluating unexplained pancreatitis varies widely, often related more to local expertise and bias rather than data. Therapeutic focus at some centers is focused primarily at suspected biliary causes (either by cholecystectomy or endoscopic biliary sphincterotomy), while in most advanced centers the focus of diagnosis and treatment is usually to identify and correct pancreatic sphincter or ductal abnormalities. Many advanced centers have evolved to the opinion that in most cases of recurrent pancreatitis, the problem lies in the pancreas itself and not in biliary tract.

Concerns about ERCP and empiric sphincterotomy in recurrent acute pancreatitis   

ERCP is often overused as a diagnostic and empiric biliary therapeutic modality in unexplained acute pancreatitis, potentially exposing the patient to unnecessary risk for a limited therapeutic benefit. Systematic evaluation with multiple imaging techniques, especially EUS and secretin-enhanced MRCP, provides more useful anatomic information, particularly regarding occult tumors, chronic pancreatitis [22], occult biliary stone disease, and pancreas divisum, and in some cases eliminates the need for ERCP entirely [7,8]. In particular, the appropriateness of diagnostic ERCP and empiric biliary sphincterotomy for findings of normal ductal anatomy to treat presumed microlithiasis or sphincter of Oddi dysfunction, which is advocated even at some advanced centers, may be questioned.

Risks of ERCP   

Available data suggest that performance of empiric biliary sphincterotomy without pancreatic stenting incurs a risk of post-ERCP pancreatitis (20% in one multicenter study [44], including a 3–4% rate of severe pancreatitis) that may equal the chance of curing the underlying cause of pancreatitis (25% in the series of Guelrud). This risk may be even higher in patients with possible sphincter of Oddi dysfunction and small ducts [129]. Enduring but unsubstantiated beliefs are that diagnostic ERCP is safe—in fact the risk is as high as for therapeutic ERCP—and that sphincter of Oddi manometry is the primary culprit. In fact, two recent multivariate analyses have shown that SO manometry utilizing the aspirating catheter in the pancreas adds no independent risk to ERCP [44,45]. Rather, it is the patient profile (female, recurrent abdominal pain, and absence of jaundice or advanced chronic pancreatitis) that places the patient at higher risk of any ERCP. Paradoxically, centers performing SO manometry often have lower pancreatitis rates after ERCP in these patients than referring community centers [44], probably because of widespread use of pancreatic stents, which have been shown to significantly reduce risk of post-ERCP pancreatitis in patients with SO dysfunction (Fig. 11). Given the risk of diagnostic ERCP in these types of patients, ERCP merely for the purpose of collecting bile for crystal analysis in patients with intact gallbladders and recurrent pancreatitis seems questionable; performance of empiric cholecystectomy is probably safer and more definitive.

Investigations other than ERCP   

Prior to considering ERCP for unexplained acute pancreatitis, we and others use a systematic approach including advanced imaging techniques such as EUS in most cases (Fig. 26). Initial evaluation of acute pancreatitis includes a detailed history regarding alcohol, medications, family history, and laboratory evaluation including liver chemistries, and amylase, lipase, triglyceride, and calcium levels. Initial imaging studies should include transabdominal ultrasound, often repeated at least once if the initial study is negative, and abdominal CT scan.

MRCP   

Magnetic resonance cholangiopancreatography [7,8] is quite useful as it can fairly reliably establish the anatomy of the bile and pancreatic ducts, identify pancreas divisum or pancreatic ductal strictures, diagnose bile duct stones, and image pancreatic or biliary duct dilation. Secretin administration not only improves imaging of the pancreatic duct, but may also provide functional information about presence and severity of outflow obstruction at the level of the sphincter or stricture. Advantages of MRCP include non-invasiveness and increasingly wide availability. MRCP is contraindicated in patients with pacemakers or cerebral aneurysm clips. Sensitivity and specificity of MRCP for detection of small bile duct stones or microlithiasis, for small pancreatic tumors, and for pancreas divisum is limited, as MRCP cannot differentiate true divisum from 'pseudodivisum' due to a small obstructing pancreatic stone or tumor (Figs 27–28).

EUS   

Endoscopic ultrasound is increasingly utilized, and in our opinion is the procedure of choice, for the initial evaluation of unexplained acute pancreatitis [9,22,32,34,46,92,116,144] (Fig. 26). Linear-array endoscopic ultrasound can detect occult biliary tract disease, such as gallstones, biliary sludge, or occult common bile duct stones. It is the method of choice for diagnosing occult pancreatic tumors including neuroendocrine tumors and IPMT as well as small adenocarcinomas, with the advantage of tissue diagnosis via fine-needle aspirate. EUS is probably the most sensitive test for chronic pancreatitis and can identify intraductal pancreatic stones that may be missed by CT or even ERCP [19,22,116]. EUS is potentially accurate in the diagnosis of pancreas divisum and other congenital anomalies. Finally, EUS is useful for identification of rare extra-pancreatic disorders that may mimic acute pancreatitis with abdominal pain and mild hyperamylasemia, such as intravascular tumors. EUS carries minimal risk when compared to ERCP. A completely normal high-quality endoscopic ultrasound essentially limits the diagnostic yield of ERCP to sphincter of Oddi dysfunction or microlithiasis. Limitations of EUS are primarily that there are relatively few endoscopists trained in its use.

Recommended approach to ERCP for acute recurrent pancreatitis   

ERCP for acute recurrent pancreatitis at our center, and many others, is reserved for directed therapy if alternative advanced investigations reveal an anatomic cause, or for sphincter of Oddi manometry if the anatomy appears to be normal. If the pancreaticobiliary anatomy is normal by EUS or MRCP, and the gallbladder is intact, we generally recommend empiric cholecystectomy in reasonable surgical candidates. In patients with apparently normal pancreaticobiliary anatomy who are postcholecystectomy or who are poor surgical candidates for cholecystectomy, we proceed with ERCP with sphincter of Oddi manometry with the primary goal of assessing for pancreatic sphincter hypertension, as increasing data and experience suggest that response to dual sphincterotomy (pancreatic plus biliary) is substantially better than that for biliary sphincterotomy alone. Empiric biliary sphincterotomy may be a reasonable but unproven treatment in patients with normal SO manometry who are suspected of microlithiasis. However, we recommend placement of a short-term pancreatic stent to reduce risk of post-ERCP pancreatitis in this high-risk subgroup of patients with normal pancreaticobiliary ductal anatomy and recurrent pancreatitis (Figs 11–14).

Because of the risk of performing ERCP, most authors recommend performance of ERCP only after two attacks of unexplained pancreatitis, unless the first is severe [3,55]. This dilemma can be circumvented by performing EUS after any unexplained episode of pancreatitis. ERCP is either unnecessary or postponed until a second attack occurs in the majority of cases.

Final diagnosis in recurrent acute pancreatitis after extensive investigation   

Final diagnoses in series of unexplained acute pancreatitis are highly variable, depending on the patient population, number of patients with intact gallbladders, methods used to evaluate the patients, and thoroughness of evaluation [89,146,162].

Our experience   

In most series, less than 20% of patients remain 'idiopathic' after extensive investigation. Results of endoscopic and other therapies are also variable depending on those factors and types of therapy performed. In our series of 102 patients with unexplained acute pancreatitis over a 5-year period, only 8% of patients remained truly 'idiopathic' after extensive investigation. Diagnosis was made uniquely by ERCP in 66%, uniquely by endoscopic ultrasound in 21%, uniquely by MRCP in 0%, and uniquely at surgery in 6% [119]. Diagnoses were sphincter of Oddi dysfunction in 28% (mostly treated with combined pancreatic and biliary sphincterotomy), anatomic causes in 23% (including primarily idiopathic chronic pancreatitis with endoscopically treatable findings such as main pancreatic duct stone or stricture in the majority), and pancreas divisum in 16%. Occult biliary stone disease was found in only 6%.

Occult neoplasms   

Of great importance was that occult neoplasms were found in 15% of our patients and included six adenocarcinomas, six intraductal papillary mucinous tumors of the pancreas, one islet cell tumor, and two ampullary tumors. All had CT scans that were normal or showed non-specific pancreatic duct dilation, and 9 out of 15 of these tumors were diagnosable (i.e. with positive cytology) only by linear array EUS and not by ERCP. Eight of 10 of these patients who were surgically explored were successfully resected.

Endoscopic treatment and results   

Endoscopic therapy was performed in 76% of all patients, but consisted of biliary sphincterotomy alone in only 18, with the remaining 59 patients requiring advanced pancreatic endotherapic techniques including pancreatic sphincterotomy, pancreatic stenting, pancreatic stone extraction with or without extracorporeal shock-wave lithotripsy, endoscopic ampullectomy including a pancreatic sphincterotomy and stent, transpapillary and/or transmural pseudocyst drainage [13,20,31], etc. Overall long-term outcomes were good with 88% long-term improvement after endoscopic therapy, similar in all major diagnostic groups. The impression from our data was that EUS is the most appropriate first test for unexplained pancreatitis, and that endoscopic diagnosis and therapy must be focused primarily on the pancreas itself, with a limited role for purely biliary diagnosis and treatment. The ultimate inference is that unexplained acute pancreatitis is best evaluated and treated at advanced centers with capability to perform advanced EUS and pancreatic ERCP techniques, as well as perform complex pancreaticobiliary surgery. Standard diagnostic and therapeutic ERCP for acute recurrent pancreatitis using conventional biliary techniques has limited benefit and significant risk, and should probably be avoided.

 Outstanding issues and future trends   

There are many issues that demand further clinical investigation, and further techniques that need to be developed with respect to ERCP in acute pancreatitis. A substantial body of prospective data exists only for ERCP in acute biliary pancreatitis. There is much controversy and a paucity of data regarding endoscopic therapy in other settings, such as pancreas divisum, and especially the role of pancreatic sphincterotomy in treatment of sphincter of Oddi dysfunction. Future studies will hopefully clarify these murky areas. The importance of pancreatic duct disruption and the need for endoscopic therapy in pancreatic necrosis need further evaluation. Evolution of strategies to evaluate and treat acute and relapsing pancreatitis will increasingly emphasize diagnosis and prediction of need for endoscopic therapy using less invasive imaging techniques such as endoscopic ultrasound and MRCP. Secretin-stimulated EUS and MRCP will play an increasingly important role in diagnosing the cause of pancreatitis, and in assessing the functional significance of duct obstruction. ERCP will hopefully then be relegated to a purely therapeutic modality in patients who are highly likely to benefit from directed endoscopic therapy. Further development of pancreatic stent technology should allow increased safety. Collaboration with laparoscopic surgery and other disciplines will open new areas for minimally invasive treatment of pancreatic disease. Finally, new techniques to achieve sphincter ablation and stricture dilation may borrow from existing technology in minimally invasive surgery and vascular interventional radiology and cardiology.

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