Chronic pancreatitis is a fibroinflammatory disease of the

Session 2C: Pancreaticobiliary Disease CHRONIC PANCREATITIS: WHEN TO SCOPE? Gregory A. Coté, MD, MS Chronic pancreatitis is a fibroinflammatory disease of the pancreas that presents with several distinct phenotypes and due to many different etiologies. In patients with known or suspected chronic pancreatitis, endoscopy is increasingly utilized for diagnosis and therapy: endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) represent the backbones of pancreatobiliary endoscopy. EUS, along with improved cross sectional imaging such as magnetic resonance cholangiopancreatography (MRCP) has largely replaced ERCP in the diagnostic algorithm. Still, ERCP represents a less invasive alternative to surgical therapies for chronic pancreatitis, particularly in the setting of an obstructed main pancreatic duct. Framed by the evidence supporting EUS and ERCP for each of these indications, this syllabus will review the principals of endoscopy in the diagnosis and treatment of chronic pancreatitis. EUS for Diagnosis 2 There are traditionally 9 criteria (4 parenchymal, 5 ductal) that indicate that a patient has pancreatic fibrosis. 3,4 Parenchymal changes include hyperechoic foci, hyperechoic strands, hypoechoic lobules, and cysts, whereas ductal changes include main or side-branch duct dilation, main duct irregularity, hyperechoic duct walls, and calcifications/stones (Figure 1). Combinations of these features can be difficult to distinguish from pancreatic cancer, particularly in pancreatic tissues with calcifications and echogenic shadowing. Patients have a very low probability of having chronic pancreatitis if none of these criteria are met; 5 3 or more criteria balance sensitivity (83%) with specificity (80-100%), compared to histological analysis. 6,7 Few studies have correlated changes detected by EUS Diagnosis In some cases, chronic pancreatitis represents an elusive diagnosis. Many patients will not present with pathognomonic changes on computed tomography (CT) scan such as parenchymal calcifications or main pancreatic duct stones. Chronic diarrhea, particularly in the setting of more fatty foods, may be a clue to exocrine pancreas insufficiency. Alternatively, routine laboratories (including serum amylase and lipase) and CT may be normal while a patient reports pancreatic-type abdominal pain: gnawing, deep and often severe pain in the epigastrium that may radiate to the back and is often exacerbated by eating. Unlike irritable bowel syndrome, which is typically associated with changes in bowel habits, and sphincter of Oddi dysfunction, which is classically associated with distinct, postprandial episodes of pain, pain related to occult (often termed minimal change ) chronic pancreatitis is more continuous in nature, unaffected by bowel habits, and infrequently associated with overt steatorrhea. Therefore, it is instructive to recall the TIGAR-O acronym for chronic pancreatitis risk factors (Table 1). 1 A diagnostic work-up for minimal change chronic pancreatitis should be considered, particularly in the setting of: 1) a reliable history suggestive of pancreatitis-type symptoms and 2) one or more TIGAR-O risk factors. While MRCP, with or without secretin enhancement, has certainly improved the diagnostic sensitivity of cross sectional imaging, endoscopy is often appropriate for diagnosis. Table 1: TIGAR-O Risk Factors for Chronic Pancreatitis Variable Toxic-metabolic Idiopathic Genetic Autoimmune Recurrent and severe acute pancreatitis Obstructive Risk factor Alcohol Tobacco Hypercalcemia Chronic renal failure Toxins/Medications Early onset Late onset Tropical Hereditary pancreatitis (cationic trypsinogen mutation) CFTR mutations SPINK 1 mutations Alpha-1 antitrypsin deficiency Isolated autoimmune CP Syndromic autoimmune CP Postnecrotic Recurrent acute pancreatitis Ischemic/vascular Pancreas divisum Intrapapillary mucinous tumor Duct obstruction (e.g., ductal adenocarcinoma) Sphincter of Oddi disorders Preampullary duodenal wall cysts Post-traumatic PD scars Session 2C: Pancreaticobiliary Disease 229

Figure 1 Figure 2 with histopathology findings from patients with minimalchange chronic pancreatitis, so the role of EUS in diagnosis of this disorder is questionable. ERCP for Diagnosis ERCP is limited to assessment of ductal characteristics of chronic pancreatitis and provides no information about parenchymal fibrosis. Chronic pancreatitis is classified based on the Cambridge criteria: 8 1. Mild >3 abnormal side branches 2. Moderate Inclusion of abnormalities of the main pancreatic duct 3. Severe Addition of pancreatic duct strictures, filling defects, or large cavities For patients with severe disease, findings from ERCP correlate with those from histopathology analysis. 8 However, in detection of early-stage chronic pancreatitis, findings from ERCP are often normal, so the overall correlation of ERCP with histopathology is only 75%. 9,10 EUS for Therapy Celiac plexus block The celiac plexus is one of several purported locations mediating pain from the pancreas. Celiac plexus neurolysis utilizes ethanol injection to ablate the celiac plexus in cases of refractory abdominal pain due to pancreatic cancer, whereas a celiac plexus block involves the injection of a local anesthetic with or without steroid to achieve a temporary (3-6 month) block in patients with chronic pancreatitis. EUS-guided celiac neurolysis or block is technically feasible given its location anterior to the celiac artery takeoff from the descending aorta. This is easily identified during EUS, although celiac ganglia are only visualized in a minority of cases. For patients undergoing celiac block, a recent trial suggested the addition of triamcinolone did not increase the proportion of patients who reported significant pain relief or reduce self-reported pain scores compared to injection of a local anesthetic (e.g., 20 ml of 0.75% bupivacaine) alone. 11 Drainage of Fluid Collections A complete discussion of pancreatic fluid collection is beyond the scope of this topic. However, a discussion of endoscopic therapy in chronic pancreatitis should include endoscopic drainage of pseudocysts since this has largely replaced surgical interventions in appropriately selected cases. A pseudocyst is an organized fluid collection, consisting of pancreatic juice enclosed by a nonepithelialized tissue. Endoscopic drainage may involve either transpapillary or transmural (transgastric, transduodenal) placement of stents. A transpapillary approach is used for smaller pseudocysts communicating with the main pancreatic duct, whereas larger pseudocysts or those not clearly communicating with the pancreatic duct are drained transmurally. Pseudocyst drainage is usually performed after allowing the cyst wall to mature for at least 4-6 weeks after the onset of acute pancreatitis. Endoscopy has high short- and long-term success for draining pseudocysts with minimal or no necrosis that abut the gastroduodenal wall and are not associated with complete pancreatic duct disconnection. 230 Session 2C: Pancreaticobiliary Disease

Figure 3 Figure 4 Transpapillary Drainage A pancreatic duct fistula can be healed in up to 90% of cases with stent placement across the disruption, while success rates plummet to < 50% with transpapillary stents that do not bridge the leak. Technical success may be lower for tail disruptions and definitely in the setting of complete pancreatic duct disruption. Transmural Drainage The goal of transmural drainage is to create an internal communication between the pseudocyst and the gastric or duodenal lumen. Traditionally, endoscopic cystgastrostomy involved piercing an endoscopically visible bulge using a needle knife catheter and electrocautery. However, the risk of bleeding is reduced from 15% to 5% using the Seldinger technique (advancing a guidewire through a 19-gauge needle). After obtaining access to the cavity, the opening is dilated and several pigtail stents are placed. EUS facilitates drainage, particularly in the setting of a pseudocyst that is not causing an endoscopically visible bulge; EUS has a higher technical success and lower morbidity versus a non-eus guided approach. ERCP for Therapy Obstructive Chronic Pancreatitis Chronic pancreatitis results in a wide spectrum of parenchymal changes (Figure 2). Patients may have diffuse, coarse parenchymal calcifications that pepper the entire gland (A), focal main duct calcifications with upstream duct dilation (B), and substantial atrophy without overt calcifications on CT scan (C), among others. Pain from CP is probably multifactorial, although one suggested mechanism is pancreatic ductal hypertension due to pancreatic duct obstruction from a stricture or stone. ERCP can alleviate pain and recurrent flares with serial dilation of pancreatic duct strictures or stone extraction. The evidence for endoscopic therapy (pancreatic sphincterotomy, pancreatic duct stents) in the setting of non-obstructive chronic pancreatitis is weak. Similar to the treatment of benign bile duct strictures, pancreatic duct strictures are managed with serial dilation and placement of one or more plastic stents until the stricture is obliterated. This usually requires 3 or more ERCPs occurring every 2-4 months for up to 1 year. Pancreatic stones are more easily removed if they are small, few in number, closer to the head of the pancreas and not impacted. For either stricture or stone management, a pancreatic sphincterotomy is usually required. Stones upstream of a pancreatic stricture require stricture dilation before extraction. Other options include direct pancreatoscopy, electrohydraulic lithotripsy and extracorporeal shock wave lithotripsy (ESWL). ESWL alone may be as effective as ESWL combined with ERCP for pancreatic stones. Short-term success rates for pancreatic duct therapy are generally lower than for biliary therapy, and recurrence rates typically higher. There are limited longitudinal data quantifying ERCP-based outcomes for the treatment of main pancreatic duct strictures and stones. Although studies have shown endoscopic therapy may improve pain, its short and long-term efficacy are inferior to surgical interventions aimed at relieving obstruction and achieving pain relief.12,13 However, the invasiveness and irreversibility of a surgical intervention often influence a patient s choice to Session 2C: Pancreaticobiliary Disease 231

proceed with endoscopy first. A patient s short-term response to duct drainage via ERCP may predict their response to subsequent surgical intervention. Recurrent Acute Pancreatitis At least 20% of individuals who suffer one episode of acute pancreatitis will be hospitalized for a recurrent episode. 14 Among patients with two or more episodes of acute pancreatitis, the long-term risk of progression to chronic pancreatitis is also 20% or more. 14,15 This is particularly applicable to patients with idiopathic, recurrent acute pancreatitis; despite advances in genetics, cross sectional imaging, up to 30% of patients with recurrent acute and chronic pancreatitis are classified as idiopathic. ERCP with biliary + pancreatic (i.e., dual ) sphincterotomy has been touted as a potential treatment for recurrent acute pancreatitis in the setting of elevated basal pancreatic sphincter pressures identified on sphincter of Oddi manometry. A recent clinical trial comparing dual sphincterotomy versus biliary sphincterotomy alone revealed no incremental benefit of pancreatic sphincterotomy in this population. 15 However, patients having elevation in basal pancreatic sphincter pressure (i.e., pancreatic sphincter of Oddi dysfunction) had a significantly greater probability of developing recurrent flares irrespective of sphincter therapy, compared to patients having normal basal pressures. Based on this study, pancreatic sphincterotomy is not currently recommended for patients with chronic pancreatitis (except to facilitate stone or stricture therapy) or unexplained recurrent, acute episodes. While the therapeutic impact of biliary, pancreatic, or dual sphincterotomies requires further investigation, elevation in basal pancreatic sphincter pressure represents a negative prognostic factor and may be an early indicator of chronic pancreatitis in this at-risk subgroup. Bile Duct Stricture Patients with chronic pancreatitis may present with obstructive jaundice due to extrinsic compression of the intrapancreatic segment of the bile duct. Differentiating malignant from benign biliary stricture may be daunting; while the diagnostic approach to the indeterminate stricture is beyond the scope of this lecture, suffice it to say that malignancy should be considered in this setting. 16 Similar to other etiologies of benign bile duct stricture, ERCP with serial dilation and stenting in the setting of a chronic pancreatitis-induced biliary stricture has reasonable short-term efficacy. However, recurrence rates are highest since the underlying etiology (chronic pancreatitis) is not addressed. Self-expandable metallic stents are increasingly used in this population, since their radial forces may improve long-term efficacy. Comparative effectiveness trials of metal stent versus multiple plastic stent are lacking. Summary EUS and ERCP represent important diagnostic and therapeutic interventions for patients with known or suspected chronic pancreatitis. The ideal case for ERCP-based therapy is main pancreatic duct obstruction with a discrete stone or stricture (be sure to rule out malignancy!) and upstream pancreatic duct dilation. Still, short-term and long-term efficacy of ERCPbased duct decompression is lower than for bile duct obstruction; therefore, the threshold for proceeding with endotherapy should be appropriately calibrated to the patient s underlying comorbidities and expectations. REFERENCES 1. Etemad B, Whitcomb DC. Chronic pancreatitis: Diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682-707. 2. Cote GA, Smith J, Sherman S, et al. Technologies for imaging the normal and diseased pancreas. Gastroenterology 2013;144:1262-71 e1. 3. Sahai AV, Zimmerman M, Aabakken L, et al. Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 1998;48:18-25. 4. Romagnuolo J. EUS in inflammatory disease of the pancreas. In: Hawes RH, Fockens P, Eds. Endosonography. Philadelphia, PA: Saunders Elsevier. 2006;155-76. 5. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;48:11-7. 6. Chong AK, Hawes RH, Hoffman BJ, et al. Diagnostic performance of EUS for chronic pancreatitis: A comparison with histopathology. Gastrointest Endosc 2007;65:808-14. 7. Albashir S, Bronner MP, Parsi MA, et al. Endoscopic ultrasound, secretin endoscopic pancreatic function test, and histology: correlation in chronic pancreatitis. Am J Gastroenterol 2010;105:2498-503. 8. Axon AT, Classen M, Cotton PB, et al. Pancreatography in chronic pancreatitis: International definitions. Gut 1984;25:1107-12. 9. Vitale GC, Davis BR, Zavaleta C, et al. Endoscopic retrograde cholangiopancreatography and histopathology correlation for chronic pancreatitis. Am Surg 2009;75:649-53; discussion 653. 10. Tamura R, Ishibashi T, Takahashi S. Chronic pancreatitis: MRCP versus ERCP for quantitative caliber measurement and qualitative evaluation. Radiology 2006;238:920-8. 11. Stevens T, Costanzo A, Lopez R, et al. Adding triamcinolone to endoscopic ultrasound-guided celiac plexus blockade does not reduce pain in patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2012;10:186-91, 191 e1. 12. Cahen DL, Gouma DJ, Laramee P, et al. Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis. Gastroenterology 2011;141:1690-5. 13. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007;356:676-84. 232 Session 2C: Pancreaticobiliary Disease

14. Yadav D, O Connell M, Papachristou GI. Natural history following the first attack of acute pancreatitis. Am J Gastroenterol 2012;107:1096-103. 15. Cote GA, Imperiale TF, Schmidt SE, et al. Similar efficacies of biliary, with or without pancreatic, sphincterotomy in treatment of idiopathic recurrent acute pancreatitis. Gastroenterology 2012;143:1502-9 e1. 16. Cote GA, Sherman S. Biliary stricture and negative cytology: What next? Clin Gastroenterol Hepatol 2011;9:739-43. Session 2C: Pancreaticobiliary Disease 233