Endoscopy plays an important role in both the diagnosis and the initial management of recurrent acute pancreatitis, as well as the investigation of refractory disease, but it has known limitations and risks. Sound selective use of these therapies, complemented with other lines of investigation such as genetic testing, can dramatically improve frequency of attacks and associated quality of life. Whether endoscopic therapy can reduce progression to chronic pancreatitis, or reduce the risk of malignancy, is debatable, and remains to be proven.
Key points
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Endoscopy plays an important role in both the diagnosis and the initial management of recurrent acute pancreatitis, as well as the investigation of refractory disease, but it has known limitations and risks.
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Sound selective use of these therapies, complemented with other lines of investigation such as genetic testing, can dramatically improve frequency of attacks and associated quality of life.
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Whether endoscopic therapy can reduce progression to chronic pancreatitis, or reduce the risk of malignancy, is debatable, and remains to be proven.
Introduction
Acute pancreatitis (AP) is a common disease, affecting 17 per 100,000 persons per year in the United States alone. Eighty percent of cases are uncomplicated and self-limited, whereby patients are expected to have a complete symptomatic and pathologic recovery. On the other hand, approximately 20% will go on to have subsequent attacks, which are described as recurrent acute pancreatitis (RAP), which is primarily dependent on whether the underlying cause is able to be treated or removed. Although there is no formally agreed on definition, RAP is generally considered as 2 or more episodes of AP with or without complete or near-complete resolution of symptoms between episodes. Occasionally, patients are labeled as having RAP but are not truly documented as meeting the standard definition of having admissions for bone fide pancreatitis as defined by 2 of 3 of the following: compatible pain, lipase and/or amylase more than 3 times normal, and/or imaging as supporting evidence. Patients with only mild pancreatic enzyme elevations are better labeled as such—pain and hyperenzymemia of unclear significance. Before embarking on many of the expensive and/or invasive studies discussed in this article, it is important to ensure that one or more of the patient’s pain admissions were, in fact, AP. Perhaps, however, abdominal pain only without documented pancreatitis is not a focus of this review for idiopathic RAP (IRAP). Certainly Sphincter of Oddi dysfunction (SOD) is a consideration in these patients and the ddx does overlap with that of IRAP, which also includes divisum, but the efficacy of sphincter of Oddi manometry (SOM)-guided sphincter treatment and minor papillotomy is less painful only in population without objective pathology.
The natural history of RAP is incompletely understood, with most data coming from population studies showing a 25% to 45% recurrence in alcohol-related AP. Although only about 10% of individual AP attacks in RAP are severe, cumulative morbidity and mortality, as well as health care- and quality of life–related costs are substantial. Most AP is due to gallstones or excessive alcohol; right upper quadrant ultrasound and a thorough history of alcohol use (past, present, and binge) are standard first-line investigations. Abstinence of alcohol significantly reduces the recurrence of alcohol-related pancreatitis, and cholecystectomy is effective at preventing recurrent biliary pancreatitis, thereby addressing the 2 most common causes of RAP. Smoking is a newly recognized risk factor, but the effect of smoking cessation on outcomes is not clear; it should lower the risk of chronic pancreatitis and cancer at the least. Despite a thorough history, routine laboratory evaluation, and routine biliary/pancreatic imaging, 30% of RAP remains unexplained and is referred to as idiopathic (IRAP).
Introduction
Acute pancreatitis (AP) is a common disease, affecting 17 per 100,000 persons per year in the United States alone. Eighty percent of cases are uncomplicated and self-limited, whereby patients are expected to have a complete symptomatic and pathologic recovery. On the other hand, approximately 20% will go on to have subsequent attacks, which are described as recurrent acute pancreatitis (RAP), which is primarily dependent on whether the underlying cause is able to be treated or removed. Although there is no formally agreed on definition, RAP is generally considered as 2 or more episodes of AP with or without complete or near-complete resolution of symptoms between episodes. Occasionally, patients are labeled as having RAP but are not truly documented as meeting the standard definition of having admissions for bone fide pancreatitis as defined by 2 of 3 of the following: compatible pain, lipase and/or amylase more than 3 times normal, and/or imaging as supporting evidence. Patients with only mild pancreatic enzyme elevations are better labeled as such—pain and hyperenzymemia of unclear significance. Before embarking on many of the expensive and/or invasive studies discussed in this article, it is important to ensure that one or more of the patient’s pain admissions were, in fact, AP. Perhaps, however, abdominal pain only without documented pancreatitis is not a focus of this review for idiopathic RAP (IRAP). Certainly Sphincter of Oddi dysfunction (SOD) is a consideration in these patients and the ddx does overlap with that of IRAP, which also includes divisum, but the efficacy of sphincter of Oddi manometry (SOM)-guided sphincter treatment and minor papillotomy is less painful only in population without objective pathology.
The natural history of RAP is incompletely understood, with most data coming from population studies showing a 25% to 45% recurrence in alcohol-related AP. Although only about 10% of individual AP attacks in RAP are severe, cumulative morbidity and mortality, as well as health care- and quality of life–related costs are substantial. Most AP is due to gallstones or excessive alcohol; right upper quadrant ultrasound and a thorough history of alcohol use (past, present, and binge) are standard first-line investigations. Abstinence of alcohol significantly reduces the recurrence of alcohol-related pancreatitis, and cholecystectomy is effective at preventing recurrent biliary pancreatitis, thereby addressing the 2 most common causes of RAP. Smoking is a newly recognized risk factor, but the effect of smoking cessation on outcomes is not clear; it should lower the risk of chronic pancreatitis and cancer at the least. Despite a thorough history, routine laboratory evaluation, and routine biliary/pancreatic imaging, 30% of RAP remains unexplained and is referred to as idiopathic (IRAP).
Defining and studying IRAP
The incidence, natural history, and treatment of IRAP have been difficult to study because there has been some lack of consensus on a definition of “idiopathic.” There are several diagnostic studies to investigate the remaining 30%, ranging from bile crystal analysis, pancreatic function testing, genetic testing for mutations associated with pancreatitis (secretin-stimulated), magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), ± secretin or elastography, and endoscopic retrograde cholangiopancreatography (ERCP) with SOM. Several of these investigations are invasive and are associated with morbidity, such as post-ERCP pancreatitis, and many are not readily available outside of tertiary care facilities; bile crystal analysis is done poorly and with inconsistent methods even in tertiary facilities and the relevance of microlithiasis is questionable, because of variability in interpretation and the small size of related studies. The thresholds for alcohol intake and triglyceride levels to be deemed relevant can be variable. SOD as defined by SOM, findings suggestive of minimal change chronic pancreatitis, and presence of pancreas divisum (PD) are examples of findings that may simply be incidental; they play controversial roles as causes or explanations, and as such, they may or may not need to be “ruled out” before categorizing someone’s pancreatitis as “unexplained.”
For all of these reasons, studies evaluating endoscopic therapy in an IRAP population can involve a heterogeneous group. Furthermore, comparing studies from different institutions across different eras is problematic considering the changes to standard of care involved in setting the threshold of calling RAP “idiopathic.” In a large single-center series involving 1241 patients with RAP, Fischer and colleagues found that ERCP with SOM yielded a diagnosis in 65.8% of cases (40.8% SOD, 18.8% PD). Ninety-two percent of these cases were amenable to endoscopic therapy. However, the outcomes of intervention were not reported.
There is known overlap between RAP and chronic pancreatitis. It is likely that many patients in the alcoholic RAP studies who also had chronic pancreatitis actually were having flares of acute-on-chronic pancreatitis; although others may have begun with RAP, but accumulated damage, such that at the time of presentation, chronic pancreatitis changes were incidentally already present. This may also occur in young patients with presumed or proven genetic pancreatitis, and in other causes that are associated with both acute and chronic pancreatitis, such as hypertriglyceridemia. Using EUS to evaluate patients after a single episode of AP and those with RAP, Yusoff and colleagues found significantly more chronic pancreatitis (usually of the small-duct or “minimal change” variety) in the RAP group than in the single-attack group (21% vs 42%), and in patients with, and without, an intact gallbladder (16% vs 39%). For EUS, one must be careful not to assess for chronic pancreatitis too close to the last acute attack, because lingering acute changes may be misinterpreted as chronic pancreatitis changes. The outcomes of RAP patients with and without chronic pancreatitis likely differ, yet the extent to which chronic pancreatitis in these studies was excluded varies from the use of inclusion criteria requiring no advanced morphologic (ductal or parenchymal) changes on cross-sectional imaging, to requiring a normal ERCP, to requiring normal pancreatic exocrine function testing. Furthermore, a substantial number of patients with acute recurrent pancreatitis suffer substantial interval chronic pain between overt attacks, some with and some without morphologic evidence of chronic pancreatitis. Conversely, other patients with clinical presentation of only RAP without interval pain have obvious calcific chronic pancreatitis. Thus the distinction between RAP and chronic pancreatitis may be clear only at either extreme.
Recurrent pancreatitis with apparent or possible causes
Biliary (Gallstone) Pancreatitis
Gallstones cause one of the most common, and treatable, forms of AP, accounting for 50% to 70% of cases. Unlike most symptomatic choledocholithiasis with ongoing biliary obstruction in which a stone too large to pass through the sphincter of Oddi (SO) becomes lodged in the distal common bile duct, biliary pancreatitis is more likely to result from small stones that transiently obstruct the pancreas drainage at the SO before spontaneously passing—as such, even small stones and sludge are likely still relevant. The resultant edema/obstruction of the common channel presumably causes elevated intraductal pressure in the pancreas and/or reflux of bile into the duct leading to the activated enzymatic cascade of AP. Because most stones (80%) pass with the onset of the attack, the lack of imaging confirmation of a persistent bile duct stone after presentation cannot be considered as evidence against a biliary cause. RAP occurs very frequently (30%–90%) if cholelithiasis is present and the gallbladder is left in situ. Cholecystectomy reduces the risk of biliary RAP to about 10%; this figure suggests that cholecystectomy is effective in preventing recurrent attacks of pancreatitis, while at the same time illustrating that cholelithiasis may be incidental in a small proportion of patients with RAP.
After endoscopic sphincterotomy became available in the 1970s, it became recognized as an effective primary therapy to prevent recurrent biliary pancreatitis in older patients, those unfit for cholecystectomy, and those who declined surgery. Laparoscopic cholecystectomy was associated with a decline in this practice. Recurrence of biliary pancreatitis with in situ gallbladder following endoscopic sphincterotomy ranged from 2% to 6% (median follow-up ranged from 12 to 51 months). However, randomized trials have shown that unless life expectancy is less than a few years, laparoscopic cholecystectomy offers a lower rate of gallbladder-related biliary sepsis, even after biliary sphincterotomy. Contrary to the belief by some, occult choledocholithiasis as a cause of postcholecystectomy RAP is rare (0%, n = 57) and does not seem to justify empiric biliary sphincterotomy for presumed choledocholithiasis in the IRAP group, especially for those with normal or near-normal liver enzymes with their RAP attacks. Even when liver enzymes are mildly abnormal, pancreatic edema and/or biliary SOD may be the more likely cause for the mild liver enzyme abnormalities.
Pancreas Divisum
PD is the most common congenital pancreatic ductal anomaly occurring in 2.7% to 22% of the Western populations; it is less common in Asians. The clinical significance of PD is controversial as the majority of individuals with PD in the general population are asymptomatic; however, PD has been implicated by some as a cause of RAP, chronic pancreatitis, and chronic or recurrent epigastric pain. For proponents of the clinical significance of PD, the relatively smaller orifice of the minor papilla as compared with the major papilla results in increased intraductal pressures in the dorsal duct and interstitium in some patients, and especially if genetically predisposed, this may result in RAP or chronic pancreatitis.
Endoscopic treatment of PD-related disease has consisted of ablation of the minor papilla via sphincterotomy or periods of stenting. The enthusiasm for these techniques has been tempered by the adverse events of stenting, and the lack of prospective controlled trials of minor papilla sphincterotomy. The only small randomized trial of PD in RAP used stenting; however, because of the risk for chronic stent-induced dorsal duct changes and need for repeat endoscopies to exchange/remove stents, minor papilla sphincterotomy has become the most widely used treatment. Post-ERCP pancreatitis (5%–15%) and sphincter restenosis (20%–30%) are the most common adverse events. Given the higher risks associated with therapy for the minor papilla compared with biliary sphincterotomy, it has become standard to routinely place a small-caliber (usually 3-Fr or 4-Fr) stent that either is without internal flanges or is made of soft material with an inner flange, and to administer 100 mg rectal indomethacin to reduce the risk of treatment-related pancreatitis.
One piece of evidence in favor of PD as a cause of RAP is its apparent concentration, or increase in prevalence, in IRAP patients who have had common causes excluded by a thorough history, routine laboratory testing, and pancreas/biliary imaging. In this group, the frequency of PD at ERCP ranges from 8% to 50% (commonly about 20%) compared with 3% to 12% in controls. This apparent doubling of prevalence in patients with the outcome implies a possible doubling of risk by the presence of the PD factor.
It is well-recognized now that PD with RAP is associated with increased prevalence of genetic abnormalities. However, one should understand that this certainly does not necessarily mean the PD anatomy and intraductal pressure is not a cofactor in these patients.
In fact, increased viscosity of secretions (due to genetic factors), in the presence of a small minor papilla orifice and PD anatomy, might explain increased penetrance of the phenotype in PD patients when they have cystic fibrosis transmembrane conductance regulator (CFTR) mutations. It is also not clear if those PD patients with genetic problems are less responsive to endoscopic therapy, or perhaps more responsive.
Lans and colleagues performed the only prospective randomized sham controlled study evaluating the efficacy of minor papilla therapy in RAP, consisting of mild bougie dilation with stenting. Nineteen patients with PD-associated RAP were randomized at the time of ERCP to papillary dilation with a graduated Soehendra catheter (4–7 Fr) and dorsal duct stenting (5 or 7 Fr) compared with sham. The stent group was followed with stent changes every 4 months for 1 year in parallel with the control group. After 1 year, the stents were removed and both groups were followed for 28 and 31 months, respectively, for the primary outcome (any RAP in follow-up). After randomization, no patients in the treatment group (n = 10) developed subsequent pancreatitis or required medical care for pain, versus 6 of the 9 patients in the control group, who experienced 7 episodes of pancreatitis during follow-up ( P <.05). In addition, 5 patients in the control group were admitted to the hospital with 2 visiting the emergency room for pain. There was also a statistically significant reduction in pain for the stent group ( P <.05) using a symptom questionnaire.
Studies of the more commonly used treatment, minor papilla sphincterotomy, have been confined to case series. In a retrospective study by Borak and colleagues, 101 patients with PD were treated with minor papilla sphincterotomy for the indications of RAP, chronic pancreatitis, and abdominal pain without pancreatitis. Telephone questionnaire responses regarding narcotic dosage, symptom improvement (using a 5-point Likert scale), and need for repeat ERCP or acute medical care were used to assess treatment response with a median follow-up of 43 months (range 14–116). Success, defined as improvement or resolution of symptoms, without additional ERCP, and without requiring narcotics for pain control was achieved in 53.2% of RAP, 18.2% in chronic pancreatitis, and 41.4% with pain alone. Secondary success as defined by having 3 or fewer ERCPs with improved symptoms and no narcotic needs was seen in 71%, 45.5%, and 52.2%, respectively. Both needle-knife (usually over a pancreatic stent) and pull-type (traction) sphincterotomies (usually a miniature sphincterotome) appear safe; restenosis rates of the 2 techniques also appear similar. Younger age may predict high restenosis after both endoscopic and surgical therapies.
The pooled results of 14 studies evaluating endoscopic therapy success in the treatment of PD with RAP are shown in Table 1 . A total of 368 patients included in the studies were treated with minor papilla stenting or sphincterotomy and 316 (86%) of them were considered treatment successes. PD associated with chronic pancreatitis or pain alone had lower treatment response rates to endoscopic therapy at 51.3% and 44.4%, respectively. Most of these studies were retrospective, with variable definitions for treatment success, involved small patient numbers, had variable follow-up, and involved heterogeneity in therapies, including both sphincterotomy and stenting. The lack of a control group when the natural history is variable, as it is in RAP, is problematic, and the lack of blinding when looking at subjective outcomes like pain response is prone to bias. It is known that placebo responses in functional dyspepsia patients can be 30% to 40%. Blinding is less important to the more objective outcomes like documented hospitalization for biochemically proven RAP.
| Author | Patients | Follow-up, mo | Response, a n (%) |
|---|---|---|---|
| Satterfield et al, 1988 | 10 | 18 | 6 (60) |
| McCarthy et al, 1988 | 19 | 14 | 17 (90) |
| Lans b et al, 1992 | 10 | 28 | 10 (100) |
| Lehman et al, 1993 | 17 | 20 | 13 (77) |
| Coleman et al, 1994 | 9 | 23 | 7 (78) |
| Kozarek et al, 1995 | 15 | 20 | 15 (100) |
| Jacob et al, 1999 | 10 | 15 | 6 (60) |
| Ertan, b , 2000 | 24 | 24 | 19 (79) |
| Heyries et al, 2002 | 24 | 39 | 20 (83) |
| Linder c et al, 2003 | 83 | NA (3–36) | 54 (66) |
| Linder c et al, 2003 | 38 | NA (1–120) | 22 (58) |
| Borak et al, 2009 | 62 | 44 | 44 (71) |
| Bierig c et al, 2006 | 16 | 19 | 15 (94) |
| Kwan et al, 2008 | 21 | 38 | 13 (62) |
| Overall | 368 | 14–44 | 316 (86) |
a Treatment response is defined as a reduction in symptoms, RAP, or hospitalizations.
b Indicates prospective trials.
It is clear that robust data are needed to assess the role of PD in RAP. The FRAMES (Frequency of Recurrent Acute pancreatitis after Minor papilla Endoscopic Sphincterotomy) study is a National Institutes of Health–funded pilot study. Romagnuolo and coinvestigators designed as a pilot a multicentered prospective series of sphincterotomy (with temporary small caliber duct stenting), and a critical step toward a multicentered randomized trial on this issue. Pain burden was carefully evaluated by a validated tool (the RAPID, Recurrent Abdominal Pain Intensity and Disability index), and blood was collected for genetic testing. The study demonstrated a low recurrence of pancreatitis 6 months after ERCP and a dramatic decrease in RAPID score after sphincterotomy from grade 4 of 4 to 1 of 4. FRAMES also showed a very high minor papilla success rate in expert hands. The minor papilla is found proximally and to the right on the endoscopic screen of the major papilla, and the most stable approach position in most patients is a “long-scope” position, advancing the scope after “shortening” in front of the major papilla. Administering secretin intravenously has been shown to help in visualization of the minor papilla orifice and improve cannulation rates. Despite the widely held concept that most patients with symptomatic PD have a prominent minor papilla, in the recent FRAMES study, half the minor papillas were very subtle, with greater than 10% of cases needing secretin just to find the minor papilla (Romagnuolo et al, Unpublished data, 2013). Methylene blue sprayed on the duodenal wall in the expected area of the minor papilla may help identify the orifice when clear pancreatic juice washes away the dye. In comparison with the reasonably high success of free catheter cannulation in the major papilla, leading and cannulating the minor papilla with a wire is needed in most cases. The FRAMES study is intended as a pilot toward feasibility of a double-blind, randomized controlled trial comparing minor papillotomy with sham treatment in patients with PD and acute recurrent pancreatitis.
Sphincter of Oddi Dysfunction (SOD)
SOD is defined manometrically as sustained basal sphincter pressures greater than 40 mm Hg (30 seconds long monitoring, in 2 leads). SOD is a common finding in IRAP with an incidence ranging from 30% to 65%. In addition, spasm of the SO is implicated as a mechanism for hypercalcemia-related pancreatitis, gallstone pancreatitis, post-ERCP pancreatitis, and perhaps some medication-induced pancreatitis. However, some authors have suggested that SOD may simply be a result of sphincter scarring from repeated pancreatitis and is not the cause of the disease. Endoscopic biliary sphincterotomy alone or combined with pancreatic sphincterotomy has been used to treat SOD, but ERCP for this indication is associated with high reported rates of post-ERCP pancreatitis. In perfusion manometry catheter systems, aspirating while perfusing is critical to avoid increasing intraductal pressures; however, it is thought that the disease and the patient are the most important risk factors for post-ERCP pancreatitis, not the manometry. Skipping the manometry does not significantly reduce the risk.
Hogan and colleagues characterized patients meeting the Rome III criteria for SOD according to biliary/pancreatic ductal dilatation, elevated liver/pancreatic biomarkers, and pain. Type II pancreatic SOD is a heterogeneous group ranging from mild lipase elevations with pain to RAP, with an elevated basal sphincter pressure found in 58% (vs 92% in type 1 [more objective findings] and 35% in type 3 [no objective findings]).
In patients with well-documented RAP, where a thorough history, routine laboratory testing, and conventional imaging have not found a cause, abnormal SOM is found in 15% to 72%. Surgical and endoscopic ablation of the biliary sphincter, pancreatic sphincter, or both have been shown to decrease future episodes of RAP. Table 2 summarizes endoscopic therapy for RAP in patients with documented SOD. The sphincter complex comprises a common sphincter and a biliary sphincter (both of which are cut when a biliary sphincterotomy is performed), and a pancreatic sphincter; as a result, depending on the relative contributions of the common versus the pancreatic sphincter to a person’s manometric pancreatic sphincter hypertension, a simple biliary endoscopic sphincterotomy (BES) can reduce pancreatic sphincter pressures substantially in some patients. In others, a dual (pancreatic and biliary) endoscopic sphincterotomy (DES) is needed to normalize the pancreatic sphincter pressures. Eversman and colleagues showed these separate sphincter complexes clinically performing SOM in both sphincter segments in 593 patients referred for IRAP, AP, chronic pancreatitis, or unexplained abdominal pain. They reported a discordance rate of 26% to 35% between the 2 sphincter segments for biliary and pancreatic SOD, respectively. In patients with prior BES, with ongoing symptoms, there was residual pancreatic sphincter hypertension in 46%, compared with only 20% residual hypertension in patients with a previous DES.
Related posts:
Advances in Pancreatic Endoscopy
Effective Endoscopic Management of Pancreatic Diseases
Role of Endoscopic Ultrasonography in the Diagnosis of Acute and Chronic Pancreatitis
Endoscopic Therapy for Chronic Pancreatitis
ERCP for Biliary Strictures Associated with Chronic Pancreatitis
Endoscopic Ultrasonography–Guided Drainage of the Pancreatic Duct
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