Introduction
Chronic pancreatitis (CP) is a chronic progressive fibroinflammatory condition of the pancreas characterized by progressive scarring resulting in permanent loss of both exocrine (acinar) and endocrine (islet cells) tissue along with morphological changes in both the pancreatic duct and the parenchyma. The annual incidence of CP1,2 ranges from 5 to 14 per 100,000; the prevalence of CP is about 50 per 100,000 persons.2 (See Figure 1)
The clinical presentation of CP occurs as a large duct disease or a small duct disease and as variants of both, with and without calcifications. Most often, pain is the major clinical symptom and presents early in the course of the disease and significantly impacts quality of life. About 30-50% of CP patients develop chronic exocrine pancreatic insufficiency resulting in malabsorption and maldigestion, with a clinical presentation of steatorrhea and weight loss. Depending on the duration of follow-up and cohorts, 26-80% of CP patients develop diabetes mellitus due to progressive loss of islet cells.5 In this article, we mainly focus on the indications and techniques of endoscopic retrograde cholangiopancreatography (ERCP) endoscopic therapy in CP patients.
ERCP – Pancreatic Endotherapy
Pain associated with CP is multifactorial. One of the primary mechanisms for pain in CP is elevated intraductal pressures,6 along with other causes such as interstitial pressure, neural inflammation, ongoing acute pancreatitis with tissue inflammation, and the presence of fluid collections.
The main goal of ERCP-based endotherapy is to decompress the main pancreas duct (MPD), to achieve complete duct clearance by alleviating outflow obstruction of the MPD (from stones or strictures), evacuating focal fluid collections, and diverting the flow from a fistula or a pancreatic duct leak.7-10 When MPD drainage is established via ERCP endotherapy, the flow of pancreatic juice to the duodenum increases and resistance to outflow decreases, thereby reducing or inhibiting the severity of exocrine pancreatic insufficiency and its symptoms such as steatorrhea. However, steatorrhea is not an indication to initiate ERCP unless the patient also has concomitant pain. While pain may improve with ERCP, improvement or preservation in pancreatic function is often uncertain and one does not guarantee the other. One prospective randomized trial of 41 patients showed endoscopic therapy with ERCP slowed the progression of exocrine insufficiency along with a reduction in pain but with no change in overt diabetes.11
ERCP for ductal decompression therapy has become an established first-line method for the treatment of painful obstructive chronic pancreatitis. In a large prospective multicenter U.S. cohort (n = 521), 52% underwent endoscopic therapy, and pancreatic surgery was performed only on 18 % of patients.12 The clinical response to endoscopic therapy is quite variable even if adequate duct clearance is achieved.10 In a cohort of >1000 CP patients with pain who underwent ERCP, MPD obstruction was caused by pancreatic stones alone, ductal strictures alone, and a combination of stones and strictures in 18%, 47%, and 32% of cases, respectively. Decompression of the MPD with ERCP yielded similar results in all these different categories of patients, with 51% of patients having no pain at all at a mean follow-up of 4.9 years.13
Management of MPD obstruction via ERCP can be achieved using pancreatic sphincterotomy, and removal of the ductal stones, with or without extracorporeal short-wave lithotripsy [ESWL] or mechanical lithotripsy, dilation of strictures, placement of pancreatic stents, and providing transpapillary drainage of pancreatic fluid collections.
Selection of Patients and Pre-ERCP Work Up
Proper patient selection results in a favorable long-term outcome with endoscopic management. Only patients with a clinical presentation of pain should be considered for ERCP. The presence of a MPD stricture in the head, neck, or proximal body of the pancreas with dilation of the upstream pancreas duct in a chronic disease with or without the presence of stone would be an indication for endoscopic therapy. ERCP should be avoided in asymptomatic patients even in the presence of MPD stricture unless malignancy is suspected and an intraductal tissue sampling is desired. Patients with an MPD obstruction located only in the tail of the pancreas are not considered candidates for ESWL and/or endoscopic therapy.14 Some studies have shown that favorable prognostic factors related to endoscopic therapy and/or ESWL include complete stone removal and MPD stricture resolution after stenting.14,15
The risk of pancreas cancer is high among patients with CP. In addition to standard laboratory testing, the pre-ERCP workup should include cross-sectional imaging to rule out pancreatic cancer and to provide high quality images of the ductal anatomy. An abdominal Computed Tomography (CT) scan with and without IV contrast (Figure 2, Figure 3) and Magnetic resonance cholangiopancreatography (MRI/MRCP) (Figure 4) will help accurately delineate the location of calcified stones in relation to the duct, the presence of any mass lesion, and an excellent overview of the ductal anatomy. Some patients may have extensive parenchymal calcifications along with ductal calcifications that may not be amenable for any endoscopic therapy. (Figure 5) CT scan before and after the ERCP therapy can also help to accurately confirm the completeness of the stone extraction. (Figure 6)
Secretin-stimulated MRCP provides better information on pancreatic ductal anatomy and may also be used to quantify pancreatic exocrine function and predict the effects of pancreatic duct drainage procedures. A recent study by Sherman et al. found that S-MRI in comparison to MRCP may better identify patients who would benefit from therapeutic ERCP.16
Endoscopic Ultrasound (EUS) may be useful in selected CP patients, although the EUS-guided sampling seems to be less sensitive to diagnose a pancreatic cancer in the presence of CP vs. absence of CP (54 % vs. 89 %).17 The yield of EUS with contrast-enhanced harmonic EUS may improve the accuracy of EUS-guided sampling.18 Still, in current practice, EUS is the mainstay of technology for the diagnosis of pancreatic cancer.
Endoscopic Pancreatic Sphincterotomy (EPS)
MPD cannulation and endoscopic pancreatic sphincterotomy (EPS) are the initial steps in the endoscopic therapy. EPS is a well-known mode of therapy and can offer symptomatic relief even without stenting in a subset of patients with papillary stenosis and allow access to removal of stones in the MPD. In a small retrospective study of 11 early onset CP patients, more than 2/3rd of patients had good pain relief following EPS alone.19 In patients with chronic pancreatitis, EPS with a standard sphincterotome or with a needle-knife offers an effective and reliable approach to both access and decompress the pancreatic duct system and the complication rate of EPS in CP patients appears to be lower than the complication rate of biliary sphincterotomy for other indications.20
When performing EPS for pain relief in CP, a routine biliary sphincterotomy is not indicated unless the common bile duct is dilated or there is an elevation of alkaline phosphatase or other clinical indication.21 An endoscopic biliary sphincterotomy (EBS) is performed prior to EPS in the setting of obstructive jaundice, cholangitis or when it is technically easier to have biliary sphincterotomy to facilitate access to the MPD. If EPS is performed after EBS, the MPD orifice is usually located between the 2 and 6 o’clock position to the right margin of the sphincterotomy. (Figure 7)
After contrast injection and obtaining a pancreatogram, the guidewire is maneuvered through into the MPD, crossing strictures as needed. (Figure 8) EPS is then performed over the guidewire using either standard or taper pull type sphincterotome. When compared to EPS with a pull sphincterotome (followed by pancreatic stenting) or a needle knife over a pancreatic stent, EPS is safer when performed with a needle knife over a pancreatic stent.22 The common expected complication of EPS are post-ERCP pancreatitis, bleeding, perforation and restenosis. Using pure cutting current for the EPS incision would avoid coagulative injury, thereby decreasing the risk of pancreatitis, although most endoscopists currently used alternating cutting and coagulating currents as are common on modern electrosurgery generators for ERCP. In a large study of 398 patients who underwent EPS, post-ERCP pancreatitis was minimized with either pancreatic duct stent placement or nasopancreatic drainage.23 EPS in CP patients has shown to have a 14% restenosis rate during a 4 year follow up.24
Minor Papilla Sphincterotomy in CP Patients
The benefit of minor papilla sphincterotomy is dependent upon the clinical setting. Lehman et al. reported that minor papilla sphincterotomy helps patients with acute recurrent pancreatitis more frequently than those with chronic pancreatitis (76.5% vs. 27.3%, p = 0.01).25 Vitale et al. followed 24 CP patients with pancreas divisum and reported significant pain relief on 2-year follow up following minor papilla sphincterotomy and stenting.26 A recent Japanese study showed that endoscopic balloon dilation (EBD) of the minor papilla is feasible and effective for the management of symptomatic pancreas divisum in CP patients.27 The same technique as EPS with a tapered pull type sphincterotome can be utilized to perform minor papilla sphincterotomy or a stent can be placed in the dorsal pancreas duct and minor papilla sphincterotomy performed over a needle knife. (Figure 9)
Pancreatic Duct Stone Management
Pancreatic duct calculi are often seen in patients with CP and cause pain by obstructing the pancreatic ducts and producing upstream ductal hypertension. Pancreatic stones may appear either as calcified stones or as radiolucent protein plugs that may or may not become calcified. A majority of the pancreatic stones are calcified and radiopaque. Although alcoholic CP often presents with calcified pancreatic stones, the stones seen in tropical pancreatitis and hereditary pancreatitis can be larger in size than those seen in the setting of alcoholic CP. Larger stone size often makes endotherapy difficult, whereas stones < 5mm are more amenable to endoscopic extraction after pancreatic sphincterotomy alone. However, in 70–90% of cases, pancreatic stones cannot be extracted without pre-ERCP fragmentation (by mechanical and/or extracorporeal shock wave lithotripsy [ESWL]).7,28 If the pancreatic duct stone is larger than 5mm, it is often preferable to perform stone extraction after ESWL or intra-ductal lithotripsy.
Extracorporeal Shock Wave Lithotripsy
ESWL is now accepted as the standard of care in the management of large MPD calculi >5 mm not amenable to routine endotherapy.29,30 ESWL is very effective in fragmenting both radio-opaque and radio-lucent calculi in the MPD. European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend ESWL prior to ERCP for large MPD calculi.2 A meta-analysis of 17 studies with a total of 588 patients looked at pain relief and duct clearance as the primary end point. They noted a duct clearance rate of 37%-100% and good pain relief, and a mean effect size (weighted correlation coefficient) for pain was 0.6215 and for duct clearance was 0.7432 (indicates moderate to high practical significance).31
ESWL is routinely used in Urology for clearance of nephrolithiasis. In many U.S. centers, Urologists perform ESWL for PD stones. Components of ESWL machines include (1) a shock wave generator, (2) a focusing system, (3) a coupling mechanism, and (4) a localization unit.32 Shock waves are generated via piezoelectric technology and the focusing system concentrates shock waves into a precise target volume where fragmentation of hard structures will take place. The coupling mechanism between the shock wave generator and the patient’s body currently consists of a cushion surrounding the shock wave generator, which is closely applied onto the patient’s skin (with a special gel similar to that used in transabdominal ultrasonography). The localization unit allows maintaining the target stone inside the target volume, using simultaneous fluoroscopy. Localization of stones using fluoroscopy is more reliable than using ultrasound. If the stone is not radiopaque, then placing a pancreatic duct stent that terminates at the level of the stone often helps in the localization of the target for ESWL. The patient is positioned prone or supine with a slight tilt to prevent the spine from being in the target volume.
If there are several stones present, the one located inside the MPD closest to the papilla is targeted first; and then the focus is gradually moved to more proximal MPD stones once distal ones have been fragmented. Usually, the stones in the tail and the side branches are not targeted as they do not significantly impede the outflow of pancreatic fluid and, if targeted, resulting stone fragments can potentially migrate into the MPD and cause worsening obstruction.32
High energy shock waves are delivered until the stone is fragmented (as seen via fluoroscopy) and although there is limited evidence on the maximum number of shock waves that may be administered per session, 5000-6000 are typically performed per session and patients are scheduled for further supplementary sessions as needed. In most centers, ESWL is done as an ambulatory procedure under general anesthesia and an abdominal radiograph is obtained 1 to 2 weeks later to assess the need for further ESWL. The most common complication of ESWL is acute pancreatitis, and this has been reported in 4.2% in a meta-analysis.33 (Figure 10)
Combining ERCP with ESWL at the Same Time
In some centers, the extracorporeal lithotripter is located within the endoscopy unit and ERCP is used in combination with ESWL and is performed by the endoscopist during same anesthesia session. In a study of 55 patients randomized to ESWL alone or ESWL combined with endoscopy, both groups had similar rates of pain relief (62% vs. 55%) and the authors concluded that combining systematic endoscopy with ESWL adds to the cost of patient care, without improving the outcome of pancreatic pain.29 A study by Cotton et al. that combined use of ESWL with endotherapy was shown to prevent pancreatic surgery in the majority of patients.34 In most studies of ESWL (alone or combined with endoscopic drainage), more than 70 to 80% patients had short term pain relief and about 60% had long term pain relief (2 to 5 years).35-37 ESWL is a relatively safe and well-tolerated procedure.38
Secretin ESWL
Injection of human secretin increases bicarbonate rich pancreatic fluid secretion. To see if this could facilitate excretion of pulverized pancreatic stones during ESWL, Choi et al. studied 233 consecutive cases and observed that secretin use resulted in significantly higher rate of complete MPDS clearance (63% vs. 46%, p = 0.021).39
Intraductal Lithotripsy
Lithotripsy is commonly used for biliary stones, but occasionally mechanical lithotripsy is also used in treating pancreatic calcifications (prior to referring patients to undergo ESWL). Standard lithotripter-compatible baskets can be used in the pancreatic duct during ERCP and, if these baskets can capture and crush stones more aggressive treatments may be obviated.28 Intraductal lithotripsy via a pancreatoscope can be performed using per oral pancreatoscopy (POP)-guided intracorporal lithotripsy using either of the two techniques: Electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL). A recent meta-analysis, showed high clinical success rates with EHL (67%) and LL (88%).40 (Figures 11,12,13)
Stone Extraction
After stone fragmentation with ESWL and pancreatic sphincterotomy, tiny stone fragments may pass spontaneously through the papilla and ERCP may not be even necessary. Endoscopic therapy is needed in patients without spontaneous clearance of pancreatic stones after adequate fragmentation by ESWL.2 If the stone is located upstream from a stricture, the stricture is generally dilated first using a dilation balloon (Hurricane; Boston Scientific, Natick, MA) or a graduated dilating catheter (Soehendra dilators; Cook Endoscopy, Winston-Salem, NC) to facilitate the stone removal.Then a small Dormia basket or stone extraction balloon is used to remove the stone fragments. (Figures 14a,b,c,d,e)
If the stones are visible on fluoroscopy, a guidewire is introduced in the duct and with minimal or no contrast injection, a basket or balloon introduced, manipulated to extract the stones starting with those closer to papilla and progressing upstream. A dormia basket may be more useful than a stone extraction balloon as often the fragmented pancreatic stones are sharp and frequently rupture the balloon.
When a pancreatic duct stricture is tight, catheter (balloon or bougie) passage may be impossible. In this setting a Soehendra stent retriever with a screw tip (8.5Fr) can be spanned through the stricture to enable subsequent passage of the dilating balloon or bougie, although this maneuver carries with it some risk of pancreatic injury.
Pancreatic duct strictures
Management of strictures secondary to CP is often challenging. Along with pancreatic duct strictures, patients often present with distal biliary strictures resulting from ongoing inflammation and fibrotic reactions in the pancreatic head, which can in turn produce a biliary stricture. The most important aim is to rule out malignancy during the initial work up if there is any concern r.e. cancer. As CP is associated with an increased risk of pancreas cancer, the emphasis should be to reasonably exclude pancreatic cancer if a MPD stricture is detected, particularly in the absence of pancreatic calcifications and in the presence of exocrine insufficiency or new late onset diabetes, without smoking or alcohol history.41,42 It has been shown that approximately 5% of patients with pancreatic cancer are initially misdiagnosed as CP.43
MPD strictures are defined as dominant strictures by the presence of at least one of the following characteristics: upstream MPD dilatation ≥ 6 mm in diameter, prevention of contrast medium outflow alongside a 6-Fr catheter inserted upstream from the stricture, or abdominal pain during continuous infusion of a naso-pancreatic catheter inserted upstream from the stricture with 1 L saline for 12 – 24 h.2 The latter maneuver is virtually never performed in modern practice, and this classification system is often not put into practice. (Figures 15a,b,c)Technical success in the management of such a dominant stricture would be defined by some as stent insertion across a dominant MPD stricture or up to the tail MPD if multiple strictures occur in the MPD. Before a stent is placed, if malignancy is still suspected, a brush cytology could be obtained. Although a clear definition for short term clinical success is lacking, the absence of pain during a full year following the stent removal implies clinical success. Refractory MPD strictures are defined as symptomatic dominant strictures that persist or relapse after 1 year of single pancreatic stent placement, or can be diagnosed in patients who cannot function without an indwelling pancreatic duct stent.2
Stricture Dilation and a Single Plastic Stent
ERCP intervention (endotherapy) is ideal for single strictures in the head while isolated strictures in the tail or multiple strictures in the body with a chain of lake appearance have unfavorable outcomes with the endotherapy.44
Historically, stricture dilation alone was used to treat single MPD strictures, but in current endoscopy practice dilation alone is not felt to represent an adequate treatment. Dilation is routinely followed by placement of a plastic pancreatic stent. MPD strictures are single in >80% of CP patients and a placement of a single plastic stent has been widely used as the initial endoscopic therapy.45
On relieving MPD stricture obstruction, pain relief was reported at short and long-term follow-up in 70–94% and 52–82% of patients, respectively.32,44 In a meta-analysis of 9 studies, long-term pain relief (24 months) was reported in 67.5 % of 536 patients (95 % confidence interval [CI] 51.5 % – 80.2 %).46
Leaving the PD stent in place for periods of up to 6 months does not always yield an adequate clinical response and stents are often needed for a longer duration.47 Prior to stent placement, tight strictures sometimes need to be dilated with Teflon bougies, a Soehendra stent retriever or a balloon dilator.48
Plastic stents are placed across the stricture and typically exchanged every 2 to 6 months or “on-demand” when the symptoms recur. Large bore stents of size 7Fr to 10Fr are progressively used when treating MPD strictures, if possible. The stent size is usually limited by the unaffected downstream duct (close to the pancreas head). In general, stent exchanges are performed for about 24 months. There is no clear consensus data on whether or not a pancreatic sphincterotomy should be performed prior to placement of plastic MPD stent, but most patients with CP often find their way to undergoing this maneuver as well.49
Criteria used for ‘definitively’ removing a stent (with no intent to replace the stent again) usually consist of (1) adequate outflow of contrast medium into the duodenum within 1 to 2 min after ductal filling upstream from the dilated stricture, immediately after stent removal plus the extraction of ductal debris, and (2) easy passage of an ERCP catheter through the dilated stricture.8
After definitive stent removal, recurrence of symptoms and strictures was reported in 27 to 38% of patients after 2 years of follow up. Mean time to recurrence of pain after definitive removal is around 2.1 years.45 The most important factor associated with higher re-stenosis rates in CP patients is the presence of concomitant pancreas divisum.45 (Figure 16)
Multiple Plastic Stenting
MPD stricture management has evolved from single stents to the placement of multiple side-by-side stents. Two 7Fr or 8.5Fr plastic stents can be placed once the stricture is dilated to 6mm with a balloon. The number of stents can be increased based on the degree of dilation in the upstream MPD beyond the stricture. Such multiple stent placements are facilitated by having two guidewires in the pancreas duct across the stricture subsequently followed by successive stent placements.
Costamagna et al. who initially proposed using multiple plastic stenting for MPD strictures not responding to a single stent placement, reported a study of 19 patients who had a MPD stricture that persisted immediately after removal of a single pancreatic stent, multiple plastic stents (8.5-11.5Fr diameter) were placed. A mean of 3 stents were used and the stents were removed after a mean of 7 months. Stricture resolution was seen in 95% and pain relief in 84% on a 38 month follow up.50 The main advantages of this technique include a low number of ERCP sessions (two) and a large dilation diameter that might account for the absence of pain relapse during a relatively long follow-up. However, further prospective controlled studies are needed to confirm these promising results.
Self-Expandable Metal Stents
Fully covered self-expanding metal stents (FCSEMS) were initially developed for palliation of malignant biliary strictures, and have subsequently been used in benign biliary strictures. Placement of FCSEMS in the MPD may be an alternative to placing multiple plastic stents or when the stricture is refractory despite several sessions of plastic stent placements. Due to tissue in-growth, only FCSEMS are used in PD strictures and FCSEMS used in this manner are applied in an “off label” manner. FCSEMS can be used only in strictures close to the papilla in the head of the pancreas and reachable by a single stent. The MPD should be large enough to accommodate 8 to 10mm stents and the stents should be shorter so that they do not extend beyond the stricture site and seal the side branches. (Figure 17)
Poley et al., in a study of 13 CP patients, demonstrated better results using FCSEMS when compared with progressive plastic stenting protocols.51 A major limitation of FCSEMS is frequent stent migration (5-33%). To reduce the risk of migration, anti-migration features such as anchoring flaps and flared ends were introduced, and these modified stents have been studied in MPD strictures in CP patients by Moon et al.52 In a systematic review of 4 prospective case series (n=61), placement of FCSEMS provided pain improvement in 85 %.53 A study of 10 patients with follow-up period of 19.8 months showed the use of FCSEMS in MPD strictures feasible, safe and effective.54 Similarly, in a U.S multicenter retrospective study of 33 CP patients with MPD strictures that were refractory to plastic stents, FCSEMS were shown to be effective, with a clinical success rate of 93%.55 The recurrence rate for treated strictures with FCSEMS was 0 % after a median follow-up of 8 months (range 5 – 14).55 About 20% of patients who receive FCSEMS for PD strictures may not tolerate these implants and develop significant post-procedure pain. This post-procedure pain is hypothesized mainly due to the greater stent diameter, and if a smaller-diameter (6 mm) FCSEMS is available, that should be further investigated regarding the post-procedure pain and development of iatrogenic strictures when using over-sized stents.
Due to the lack of controlled data, further trials are needed to assess the long-term safety and efficacy of using FCSEMS in intrapancreatic strictures in the setting of CP before this method can be adopted in routine clinical practice, but it is within the standard of care to consider and use these devices in this setting.
Transpapillary Endoscopic Drainage of Pancreatic Fluid Collections and Leaks
Pancreatic Fluid Collections (PFC) may be drained via a transpapillary or transmural approach or, sometimes, a combination of both. Transpapillary endoscopic drainage with plastic stent placement is recommended for pseudocysts communicating to the MPDs, ductal leaks in CP, and if the site of MPD disruption could be reached or site of obstruction could be bypassed. However, if bridging the ductal obstruction or disruption is unsuccessful, then transmural or percutaneous drainage would typically be necessary.
The main advantage of transpapillary drainage of PFCs and leaks is a near-total avoidance of bleeding. If a symptomatic PFC communicates with the MPD and is not approachable transmurally, placement of a plastic pancreatic stent with or without EPS is a helpful approach. The upstream end of the stent, if unable to bridge the site of the leak then, should terminate in the PFC itself. An ideal approach would be to bridge the disruption site as that would restore the duct into continuity. A successful resolution of PD disruption by transpapillary stent placement depends on the ability to bridge the disrupted duct with a stent.56 If there is an obstructive lesion such as a stone or stricture between the leak site and the duodenal papilla, it is prudent to place a stent bridging across the obstruction. In a retrospective study of 110 patients, a combined transpapillary PD stenting improves treatment outcomes in patients undergoing endoscopic transmural drainage of PFC, although in practice if transmural drainage is performed then transampullary drainage is not usually warranted.57
While transpapillary stenting helps with improved outcomes in walled-off necrosis, a large multicenter retrospective study showed that transpapillary stenting may have no added benefit in the treatment outcomes in patients undergoing EUS-guided transmural drainage of pancreatic pseudocysts.58 Most endoscopists perform ERCP with pancreatic duct stenting in patients with pancreatic duct disruption during endotherapy for walled-off pancreatic necrosis but not during transmural drainage in patients with pancreatic pseudocysts, even in cases of confirmed main pancreatic disruption as it negatively affects treatment outcomes. However, large prospective randomized trials are necessary to confirm these conclusions.
Biliary Strictures Secondary to CP
Biliary strictures occur secondary to CP in 3% – 23% of patients.59 Clinical presentation of biliary strictures in CP varies widely from asymptomatic lab abnormalities (elevated alkaline phosphatase) to jaundice with or without cholangitis. Patients with persistent biliary obstruction would benefit from biliary decompression with dilation and stent placement.
Summary
In patients with symptomatic obstructive chronic pancreatitis with a dilated pancreatic duct, ERCP is the first line of management to treat stones and strictures. Further studies are needed in using FCSEMS for pancreatic duct strictures and EUS-guided novel interventions.
References
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