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Chronic pancreatitis (CP) confronts clinicians and patients alike with a tragic Catch 22. Treatments are most likely to be effective when delivered early in the disease, but the morphological and functional changes that are required for diagnosis typically occur late, when damage is already irreversible.
To enhance our current understanding of CP and to identify novel therapies, David B. Adams, M.D., Interim Chair of the Department of Surgery and Co-Medical Director of MUSC’s Digestive Disease Service Line, Katherine A. Morgan, M.D., Interim Head of the Division of Gastrointestinal and Laparoscopic Surgery and Clinical Director of the Islet Transplant Program, and their colleagues organized a multidisciplinary symposium on CP—inviting gastroenterologists, endoscopists, and surgeons, typically siloed at different conferences, to the same forum for a comprehensive and collaborative discussion of CP. Some of the recent findings about the pathophysiology of and risk factors for CP and new directions in diagnosis and management are summarized here.
Chronic pancreatitis is defined as a chronic inflammatory state resulting in scarring that damages the architecture and the function of the pancreas. It leads to exocrine and endocrine deficiencies, malnutrition, and, in most patients, debilitating pain.
Mutations in a number of genes (e.g., PRSS1, CFTR, SPINK1) have been linked to CP. In healthy people, PRSS1 governs the production of trypsinogen, a pancreatic enzyme that, in its active form trypsin, aids in the digestion of food and then breaks down when no longer needed. In patients with hereditary pancreatitis and a PRSS1 mutation, trypsin is either activated too early or not broken down properly, leading to excessive levels that can damage pancreatic tissue and cause inflammation, increasing the risk for CP and pancreatic cancer.
Alcoholism was once thought to be the primary cause of CP, leading to negative stereotyping of these patients.2 Although alcohol abuse is the single most common explanation, it accounts for only 30% to 40% of all cases seen at referral centers.3 Smoking has also emerged as an important risk factor, increasing the rate of virtually every complication of CP, and the risk is increased in patients with a history of both smoking and alcohol abuse.3 Smoking cessation may be a critical intervention in slowing the progression from acute to chronic pancreatitis and yet few clinicians ask patients about their smoking histories or encourage smoking cessation.
Although genetic mutations play an important role in the etiology of CP, an inciting event, such as an episode of acute pancreatitis, is typically necessary to trigger the fibrotic cascade that will, over time, destroy the pancreas. Patients with a history of acute pancreatitis should be closely monitored for the development of CP and every attempt made to prevent recurrent episodes of acute pancreatitis.
Moderate to severe CP is now diagnosed with imaging tools such as magnetic resonance cholangiopancreatography (MRCP), which allows noninvasive visualization of pancreatic ducts, and endoscopic ultrasound (EUS), which allows visualization of both ducts and pancreatic tissue.4-5 In one study, availability of MRCP studies led to a substantial change in clinical management for 67 of 171 patients.4 However, detecting CP before the onset of overt scarring, when intervention has the best chance of success, remains a challenge. Endoscopic ultrasound, in which a small ultrasound transducer fitted on the tip of an endoscope is inserted into the mouth and advanced to the stomach and upper intestine, can provide precise and detailed imaging of the pancreas that correlates well with histological findings.6 Precision imaging of tissue coupled with a low-risk profile has led to EUS largely replacing endoscopic retrograde cholangiopancreatography (ERCP) as a diagnostic modality for CP.5
Endoscopic ultrasound is superior to magnetic resonance imaging (MRI) or computed tomography (CT) for detecting early-stage disease because it can identify more subtle changes (e.g., very small pancreatic cysts or dilated side branch ducts).5 More timely diagnosis may encourage patients to adopt lifestyle changes that could slow progression of the disease. According to Gregory A. Coté, M.D., an endoscopist specializing in CP who recently joined MUSC as an Associate Professor in the Division of Gastroenterology and Hepatology, “Having objective evidence of damage in the pancreas helps us drive the message home and helps us convince patients to quit smoking and drinking, where relevant.” Finding an etiology for a patient’s pain also lessens the need for further downstream diagnostic testing.
Physicians can find these patients—who can have debilitating, chronic pain, often without a firm diagnosis—difficult to manage. Too often, they assume that little can be done for them. To the contrary, interventions, whether medical, endoscopic, or surgical, are available to provide relief for pain and/or improve quality of life.
Medical therapy is the first-line treatment for most patients and focuses on treating symptoms, the most important of which is pain, and addressing exocrine (i.e., inadequate levels of pancreatic enzymes) and endocrine (i.e., diabetes) insufficiencies associated with CP. Patients with hereditary CP are an exception because of the more aggressive disease course. For these patients, surgical options may be considered sooner.
Patients often experience excruciating pain long before the morphological and functional changes needed to establish a definitive diagnosis of CP can be detected, and their pleas for pain relief can be mistaken for aberrant drug-seeking behavior.
The etiology of pain in CP is not fully understood, but the build-up of fluid and increased pressure caused by obstruction of the pancreatic and bile ducts and inflammation of nerves responsible for pain signaling from the pancreas are thought to play important roles. The severity of the pain does not correlate well with the extent of disease. Patients with early CP sometimes feel more pain than patients with irreversible fibrotic damage, whereas some patients with even severe CP feel no pain at all.
Although the “textbook” description of CP pain is an upper abdominal pain radiating to the back, the pain can in fact be variable in severity and duration. Relentless pain, even of lesser severity, takes the greatest toll on patient quality of life.1
Failure by the physician to acknowledge that a patient’s life has been dramatically altered by pain can alienate the patient and make treatment adherence less likely. According to Jayne Quinn, BSN, RN-BC, CHPN, a pain resource coordinator at MUSC, “Not believing the patient is very damaging. You can’t have a satisfactory therapeutic relationship with a patient if they don’t feel listened to.”
It is important to begin pain management soon after the symptom arises and before a chronic pain syndrome, which involves changes in neurological pathways, can become established. Once such syndromes are entrenched, pain will continue despite resolution of the problem in the pancreas, just as an amputated limb continues to hurt. Although the brain can be reprogrammed over time to give patients relief from such chronic pain syndromes, it is far easier to treat pain early. Nonsteroidal anti-inflammatory drugs, nonopioid analgesics, long-acting opioids, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and other centrally acting neuromodulators are among the agents that can effectively relieve pain. Nonopioid therapies should be considered first, but opioids will be required in some patients. It is advised to begin with less potent opioids, progressing to more potent ones only as needed. Online training opportunities in proper opioid management are available to physicians. Nonpharmacological therapies, including yoga, meditation, mind-body exercises, and biofeedback, can also be important tools for patients in managing their pain. Patients can begin to take back control over their lives by recognizing triggers for their pain and understanding strategies they can use to minimize it (for more information, visit www.painaction.com).
Diet and Pancreatic Enzyme Replacement Therapy
Many patients with CP secrete insufficient quantities of pancreatic enzymes, leading to malabsorption.7
Often, they are malnourished or have fat-soluble vitamin, B12, or trace element insufficiencies,7 leading to metabolic bone disease (i.e., osteoporosis, osteopenia) in some. Pain can deter patients from eating, further exacerbating the problem.
Patients with CP often experience exocrine pancreatic insufficiency, leading to oily stools. Some cases of steatorrhea are obvious, while others may be subtle and require blood and stool studies to establish exocrine insufficiency. Low-fat diets are sometimes recommended in these patients. However, MUSC clinical dietitian Maria Nestleroad, MS, RD, LD, CNSC, who often works with patients with CP, worries that recommending a low-fat diet could be harmful in an already malnourished patient. “Instead, I work on diet plans tailored to the needs of each patient, so they can eat what they can tolerate,” says Nestleroad. Patients with CP will tolerate frequent small meals better than less frequent heavier ones.
Proper nutrition is especially important in patients with CP who are considering surgery, because outcomes can be worse in malnourished patients.7 Vitamin deficiencies should be addressed, and temporary jejunal feeding tubes are recommended for patients who cannot obtain adequate nutrition orally.
Pancreatic enzyme replacement therapy is often necessary to improve digestion and nutrient absorption in patients with CP. Compliance can be an issue, as a number of pills must be taken with every meal. Pills should be taken during and after the meal, not before, to better mimic how the healthy pancreas works.
Management of Pancreatogenic Diabetes
Many patients with CP will develop diabetes. Though type 1 and type 2 diabetes mellitus can occur in these patients, type 3c diabetes, is specific to them. Type 3c diabetes develops when entire islet cells (not just ß-cells) are lost and has a higher rate of treatment-induced hypoglycemia than other types of diabetes.8
Strong consensus exists that fasting glucose and HbA1c should be measured each year in patients with CP; that abnormal findings should be further evaluated with a 75-g oral glucose tolerance test; and that specifically tailored medical nutrition and pharmacological therapies should be used to treat diabetes.9 Nutrition goals should be preventing malnutrition, controlling symptoms of steatorrhea, and minimizing meal-induced hyperglycemia. Most patients with type 3c diabetes will need insulin, some requiring an insulin pump, and the insulin sensitizer metformin may prove an effective adjunctive therapy.9
Endoscopic treatments for CP-associated pain include celiac plexus block, in which EUS is used to direct a small needle into the celiac plexus and inject a local anesthetic with or without a steroid. The celiac plexus is a bundle of nerves in the upper abdomen that transmits pain signals from the pancreas to the spinal cord. Endoscopic retrograde cholangiopancreatography (ERCP), which involves the placement of a catheter through the endoscope and into the pancreatic and bile ducts, can be used to improve drainage (blockage of the duct may cause pain) by removing stones, expanding the opening of the duct by cutting away fibrotic tissue, deploying a balloon to stretch the tube draining the pancreas, or placing stents. Often, endoscopic procedures must be repeated several times for efficacy. However, some patients prefer endoscopy, according to B. Joseph Elmunzer, M.D., who joined MUSC in July 2014 as the Peter B. Cotton Endowed Chair in Endoscopic Innovation and Associate Professor in the Division of Gastroenterology: “They don’t have any recovery time in terms of time off of work or time away from family. They prefer three or four ERCPs over the course of six months to one operation.”
Both Coté and Elmunzer are working to optimize endoscopic interventions. Coté is leading a multisite clinical trial (NCT01221311) testing whether a single expandable silicone-coated metallic stent can be used instead of the many small plastic stents currently used to fully treat a blocked bile duct caused by CP or other noncancerous conditions. If the metallic stent is shown to be effective, it would mean patients would undergo fewer procedures than are currently required to implant the numerous plastic stents. Elmunzer recently reported the results of a clinical trial showing that, compared with placebo, rectal indomethacin significantly reduced the incidence of the most common post-ERCP complication—acute pancreatitis.10 Elmunzer and Coté plan to develop a robust clinical trials platform at MUSC to encourage endoscopic innovation, improving diagnosis and treatment for patients with CP and other pancreatobiliary diseases.
Surgical options (a Frey or Puestow procedure) are also available for draining a dilated pancreatic duct.11 The procedures show little benefit in patients whose duct is not dilated or whose tissue is fibrotic. If damage is localized to a particular region, then either the head (Whipple procedure) or the tail (distal pancreatectomy) of the pancreas can be removed in an effort to control pain.11
For patients without benefit from prior surgeries or for those with diffuse small duct disease, where damage is not regionalized, total pancreatectomy and islet autotransplantation (TP-IAT), pioneered at the University of Minnesota,12 is a novel treatment option. Patients with hereditary pancreatitis are also good candidates. “In these patients, there is more of a push for islet cell transplant. Once they start to have problems, they will continue to have problems,” says Morgan.
In TP-IAT, islet cells isolated from the excised pancreas are reinfused into the patient via the portal vein of the liver in hopes of preventing brittle diabetes. In the year after TP-IAT, patients report better quality of life and decreased reliance on narcotic analgesics.13 After TP-IAT, some patients are free of diabetes, while in others it becomes much more manageable. Although some patients may require higher insulin doses after TP-IAT, a recent study by Adams, Morgan, and colleagues showed that the necessity of these higher doses does not negatively affect quality of life.14 All patients undergoing TP-IAT will need pancreatic replacement therapy for life, and patients should realize that, though the goal of the procedure is pain relief, there will be postoperative pain that will resolve over time.
The decision whether an endoscopic or surgical approach would be better in a particular patient is best made with the input of a multidisciplinary team that includes endoscopists, surgeons, and gastroenterologists. Peter B. Cotton, M.D., Professor in the Division of Gastroenterology and Hepatology and a pioneer in endoscopic innovation, champions the importance of such collaboration and made it a founding principle of MUSC’s Digestive Disease Center: “It’s been said that if you have only a hammer, everything looks like a nail. If you are an endoscopist, you might jump on the ERCP wagon too quickly; and if you are a surgeon, you might consider only surgical solutions. A multidisciplinary approach is essential.”
Endoscopy-based approaches are important treatment options for patients who are not candidates for surgery or who refuse it. However, recent studies have shown that surgery offers more durable and cost-effective benefits in select patients.11, 15-16
The February 2014 symposium organized by MUSC focused attention on the plight of CP patients and the need to advance their therapeutic options, leading The National Institute of Diabetes and Digestive and Kidney Diseases to hold a workshop on CP in July 2014. The workshop was intended to identify best practices for the treatment of CP and to clear the way for clinical trials of novel therapies by establishing a patient registry and identifying consistent outcome measures. This renewed, multidisciplinary focus on CP and the resolve of clinicians and governmental agencies to identify promising therapies and assess them in clinical trials offer hope for a brighter future for this sometimes neglected
1 Mullady DK, et al; for the NAPS2 Consortium. Type of pain-associated complications, quality of life, disability and resource utilization in chronic pancreatitis: a prospective cohort study. Gut. 2011 Jan;60(1):77-84.
2 Shelton CA, Whitcomb DC. Genetics and treatment options for recurrent acute and chronic pancreatitis. Curr Treat Options Gastroenterol. 2014 Sep;12(3):359-371.
3 Coté GA, et al; for the North American Pancreatitis Study Group. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis.
Clin Gastroenterol Hepatol. 2011 Mar;9(3):266-273.
4 Tirkes T, Sandrasegaran K, Sanyal R, Sherman S, Schmidt CM, Cote GA, Akisik F. Secretin-enhanced MR cholangiopancreatography: spectrum of findings. Radiographics. 2013 Nov-Dec;33(7):1889-1906.
5 Coté GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology. 2013 Jun;144(6):1262-1271.e1.
6 LeBlanc JK, Chen J-H, Al-Haddad M, Juan M, Okumu W, McHenry L, Cote G, Sherman S, DeWitt JM. Endoscopic ultrasound and histology in chronic pancreatitis: how are they associated? Pancreas 2014 April;43(3):440-444.
7 Rasmussen HH, et al. Nutrition in chronic pancreatitis. World J Gastroenterol. 2013 Nov 14;19(42):7267-7275.
8 Gupta AR, et al. Chronic pancreatitis. Curr Opin Gastroenterol 2014;30:500-505.
9 Rickels MR, et al; for the PancreasFest recommendation conference participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology. 2013 Jul-Aug; 13(4): 336-342.
10 Elmunzer BJ, et al; for the U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012 Apr 12;366(15):1414-1422.
11 Glass LM, Whitcomb DC, et al; for the North American Pancreatic Study Group. Spectrum of Use and Effectiveness of Endoscopic and Surgical Therapies for Chronic Pancreatitis in the United States. Pancreas. 2014 May ; 43(4): 539-543.
12 Sutherland DE, et al. Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes. Transplantation. 2008 Dec 27;86(12):1799-1802.
13 Morgan K, Owczarski SM, Borckardt J, Madan A, Nishimura M, Adams DB. Pain control and quality of life after pancreatectomy with islet autotransplantation for chronic pancreatitis. J Gastrointest Surg. 2012 Jan;16(1):129-133.
14 Dorlon M, Owczarski S, Wang H, Adams D, Morgan K. Increase in postoperative insulin requirements does not lead to decreased quality of life after total pancreatectomy with islet cell autotransplantation for chronic pancreatitis. Am Surg. 2013 Jul;79(7):676-680.
15 Dite P, Ruzicka M, Zboril V, Novotny I. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003;35:553-558.
16 Cahen DL, Gouma DJ, Nio Y, Rauws EA, Boermeester MA, Busch OR, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007;356:676-684.
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Watch a CME-eligible telepresentation for additional CME credit (1.0 AMA PRA Category 1 CreditsTM) in which Dr. Gregory Coté, an endoscopist, and Dr. Katherine Morgan, a surgeon, discuss new directions in the diagnosis and management of chronic pancreatitis.
Download Dr. Coté's PowerPoint slides here.
Date of Release: October 1, 2014
Date of Expiration: October 1, 2016
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Peter B. Cotton, M.D., serves as a consultant for Olympus America and Cook Medical, receives device royalties from Cook Medical, and is on the advisory board of SE Healthcare Quality Consulting and Apollo Endosurgery. Gregory A. Coté, M.D., receives research grants from Boston Scientific and serves as a consultant for both Boston Scientific and Olympus America. David B. Adams, M.D., Katherine A. Morgan, M.D., B. Joseph Elmunzer, M.D., and Kimberly McGhee have no relevant financial relationships to disclose.
A telepresentation by Gregory A. Coté, M.D., and Katherine A. Morgan, M.D., was broadcast on October 21, 2014 by South Carolina AHEC to its member sites. The live activity was approved for a maximum of 1.0 AMA PRA Category 1 Credits TM, as was the recorded version that is made available here and at MUSChealth.org/Progressnotescme for those who did not attend the session.