Chronic Pancreatitis – An Overview

Chronic Pancreatitis – An Overview

Summary

Chronic pancreatitis is a syndrome characterized by long-term inflammation of the pancreas, which leads to irreversible scarring, fibrosis, atrophy, and subsequent loss of the exocrine and endocrine functions of the organ. The etiology of this disease is varied, including excessive alcohol intake, smoking, metabolic abnormalities, autoimmune responses, genetic factors, mechanical obstruction, or idiopathic causes. Clinical manifestations of chronic pancreatitis may include chronic pain, which can be either constant or intermittent, digestive issues, diabetes mellitus, and weight loss; however, some patients can remain asymptomatic.

Due to the slow and progressive nature of chronic pancreatitis and because morphological changes are very subtle and nonspecific at early stages, the definitive diagnosis often occurs later in the course of the disease when unequivocal signs like calcifications or ductal abnormalities can be visualized. Diagnostic tools may include clinical evaluation, laboratory tests, imaging studies, and endoscopic techniques, while management options include lifestyle changes, medical intervention, and/or surgery.

Introduction to Chronic Pancreatitis

The pancreas is a large elongated organ that lies obliquely in the retroperitoneal space of the abdominal cavity and across the posterior abdominal wall. It can be divided into five sections, namely the uncinate process, head, neck, body, and tail, and it also has an internal system of ducts comprised of the main pancreatic duct (of Wirsung) and the accessory pancreatic duct. The pancreas has both endocrine and exocrine functions, synthesizing and releasing digestive enzymes, including peptidases, amylases, nucleases, and lipases; and also hormones such as insulin (released by the beta cells), glucagon (released by the alpha cells), and somatostatin (released by the delta cells), thus regulating the metabolism of glucose, lipids, and proteins in the body. (1)

Chronic pancreatitis is a progressive disease that is characterized by fibrosis, inflammation, and scarring of the pancreas, leading to permanent damage to the organ and eventual loss of both exocrine and endocrine functions.

Etiology of Chronic Pancreatitis

Causes of chronic pancreatitis are varied, and although for many years it was believed that alcoholism was the leading cause, it has been recently demonstrated that the etiology is multifactorial and can include genetic factors (hereditary pancreatitis or cystic fibrosis), ductal obstruction (stones, tumors, trauma), autoimmune diseases (autoimmune pancreatitis or systemic lupus erythematosus), chemotherapy, and cigarette smoking; being alcohol abuse the attributable etiology in less than 50% of cases. Furthermore, less than 10% of patients who have alcohol abuse go on to develop chronic pancreatitis. (2-6)

Epidemiology of Chronic Pancreatitis

Since chronic pancreatitis is insidious and the diagnosis usually occurs after several years, the prevalence of this disease is hard to ascertain. However, it has been estimated to be around 37 to 42 cases per 100,000 patients. (7-13) Although chronic pancreatitis can develop at an early age in patients with a genetic risk, in the United States, this disease is commonly diagnosed in patients around 35 to 55 years of age, with an average age of 45 years. Men are 1.5 to 3 times more affected than women, and patients of African American race are more likely to experience severe pain and show advanced morphological changes on imaging techniques when compared to patients of Caucasian race. (14, 15)

Physiopathology of Chronic Pancreatitis

The development of chronic pancreatitis seems to be multifactorial, involving genetic and environmental factors. Genetic factors imply the mutation of various genes, the most recognized one being the cationic trypsinogen (PRSS1) gene, which has an autosomal dominant inheritance pattern and has been shown to independently lead to the development of acute and chronic pancreatitis (hereditary pancreatitis); however, in some cases, the mutation of this gene can occur de novo. O

ne theory states that damage to the pancreas occurs as a result of calcification and stone development caused by the formation of plugs of protein within pancreatic structures as the result of impaired bicarbonate secretion. While another theory suggests that pancreatic parenchymal damage occurs as a result of the activation of digestive enzymes within the gland due to genetic or external factors, such as excessive alcohol consumption. (6, 15-18)

Clinical Findings in Chronic Pancreatitis

Patients with acute pancreatitis present with sudden onset abdominal pain that radiates to the back; however, patients with chronic pancreatitis can be asymptomatic. Nevertheless, the most common symptom that appears in up to 80% of cases is long-term abdominal pain (with or without radiation to the back) that can either be constant or present intermittently alternated with extended pain-free periods. In some cases, the pain appears or becomes worse after food intake (postprandial pain), and it is the most frequent cause of hospitalization, becoming a strong predictor of reduced quality of life, especially when it is constant. Other common signs and symptoms of chronic pancreatitis can also include: (12, 19-31)

• Weight loss
• Postural guarding, leaning forward.
• Nausea and/or vomiting.
• Diarrhea.
• Steatorrhea.
• Glucose intolerance or pancreatogenic diabetes (Type 3c diabetes) in advanced disease.
• Signs of malnutrition in advanced disease.

A detailed medical history should include a review of systems, focusing on the onset of symptoms, frequency, location, intensity, duration, and stool appearance. It is equally important to interrogate the patient about their past medical history, social history (including cigarette smoking and alcohol intake), and family history to consider other possible differential diagnoses.

Diagnosis of Chronic Pancreatitis

Although there is not a single gold-standard test to diagnose chronic pancreatitis, a wide range of assessment tools can be used to accurately diagnose this disease at its early stages in order to provide timely care and improve the patient’s quality of life. Depending on the particular case, diagnosis can be achieved by using a combination of clinical evaluation, laboratory tests, imaging studies, and endoscopic techniques:

Laboratory Tests

Laboratory tests useful to aid in the diagnosis and assessment of chronic pancreatitis can include: (32-35)

• Complete blood count (CBC).
• Basic metabolic panel (BMP).
• Liver function tests (LFTs).
• Lipid panel.
• Pancreatic function tests, including secretin-pancreozymin stimulation test, amino acid consumption test, serum trypsinogen test, and fecal elastase-1 test, among others.
• Inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
• 72-hour quantitative fecal fat in case of suspected steatorrhea.
• In pediatric patients, genetic testing for CFTR (cystic fibrosis transmembrane conductance regulator) may be warranted.

It is important to note that both lipase and amylase levels can be either increased or at normal range (due to significant pancreatic scarring and fibrosis); therefore, it should not be considered diagnostic or prognostic.

Imaging Studies

Imaging studies are essential since they can serve to identify morphological changes in the pancreas, such as organ enlargement, calcifications (hallmark sign, often seen as a “chain of lakes”), ductal dilation or obstruction, and parenchymal atrophy, which are suggestive of chronic pancreatitis. (12, 36) Abdominal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are the most commonly used imaging modalities for the diagnosis of chronic pancreatitis. Magnetic resonance cholangiopancreatography (MRCP) can also be used due to its high sensitivity and specificity to diagnose this disease when the results of other imaging techniques are normal, but the suspicion of chronic pancreatitis remains. (13, 36)

Endoscopic Assessment

Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) can be useful in visualizing ductal and parenchymal morphological changes and functional abnormalities early in the course of chronic pancreatitis. However, these tests are commonly used only after non-invasive imaging tests have failed to reveal pancreatic calcifications and/or there is no evidence of steatorrhea. Furthermore, since MRCP is available, ERCP is often used only in cases where therapeutic intervention is warranted to relieve obstruction in the pancreatic duct. (36-39)

Management of Chronic Pancreatitis

The management of chronic pancreatitis involves several interventions aimed at improving the patient’s quality of life, controlling abdominal pain, and preventing disease-related complications.

Lifestyle Changes

In order to prevent further damage to the pancreas and exacerbate symptoms, patients must be instructed to avoid alcohol consumption as well as refrain from smoking. An exercise routine adapted to the patient’s physical condition and a healthy low-fat, high-protein diet is also necessary, along with portion size control and supplementation with pancreatic enzymes and fat-soluble vitamins. In some cases of advanced disease, tube feeding may be required to ensure adequate nutrition.

Medical Management

The main goal of medical management is to prevent further damage to the organ and achieve pain control. Supplementation with pancreatic enzymes and fat-soluble vitamins may be used along with non-steroidal anti-inflammatory drugs (NSAIDs) to control disease-related symptoms. When pain management has not been achieved, a trial of opioids may be necessary. (12, 19, 38)

Surgery

Extracorporeal shock wave lithotripsy (ESWL) may be used for stone fragmentation before attempting surgery; however, a surgical approach may still be necessary in cases of severe chronic pancreatitis when other management options previously used have failed or when it is the only way to remove a significant obstruction in the pancreatic duct. In some cases, a partial or total pancreatectomy may need to be performed. (32, 40-42)

Prognosis of Chronic Pancreatitis

The prognosis for patients with chronic pancreatitis depends on many factors, like continued smoking and/or alcohol intake, age at diagnosis, concomitant liver disease, and the presence of other comorbidities and disease-related complications. Overall, the survival rate at 10 years is around 70%, decreasing to roughly 40% to 50% at 20 years. (43, 44)

Complications

Chronic pancreatitis can lead to a range of complications that can significantly impact a patient’s quality of life; therefore, it is crucial to regularly monitor patients with this disease to detect and manage complications early. The most common complications include:

Chronic pain

Chronic pain is the most common and debilitating complication of chronic pancreatitis. Continued inflammation and damage to the pancreas can lead to persistent and severe pain that is often difficult to manage. (31, 32)

Malnutrition and Other Digestive Issues

The pancreas plays an important role by producing enzymes that aid in digestion. In chronic pancreatitis, damage to the pancreas impairs the organ’s ability to produce enough enzymes to digest food properly, eventually leading to malnutrition and a myriad of digestive symptoms, such as bloating, nausea, constipation, and diarrhea.

Diabetes

Up to 70 to 90% of patients with chronic pancreatitis end up developing pancreatogenic diabetes mellitus (also known as Type 3c diabetes mellitus) due to impaired production of insulin. Therefore, screening for diabetes mellitus is recommended in all patients with chronic pancreatitis. (45-48)

Metabolic Bone Disease

Metabolic bone disease, also known as chronic pancreatitis-associated osteopathy, can develop in approximately 65% of patients in the form of either osteopenia or osteoporosis, therefore increasing the risk of low trauma fractures in this population. (49, 50)

Pancreatic Pseudocysts

Pancreatic pseudocysts are collections of fluid that can form in the pancreas secondary to the effects of chronic pancreatitis. These cysts can appear in up to 40% of cases and, depending on their size and location, can lead to biliary obstruction or gastroduodenal outlet obstruction. In severe cases, pancreatic pseudocysts may need to be drained or surgically removed. (51)

Pancreatic Cancer

The risk of developing pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), is around 4% to 5% in patients with chronic pancreatitis. Chronic inflammation of the pancreas can cause cellular changes that can eventually lead to cancer. Therefore, patients with chronic pancreatitis, especially those with complications like diabetes mellitus, should be regularly monitored for signs of pancreatic cancer. (52-54)

See Also

What is Dysphagia

Gastroesophageal Reflux Disease

Esophageal Cancer

Malabsorption Syndrome

Inflammatory Bowel Disease

Peptic Ulcer Disease

Acute Diarrhea in Adults

Acute Abdomen

References

1. Mahadevan V. Anatomy of the pancreas and spleen. Surgery (Oxford). 2019;37(6):297-01. Available from: https://www.sciencedirect.com/science/article/pii/S026393191930095X
2. Singhvi A, Yadav D. Myths and realities about alcohol and smoking in chronic pancreatitis. Curr Opin Gastroenterol. 2018 Sep;34(5):355-361. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646881/
3. Pham A, Forsmark C. Chronic pancreatitis: review and update of etiology, risk factors, and management. F1000Res. 2018;7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958317/
4. Conwell DL, Banks PA, Sandhu BS, et al. Validation of Demographics, Etiology, and Risk Factors for Chronic Pancreatitis in the USA: A Report of the North American Pancreas Study (NAPS) Group. Dig Dis Sci 2017;62:2133–2140. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040886/
5. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009;169:1035–45. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785300/
6. Pfutzer R, Myers E, Applebaum-Shapiro S, et al. Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis. Gut 2002;50:271–2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1773118/
7. Shuja A, Rahman AU, Skef W, Smotherman C, Guan J, Malespin M, et al. A longitudinal analysis of the epidemiology and economic impact of inpatient admissions for chronic pancreatitis in the United States. Ann Gastroenterol. 2018 Jul-Aug;31(4):499-505. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033763/
8. Beyer G, D’Haese JG, Ormanns S, Mayerle J. [Chronic Pancreatitis and Pancreatic Cancer – Tumor Risk and Screening]. Dtsch Med Wochenschr. 2018 Jun;143(12):895-906. Available from: https://pubmed.ncbi.nlm.nih.gov/29898491/
9. Kleeff J, Whitcomb DC, Shimosegawa T, Esposito I, Lerch MM, Gress T, et al. Chronic pancreatitis. Nat Rev Dis Primers. 2017 Sep 7;3:17060. Available from: https://pubmed.ncbi.nlm.nih.gov/28880010/
10. Olesen SS, Mortensen LH, Zinck E, Becker U, Drewes AM, Nøjgaard C, et al. Time trends in incidence and prevalence of chronic pancreatitis: A 25-year population-based nationwide study. United European Gastroenterol J. 2021 Feb;9(1):82-90. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259237/
11. Yadav D, Timmons L, Benson JT, et al. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011;106:2192–9. Available from: https://pubmed.ncbi.nlm.nih.gov/21946280/
12. Dominguez-Munoz JE, Lucendo A, Carballo LF, et al. A Spanish multicenter study to estimate the prevalence and incidence of chronic pancreatitis and its complications. Rev Esp Enferm Dig 2014;106:239–45. Available from: https://pubmed.ncbi.nlm.nih.gov/25075654/
13. Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis. Pancreas. 2014;43(8):1143-1162. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434978/
14. Wilcox CM, Sandhu BS, Singh V, et al. Racial Differences in the Clinical Profile, Causes, and Outcome of Chronic Pancreatitis. Am J Gastroenterol 2016;111:1488–1496. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196097/
15. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120(3):682-707. Available from: https://pubmed.ncbi.nlm.nih.gov/11179244/
16. Balázs A, Balla Z, Kui B, Maléth J, Rakonczay Z, Duerr J, et al. Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis. Front Physiol. 2018;9:632. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987707/
17. Issa Y, van Santvoort HC, van Dieren S, Besselink MG, Boermeester MA, Ahmed Ali U. Diagnosing Chronic Pancreatitis: Comparison and Evaluation of Different Diagnostic Tools. Pancreas. 2017 Oct;46(9):1158-1164. Available from: https://pubmed.ncbi.nlm.nih.gov/28902786/
18. Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 2013;45:1216–20. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909499/
19. Belyaev O, Uhl W. Chronische Pankreatitis – ein Update aus Sicht des Chirurgen [Chronic Pancreatitis – An Updated Surgical Perspective]. Zentralbl Chir. 2018 Dec;143(6):586-595. Available from: https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-0647-7088
20. Wynne K, Devereaux B, Dornhorst A. Diabetes of the exocrine pancreas. Journal of Gastroenterology and Hepatology. 2019 Feb;34(2):346-354. Available from: https://onlinelibrary.wiley.com/doi/10.1111/jgh.14451
21. Forsmark CE. Diagnosis and Management of Exocrine Pancreatic Insufficiency. Current Treatment Options in Gastroenterology. 2018;16(3):306-15. Available from: https://link.springer.com/article/10.1007/s11938-018-0186-y
22. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology. 1994 Nov;107(5):1481–7. Available from: https://www.gastrojournal.org/article/0016-5085(94)90553-3/pdf
23. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology. 1984 May;86(5 Pt 1):820-8. Available from:https://pubmed.ncbi.nlm.nih.gov/6706066/
24. Cavallini G, Frulloni L, Pederzoli P, Talamini G, Bovo P, Bassi C, et al. Long-term follow-up of patients with chronic pancreatitis in Italy. Scand J Gastroenterol. 1998 Aug;33(8):880-9. Available from: https://pubmed.ncbi.nlm.nih.gov/9754738/
25. Lankisch PG, Löhr-Happe A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion. 1993;54(3):148-55. Available from: https://pubmed.ncbi.nlm.nih.gov/8359556/
26. Olesen SS, Kuhlmann L, Novovic S, Nøjgaard C, Kalaitzakis E, Jensen NM, et al; Scandinavian Baltic Pancreatic Club. Association of multiple patient and disease characteristics with the presence and type of pain in chronic pancreatitis. J Gastroenterol Hepatol. 2020 Feb;35(2):326-333. Available from: https://pubmed.ncbi.nlm.nih.gov/31314128/
27. Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut 2011;60:77-84. Available from: https://gut.bmj.com/content/60/1/77
28. Olesen SS, Poulsen JL, Broberg MC, Madzak A, Drewes AM. Opioid treatment and hypoalbuminemia are associated with increased hospitalisation rates in chronic pancreatitis outpatients. Pancreatology. 2016 Sep-Oct;16(5):807-13. Available from: https://pubmed.ncbi.nlm.nih.gov/27320721/
29. Olesen SS, Juel J, Nielsen AK, Frøkjær JB, Wilder-Smith OH, Drewes AM. Pain severity reduces life quality in chronic pancreatitis: Implications for design of future outcome trials. Pancreatology. 2014;14(6):497-02. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1424390314009946?via%3Dihub
30. de las Heras G, de la Peña J, López Arias MJ, Gonzalez-Bernal AC, Martín-Ramos L, Pons-Romero F. Drinking habits and pain in chronic pancreatitis. J Clin Gastroenterol. 1995 Jan;20(1):33-6. Available from: https://pubmed.ncbi.nlm.nih.gov/7884174/
31.  Machicado JD, Amann ST, Anderson MA, et al. Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities. Am J Gastroenterol 2017;112:633–642. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828017/
32. Nair RJ, Lawler L, Miller MR. Chronic pancreatitis. Am Fam Physician. 2007;76(11):1679-1688. Available from: https://www.aafp.org/pubs/afp/issues/2007/1201/p1679.html
33. Chase CW, Barker DE, Russell WL, Burns RP. Serum amylase and lipase in the evaluation of acute abdominal pain. Am Surg. 1996;62(12):1028-1033. Available from: https://pubmed.ncbi.nlm.nih.gov/8955242/
34. Munoz A, Katerndahl DA. Diagnosis and management of acute pancreatitis. Am Fam Physician. 2000;62(1):164-174. Available from: https://pubmed.ncbi.nlm.nih.gov/10905786/
35. Chowdhury RS, Forsmark CE. Pancreatic function testing. Alimentary Pharmacology & Therapeutics. 2003;17(6):733-50. Available from: https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2036.2003.01495.x
36. Issa Y, Kempeneers MA, van Santvoort HC, Bollen TL, Bipat S, Boer-meester MA. Diagnostic performance of imaging modalities in chronic pancreatitis: a systematic review and meta-analysis. Eur Radiol. 2017;27(9):3820-3844. Available from: https://pubmed.ncbi.nlm.nih.gov/28130609/
37. Frøkjær JB, Akisik F, Farooq A, Akpinar B, Dasyam A, Drewes AM, et al, Working group for the International (IAP – APA – JPS – EPC) Consensus Guidelines for Chronic Pancreatitis. Guidelines for the Diagnostic Cross Sectional Imaging and Severity Scoring of Chronic Pancreatitis. Pancreatology. 2018 Oct;18(7):764-773. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1424390318306628?via%3Dihub
38. Min M, Patel B, Han S, Bocelli L, Kheder J, Vaze A, et al. Exocrine Pancreatic Insufficiency and Malnutrition in Chronic Pancreatitis: Identification, Treatment, and Consequences. Pancreas. 2018 Sep;47(8):1015-1018. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462188/
39. Bordaçahar B, Couvelard A, Vullierme MP, Bucchini L, Sauvanet A, Dokmak S, Ruszniewski P, et al. Predicting the efficacy of surgery for pain relief in patients with alcoholic chronic pancreatitis. Surgery. 2018 Nov;164(5):1064-1070. Available from: https://pubmed.ncbi.nlm.nih.gov/30029988/
40. Dumonceau JM, Costamagna G, Tringali A, et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial. Gut 2007;56:545–52. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856858/
41. Vaysse T, Boytchev I, Antoni G, et al. Efficacy and safety of extracorporeal shock wave lithotripsy for chronic pancreatitis. Scand J Gastroenterol 2016;51:1380–5. Available from: https://pubmed.ncbi.nlm.nih.gov/27595309/
42. Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Updated August 2018. Endoscopy 2019;51:179–193. Available from: https://pubmed.ncbi.nlm.nih.gov/30654394/
43. McNabb-Baltar J, Suleiman SL, Banks PA, Conwell DL. Outcomes of Chronic Pancreatitis in the Emergency Department. Dig Dis Sci. 2018 Nov;63(11):2874-2879. Available from: https://pubmed.ncbi.nlm.nih.gov/30039239/
44. Skube ME, Beilman GJ. Surgical treatment of pain in chronic pancreatitis. Curr Opin Gastroenterol. 2018 Sep;34(5):317-321. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558956/
45. Bellin MD, Whitcomb DC, Abberbock J, et al. Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the United States. Am J Gastroenterol 2017;112:1457–1465. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168293/
46. Ahmed Ali U, Issa Y, van Goor H, et al. Dutch Chronic Pancreatitis Registry (CARE): design and rationale of a nationwide prospective evaluation and follow-up. Pancreatology 2015;15:46–52. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1424390314010230?via%3Dihub
47. Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology 2013;13:336–42. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830751/
48. Sheth SG, Conwell DL, Whitcomb DC, et al. Academic Pancreas Centers of Excellence: Guidance from a multidisciplinary chronic pancreatitis working group at PancreasFest. Pancreatology 2017;17:419–430. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525332/
49. Duggan SN, Smyth ND, Murphy A, et al. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014;12:219–28. Available from: https://pubmed.ncbi.nlm.nih.gov/23856359/
50. Tignor AS, Wu BU, Whitlock TL, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol 2010;105:2680–6. Available from: https://pubmed.ncbi.nlm.nih.gov/20736937/
51. Machicado JD, Chari ST, Timmons L, et al. A population-based evaluation of the natural history of chronic pancreatitis. Pancreatology 2018;18:39–45. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794616/
52. Algul H, Treiber M, Lesina M, et al. Mechanisms of disease: chronic inflammation and cancer in the pancreas–a potential role for pancreatic stellate cells? Nat Clin Pract Gastroenterol Hepatol 2007;4:454–62. Available from: https://pubmed.ncbi.nlm.nih.gov/17667994/
53. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328:1433–7. Available from: https://pubmed.ncbi.nlm.nih.gov/8479461/
54. Liao KF, Lai SW, Li CI, et al. Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan. J Gastroenterol Hepatol 2012;27:709–13. Available from: https://pubmed.ncbi.nlm.nih.gov/21929650/