Review Article The Korean Journal of Pancreas and Biliary Tract 2017;22:63-71 https://doi.org/10.15279/kpba.2017.22.2.63 pissn 1976-3573 eissn 2288-0941 만성췌장염의임상상, 자연경과및합병증 한림대학교의과대학한림대학교성심병원내과 추진우 문성훈 Clinical Features, Natural History, and Complications of Chronic Pancreatitis Jin Woo Choo, Sung-Hoon Moon Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea Chronic pancreatitis is a debilitating disease characterized by abdominal pain, exocrine insufficiency, and diabetes mellitus and has had great social, economic, and psychological impacts. Traditional definition of chronic pancreatitis has been based on irreversible histological findings such as self-sustaining chronic inflammation, fibrosis, and eventual destruction of ductal, exocrine, and endocrine tissues. In contrast, the traditional characteristics of acute pancreatitis have been thought as a complete recovery of pancreatic function and morphology during the convalescence period. Acute and chronic pancreatitis have been considered separated disease entities. However, the current idea regarding the natural course of pancreatitis is that acute pancreatitis can progress to the intermediate step of recurrent acute pancreatitis, and finally to chronic pancreatitis. This evolution can be characterized by a sequence of necrotic and fibrotic events, or described by sentinel acute pancreatitis event (SAPE) hypothesis. Therefore, chronic pancreatitis is better defined as a progressive inflammatory and fibrotic disease of the pancreas with clinical features of abdominal pain, malnutrition, diabetes mellitus and imaging features of pancreatic parenchymal/ ductal calcifications. The complications of chronic pancreatitis include pseudocyst, pseudoaneurysm, fistula, biliary stricture, and duodenal stricture. This review describes the progression from acute to chronic pancreatitis, the mechanisms and nature of abdominal pain, steatorrhea, pancreatogenic diabetes mellitus, pseudocyst, pseudoaneurysm, and biliary stricture associated with chronic pancreatitis. Keywords: Pancreatitis, Chronic, Abdominal pain, Natural history, Diabetes mellitus Received Sep. 26, 2016 Revised Nov. 8, 2016 Accepted Nov. 23, 2016 Corresponding author : Sung-Hoon Moon Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22 Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang 14068, Korea Tel. +82-31-380-3789 Fax. +82-31-380-5912 E-mail; endomoon@naver.com This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2017 by The Korean Journal of Pancreas and Biliary Tract Copyright 2017 by Korean Pancreatobiliary Association 63
Clinical Features of Chronic Pancreatitis 서론,, (malnutrition), (calcification)..,, (acinar cell). Whitcomb (mechanistic). 1, (exocrine insufficiency) (endocrine insufficiency).. 20-25 50%,. 2,,. 췌장염의진행과정. 3,4 1984. 5 (continuum). 6,7 " - (necrosis-fibrosis sequence hypothesis)". -. 8 - (latent stage), (compensatory stage), (transitional stage) (advanced stage). 9. Whitcomb "sentinel acute pancreatitis event (SAPE) ". 10 SAPE (resident macrophage). - (transforming growth factor-beta) (pancreatic stellate cell),,. (ischemia) (cytokine). 10 14 ( 8,492 ). 7 22%, 10%. 36%.,. 7 임상상과자연경과, (steatorrhea).,.,, (,, ). 64 https://doi.org/10.15279/kpba.2017.22.2.63
Jin Woo Choo, et al. 1. 복통.,.. 1) 복통의발생기전 2... 11,12 (noceceptive nerves) (alteration).,, (peripheral and central sensitization) (hyperalgesia), (allodynia)..,,. Dimcevski 13 12 10,, (electroencephalogram) (projection).,, (referred pain). 13 pregabalin. 14-16. 17 2) 복통의양상및자연경과....... 18,., burn out. 19 Lankisch 20 10 burn out. Ammann Muellhaupt 18 207. 2 A (short episodes/relapsing) 10.. B (constant/prolonged episodes). B 65
Clinical Features of Chronic Pancreatitis A. 11 burn-out. 18 Mullady 21,. 20 540. (pattern; intermittent vs. chronic) (severity; mild to moderate vs. severe) 5 (Table 1). 540 77% A (episodes of mild to moderate pain, usually controlled by medication), B (constant mild to moderate pain, usually controlled by medication), C (usually pain free with episodes of severe pain), D (constant mild pain plus episodes of severe pain), E (constant severe pain that does not change) 14.0%, 9.2%, 30.9%, 38.2%, 7.7%. 21 B, D E (Ammann B ) 55%, 45% A C, (Ammann A ) Ammann.,,.,,. (p = 0.725) (p = 0.142) Zurich burn out 18,19. Mullady 21 Wilcox 22 518 2015. Mullady 21 45% D 15.6%. 22 burn-out. Zurich 2005. 23 (Dutch Pancreatitis Study Group) 2010 1,218. 24, (probable chronic pancreatitis), (definite chronic pancreatitis). 2 80%. 24,25 2. 지방변증 (exocrine) 10%.. Table 1. Pain patterns of chronic pancreatitis 21,22 Pattern No pain No pain Definition Temporal nature (Ammann type*) Pain severity A Usually pain free, but episodes of mild to moderate pain Intermittent (A) Mild-moderate B Constant mild to moderate pain Constant (B) Mild-moderate C Usually free of abdominal pain, but episodes of severe pain Intermittent (A) Severe D Constant mild to moderate pain plus episodes of severe pain Constant (B) Severe E Constant severe pain Constant (B) Severe *Ammann et al. 19 classified the pattern of abdominal pain in chronic pancreatitis as either intermittent/short-lived pain episodes (Type A) or prolonged period of persistent (daily) and/or clusters of recurrent severe pain exacerbations (Type B). 66 https://doi.org/10.15279/kpba.2017.22.2.63
Jin Woo Choo, et al. (gastric lipase).. 50-80% 10-20. 19,20,26 13.1, 26.3 16.9. 26 3. 당뇨병 (islet cell) (tropical pancreatitis). 40-80%. 26,27 19.8, 26.3, 11.9. 26 6-10. 19,28. 29 III. Other specific types C. Diseases of exocrine pancreas 3c. 30,31 5-10%. 27,. 3c (pancreatic polypeptide response) 1, 2, (HbA 1c ). 31 National Institute of Diabetes and Digestive and Kidney Disease National Cancer Institute 3c (incretin). 32 4. 췌장석회화,,, (Fig. 1). 33,34 0-4%, 8-25 37-59%, 14-36 80-91%. 23,26,. 23,35-38 Lee 39 A B Fig. 1. Abdominal computed tomography findings of a 49 year-old male with alcoholic chronic pancreatitis. Pancreatic ductal calcification (A, circle) and parenchymal calcifications (B) are seen. 67
Clinical Features of Chronic Pancreatitis 59 59.3% 51.6 88.1%.,,. Campisi 40 790 13.0% 68% 13.6%, 4.8%, 5.8%, 3.9% 3.9%. 67%, 88%, 91% 100%. 40 5. 가성낭종및가성동맥류 25% (Fig. 2). 19,20,26,41,42 20-40%,,, (fistula).,,.. 2016 521 167 (32%) 37%, 26% (p < 0.05). 43 1,159 344 (29.7%) 39.9% (228/572), 19.8% (116/587). 44 21% 5-10%. 45,46. (Fig. 3). 34 (13 ) (21 ) 6.6 4 (11.8%). 47 4 3 1 A B Fig. 2. Abdominal computed tomography findings of a 57 year-old male with alcoholic chronic pancreatitis. Pancreatic duct stone (arrow) with upstream dilatation (A) and pseudocyst (B) are noted. 68 https://doi.org/10.15279/kpba.2017.22.2.63
Jin Woo Choo, et al. 5. 46 6. 담도협착..,, (Fig. 4). 10%. 48 1,159 16% (186 ) 12.5% (145 ), 44 521 17.9% (93 ) 11.7% (61 ) 11.5% (60 ). 43 결론 A C Fig. 3. Serial imaging findings of 53 year-old male with alcoholic recurrent pancreatitis. Abdominal computed tomography showed ruptured pseudoaneurysm (A). Emergency angiography demonstrated pseudoaneurysm of the splenic artery (B). After embolization with coils and glue (C), no contrast leakage is seen (D). B D.,.,,.. A B Fig. 4. Imaging findings of a 59 year-old male with alcoholic chronic pancreatitis. Abdominal computed tomography showed pancreatic calcifications with bile duct dilatation (A). Endoscopic retrograde cholangiography showed intrapancreatic bile duct stricture with proximal duct dilatation (B). 69
Clinical Features of Chronic Pancreatitis. 국문색인 : 만성췌장염, 복통, 자연경과, 당뇨병 요약,,,... 10%, 36%,. 1) 2).. "burn out". 10% 50-80%. 40-80%. 3c.. 25%.. 10%,,. Conflicts of Interest The author has no conflicts to disclose. REFERENCES 1. Whitcomb DC, Frulloni L, Garg P, et al. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology 2016;16:218-224. 2. Braganza JM, Lee SH, McCloy RF, et al. Chronic pancreatitis. Lancet 2011;377:1184-1197. 3. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756-759. 4. Whitcomb DC. Mechanisms of disease: advances in understanding the mechanisms leading to chronic pancreatitis. Nat Clin Pract Gastroenterol Hepatol 2004;1:46-52. 5. Singer MV, Gyr K, Sarles H. Revised classification of pancreatitis. Report of the Second International Symposium on the Classification of Pancreatitis in Marseille, France, March 28-30, 1984. Gastroenterology 1985;89:683-685. 6. Klöppel G, Maillet B. Chronic pancreatitis: evolution of the disease. Hepatogastroenterology 1991;38:408-412. 7. Sankaran SJ, Xiao AY, Wu LM, Windsor JA, Forsmark CE, Petrov MS. Frequency of progression from acute to chronic pancreatitis and risk factors: a meta-analysis. Gastroenterology 2015;149:1490-1500.e1. 8. Witt H, Apte MV, Keim V, Wilson JS. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 2007;132:1557-1573. 9. Otsuki M. Chronic pancreatitis. The problems of diagnostic criteria. Pancreatology 2004;4:28-41. 10. Whitcomb DC. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999;45:317-322. 11. Ebbehøj N, Borly L, Bülow J, Henriksen JH, Heyeraas KJ, Rasmussen SG. Evaluation of pancreatic tissue fluid pressure measurements intraoperatively and by sonographically guided fine-needle puncture. Scand J Gastroenterol 1990;25:1097-1102. 12. Jalleh RP, Aslam M, Williamson RC. Pancreatic tissue and ductal pressures in chronic pancreatitis. Br J Surg 1991;78:1235-1237. 13. Dimcevski G, Sami SA, Funch-Jensen P, et al. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology 2007;132:1546-1556. 14. Frøkjær JB, Bouwense SA, Olesen SS, et al. Reduced cortical thickness of brain areas involved in pain processing in patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2012;10:434-438.e1. 15. Frøkjær JB, Olesen SS, Gram M, et al. Altered brain microstructure assessed by diffusion tensor imaging in patients with chronic pancreatitis. Gut 2011;60:1554-1562. 70 https://doi.org/10.15279/kpba.2017.22.2.63
Jin Woo Choo, et al. 16. Olesen SS, Bouwense SA, Wilder-Smith OH, van Goor H, Drewes AM. Pregabalin reduces pain in patients with chronic pancreatitis in a randomized, controlled trial. Gastroenterology 2011;141:536-543. 17. Pasricha PJ. Unraveling the mystery of pain in chronic pancreatitis. Nat Rev Gastroenterol Hepatol 2012;9:140-151. 18. Ammann RW, Muellhaupt B. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116:1132-1140. 19. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medicalsurgical series of 245 patients. Gastroenterology 1984;86(5 Pt 1) :820-828. 20. 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;54:148-155. 21. 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. 22. Wilcox CM, Yadav D, Ye T, et al. Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol Hepatol 2015;13:552-650. 23. Müllhaupt B, Truninger K, Ammann R. Impact of etiology on the painful early stage of chronic pancreatitis: a long-term prospective study. Z Gastroenterol 2005;43:1293-1301. 24. 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. 25. Park WG. Clinical chronic pancreatitis. Curr Opin Gastroenterol 2016;32:415-421. 26. 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;107:1481-1487. 27. Cui Y, Andersen DK. Pancreatogenic diabetes: special considerations for management. Pancreatology 2011;11:279-294. 28. Ammann RW, Buehler H, Muench R, Freiburghaus AW, Siegenthaler W. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients. Pancreas 1987;2:368-377. 29. Hutchins RR, Hart RS, Pacifico M, Bradley NJ, Williamson RC. Longterm results of distal pancreatectomy for chronic pancreatitis in 90 patients. Ann Surg 2002;236:612-618. 30. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35 Suppl 1:S64-S71. 31. Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology 2013;13:336-342. 32. Andersen DK, Andren-Sandberg Å, Duell EJ, et al. Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop. Pancreas 2013;42:1227-1237. 33. Lee HS, Kim TN, Lee DH, et al. Korean guideline for chronic pancreatitis. Korean J Pancreas Biliary Tract 2008;13:38-48. 34. Lee JK. Clinical update on diagnosis of chronic pancreatitis. Korean J Pancreas Biliary Tract 2009;14:3-9. 35. Maisonneuve P, Lowenfels AB, Müllhaupt B, et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54:510-514. 36. Nakamura Y, Ohmori T, Higuchi S, Maruyama K. Certain background factors exhibit an association with an increased risk for pancreatic calcification among Japanese male alcoholics. Pancreas 2005;31:225-231. 37. Cavallini G, Talamini G, Vaona B, et al. Effect of alcohol and smoking on pancreatic lithogenesis in the course of chronic pancreatitis. Pancreas 1994;9:42-46. 38. Lankisch MR, Imoto M, Layer P, DiMagno EP. The effect of small amounts of alcohol on the clinical course of chronic pancreatitis. Mayo Clin Proc 2001;76:242-251. 39. Lee JW, Kim HG, Lee DW, et al. Association between smoking and the progression of computed tomography findings in chronic pancreatitis. Gut Liver 2016;10:464-469. 40. Campisi A, Brancatelli G, Vullierme MP, Levy P, Ruszniewski P, Vilgrain V. Are pancreatic calcifications specific for the diagnosis of chronic pancreatitis? A multidetector-row CT analysis. Clin Radiol 2009;64:903-911. 41. Aghdassi A, Mayerle J, Kraft M, Sielenkämper AW, Heidecke CD, Lerch MM. Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis. Pancreas 2008;36:105-112. 42. Baillie J. Pancreatic pseudocysts (Part I). Gastrointest Endosc 2004;59:873-879. 43. Romagnuolo J, Talluri J, Kennard E, et al. Clinical profile, etiology, and treatment of chronic pancreatitis in North American women: analysis of a large multicenter cohort. Pancreas 2016;45:934-940. 44. 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. 45. Balachandra S, Siriwardena AK. Systematic appraisal of the management of the major vascular complications of pancreatitis. Am J Surg 2005;190:489-495. 46. Kirby JM, Vora P, Midia M, Rawlinson J. Vascular complications of pancreatitis: imaging and intervention. Cardiovasc Intervent Radiol 2008;31:957-970. 47. Vander Mijnsbrugge W, Laleman W, Van Steenbergen W, Heye S, Verslype C, Maleux G. Long-term clinical and radiological outcome of endovascular embolization of pancreatitis-related pseudoaneurysms. Acta Radiol 2017;58:316-322. 48. Abdallah AA, Krige JE, Bornman PC. Biliary tract obstruction in chronic pancreatitis. HPB (Oxford) 2007;9:421-428. 71