Synopsis  

Chronic pancreatitis is an inflammatory process of the pancreas characterized pathologically by irreversible destruction of parenchymal and ductal architecture. Clinically, pain is the predominant symptom. Pain may be due to elevated pancreatic ductal or parenchymal pressures, and therapeutic efforts are directed at reducing pancreatic secretion or reducing pancreatic ductal or parenchymal pressure. A variety of interventions are utilized, including pharmacological therapy (pancreatic enzymes, octreotide), surgical procedures (resective, decompressive, and denervative), and endoscopic techniques.

Endoscopic therapy for chronic pancreatitis has evolved over the past 15 years, with the incorporation of endoscopic techniques previously reserved for the treatment of biliary tract disorders such as bile duct stones, strictures, and leaks. Endoscopic therapy for chronic pancreatitis will be highlighted in this chapter and extensive literature review will accompany the discussion of a variety of techniques. The endoscopic techniques, safety, and clinical efficacy of the endoscopic management of pancreatic duct strictures are reviewed. Particular attention is paid to duration of stenting, complications associated with stents, and the long-term follow-up of patients undergoing endoscopic therapy. Management of pancreatic duct stones utilizing various stone extraction techniques and the usefulness of incorporating extracorporeal shock-wave lithotripsy into the armamentarium is also discussed. The role of sphincter of Oddi dysfunction in pancreatic disease and the technique of pancreatic sphincterotomy is highlighted. The management of biliary obstruction as a complication of chronic pancreatitis will also be discussed. The results of endoscopic management of pancreatic pseudocysts will be briefly reviewed; however, more exhaustive discussion of the technique will appear in a subsequent chapter. Endoscopic therapy of chronic pancreatitis is an expanding area for the interventional endoscopist. The appropriate selection of candidates for various pancreatic interventions is important to achieve the best results.

 Chronic pancreatitis   

Chronic pancreatitis is an inflammatory process of the pancreas that may result in chronic, disabling abdominal pain, fat and protein maldigestion, and diabetes mellitus. The histological hallmarks of chronic pancreatitis are irreversible destruction of the pancreatic parenchyma and ductal architecture associated with fibrosis, protein plugs, and ductal calculi [1]. Pain is the predominant symptom of chronic pancreatitis and its pathogenesis is multifactorial. Pain may be caused by pancreatic or extrapancreatic processes (Fig. 1) [2,3]. Pancreatic duct and parenchymal pressures are generally increased in chronic pancreatitis, whether the main pancreatic duct is dilated or normal in diameter [4]. Such elevated parenchymal and duct pressures contribute to pancreatic ischemia, which appears to play a significant role in the pain of chronic pancreatitis [5,6]. Therapeutic efforts are directed at reducing pancreatic parenchymal and ductal hypertension. Pharmacological agents, endoscopic techniques, and surgical procedures (resective, drainage, and denervative) have been employed to reduce pain, with variable results. The complexity and multiplicity of the causes of pain in chronic pancreatitis may well explain the mixed results achieved by current methods of therapy.

 Treatments for chronic pancreatitis   

Most therapeutic efforts in the treatment of chronic pancreatitis are directed toward correction of the etiological factors, including relief of obstructions and control of symptoms.

Medical therapy   

Medical therapy consisting of analgesics, dietary alterations, nerve blocks, enzyme supplements, intervals of pancreatic rest, and suppression of pancreatic secretion (octreotide) is variably effective in relieving pain. Further options or alternatives to medical therapy are sought by patients with uncontrolled, persistent pain.

Surgical therapy   

Surgical therapy has been the main therapeutic recourse for patients with disabling symptoms that fail to improve with standard medical therapy. A surgical drainage procedure is usually performed in the setting of a dilated main pancreatic duct, whereas pancreatic resection and/or denervation are reserved for those patients with normal or small diameter ducts. Immediate pain relief is seen in 70–90% of patients following surgical drainage procedures. However, pain recurs in 20–50% of patients during long-term follow-up. Surgical drainage procedures are associated with a morbidity of 20–40%, and a mortality averaging 4% [7].

Endoscopic treatment for chronic pancreatitis   

Since its inception and initial application in the early 1970s, endoscopic therapy has revolutionized the approach to a variety of biliary tract disorders. Within the past 10 years, similar endoscopic techniques have been applied and adapted to diseases of the pancreas [8].

Safety issues   

These techniques, however, have not been widely utilized because of concern about prohibitive morbidity and the difficulty in achieving technical success. It was not until the relative safety of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy in acute gallstone pancreatitis was recognized that the indications for endoscopic therapy in disorders of the pancreas were expanded [8–10]. Pharmacological agents such as gabexate and interleukin-10 have shown promise in reducing the incidence and severity of pancreatitis in patients undergoing therapeutic ERCP and may add further safety to endoscopic interventions of the pancreas [11,12].

Indications for endoscopic treatment   

Endoscopic therapy is now being applied in the setting of chronic pancreatitis for patients presenting with pain and/or clinical episodes of acute pancreatitis [13,14]. One of the aims of endoscopic therapy is to alleviate the obstruction to exocrine juice flow. Certain pathological alterations of the pancreatic duct, the bile duct, and/or the sphincter lend themselves to endoscopic therapy. Outflow obstruction may be caused by ductal strictures (biliary or pancreatic), pancreatic stones, pseudocysts, and minor or major papilla stenosis. Although the endoscopic approach has never been directly compared with surgery, endoscopic drainage is appealing in that it may offer an alternative to surgical drainage procedures, with generally less morbidity and mortality. Furthermore, endoscopic procedures do not preclude subsequent surgery, should that be necessary. Moreover, the outcome from reducing the intraductal pressure by endoscopic methods may be a predictor for the success of surgical drainage [15].

Results of endoscopic treatment   

Outcome data following endoscopic therapy in chronic pancreatitis are rapidly accumulating. The data in this area, however, are often difficult to interpret because of the heterogeneous populations with one or more pathological processes being treated (e.g. pancreatic duct stones, strictures, pseudocysts) and because of the multiple therapies performed in a given patient (e.g. stricture dilation, stone extraction, biliary and/or pancreatic sphincterotomy).

Figure 2 lists the currently available endoscopic techniques for the treatment of acute and chronic pancreatitis, and their complications. This figure is (intentionally) all-inclusive, because differentiating acute recurrent pancreatitis from exacerbations of chronic pancreatitis may be clinically difficult [16]. In this chapter, we analyse the current state of the art of some of these exciting new applications of endoscopy in the treatment of chronic pancreatitis.

 Pancreatic ductal strictures   

Benign strictures of the main pancreatic duct may be a consequence of generalized or focal inflammation, or necrosis around the main pancreatic duct. Given the putative role of ductal hypertension in the genesis of symptoms (at least in a subpopulation of patients), the utility of pancreatic duct stents for treatment of dominant pancreatic duct strictures is being evaluated [17–26]. In experimental models, pancreatic duct stents have been shown to reduce elevated ductal pressures significantly, although not as effectively as surgical measures [27]. The best candidates for stenting are those patients with a distal stricture (in the pancreatic head) and upstream dilation (type IV lesion) [17]. The majority of patients with a stricture have associated calcified pancreatic duct stones. For optimal results, the therapy must address both the stones and stricture. Underlying malignancy as the cause of the pancreatic stricture must be excluded by non-invasive and tissue sampling means [28–30].

Pancreatic stent placement techniques   

Most pancreatic stents are simply standard polyethylene biliary stents with extra side holes at approximately 1 cm intervals to permit better side branch juice flow (Fig. 3). Stents made of other materials have received limited evaluation.

The technique for placing a stent in the pancreatic duct is similar to that used for inserting a biliary stent. In most patients, a pancreatic sphincterotomy (with or without a biliary sphincterotomy) via the major or minor papilla is performed to facilitate placement of accessories and stents. A guidewire must be maneuvered upstream to the narrowing. Hydrophilic flexible tip wires are especially helpful for bypassing strictures. Torqueable wires are occasionally necessary to achieve this goal. High-grade strictures require dilation prior to insertion of the endoprosthesis. This may be performed with hydrostatic balloon dilating catheters or graduated dilating catheters (Figs. 4 and 5).

Extremely tight strictures may permit passage of only a small caliber guidewire. Such wires may be left in situ overnight and usually permit dilator passage the next day. Alternatively, 3 Fr angioplasty balloons or the Soehendra stent retriever may be helpful [31]. The Soehendra stent retriever is rarely used due to concern for excessive duct damage from the device [32,33]. Although one preliminary report [34] suggested that luminal patency of the duct persisted at a mean time of 5 months following balloon dilation alone, most authorities have observed recurrence of strictures after one-time dilation and therefore advocate stenting [15].

As a rule, the diameter of the stent should not exceed the size of the downstream duct. Therefore, 5, 7, or 8.5 Fr stents are commonly used in smaller ducts, whereas 10–11.5 Fr stents or dual side-by-side 5–7 Fr stents may be inserted in patients with severe chronic pancreatitis and a dilated main pancreatic duct. The tip of the stent in the pancreas must extend upstream to the narrowed segment and into a straight portion of the pancreatic duct to avoid stent tip erosion through the duct wall.

For diagnostic trials of pancreatic stenting in patients with nearly daily pain, most stents are left in place for 3–4 weeks. When long-term pancreatic stents are placed for therapy, stents have remained in place for 3–116 months [17,24].

Stents are known to occlude within the first several weeks [35]; however, clinical improvement may persist much longer, possibly due to siphoning of the pancreatic juice along the stent. At this time, self-expanding metallic stents play no role in the management of refractory pancreatic strictures due to the high occlusion rate from mucosal hyperplasia [36].

Efficacy of pancreatic duct stenting   

The results of pancreatic duct stent placement (usually with ancillary procedures) are detailed in Fig. 6[17–26]. Successful stent placement was achieved in 82–100% of patients. Sixty-six per cent of patients with successful stent placement were reported to benefit from therapy during a mean follow-up to 8–39 months (N.B., many patients still had their stent in place during the follow-up period).

Cremer and colleagues   

Cremer and colleagues [17] reported their experience with pancreatic duct stenting in 76 patients with severe chronic pancreatitis (primarily alcohol related) complicated by a distal pancreatic duct stricture and upstream dilation. A 10 Fr stent was successfully placed in 75 patients (98.7%) through the major (n = 54) or minor papilla (n = 21). All patients had undergone biliary and pancreatic sphincterotomy, stricture dilation, and extracorporeal shock-wave lithotripsy (ESWL) (most patients) to fragment pancreatic duct stones.

A dramatic decrease or complete relief of pain was initially observed in 94% of patients and was associated with a decrease in the main pancreatic duct diameter. Clinically, stents were thought to remain patent for a mean time of 12 months (range: 2–38 months). Disappearance of the stricture was observed in only 7 of 64 non-operated patients after 13 months (range: 2–30 months).

Eleven patients underwent pancreatico-jejunostomy after confirmation of pain reduction with main pancreatic duct decompression. The remainder required repeated stent changes. Fifty-five per cent of non-operated patients remained symptom-free at a mean follow-up of 3 years [19].

Early complications were related to pancreatic and/or biliary sphincterotomy (cholangitis in three patients and hemobilia in 10). Intraductal infection due to stent clogging developed in eight patients, and three had their stent migrate inwardly. Stent therapy was believed by the authors to be an acceptable medium-term treatment of pain associated with main pancreatic duct stricture. Unfortunately, because the stricture persists in the majority of patients, compliance with long-term use of plastic stents (i.e. multiple stent changes are required) would be difficult. As a result, the expandable stents (18 Fr diameter, 23 mm long) have been tried in 29 patients [19].

Early follow-up to 6 months was encouraging, because stent clogging did not occur during this short follow-up interval. However, during longer-term follow-up, mucosal hyperplasia (i.e. tissue ingrowth) resulted in stent occlusion in the majority of patients [36]. Because these stents are not removable by endoscopic techniques, their use should be limited, perhaps, to patients in whom resective therapy (during which the stent and head of pancreas would both be removed) is the next step. Evaluation of the covered metal stents is in progress.

Ponchon and colleagues   

Ponchon and colleagues [25] successfully placed 10 Fr multiside hole stents after biliary and pancreatic sphincterotomy and balloon dilation of strictures in 28 of 33 patients (85%) with a distal pancreatic duct stricture and upstream dilation. This was a highly selected subgroup, because patients with multiple sites of strictures, pancreatic duct stones, pancreas divisum, common bile duct narrowing with cholestasis, any duodenal impingement, or the presence of a pseudocyst larger than 1 cm were excluded. The stents were exchanged at 2-month intervals for a total stenting duration of 6 months.

Twenty-three patients were observed for at least 1 year after removal of the stent and comprised the basis of the report. During the stenting period, 21 of 23 patients (91%) had resolution or reduction in pain, usually within days of stent insertion, and 17 patients (74%) discontinued analgesic medications. Initial relief of symptoms correlated with a decreased diameter (2 mm; P < 0.01) of the main pancreatic duct. Twelve patients (52%) had a persistent beneficial outcome for at least 1 year after stent removal. Disappearance of the stenosis on pancreatography at stent removal (P < 0.05) and 1 year later (P < 0.005) and reduction in the pancreatic duct diameter (2 mm) were significantly associated with pain relief. Complications of therapy occurred in 10 patients (30%), and included mild pancreatitis (resolved within 48 h) in 9 and development of a communicating pseudocyst in 1.

Smits and colleagues   

Smits and colleagues [24] evaluated the long-term efficacy of pancreatic duct stenting (5 or 7 Fr in 9 patients and 10 Fr in 40) in a heterogeneous group of 51 patients with pancreatic duct strictures (44 dominant, 7 multiple) located in the head (n = 38), body (n = 14), or tail (n = 6), and upstream dilation. Associated pancreatic pathology treated at the time of stenting included pancreatic duct stones (n = 17), pseudocysts (n = 10), common bile duct strictures with concomitant cholestasis (n = 12), and pancreas divisum (n = 3). Stents were successfully placed in 49 patients (96%) after pancreatic sphincterotomy (n = 31) and stricture dilation (n = 9).

Patients were re-evaluated within 3 months of stent placement and were followed for a median duration of 34 months. Responders underwent stent exchanges (approximately every 3 months) until such time as the stricture patency was improved. Clinical benefit was noted in 40 of 49 patients (82%) during the stenting period. In 16 of these 40 patients, the stents were still in situ at the time of the report and offered continued clinical improvement over periods ranging from 6 to 116 months. In 22 of the 40 patients, the stents were electively removed. All 22 patients experienced persistent clinical improvement during periods ranging between 6 and 41 months (median: 28.5 months) after stent removal. There were no demographic (age, sex, duration of pancreatitis, alcohol abuse) ERCP findings (single or multiple strictures, presence of pancreatic duct stones, pseudocyst, or biliary stricture) or additional interventions (stricture dilation, removal of stones, drainage of pseudocyst, stenting of bile duct stricture) that predicted the clinical outcome.

Ashby and Lo   

Ashby and Lo [40], from the United States, reported results of pancreatic stenting for strictures that differed from the European experience. Although relief of symptoms was common (86% had significant improvement in their symptom score), this was usually not evident until day 7. More disappointing was the lack of long-term benefit, with recurrence of symptoms within 1 month of stenting. This study was relatively small (21 successfully stented patients) and included five patients with pancreatic cancer. Possible explanations for the less favourable results were that sphincterotomy was not performed and strictures were not dilated routinely before stent placement (to improve pancreatic duct drainage).

Hereditary and early onset pancreatitis   

Pancreatic endotherapy was evaluated in patients with hereditary pancreatitis and idiopathic early onset chronic pancreatitis. In a report by Choudari et al. 27 consecutive patients with hereditary chronic pancreatitis underwent endoscopic or surgical therapy of the pancreatic duct. Nineteen (70%) underwent endoscopic therapy and 8 patients (30%) underwent surgery as their primary treatment.

After a mean follow-up of 32 months, 50% of patients undergoing endoscopic therapy were symptom free, 38% were improved, and 12% were unchanged with respect to pain. After surgery, 38% were symptom free, 25% were improved, and 37% were unchanged [38]. In a cohort of patients with painful, early onset idiopathic chronic pancreatitis (aged 16–34 years) and a dilated pancreatic duct, 11 patients underwent endoscopic therapy and were followed for over 6 years. The median interval between onset of symptoms and endoscopic therapy was 5 years (3–10 years). Pancreatic sphincterotomy and stent insertion provided short-term relief in 11 patients (100%).

Complications included fever in 3 patients and cholecystitis in 1 patient. Four patients (37%) developed recurrent pain felt due to recurrent pancreatic strictures or stones, and underwent further endoscopic therapy [39] These two patient populations of hereditary and early onset idiopathic chronic pancreatitis illustrate the value of endoscopic therapy in affording short-term and medium-term pain relief. Repeat endoscopic therapy is not uncommon.

Predicting the outcome   

There are few studies that were designed to identify subgroups of patients with chronic pancreatitis who were most likely to benefit from stenting. In a preliminary report, 65 chronic pancreatitis patients with duct dilation (> or = to 6 mm), obstruction (usually a stricture with a diameter of 1 mm or less), obstruction and dilation, or no obstruction or dilation underwent pancreatic duct stenting for 3–6 months [37]. The presence of both obstruction and dilation was a significant predictor of improvement.

Duration of stenting   

The appropriate duration of pancreatic stent placement and the interval from the placement to change of the pancreatic stent is not known. Two options are available [15]: (1) The stent can be left in place until symptoms or complications occur; (2) the stent can be left in place for a predetermined interval (e.g. 3 months). If the patient fails to improve, the stent should be removed because ductal hypertension is unlikely to be the cause of pain. If the patient has benefited from stenting, one can remove the stent and follow the patient clinically, continue stenting for a more prolonged period, or perform a surgical drainage procedure. (This latter option assumes that the results of endoscopic stenting will predict the surgical outcome.) There are limited data to support any of these options.

In a recent preliminary report, Borel et al. evaluated the effect of definitive pancreatic duct stent placement only exchanged out on demand when symptoms recurred. In 42 patients, a single 10 Fr stent was inserted into the main pancreatic duct following pancreatic sphincterotomy. The patients were followed for a median of 33 months with respect to pain reduction, weight gain or loss, and recurrence of symptoms. With recurrence of symptoms, the stent was exchanged. Of the 42 patients, 72% had pain relief with pancreatic stenting (pain score reduced > 50%) and 69% gained weight. Two-thirds of the patients (n = 28) required only the single pancreatic stent placement and 12 patients required a stent exchange after a median of 15 months. Two patients required repeated stent exchanges for recurrence of pain. Persistence or recurrence of pain was significantly associated with the development of cholestasis and continued alcohol abuse. These authors conclude that long-term pancreatic stenting appears to be an effective, and possibly a superior, option compared to temporary stenting [42].

Does response to stenting predict the outcome of surgery?   

The question may be posed: In patients with chronic pancreatitis and a dilated pancreatic duct, will the response to pancreatic stent placement predict the response to surgical duct decompression? In a preliminary report of a randomized controlled trial (n = 8), McHenry and associates evaluated the utility of short-term (12 weeks) pancreatic duct stenting to relieve pain and to predict the response to surgical decompression in patients with chronic pancreatitis and a dilated main pancreatic duct [43]. Four of eight patients benefited from stenting, while no control patient improved. Among five patients who underwent a Puestow procedure following stent therapy, four had pain relief. Improvement with the pancreatic stent was seen in two of four patients responding to surgery; one patient benefited from the stent but did not improve with surgery. In another preliminary series, reported by DuVall and colleagues [44], endoscopic therapy predicted the outcome from surgical decompression in 9 of 11 patients (82%; positive and negative predictive values were 80% and 83%, respectively) during a 2-year postoperative follow-up interval.

Several institutions have recently reported that symptomatic improvement may persist after pancreatic stent removal despite stricture persistence [17,23–25]. When summarizing the results of two studies (n = 54) that evaluated the efficacy of pancreatic duct stenting for dominant strictures, 65% of patients had persistent symptom improvement after stent removal, although the stricture resolved in only 33% (Fig. 7). Although these data indicate that complete stricture resolution is not a prerequisite for symptom improvement, several other factors may account for this outcome. First, other therapies performed at the time of stenting (e.g. pancreatic stone removal, pancreatic sphincterotomy) may contribute to patient benefit. Second, many of the unresolved strictures had improved luminal patency (but without return of lumen diameter to normal). Third, the pain of chronic pancreatitis tends to decrease with time and may resolve when marked deterioration of pancreatic function occurs [40].

Long-term follow-up   

In the largest multicenter trial, Rosch et al. reported on the long-term follow-up of over 1000 patients with chronic pancreatitis undergoing initial endoscopic therapy during the period 1989–95. Some of these patients were previously reported with shorter follow-up as noted in Fig. 6.

A total of 1211 patients from eight centers in Europe with pain and obstructive chronic pancreatitis underwent endoscopic therapy including endoscopic pancreatic sphincterotomy, pancreatic stricture dilation, pancreatic stone removal, pancreatic stent placement, or a combination of these methods. Over a mean period of 4.9 years (range: 2–12 years) 1118 patients (84%) were followed for symptomatic improvement and need for pancreatic surgery. Success of endoscopic therapy was defined as a significant reduction or elimination of pain and reduction in pain medication. Partial success was defined as reduction in pain though further interventions were necessary for pain relief. Failure of endoscopic therapy was defined as the need for pancreatic decompressive surgery or patients that were lost to follow-up.

Over long-term follow-up, 69% of patients were successfully treated with endoscopic therapy and 15% experienced a partial success. Twenty per cent of patients required surgery with a 55% significant reduction in pain. Five per cent of patients were lost to follow-up. The group of patients that had the highest frequency of completed treatment were patients with stones alone (76%) as compared to patients with strictures alone (57%) and patients with strictures and stones (57%) (P < 0.001). Interestingly, the percentage of patients with no or minimal residual pain at follow-up was similar in all groups (strictures alone 84%, stones alone 84%, and strictures plus stones 87%) (P = 0.677). The authors of this report concluded that endoscopic therapy of chronic pancreatitis in experienced centers is effective in the majority of patients, and the beneficial response to successful endoscopic therapy in chronic pancreatitis is durable and long-term [26].

Only randomized controlled studies comparing surgical, medical, and endoscopic techniques will allow us to determine the true long-term efficacy of pancreatic duct stenting for stricture therapy. There remain many unanswered questions: Which patients are the best candidates? Is proximal pancreatic ductal dilation a prerequisite? Does the response to stenting depend on the etiology of the chronic pancreatitis? Finally, as noted, how does endoscopic therapy compare with medical and surgical management?

Complications associated with pancreatic stents   

True complication rates are difficult to decipher due to (1) the simultaneous performance of other procedures (e.g. pancreatic sphincterotomy, stricture dilation), (2) the heterogeneous patient populations treated (i.e. patients with acute or chronic pancreatitis), and (3) the lack of uniform definitions of complications and a grading system of their severity [47]. Complications related directly to stent therapy are listed in Fig. 8[47,49].

Occlusion   

The pathogenesis of pancreatic stent occlusion on scanning electron microscopy also mirrors biliary stent blockage with typical biofilm and microcolonies of bacteria mixed with crystals, similar to biliary sludge. The rate of pancreatic stent occlusion appears to be similar to that for biliary stents [35]. We found that 50% of pancreatic stents (primarily 5–7 Fr) were occluded within 6 weeks of placement and 100% of stents were occluded at more than 9 weeks when carefully evaluated by water flow methods. More than 80% of these early occlusions were not associated with adverse clinical events. In such circumstances, the stent is perhaps serving as a dilator or a wick. Similarly, stents reported to be patent for as long as 38 months [17] are clinically patent but would presumably be occluded by water flow testing.

Migration   

Stent migration may be upstream (i.e. into the duct) or downstream (i.e. into the duodenum). Migration in either direction may be heralded by return of pain or pancreatitis. Johanson and associates [50] reported inward migration in 5.2% of patients and duodenal migration in 7.5%. These events occurred with single intraductal and single duodenal stent flanges. Rarely, surgery is needed to remove a proximally migrated stent. Modifications in pancreatic stent design have greatly reduced the frequency of such occurrences. Dean and associates [51] reported no inward migration in 112 patients stented with a four-barbed (two internal and two external) stent. We have had no inward migration in greater than 3000 stents with a duodenal pigtail.

Stent-induced duct changes   

Although therapeutic benefit has been reported for pancreatic stenting, it is evident that morphological changes of the pancreatic duct directly related to this therapy occur in the majority of patients. In summarizing the results of seven published series [52–55,57–59], new ductal changes were seen in 54% (range: 33–83%) of 297 patients. Limited observations to date indicate a tendency of these ductal changes to improve with time following stent change and/or removal [44,45,47,50,52,53,55,57–59].

The long-term consequences of these stent-induced ductal changes remain uncertain. Moreover, the long-term parenchymal effects have not been studied in humans. In a pilot study, six mongrel dogs underwent pancreatic duct stenting for 2–4 months [49]. Radiographic, gross, and histological abnormalities developed in all dogs. The radiographic findings (stenosis in the stented region with upstream dilation) were associated with gross evidence of fibrosis, which increased proportionally with the length of the stenting period. Histological changes of obstructive pancreatitis were present in most experimental dogs.

Although follow-up after stent removal was short, the atrophy and fibrosis seen were not likely to be reversible. In a recently reported study [59], parenchymal changes (hypoechoic area around the stent, heterogeneity, and cystic changes) were seen on endoscopic ultrasound in 17 of 25 patients undergoing short-term pancreatic duct stenting. Four patients who had parenchymal changes at stent removal had a follow-up study at a mean time of 16 months. Two patients had (new) changes suggestive of chronic pancreatitis (heterogeneous echotexture, echogenic foci in the parenchyma, and a thickened hyperechoic irregular pancreatic duct) in the stented region. While such damage in a normal pancreas may have significant long-term consequences, the outcome in patients with advanced chronic pancreatitis may be inconsequential.

Brief mini-stents   

If brief interval stenting is needed (such as for pancreatic sphincterotomy, we now commonly use small diameter stents (3 or 4 Fr) with no intraductal barb [83](Fig. 3). Depending on their length, 80–90% of these stents migrate out of the duct spontaneously. Further studies addressing issues of stent diameter as well as composition and duration of therapy as they relate to safety and efficacy are needed. Additionally, further evaluation of expandable stents, particularly the coated models, is awaited.

 Pancreatic ductal stones   

Causes of pancreatic ductal stones   

Worldwide, alcohol consumption appears to be the most important factor associated with chronic calcifying pancreatitis. Although the exact mechanism of intraductal stone formation has not been clearly elucidated, considerable progress in this area has been made [60]. Alcohol appears to be directly toxic to the pancreas and produces a dysregulation of secretion of pancreatic enzymes (including zymogens), citrate (a potent calcium chelator), lithostathine (pancreatic stone protein), and calcium. These changes favour the formation of a nidus (a protein plug), followed by precipitation of calcium carbonate to form a stone [60,61].

Stones cause obstruction   

The rationale for intervention is based on the premise that pancreatic stones increase the intraductal pressure (and probably the parenchymal pressure, with resultant pancreatic ischemia) proximal to the obstructed focus. Reports indicating that endoscopic (with or without ESWL) or surgical removal of pancreatic calculi results in improvement of symptoms support this notion [15]. Moreover, stone impaction may cause further trauma to the pancreatic duct, with epithelial destruction and stricture formation [53,55]. Thus, identification of pancreatic ductal stones in a symptomatic patient warrants consideration of removal. One or more large stones in the head with upstream asymptomatic parenchymal atrophy probably warrant therapy also.

Endoscopic techniques for stone extraction   

Pancreatic sphincterotomy   

A major papilla pancreatic sphincterotomy (in patients with normal anatomy, i.e. no pancreas divisum) is usually performed to facilitate access to the duct prior to attempts at stone removal. There are two methods available to cut the major pancreatic sphincter [63,64]. A standard pull type sphincterotome (with or without a wire guide) is inserted into the pancreatic duct and orientated along the axis of the pancreatic duct (usually in the 12–1 o'clock position). Although the landmarks to determine the length of incision are imprecise, authorities recommend cutting 5–10 mm [63] (Fig. 9A). The cutting wire should not extend more than 6–7 mm up the duct when applying electrocautery so as to prevent deep ductal injury. Alternatively, a needle knife can be used to perform the sphincterotomy over a previously placed pancreatic stent [63,64].

Biliary sphincterotomy also?   

Some authorities favour performing a biliary sphincterotomy prior to the pancreatic sphincterotomy because of the high incidence of cholangitis if this is not done [64]. Patients with alkaline phosphatase elevation from chronic pancreatitis-induced biliary strictures are especially at risk for cholangitis (if no biliary sphincterotomy is performed) [65]. Such complications were not found by others [23,24,64,65]. Performing a biliary sphincterotomy first, however, can expose the pancreatico-biliary septum and allow the length of the cut to be gauged more accurately.

Pancreas divisum   

In patients with pancreas divisum, a minor papilla sphincterotomy is usually necessary. The technique is similar to that of major papilla sphincterotomy, except that the direction of the incision is usually in the 10–12 o'clock position and the length of the sphincterotomy is limited to 4–8 mm.

Stone removal   

The ability to remove a stone by endoscopic methods alone is dependent on stone size and number, duct location, presence of downstream stricture, and the degree of impaction [67,68]. Downstream strictures usually require dilation with either catheters or hydrostatic balloons. Standard stone-retrieval balloons and baskets are the most common accessories used to remove stones. Passage of these instruments around a tortuous duct can be difficult, but use of over-the-wire accessories are usually helpful. Stone removal is then performed in a fashion similar to bile duct stone extraction (Fig. 10) Occasionally, mechanical lithotripsy is necessary, particularly when the stone is larger in diameter than the downstream duct or the stone is proximal to a stricture. A rat tooth forceps may be helpful when a stone is located in the head of the pancreas close to the pancreatic orifice.

Results of endoscopic treatment for stones   

Sherman and colleagues   

Sherman and colleagues attempted to identify those patients with predominately main pancreatic duct stones most amenable to endoscopic removal and to determine the effects of such removal on the patients' clinical course [67].

Thirty-two patients with ductographic evidence of chronic pancreatitis and pancreatic duct stones underwent attempted endoscopic removal using various techniques, including bile duct and/or pancreatic duct sphincterotomy, stricture dilation, pancreatic duct stenting, stone basketing, balloon extraction, and/or flushing. Of these patients, 72% had complete or partial stone removal, and 68% had significant symptomatic improvement after endoscopic therapy. Symptomatic improvement was most evident in the group of patients with chronic relapsing pancreatitis (vs. those presenting with chronic continuous pain alone; 83% vs. 46%).

Factors favouring complete stone removal included (1) three or fewer stones, (2) stones confined to the head or body of the pancreas, (3) absence of a downstream stricture, (4) stone diameter less than or equal to 10 mm, and (5) absence of impacted stones.

After successful stone removal, 25% of patients had regression of the ductographic changes of chronic pancreatitis, and 42% had a decrease in the main pancreatic duct diameter. The only complication from therapy was mild pancreatitis, occurring in 8%.

Smits and colleagues   

Smits and colleagues reported [68] results of 53 patients with pancreatic duct stones treated primarily by endoscopic methods alone (8 had ESWL). Stone removal was successful in 42 patients (79%; complete in 39 and partial in 3), with initial relief of symptoms in 38 (90%). Similar to the results reported by Sherman et al. [67], in this series, 3 of 11 patients (27%) with failed stone removal had improvement in symptoms, suggesting that some of the clinical response may be related to other therapies performed at the time of attempted stone removal (e.g. pancreatic sphincterotomy).

During a median follow-up of 33 months, 13 patients had recurrent symptoms due to stone recurrence. The stones were successfully removed in 10 (77%). No factor evaluated (etiology of pancreatitis, presentation with pain or pancreatitis, presence of single or multiple stones, location of stones, presence or absence of a stricture) was shown to predict successful stone treatment (defined as complete or partial removal of stones, resulting in relief of symptoms).

Cremer and colleagues   

Cremer and colleagues [37] reported results of 40 patients with pancreatic duct stones who were treated by endoscopic methods alone. Complete stone clearance was achieved in only 18 (45%). However, immediate resolution of pain occurred in 77%. During a 3-year follow-up, 63% remained symptom free. Clinical steatorrhea improved in 11 of 15 patients (73%).

Summary results   

Figure 11 summarizes six selected series [37,67–71] reporting the results of pancreatic stone removal by endoscopic methods alone. Complete stone clearance was achieved in 93 of 147 patients (63%). The major complication rate was 9% (primarily pancreatitis), and the mortality rate was 0%. Cremer et al. [37] reported bleeding in 3% and retroperitoneal perforation in 1.4%. Sepsis was an infrequent complication. During a 2.5-year (approximate) follow-up, 74% of patients had improvement in their symptoms.

Endoscopic therapy with ESWL   

As noted, endoscopic methods alone will likely fail in the presence of large or impacted stones and stones proximal to a stricture. ESWL can be used to fragment stones and facilitate their removal (Fig. 12). Thus, this procedure is complementary to endoscopic techniques and improves the success of non-surgical ductal decompression.

Sauerbruch and colleagues   

Sauerbruch and colleagues [76] were the first (in 1987) to report the successful use of ESWL in the treatment of pancreatic duct stones. Since that time, more than 400 patients have been reported in the literature [66,74–81]. Patients with obstructing prepapillary concrement and upstream ductal dilation appear to be the best candidates for ESWL. In the largest reported series, 123 patients with main pancreatic duct stones and proximal dilation were treated with an electromagnetic lithotriptor, usually before pancreatic duct sphincterotomy [66]. Stones were successfully fragmented in 99%, resulting in a decrease in duct dilation in 90%. The main pancreatic duct was completely cleared of all stones in 59%. Eighty-five per cent of patients noted pain improvement during a mean follow-up of 14 months. However, 41% of patients had a clinical relapse due to stone migration into the main pancreatic duct, progressive stricture, or stent occlusion.

This same center compared their results of pancreatic stone removal prior to the availability of ESWL and after the introduction of adjunctive ESWL therapy [37]. Stones were successfully cleared in 18 of 40 patients (45%) by endoscopic methods alone, compared with 22 of 28 (78.6%) with ESWL. Figure 13 summarizes the results of nine selected series reporting the efficacy and safety of adjunctive ESWL [66,67,74,75,77–81]. Complications in these series were related primarily to the endoscopic procedure.

Although ultrasound-focused ESWL has been reported to achieve stone fragmentation, such focusing is clearly more difficult. In the series reported by Schneider and associates [77], stone localization was achieved in 17 of 119 sessions (14%) when only ultrasonography was used to monitor the position of the stone.

The Brussels group   

The Brussels group [79] studied 70 pancreatic stone patients who underwent attempts at endoscopic removal, with adjunctive ESWL used in 41 (59%). This was a fairly homogeneous group of patients in that those with strictures, previous pancreatic surgery, and failed pancreatic sphincterotomy were excluded. The authors evaluated the immediate technical and clinical results and reviewed the long-term outcome in patients followed for more than 2 years.

Complete (n = 35) or partial (n = 20) stone removal was achieved in 79%, and was more frequently observed when ESWL was performed (P < 0.005) and in the absence of a non-papillary ductal substenosis or complete main duct obstruction (P < 0.05). Complete stone clearance was most frequently observed with single stones or stones confined to the head (P < 0.05). In the multivariate analysis, ESWL was the only independent factor influencing the technical results of endoscopic management. In this series, the number of ERCPs performed per patient was reduced from 3.4 to 2.7 after the introduction of ESWL (P < 0.01). Of the 56 patients with pain on admission, 53 (95%) were pain free (n = 41) or had a reduction in pain (n = 12).

In both the univariate and multivariate analyses, a significant association was found between immediate disappearance of pain and complete or partial main pancreatic duct clearance. During the first 2 years of follow-up after therapy, 25 of 46 (54%) patients were totally pain free, whereas the frequency of pain attacks in the remaining 21 was halved. This frequency of recurrent symptoms (46%) is comparable to that of surgical series [82].

Long-term pain relief was associated with (1) earlier treatment after disease onset (P < 0.005), (2) a low frequency of pain attacks before therapy (P < 0.05), and (3) absence of non-papillary substenosis of the main pancreatic duct (P < 0.05).

Interestingly, outcome was not associated with prior or continued alcohol intake. In the multivariate analysis, pain recurrence was independently associated with the frequency of pain attacks before therapy, the duration of disease, and the presence of non-papillary stenosis of the main pancreatic duct. It was suggested that such substenosis can induce ductal hypertension by blocking migration of fragmented stones or by progressing to higher-grade stenosis. Twenty per cent underwent subsequent pancreatic surgical procedures. Of the remaining 28 patients, there was statistically significant improvement in mean pain scores, narcotic use, and hospitalizations when comparing intervals before and after stone therapy [83].

Kozarek and colleagues   

Kozarek and colleagues performed a retrospective review of the efficacy of ESWL as an adjunct to endoscopic therapy in 40 patients who underwent a total of 46 ESWL sessions (an average of 1.15 sessions/patient). Eighty per cent of patients did not require surgery and had significant pain relief, reduced number of hospitalizations, and reduced narcotic use as compared to the pre-ESWL period over a mean 2.4-year follow-up [80].

Farbacher and colleagues   

Farbacher and colleagues retrospectively reviewed the efficacy of pancreatic stone clearance with endoscopic and ESWL therapy. Technical success was achieved in 85% of the 125 patients. The majority of the patients (111 of 125) required piezoelectric ESWL for stone fragmentation. ESWL was safe, without any serious complications.

Middle-aged patients in the early stages of chronic pancreatitis with stones in a prepapillary location were the best candidates for successful treatment and required the least number of ESWL treatment sessions [81]. These aforementioned studies reaffirm that ESWL as an adjunct to endoscopic pancreatic therapy is effective, and the results of the combined modality may obviate the need for surgery. The results of endoscopic therapy in conjunction with ESWL for pancreatic stone disease compare favourably to the outcomes in surgically treated patients.

Intraductal lithotripsy   

Intraductal lithotripsy via mother/baby scope systems has largely failed due to inability to maneuver within the relatively narrow ductal system. Results with fluoroscopy-guided laser lithotripsy were similarly poor [71]. Pancreatoscopy (via a 'mother–baby' scope system) can be used to directly visualize laser fiber contact with the stone and fragmentation. Experience is limited to date [70,83].

Medical treatment for stones   

Stone dissolution via ductal irrigation (contact dissolution) or oral agent is an attractive endoscopic adjunct for stone removal.

Citrate   

Sahel and Sarles found that intraduodenal infusion of citrate in dogs significantly increased the citrate concentration in pancreatic juice [85]. This led to a non-randomized study of oral citrate in 18 patients with chronic pancreatitis, 17 of whom had pancreatic duct stones. Seven patients responded during a mean duration of therapy of 9.5 months, with a mean stone size reduction of 21% and an improvement in symptoms [61].

Berger et al. [86] performed nasopancreatic drainage in six patients with main pancreatic duct stones. The pancreatic duct was perfused with a mixture of isotonic citrate and saline at 3 ml/min for 4 days. A stone-free state was achieved in all cases.

Pancreatic pain disappeared during the perfusion, and four patients remained free of pain during the follow-up period (1–12 months). The remaining two patients had repeat therapy, which resulted in pain resolution. Pancreatic exocrine function was evaluated by the Lundh test in five patients before and after therapy. An increase of 50–360% was observed in enzyme output in three patients, while no improvement was noted in the remaining two patients. Trimethadione, an epileptic agent and a weak organic acid, has been shown in vitro to induce a concentration-dependent increase in calcium solubility [61].

Trimethadione   

Noda et al. [87] showed promising results for trimethadione in a dog model of pancreatic stones. Unfortunately, the doses used in the dogs, if extrapolated to humans, could potentially be toxic. At the present time, no rapidly effective solvent for human use is available to treat pancreatic stones. Further trials in humans are needed to establish a role for medical therapy (either alone or as an aid to endoscopic measures) in treating patients with symptomatic pancreatic duct stones.

Overall results for stone treatment   

These data suggest that removal of pancreatic duct stones may result in symptomatic benefit. Longer follow-up is necessary to determine the stone recurrence rate and whether endoscopic success results in longstanding clinical improvement or permanent regression of the morphological changes. Overall, endoscopists are encouraged to remove pancreatic duct stones in symptomatic patients when the stones are located in the main duct (in the head, body, or both) and are thus readily accessible.

The currently available data suggest that the clinical outcome after successful endoscopic removal is similar to surgical outcome, with lower morbidity and mortality [88]. Moreover, recurrence of symptoms due to migrated stone fragments can be treated again by endoscopy with or without ESWL.

On the other hand, re-operation rates for recurrent pain after surgery are as high as 20%, with a striking increase in morbidity and mortality after repeated surgery [82]. Controlled trials comparing endoscopic, surgical, and medical therapies are awaited.

 Pancreatic pseudocysts   

Pancreatic pseudocysts may complicate the course of chronic pancreatitis in 20–40% of cases [89,90]. Traditionally, surgery has been the treatment of choice for such patients. The introduction of ultrasound- and CT-guided needle and catheter drainage techniques provided a non-operative alternative for managing patients with pseudocysts.

Endoscopic treatment for pseudocysts   

More recently, an endoscopic approach has been applied for this indication. The aim of endoscopic therapy is to create a communication between the pseudocyst cavity and the bowel lumen. This can be done by a transpapillary and/or a transmural approach. The route taken depends on the location of the pseudocyst and whether it communicates with the pancreatic duct or compresses the gut lumen. More than 400 cases of endoscopically managed pseudocysts have been reported (Fig. 14) [91–100]. The results indicate that endoscopic therapy is associated with a high technical success rate (80–95%), acceptably low complication rates (equal to or less than surgical rates), and a pseudocyst recurrence rate of 10–20% [95].

In the largest series reported [97], 100 of 108 patients (93%) had their pseudocysts successfully drained. Pseudocysts recurred in 13 (13%). The presence of chronic pancreatitis, obstructed pancreatic duct, ductal stricture, necrosis on CT scan, and a pseudocyst greater than 10 cm in size were not predictive of recurrent pseudocyst disease. Endoscopic therapy also has been shown to be effective in the management of partial [100] and complete pancreatic ductal disruptions [104], pancreatico-cutaneous fistulas, infected fluid collections [102], pancreatic ascites, pancreatic pleural effusions [9,103], and traumatic duct disruptions [103,104]. These studies and others [105] confirm the relative safety of endoscopic intervention in peripancreatic fluid collections (Fig. 14).

This topic is reviewed in detail by Howell in this same series.

 Biliary obstruction in chronic pancreatitis   

Intrapancreatic common bile duct strictures have been reported to occur in 2.7–45.6% of patients with chronic pancreatitis (Fig. 15). Such strictures are a result of a fibrotic inflammatory restriction or compression by a pseudocyst [107]. In one ERCP series, a common bile duct stricture was seen in 30% of patients, and was associated with persistent cholestasis, jaundice, or cholangitis in 9% [108]. Because longstanding biliary obstruction can lead to secondary biliary cirrhosis and/or recurrent cholangitis, biliary decompression has been recommended. Surgical therapy has been the traditional approach. Based on the excellent outcome (with low morbidity) from endoscopic biliary stenting in postoperative stricture [109], however, evaluation of similar techniques for bile duct strictures complicating chronic pancreatitis was undertaken.

Standard biliary stents   

Deviere and colleagues   

Deviere and colleagues [108] evaluated the use of biliary stenting (one or two plastic 10 Fr C-shaped stents) in 25 chronic pancreatitis patients with bile duct obstruction and significant cholestasis (alkaline phosphatase > two times the upper limits of normal). Nineteen patients had jaundice and seven presented with cholangitis.

Following stent placement, cholestasis, hyperbilirubinemia, and cholangitis resolved in all patients. Late follow-up (mean: 14 months; range: 4–72 months) of 22 patients was much less satisfactory. One patient died of acute cholecystitis and postsurgical complications, whereas a second died 10 months after stenting of sepsis, which was believed to be due to stent blockage or dislodgement. Stent migration occurred in 10 patients and stent occlusion in eight, resulting in cholestasis with or without jaundice (n = 12), cholangitis (n = 4), or no symptoms (n = 2).

These patients were treated with stent replacement, surgery, or both (n = 7). Ten patients continued to have a stent in place (mean follow-up: 8 months) and remained asymptomatic. Because of resolution of their biliary stricture, only three patients required no further stents. The initial observation of this study is that biliary drainage is an effective therapy for resolving cholangitis or jaundice in patients with chronic pancreatitis and a biliary stricture. The long-term efficacy of this treatment, however, is much less satisfactory, because stricture resolution rarely occurs.

The Amsterdam group   

The Amsterdam group reported their results of placing 10 Fr biliary stents in 52 chronic pancreatitis patients with cholestasis [15]. Jaundice and cholestasis disappeared within 2 weeks after stent insertion in all patients. During a median follow-up duration of 32 months (range: 3 months to 10 years), 17 patients (33%) had their stent removed without return of cholestasis. Complete resolution of the stricture was seen in 10 of the 17 patients. This suggested that complete resolution of the stricture was not necessary for long-term relief of symptoms and cholestasis.

Barthet and colleagues   

Barthet and colleagues [110] also found that biliary stenting is not a definitive therapy for chronic pancreatitis patients with a distal common bile duct stricture. In their series of 19 patients (mean duration of stenting: 10 months) only 2 had complete clinical (resolution of symptoms), biological (normalization of cholestatic liver tests), and radiological (resolution of biliary stricture and upstream dilation) recovery. Six of 10 (60%) possible clinical successes, 8 of 19 (42%) possible biological successes, and 3 of 19 (16%) possible radiological successes were obtained.

Metal stents for biliary obstruction?   

Because of the disappointing results with plastic stents and the concern for the high morbidity associated with surgically performed biliary drainage procedures in alcoholic (frequently debilitated) patients, the group from Brussels evaluated the use of uncoated expandable metal stents for this indication [112].

Twenty patients were treated with a 34-mm long metal stent, which becomes 10 mm in diameter when fully expanded. The short length of the stent was chosen so surgical bypass (e.g. choledochoduodenostomy) would still be possible if necessary. Cholestasis (n = 20), jaundice (n = 7), and cholangitis (n = 3) resolved in all patients. Eighteen patients had no further biliary problems during a follow-up period of 33 months (range: 24–42 months). Two patients (10%) developed epithelial hyperplasia within the stent, resulting in recurrent cholestasis in one and jaundice in the other. These patients were treated endoscopically with standard plastic stents, with one of these patients ultimately requiring surgical drainage. The authors concluded that this therapy could be an effective alternative to surgical biliary diversion, but longer follow-up and controlled trials are necessary to confirm these results.

In a recent abstract report, the Amsterdam group reported the long-term follow-up (mean 50 months) of a cohort of 13 patients with chronic pancreatitis-induced biliary strictures who had undergone uncovered biliary Wallstent placement. Endoscopic Wallstent was successfully placed in all patients between 1994 and 1999. Nine patients (69%) were successfully treated and 4 patients failed Wallstent therapy. Of the nine patients treated successfully, four (44%) patients required repeated endoscopic intervention (three with a second Wallstent and one patient requiring cleaning with a balloon). One patient eventually required surgical biliary diversion and three patients are continuing to need endoscopic plastic stents through the Wallstent to maintain biliary patency [136].

Biodegradable stents   

A recent exciting development in stent technology, utilizing bioabsorbable poly L lactide (PLLA) polymer strands woven into the tubular mesh design similar to the metallic stent, was reported by Haber et al. [111]. The PLLA stent is unique in that it undergoes slow hydrolytic degradation and disintegration after 6–18 months. In the feasibility study in patients with malignant obstructive jaundice, the endoscopic technique for placement of the bioabsorbable biliary stent was similar to present expandable stents and was technically successful in 48 of 50 patients. The unique feature of this stent is that it may obviate the need for follow-up endoscopy to remove/replace the stent and may potentially be an effective long-term option in benign, chronic pancreatitis-induced biliary strictures.

Stenting for biliary strictures and chronic pancreatitis: conclusion   

The aforementioned studies indicate that plastic biliary stents are a useful alternative to surgery for short-term treatment of chronic pancreatitis-induced common bile duct strictures complicated by cholestasis, jaundice, and cholangitis. This therapy also should be considered for high-risk surgical patients. Because the long-term efficacy of this treatment is much less satisfactory, however, operative intervention appears to be a better long-term solution for this problem in average-risk patients. More data on the long-term outcome, preferably in controlled trials, are necessary before the expandable metal stents can be advocated for this indication. Trials of membrane-coated metal stents, bioabsorbable stents, and removable coil spring stents are awaited.

 Sphincter of Oddi dysfunction in chronic pancreatitis   

Although sphincter of Oddi dysfunction (SOD) is a known cause of acute recurrent pancreatitis, its role in the pathogenesis of chronic pancreatitis is much less certain [113].

Pathogenesis of SOD in chronic pancreatitis   

A direct effect of alcohol on the sphincter of Oddi has been postulated [114]. In studies performed in humans with T tubes, it was demonstrated that intragastric or intravenous [115] administration of alcohol increased the sphincter tone.

Moreover, Guelrud and colleagues [106] showed that local instillation of alcohol on the papilla of Vater produced a significant increase in the basal pancreatic sphincter pressure at sphincter of Oddi manometry in both cholecystectomy patients and patients with chronic pancreatitis. The authors postulated that the increased motor activity of the sphincter of Oddi may raise the intraductular pancreatic pressure and result in disruption of small pancreatic ductules, and back flow of pancreatic juice into the parenchyma, with subsequent injury.

Other investigators have refuted these findings by showing that intravenous or intragastric administration of alcohol in humans results in a decrease in sphincter of Oddi basal pressures at manometry [117].

In a preliminary study, Morita et al. showed that chronic alcohol administration in the Japanese monkey resulted in an increase in sphincter of Oddi mean basal pressure from 9 to 20 mmHg (P < 0.01), while phasic amplitude decreased by 75% and the pancreatic ductal secretory rate nearly doubled [118].

Frequency of SOD in chronic pancreatitis   

More recent studies using modern manometric techniques have shown a high frequency of basal sphincter pressure abnormalities, especially the pancreatic sphincter, in patients with established chronic pancreatitis [119]. Results of other studies using sphincter of Oddi manometry refute these findings and have shown no difference in the dynamics of the pancreatic sphincter in patients with chronic pancreatitis and controls [120]. Such data suggest the sphincter, at times, becomes dysfunctional as part of the overall general scarring process or has a role in the pathogenesis of chronic pancreatitis.

Surgical sphincter ablation   

The surgical literature, although limited, suggests that sphincter ablation therapy (both the biliary and pancreatic sphincters) alone for patients with chronic pancreatitis and manometrically documented or suspected SOD benefits 30–60% of patients [121,122]. Bagley and associates reported a surgical series [123] of 67 patients with mild to moderate chronic pancreatitis undergoing empirical biliary and pancreatic sphincterotomy (n = 33) or sphincteroplasty (n = 34). During a 5-year follow-up, 44% of patients had pain relief. The outcome for patients with idiopathic chronic pancreatitis was similar to that for patients with alcohol-induced chronic pancreatitis. However, 92% (11/12) of patients who stopped alcohol consumption were clinically improved, compared with 12.5% (2/16) of those who continued to drink.

Endoscopic pancreatic sphincterotomy   

Because endoscopic pancreatic sphincterotomy has been performed infrequently in most institutions, its role in the management of pancreatic sphincter stenosis has not been defined. Kozarek et al. reported resolution of pain and clinical episodes of pancreatitis after pancreatic sphincterotomy in 6 of 10 patients (1-year follow-up) with chronic pancreatitis and suspected or manometrically documented pancreatic SOD [63]. Okolo et al. retrospectively evaluated 55 patients who had undergone endoscopic pancreatic sphincterotomy over a 4 year period. After a median follow-up of 16 months, 62% of patients reported improvement of pain scores. Patients with pancreatic sphincter dysfunction (n = 15) had significant improvement in pain (73%) compared to patients with pancreatographic evidence of chronic pancreatitis (58%) [137]. The utility of endoscopic sphincter ablation as the only therapy in patients with chronic pancreatitis awaits further study, preferably in controlled randomized trials.

 Pancreas divisum   

Pancreas divisum is the most common congenital variant of pancreatic ductal anatomy, occurring in 7% of autopsy series [124]. Most commonly, in the setting of chronic pancreatitis, minor papilla sphincterotomy is performed to provide access to the duct to effect stone retrieval or facilitate endoprosthesis placement [9].

Pancreas divisum: a cause of pancreatitis?   

It has been postulated that in a subpopulation of pancreas divisum patients, the minor papilla orifice appears to be critically small, such that excessively high intrapancreatic dorsal duct pressures occur during active secretion [124]. This may result in pancreatic pain or pancreatitis [125]. Although most authorities agree that pancreas divisum is a definite cause of acute recurrent pancreatitis, its role in the pathogenesis of chronic pancreatitis is much more controversial. Several lines of evidence favour the association of pancreas divisum and pancreatitis, including (1) the presence of pancreatographic and histological changes of chronic pancreatitis isolated to the dorsal pancreas, (2) an increased incidence of pancreas divisum in patients with idiopathic pancreatitis, and (3) symptomatic benefit following dorsal duct drainage, endoscopically or surgically [124].

Minor papilla ablation   

Although minor papilla sphincter therapy by endoscopic or surgical techniques has been shown to be effective for patients with pancreas divisum and acute recurrent pancreatitis, the outcome for patients with chronic pancreatitis has usually been much less satisfactory [21,56,126–132] (Fig. 16). In summarizing 54 patients undergoing dorsal duct decompressive therapy by minor papilla sphincterotomy and/or dorsal duct stenting, only 44% improved during a mean follow-up of 22 months.

A recent 4-year follow-up summary from our institution showed a similar 62–70% symptom improvement rate for pancreas divisum patients with and without dorsal duct chronic pancreatitis changes. These data suggest that methods used to select patients with pancreas divisum and chronic pancreatitis who are likely to benefit from endoscopic therapy need further investigation. The role of botulinum toxin use in predicting pain relief warrants further study [133].

Until such methods are identified, minor papilla sphincterotomy (as the only therapy) for patients with chronic pancreatitis should preferably be done in a research setting and restricted to patients who are disabled by pain.

 Outstanding issues and future trends   

Endoscopic therapy of chronic pancreatitis is an expanding area for the interventional endoscopist. The techniques employed are very similar to the endoscopic interventions utilized in the biliary tree but tend to be more tedious. The appropriate selection of candidates for the various pancreatic interventions appears to be important to obtain optimal results of therapy. The continued improvement in resolution of magnetic resonance cholangiopancreatography may allow for suitable patient selection for endoscopic therapy without the need to perform an initial diagnostic ERCP [134,135].

Over the past decade, multiple series totaling a few thousand patients have demonstrated the medium-term effectiveness of endoscopic interventions in chronic pancreatitis, rivaling the medium-term outcomes from surgery in this disease. ESWL has proven to be indispensable in the management of patients with pancreatic stones. However, well-designed, long-term controlled studies comparing endoscopy to surgery in the management of patients with chronic pancreatitis are lacking. Further outcome and cost efficacy studies are awaited. The inexperienced endoscopist should exercise caution in application of newer pancreatic techniques as they are technically demanding and associated with a small but significant complication rate.

Acknowledgement   

We greatly appreciate the assistance of Joyce Eggleston in the preparation of this document.

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