Endoscopic therapy in chronic pancreatitis.

Pancreas divisum is the most common congenital variant of pancreatic ductal anatomy and occurs when the dorsal and ventral PDs fail to fuse during the second month of gestation. With duct nonunion, the major portion of the pancreatic exocrine juice drains into the duodenum via the dorsal duct and minor papilla. It has been proposed that relative obstruction of pancreatic exocrine juice flow through the minor papilla could result in pancreatic-type abdominal pain, acute pancreatitis, or CP in a subpopulation of pancreas divisum patients [ 73 ]. Endoscopic attempts to decompress the dorsal duct in symptomatic pancreas divisum patients have been performed primarily by dilation, stent insertion, and/or minor papilla sphincterotomy. The reported symptom improvement following endoscopic therapy for pancreas divisum in the setting of CP is much lower than for the recurrent acute pancreatitis. In 52 patients treated (11 with CP) by minor papilla sphincterotomy, Lehman et al. [ 74 ] reported that 27% of the CP group benefited compared with 76.5% of the acute recurrent pancreatitis group followed up for periods between 6 months and 1.5 years. A longer-term study (median follow-up of 43 months) of 113 pancreas divisum patients (22 had CP) treated by minor papilla therapy was reported by Borak et al. [ 75 ]. Primary and secondary success rates for CP were 18.2% and 45.5% vs. 53.2% and 71% in the acute and recurrent pancreatitis groups, respectively. These data show that minor papilla therapy of pancreas divisum patients with CP is less effective than the same therapy in patients with acute recurrent pancreatitis. However, endoscopic therapy can still be offered to patients with disabling symptoms. It should be appreciated that the endoscopic approach to ductal disease in patients with pancreas divisum is the same as in nondivisum patients.

Pseudocysts are encapsulated collections of pancreatic juice, pure and/or containing inflammatory/necrotic debris, which are situated either outside or within the limits of the pancreas from which they arise. They complicate the course of CP in 20-40% of patients, and spontaneous resolution occurs in < 10% of cases, mostly for collections < 3 cm in diameter [ 58 , 59 ]. In CP, pseudocysts can occur as a result of rupture of a side branch or the main PD itself due to PD hypertension, or they may occur as a consequence of the ongoing inflammatory process. Although many pseudocysts fail to resolve spontaneously, not all require drainage. The American Society of Gastrointestinal Endoscopy recommends that pseudocyst drainage should be considered for 1) symptomatic lesions (abdominal pain, gastric outlet obstruction, early satiety, weight loss, or jaundice), 2) infected cysts, or 3) enlarging cysts [ 60 ]. If a collection develops due to an episode of acute-on-chronic pancreatitis, endoscopic drainage is usually considered after a minimum of 4-6 weeks to allow liquefaction of necrosis (thick debris does not drain well through small-diameter endoscopic stents) and for a formed wall to develop [ 61 ]. If drainage cannot be delayed due to sepsis, surgical debridement (or in selected cases, endoscopic necrosectomy with abundant lavage) is recommended [ 62 ]. Optimal management of a pseudocyst requires a multidisciplinary approach with input from surgery, gastroenterology, and interventional radiology. The technical and long-term success of endoscopic pseudocyst drainage increase for a single-compartment cyst with a mature wall and absence of necrosis. Selection of the route (transpapillary vs. transmural) of endoscopic drainage depends on the presence of communication between the pseudocyst and pancreatic ductal system and on the size of the cyst. This information can be ascertained from any combination of imaging with EUS, magnetic resonance cholangiopancreatography (MRCP) with secretin stimulation, or ERP. Endoscopic transmural drainage is chosen if the cyst is not communicating with the duct, whereas the transpapillary route is preferred if there is communication with PD and the cyst size is relatively small (usually < 5-6 cm). If the communicating pseudocyst is particularly large, combined transpapillary and transmural drainage can be performed. Transpapillary drainage usually requires a pancreatic sphincterotomy prior to placement of the pancreatic stent. Conventional transmural drainage can be performed without EUS guidance when 1) gastric bulge/luminal impression by the cyst is present, 2) collateral blood vessels from portal hypertension are absent, and 3) the distance from the pseudocyst to the gastric/duodenal lumen on imaging studies is < 1 cm. For pseudocysts that are not amenable to such conventional endoscopic drainage, EUS-guided drainage has been shown to be equally successful, with no increased risk of complications [ 63 ]. Broad-spectrum antibiotic coverage by the intravenous route is given immediately prior to the endoscopic drainage procedure. The aim of direct cystenterostomy is to create a communication between the cyst lumen and the gastric or duodenal lumen. The first step is to puncture the gut wall at the apex of the visible bulge ( Fig. 3A and 3B ) using a needle knife via a duodenoscope or, if EUS is indicated, a 19-gauge fine needle aspiration (FNA) needle via a linear echoendoscope [ 64 , 65 ]. Once the puncture is achieved, a guide wire is advanced through the needle knife or FNA needle into the cyst cavity and looped 360° to secure positioning under fluoroscopic guidance ( Fig. 3C ). The newly created tract is then balloon dilated to 8-10 mm in size, or larger if necrotic material is present ( Fig. 3D ). This is usually followed by vigorous flow of pseudocyst fluid into the gut lumen, prior to which care should be taken to have aspiration precautions in place, with the head of the fluoroscopy table elevated and oropharyngeal suction. Two or more double pigtail stents are placed transmurally into the cyst cavity. Pre-assembled EUS-guided puncture kits are now commercially available to circumvent numerous steps of cyst entry, exchange of guide wires, and stent placement. A nasocystic drain is placed in the presence of significant debris/necrosis or infection to allow for lavage of the cyst cavity. After drainage, the size of the cyst cavity is followed via ultrasound or CT scan at 4-6-week intervals to assess resolution. Once the cyst resolves, the transmural stents can be removed. If a pancreatogram had not been obtained and ductal disease treated at the initial endoscopic procedure, this should be done at the time of stent removal. Procedural technical success ranges from 85 to 100%, and the rate of successful resolution of the cyst was approximately 90% in pooled patients from multiple series [ 66 ]. In these series, the long-term recurrence rate was 10-15%, and complications rates, primarily bleeding and perforation, were 10-34%. More recent studies [ 63 , 67 , 68 ] showed similar results with technical success > 90%, long-term cyst and symptom resolution rates ranging from 71 to 91%, and recurrence rates ranging from 16 to 18%. Baron et al. [ 69 ] reported that the rate of pseudocyst resolution was higher (92%) in patients with CP than in those with acute pancreatitis (74%), with comparable complication rates between the two groups (17% and 19%, respectively, p value not significant). These excellent results support the use of endoscopic drainage in appropriate patients, and the overall complication rates compare favorably to surgical interventions.

CP is a debilitating disease with pain as its major presentation. The cause of pain is multifactorial and is thought to arise from several complications, such as ductal strictures, ductal stones, pseudocysts, and pancreatic cancer, which contribute to significant morbidity and mortality. A multidisciplinary approach on a case-by-case basis involving medical, endoscopic, and surgical management is the ideal approach for treatment of CP. Although two randomized studies have shown that surgical management is more durable for the treatment of pain in a select group of patients with PD strictures/stones in the head and upstream dilation, it may not always be a feasible option due to patient comorbidities or preferences. Endotherapy can be performed with various combinations of pancreatic sphincterotomy, stent placement, stricture dilation, ESWL, stone removal, pseudocyst drainage, and EUS-guided access and therapy. Endoscopic management has shown reasonable success in select patient populations, although the true rate of success is difficult to determine due to the retrospective nature of the majority of studies as well as to the variability in natural history and the multifactorial nature of pain in CP. Further randomized comparative controlled trials are warranted to define the role of endoscopic treatment of CP. Further refinements in endoscopic equipment dedicated to the pancreas and advancements in technology may help to improve the outcomes of endoscopic treatment.

Common bile duct stricture in CP can be malignant or from benign disease. It is important to exclude malignancy with a CT scan of the abdomen with pancreatic protocol and EUS with or without FNA prior to endoscopic treatment if there is clinical suspicion. Once the biliary stricture is determined to be benign, it is important to identify correctable causes, such as a pseudocyst causing extrinsic compression on the bile duct or pancreatic inflammation/edema in the setting of acute exacerbation of CP. The precise incidence of benign biliary strictures (BBSs) secondary to fibrosis and calcification within the pancreatic head is unknown and varies from 3 to 46% [ 76 ]. This type of BBS is irreversible without intervention and can result in jaundice, cholangitis, and progressive secondary biliary cirrhosis. Indications for biliary decompression in CP include symptoms (e.g., jaundice, cholangitis), biliary cirrhosis, common bile duct stones, progression of biliary stricture, and persistent asymptomatic elevation of alkaline phosphatase and/or bilirubin for > 1 month (a threshold twice the upper limit of normal values is often chosen for alkaline phosphatase) [ 77 ]. Hammel et al. [ 78 ] reported regression of hepatic fibrosis when the CBD was surgically drained. Although traditionally, BBSs in CP are treated by surgery with good long-term success, there is significant surgical morbidity in frequently debilitated patients with alcoholic CP and associated liver disease. Deviere et al. [ 79 ] were first to report the use of endoscopic treatment of the BBS in CP with endoscopic sphincterotomy, followed by insertion of one or two 10 Fr biliary stents with as-needed stent changes. Although technical success and short-term resolution of cholestasis and cholangitis was 100%, long-term (mean, 14 months; range, 4 to 72) stricture resolution was much less satisfactory, occurring at a rate of 12%. Another study also indicated low stricture resolution rates of only 10-38% over a mean follow up of 18-58 months [ 25 ]. Subsequent studies involving serial placement of multiple simultaneous biliary stents to achieve gradual dilation of the BBS improved outcomes, with a long-term resolution rate of BBSs with multiple plastic stents ranging from 44 to 92% over a 12 to 48-month follow-up period [ 80 - 82 ]. SEMSs (uncovered and partially covered) designed for permanent placement were evaluated for BBSs in the setting of CP. Again, technical success and initial reversal of cholestasis and cholangitis were 100%, although at long-term follow-up ranging from 22 to 50 months, the stents were occluded in 10-62% of cases. Stent patency rate dropped from 100% at 12 months to 40% at 24 months and 37.5% at 30 months [ 83 - 85 ]. In such patients, subsequent options are to refer for surgery or repeat endoscopic procedures for stent-in-stent placement. In an attempt to decrease the number of serial endoscopic procedures and avoid the disadvantage of clogged permanent stents. Kaheleh et al. [ 86 ] reported stricture resolution after a median stent interval of 4 months (range, 1 to 28) with a partially covered metal stent and no recurrent symptoms during a 12-month (range, 3 to 26) follow-up period after stent removal in 17 of 22 (77%) patients with CP. The same group had less success with fully covered stents. Eleven of 19 patients (58%) stented for a median of 3.3 months with a fully covered metal stent showed resolution of their stricture and no recurrent symptoms after stent removal during a 3.8-month follow-up period [ 87 ]. Briefly, in selected patients who are high-risk surgical candidates and those who wish to undergo endoscopic treatment for BBSs, endoscopic stenting with multiple plastic stents and/or self-expandable removable metal stents appears to be a potentially useful second-line therapy. However, more data on long-term outcomes, preferably in randomized trials in large numbers of patients, will be necessary before this therapy can be advocated as routine. One of the mechanisms of pain related to CP is peripancreatic and celiac neuronal inflammation. There has been long-standing interest in decreasing neuronal inflammation with steroids and decreasing the perception of pain with anesthetic nerve block or neurolysis with alcohol. Neurolysis is usually reserved for malignant diseases because of concerns regarding the long-term effects of alcohol injection, including retroperitoneal fibrosis. Percutaneous (via lumbosacral muscles) or surgical approaches were used previously; however, transgastric EUS-guided celiac plexus block (EUS-CPB) has gained favor in the last decade due to the high success rate, lower complication rates, and simplicity of performing the procedure. In this technique, a curvilinear array echoendoscope is used to identify the origin of the celiac trunk from the abdominal aorta. A recent report [ 88 ] also detailed the successful use of a prototype forward-viewing echoendoscope for performing celiac plexus neurolysis. The Mayo group showed that celiac ganglia can be directly visualized on EUS in 81% of patients [ 89 ] and that performing celiac ganglia block was technically feasible [ 90 ]. However, to date, there have been no studies comparing celiac ganglia block vs. celiac plexus block. Sakamoto et al. [ 91 ] recently showed that EUS-guided broad plexus neurolysis over the superior mesenteric artery using a 25-gauge needle gave better pain relief in pancreatic cancer patients than did conventional celiac plexus neurolysis. Whether this technique is applicable in cases of chronic pancreatitis using broad plexus block is still unknown. For celiac plexus or ganglia block, a 22- or 19-gauge EUS FNA needle is used for injection into the celiac region or, if feasible, directly in to the celiac ganglion. Once the FNA needle is advanced to the appropriate location, aspiration is first performed to make certain a vascular puncture has not occurred. Bupivacaine is first injected, followed by triamcinolone. Injection can be performed on one or both sides of the celiac trunk. In a prospective randomized trial, LeBlanc et al. [ 92 ] showed no difference in technical success, symptom response, or complication rates between one and two sites of injection during the same EUS-CPB session. Owing to the risk of hypotension, patients should be closely monitored for 2-4 hours after the procedure. In a retrospective series [ 93 ] and two prospective series [ 94 , 95 ], the overall success rate for EUS-CPB was 95%. The short-term pain improvement rate was 50-55%, and long-term pain relief at 12 weeks was 26%, whereas that at 24 weeks was 10%. Younger patients (< 45 years of age) and those with previous pancreatic surgery for CP were unlikely to have pain relief with EUS-CPB [ 94 ]. In a recent meta-analysis of 221 pooled patients from six studies, Kaufman et al. [ 96 ] found that the rate of short-term relief of abdominal pain from CP was 51.46%. Another meta-analysis of 376 patients from nine studies conducted by Puli et al. [ 97 ], which included both celiac plexus block and neurolysis for chronic pancreatitis, showed 59.45% short-term pain relief. Celiac ganglion injection under endosonographic guidance yielded pain improvement in five of 13 (38%) patients with CP when steroids were used vs. four of five (80%) patients receiving alcohol [ 90 ]. To date, there have been no studies comparing celiac plexus injection to sham controls [ 98 ], and there have been no head-to-head studies comparing neurolysis to nerve block in patients with chronic pancreatitis. Due to a lack of definite data, the relatively low response rates, and the requirement for repeat procedures, given the short duration of pain relief, EUS-CPB should be considered a temporizing measure reserved for cases in which oral analgesia is ineffective or in patients intolerant to medication side effects pending a more definitive intervention.

Chronic pancreatitis (CP) is a continuous inflammatory disease of the pancreas characterized by irreversible morphological changes that typically cause pain and/or permanent loss of function [ 1 ]. Patients with chronic pancreatitis are also at risk for developing pancreatic cancer. The aim of endoscopic therapy is to control symptoms, prevent progression of the disease, and correct complications. Pain is one of the main symptoms of chronic pancreatitis, and its etiology is multifactorial. Pain can result from increased pressure in the main pancreatic duct (PD) leading to intraparenchymal/interstitial hypertension or from peripancreatic/celiac neural inflammation [ 2 , 3 ]. Intraductal hypertension occurs primarily due to obstruction of pancreatic juice outflow from PD strictures, intraductal stones, decreased compliance of the main PD, and major/minor papillary sphincter stenosis [ 4 ]. Other factors that may indirectly contribute to pain include the complications of CP, such as pseudocysts, PD leaks/ascites, and biliary and duodenal obstruction. The role of endoscopic therapy in CP to alleviate pain by reducing outflow obstruction of the PD and by decreasing ductal hypertension has recently become the subject of debate. Two studies comparing endoscopic therapy to surgery have shown that surgical outcomes for pain relief were more durable [ 5 , 6 ]. However, the subjectivity of pain assessment, lack of blinding, and small sample size in these studies may have led to bias. Additionally, the specific disease characteristics, such as the presence of multiple pancreatic stones and the locations of the strictures, were not clearly described in the surgical group, which suggests there was a possibility of chance randomization of more refractory patients to the endoscopy treatment group. Hence, some authors [ 7 ] have suggested that endoscopic management plays a specific role in carefully selected patients as primary interventional therapy when medical measures fail or in high-risk surgical candidates. Endotherapy for CP is also utilized as a bridge to surgery or as a means to assess potential response to pancreatic surgery [ 8 ]. Finally, endotherapy is employed selectively by the authors for treatment of recurrent abdominal pain or complications after pancreatic surgery for CP. Other endoscopic therapies to relieve pain include the use of endoscopic ultrasound (EUS) to provide EUS-guided celiac block for CP. The role of endotherapy in improving pancreatic function is less clear, with a large multicenter study [ 9 ] showing no improvement in pancreatic function. However, one secretin-enhanced magnetic resonance cholangiopancreatography study suggested that pancreatic exocrine function can improve after endoscopic therapy [ 10 ], and another study showed that the development of clinical steatorrhea was delayed for about 10 years when compared with the natural history of chronic pancreatitis [ 11 ].